Generation and characterization of Ccdc28b mutant mice links the Bardet-Biedl associated gene with mild social behavioral phenotypes.

CCDC28B (coiled-coil domain-containing protein 28B) was identified as a modifier in the ciliopathy Bardet-Biedl syndrome (BBS). Our previous work in cells and zebrafish showed that CCDC28B plays a role regulating cilia length in a mechanism that is not completely understood. Here we report the generation of a Ccdc28b mutant mouse using CRISPR/Cas9 (Ccdc28b mut). Depletion of CCDC28B resulted in a mild phenotype. Ccdc28b mut animals i) do not present clear structural cilia affectation, although we did observe mild defects in cilia density and cilia length in some tissues, ii) reproduce normally, and iii) do not develop retinal degeneration or obesity, two hallmark features of reported BBS murine models. In contrast, Ccdc28b mut mice did show clear social interaction defects as well as stereotypical behaviors. This finding is indeed relevant regarding CCDC28B as a modifier of BBS since behavioral phenotypes have been documented in BBS. Overall, this work reports a novel mouse model that will be key to continue evaluating genetic interactions in BBS, deciphering the contribution of CCDC28B to modulate the presentation of BBS phenotypes. In addition, our data underscores a novel link between CCDC28B and behavioral defects, providing a novel opportunity to further our understanding of the genetic, cellular, and molecular basis of these complex phenotypes.

Genetic compensation for cilia defects in cep290 mutants by upregulation of cilia-associated small GTPases.

Mutations in CEP290 (also known as NPHP6), a large multidomain coiled coil protein, are associated with multiple cilia-associated syndromes. Over 130 CEP290 mutations have been linked to a wide spectrum of human ciliopathies, raising the question of how mutations in a single gene cause different disease syndromes. In zebrafish, the expressivity of cep290 deficiencies were linked to the type of genetic ablation: acute cep290 morpholino knockdown caused severe cilia-related phenotypes, whereas deficiencies in a CRISPR/Cas9 genetic mutant were restricted to photoreceptor defects. Here, we show that milder phenotypes in genetic mutants were associated with the upregulation of genes encoding the cilia-associated small GTPases arl3, arl13b and unc119b. Upregulation of UNC119b was also observed in urine-derived renal epithelial cells from human Joubert syndrome CEP290 patients. Ectopic expression of arl3, arl13b and unc119b in cep290 morphant zebrafish embryos rescued Kupffer's vesicle cilia and partially rescued photoreceptor outer segment defects. The results suggest that genetic compensation by upregulation of genes involved in a common subcellular process, lipidated protein trafficking to cilia, may be a conserved mechanism contributing to genotype-phenotype variations observed in CEP290 deficiencies. This article has an associated First Person interview with the first author of the paper.

Standardising outcome reporting for clinical trials of interventions for heavy menstrual bleeding: Development of a core outcome set.

OBJECTIVE: To develop a core outcome set for heavy menstrual bleeding (HMB). DESIGN: Core outcome set (COS) development methodology described by the COMET initiative. SETTING: University hospital gynaecology department, online international survey and web-based international consensus meetings. POPULATION OR SAMPLE: An international collaboration of stakeholders (clinicians, patients, academics, guideline developers) from 20 countries and 6 continents. METHODS: Phase 1: Systematic review of previously reported outcomes to identify potential core outcomes. Phase 2: Qualitative studies with patients to identify outcomes most important to them. Phase 3: Online two-round Delphi survey to achieve consensus about which outcomes are most important. Phase 4: A consensus meeting to finalise the COS. MAIN OUTCOME MEASURES: Outcome importance was assessed in the Delphi survey on a 9-point scale. RESULTS: From the 'long list' of 114, 10 outcomes were included in the final COS: subjective blood loss; flooding; menstrual cycle metrics; severity of dysmenorrhoea; number of days with dysmenorrhoea; quality of life; adverse events; patient satisfaction; number of patients going on to have further treatment for HMB and haemoglobin level. CONCLUSIONS: The final COS includes variables that are feasible for use in clinical trials in all resource settings and apply to all known underlying causes of the symptom of HMB. These outcomes should be reported in all future trials of interventions, their systematic reviews, and clinical guidelines to underpin policy.

Luteal phase support for women trying to conceive by intrauterine insemination or sexual intercourse.

BACKGROUND: Ovulation induction may impact endometrial receptivity due to insufficient progesterone secretion. Low progesterone is associated with poor pregnancy outcomes. OBJECTIVES: To assess the effectiveness and safety of luteal phase support (LPS) in infertile women trying to conceive by intrauterine insemination or by sexual intercourse. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, LILACS, trial registries for ongoing trials, and reference lists of articles (from inception to 25 August 2021). SELECTION CRITERIA: Randomised controlled trials (RCTs) of LPS using progestogen, human chorionic gonadotropin (hCG), or gonadotropin-releasing hormone (GnRH) agonist supplementation in IUI or natural cycle. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary outcomes were live birth rate/ongoing pregnancy rate (LBR/OPR) and miscarriage.  MAIN RESULTS: We included 25 RCTs (5111 participants). Most studies were at unclear or high risk of bias. We graded the certainty of evidence as very low to low. The main limitations of the evidence were poor reporting and imprecision. 1. Progesterone supplement versus placebo or no treatment  We are uncertain if vaginal progesterone increases LBR/OPR (risk ratio (RR) 1.10, 95% confidence interval (CI) 0.81 to 1.48; 7 RCTs; 1792 participants; low-certainty evidence) or decreases miscarriage per pregnancy compared to placebo or no treatment (RR 0.70, 95% CI 0.40 to 1.25; 5 RCTs; 261 participants). There were no data on LBR or miscarriage with oral stimulation. We are uncertain if progesterone increases LBR/OPR in women with gonadotropin stimulation (RR 1.24, 95% CI 0.80 to 1.92; 4 RCTs; 1054 participants; low-certainty evidence) and oral stimulation (clomiphene citrate or letrozole) (RR 0.97, 95% CI 0.58 to 1.64; 2 RCTs; 485 participants; low-certainty evidence). One study reported on OPR in women with gonadotropin plus oral stimulation; the evidence from this study was uncertain (RR 0.73, 95% CI 0.37 to 1.42; 1 RCT; 253 participants; low-certainty evidence). Given the low certainty of the evidence, it is unclear if progesterone reduces miscarriage per clinical pregnancy in any stimulation protocol (RR 0.68, 95% CI 0.24 to 1.91; 2 RCTs; 102 participants, with gonadotropin; RR 0.67, 95% CI 0.30 to 1.50; 2 RCTs; 123 participants, with gonadotropin plus oral stimulation; and RR 0.53, 95% CI 0.25 to 1.14; 2 RCTs; 119 participants, with oral stimulation). Low-certainty evidence suggests that progesterone in all types of ovarian stimulation may increase clinical pregnancy compared to placebo (RR 1.38, 95% CI 1.10 to 1.74; 7 RCTs; 1437 participants, with gonadotropin; RR 1.40, 95% CI 1.03 to 1.90; 4 RCTs; 733 participants, with gonadotropin plus oral stimulation (clomiphene citrate or letrozole); and RR 1.44, 95% CI 1.04 to 1.98; 6 RCTs; 1073 participants, with oral stimulation). 2. Progesterone supplementation regimen  We are uncertain if there is any difference between 300 mg and 600 mg of vaginal progesterone for OPR and multiple pregnancy (RR 1.58, 95% CI 0.81 to 3.09; 1 RCT; 200 participants; very low-certainty evidence; and RR 0.50, 95% CI 0.05 to 5.43; 1 RCT; 200 participants, very low-certainty evidence, respectively). No other outcomes were reported for this comparison. There were three different comparisons between progesterone regimens. For OPR, the evidence is very uncertain for intramuscular (IM) versus vaginal progesterone (RR 0.59, 95% CI 0.34 to 1.02; 1 RCT; 225 participants; very low-certainty evidence); we are uncertain if there is any difference between oral and vaginal progesterone (RR 1.25, 95% CI 0.70 to 2.22; 1 RCT; 150 participants; very low-certainty evidence) or between subcutaneous and vaginal progesterone (RR 1.05, 95% CI 0.54 to 2.05; 1 RCT; 246 participants; very low-certainty evidence). We are uncertain if IM or oral progesterone reduces miscarriage per clinical pregnancy compared to vaginal progesterone (RR 0.75, 95% CI 0.43 to 1.32; 1 RCT; 81 participants and RR 0.58, 95% CI 0.11 to 3.09; 1 RCT; 41 participants, respectively). Clinical pregnancy and multiple pregnancy were reported for all comparisons; the evidence for these outcomes was very uncertain. Only one RCT reported adverse effects. We are uncertain if IM route increases the risk of adverse effects when compared with the vaginal route (RR 9.25, 95% CI 2.21 to 38.78; 1 RCT; 225 participants; very low-certainty evidence). 3. GnRH agonist versus placebo or no treatment  No trials reported live birth. The evidence is very uncertain about the effect of GnRH agonist in ongoing pregnancy (RR 1.10, 95% CI 0.70 to 1.74; 1 RCT; 291 participants, very low-certainty evidence), miscarriage per clinical pregnancy (RR 0.73, 95% CI 0.26 to 2.10; 2 RCTs; 79 participants, very low-certainty evidence) and clinical pregnancy (RR 1.00, 95% CI 0.68 to 1.47; 2 RCTs; 340 participants; very low-certainty evidence), and multiple pregnancy (RR 0.28, 95% CI 0.11 to 0.70; 2 RCTs; 126 participants). 4. GnRH agonist versus vaginal progesterone  The evidence for the effect of GnRH agonist injection on clinical pregnancy is very uncertain (RR 1.00, 95% CI 0.51 to 1.95; 1 RCT; 242 participants). 5. HCG injection versus no treatment  The evidence for the effect of hCG injection on clinical pregnancy (RR 0.93, 95% CI 0.40 to 2.13; 1 RCT; 130 participants) and multiple pregnancy rates (RR 1.03, 95% CI 0.22 to 4.92; 1 RCT; 130 participants) is very uncertain. 6. Luteal support in natural cycle No study evaluated the effect of LPS in natural cycle. We could not perform sensitivity analyses, as there were no studies at low risk of selection bias and not at high risk in other domains. AUTHORS' CONCLUSIONS: We are uncertain if vaginal progesterone supplementation during luteal phase is associated with a higher live birth/ongoing pregnancy rate. Vaginal progesterone may increase clinical pregnancy rate; however, its effect on miscarriage rate and multiple pregnancy rate is uncertain. We are uncertain if IM progesterone improves ongoing pregnancy rates or decreases miscarriage rate when compared to vaginal progesterone. Regarding the other reported comparisons, neither oral progesterone nor any other medication appears to be associated with an improvement in pregnancy outcomes (very low-certainty evidence).

Interventions for heavy menstrual bleeding; overview of Cochrane reviews and network meta-analysis.

BACKGROUND: Heavy menstrual bleeding (HMB) is excessive menstrual blood loss that interferes with women's quality of life, regardless of the absolute amount of bleeding. It is a very common condition in women of reproductive age, affecting 2 to 5 of every 10 women. Diverse treatments, either medical (hormonal or non-hormonal) or surgical, are currently available for HMB, with different effectiveness, acceptability, costs and side effects. The best treatment will depend on the woman's age, her intention to become pregnant, the presence of other symptoms, and her personal views and preferences. OBJECTIVES: To identify, systematically assess and summarise all evidence from studies included in Cochrane Reviews on treatment for heavy menstrual bleeding (HMB), using reviews with comparable participants and outcomes; and to present a ranking of the first- and second-line treatments for HMB. METHODS: We searched for published Cochrane Reviews of HMB interventions in the Cochrane Database of Systematic Reviews. The primary outcomes were menstrual bleeding and satisfaction. Secondary outcomes included quality of life, adverse events and the requirement of further treatment. Two review authors independently selected the systematic reviews, extracted data and assessed quality, resolving disagreements by discussion. We assessed review quality using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) 2 tool and evaluated the certainty of the evidence for each outcome using GRADE methods. We grouped the interventions into first- and second-line treatments, considering participant characteristics (desire for future pregnancy, failure of previous treatment, candidacy for surgery). First-line treatments included medical interventions, and second-line treatments included both the levonorgestrel-releasing intrauterine system (LNG-IUS) and surgical treatments; thus the LNG-IUS is included in both groups. We developed different networks for first- and second-line treatments. We performed network meta-analyses of all outcomes, except for quality of life, where we performed pairwise meta-analyses. We reported the mean rank, the network estimates for mean difference (MD) or odds ratio (OR), with 95% confidence intervals (CIs), and the certainty of evidence (moderate, low or very low certainty). We also analysed different endometrial ablation and resection techniques separately from the main network: transcervical endometrial resection (TCRE) with or without rollerball, other resectoscopic endometrial ablation (REA), microwave non-resectoscopic endometrial ablation (NREA), hydrothermal ablation NREA, bipolar NREA, balloon NREA and other NREA. MAIN RESULTS: We included nine systematic reviews published in the Cochrane Library up to July 2021. We updated the reviews that were over two years old. In July 2020, we started the overview with no new reviews about the topic. The included medical interventions were: non-steroidal anti-inflammatory drugs (NSAIDs), antifibrinolytics (tranexamic acid), combined oral contraceptives (COC), combined vaginal ring (CVR), long-cycle and luteal oral progestogens, LNG-IUS, ethamsylate and danazol (included to provide indirect evidence), which were compared to placebo. Surgical interventions were: open (abdominal), minimally invasive (vaginal or laparoscopic) and unspecified (or surgeon's choice of route of) hysterectomy, REA, NREA, unspecified endometrial ablation (EA) and LNG-IUS. We grouped the interventions as follows. First-line treatments Evidence from 26 studies with 1770 participants suggests that LNG-IUS results in a large reduction of menstrual blood loss (MBL; mean rank 2.4, MD -105.71 mL/cycle, 95% CI -201.10 to -10.33; low certainty evidence); antifibrinolytics probably reduce MBL (mean rank 3.7, MD -80.32 mL/cycle, 95% CI -127.67 to -32.98; moderate certainty evidence); long-cycle progestogen reduces MBL (mean rank 4.1, MD -76.93 mL/cycle, 95% CI -153.82 to -0.05; low certainty evidence), and NSAIDs slightly reduce MBL (mean rank 6.4, MD -40.67 mL/cycle, -84.61 to 3.27; low certainty evidence; reference comparator mean rank 8.9). We are uncertain of the true effect of the remaining interventions and the sensitivity analysis for reduction of MBL, as the evidence was rated as very low certainty. We are uncertain of the true effect of any intervention (very low certainty evidence) on the perception of improvement and satisfaction. Second-line treatments Bleeding reduction is related to the type of hysterectomy (total or supracervical/subtotal), not the route, so we combined all routes of hysterectomy for bleeding outcomes. We assessed the reduction of MBL without imputed data (11 trials, 1790 participants) and with imputed data (15 trials, 2241 participants). Evidence without imputed data suggests that hysterectomy (mean rank 1.2, OR 25.71, 95% CI 1.50 to 439.96; low certainty evidence) and REA (mean rank 2.8, OR 2.70, 95% CI 1.29 to 5.66; low certainty evidence) result in a large reduction of MBL, and NREA probably results in a large reduction of MBL (mean rank 2.0, OR 3.32, 95% CI 1.53 to 7.23; moderate certainty evidence). Evidence with imputed data suggests hysterectomy results in a large reduction of MBL (mean rank 1.0, OR 14.31, 95% CI 2.99 to 68.56; low certainty evidence), and NREA probably results in a large reduction of MBL (mean rank 2.2, OR 2.87, 95% CI 1.29 to 6.05; moderate certainty evidence). We are uncertain of the true effect for REA (very low certainty evidence). We are uncertain of the effect on amenorrhoea (very low certainty evidence). Evidence from 27 trials with 4284 participants suggests that minimally invasive hysterectomy results in a large increase in satisfaction (mean rank 1.3, OR 7.96, 95% CI 3.33 to 19.03; low certainty evidence), and NREA also increases satisfaction (mean rank 3.6, OR 1.59, 95% CI 1.09 to 2.33; low certainty evidence), but we are uncertain of the true effect of the remaining interventions (very low certainty evidence). AUTHORS' CONCLUSIONS: Evidence suggests LNG-IUS is the best first-line treatment for reducing menstrual blood loss (MBL); antifibrinolytics are probably the second best, and long-cycle progestogens are likely the third best. We cannot make conclusions about the effect of first-line treatments on perception of improvement and satisfaction, as evidence was rated as very low certainty. For second-line treatments, evidence suggests hysterectomy is the best treatment for reducing bleeding, followed by REA and NREA. We are uncertain of the effect on amenorrhoea, as evidence was rated as very low certainty. Minimally invasive hysterectomy may result in a large increase in satisfaction, and NREA also increases satisfaction, but we are uncertain of the true effect of the remaining second-line interventions, as evidence was rated as very low certainty.

Upgrading the evidence for the use of ambroxol in Gaucher disease and GBA related Parkinson: Investigator initiated registry based on real life data.

Ambroxol hydrochloride is an oral mucolytic drug available over-the-counter for many years as cough medicine. In 2009 it was identified as a pharmacological chaperone for mutant glucocerebrosidase, albeit in a several-fold higher dose. Unfortunately, there have been no pharma-driven clinical trials to establish its use. Thus, real-world observational data are needed on the safety and efficacy of ambroxol for patients with Gaucher disease (GD) and GBA-Parkinson disease (GBA-PD). Clinicians treating patients with ambroxol for GD and GBA-PD were approached to collaborate in an investigator-initiated registry. Anonymized data were collected, including demographics, GD type, GD-specific therapy (when applicable), adverse events (AEs), and, when available, efficacy data. We report the data of the first 41 patients (25 females) at a median (range) age 17 (1.5-74) from 13 centers; 11 with GD type 1(four diagnosed with PD), 27 with neuronopathic GD (nGD), and three GBA mutation carriers with PD. The median (range) treatment period and maximum dose of ambroxol were 19 (1-76) months and 435 (75-1485) mg/day, respectively. One patient with type 2 GD died of her disease. No other severe AEs were reported. Twelve patients experienced AE, including minor bowel discomfort, cough, allergic reaction, mild proteinuria, dizziness and disease progression. Clinical benefits were reported in 25 patients, including stable or improved neurological status, increased physical activity, and reduced fatigue. Until the approval of specific therapies for nGD and disease-modification for GBA-PD, these preliminary data may be encouraging to physicians and patients who consider an off-label use of ambroxol.

Endometrial resection and ablation versus hysterectomy for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) is common in otherwise healthy women of reproductive age, and can affect physical health and quality of life. Surgery is usually a second-line treatment of HMB. Endometrial resection/ablation (EA/ER) to remove or ablate the endometrium is less invasive than hysterectomy. Hysterectomy is the definitive treatment and can be via open (laparotomy) approach, or via minimally invasive approaches (vaginally or laparoscopically). Each approach has its own advantages and risk profile. OBJECTIVES: To compare the effectiveness, acceptability and safety of endometrial resection or ablation versus different routes of hysterectomy (open, minimally invasive hysterectomy, or unspecified route) for the treatment of HMB. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility specialised register, CENTRAL, MEDLINE, Embase and PsycINFO (July 2020), and reference lists, grey literature and trial registers. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared techniques of endometrial resection/ablation with hysterectomy (by any technique) for the treatment of HMB in premenopausal women. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 10 RCTs (1966 participants) comparing EA/ER to hysterectomy (open (abdominal), minimally invasive (laparoscopic or vaginal), or unspecified (or at surgeon's discretion) route of hysterectomy). The results were rated as moderate-, low- and very low-certainty evidence. Endometrial resection/ablation versus open hysterectomy We found two trials. Women having EA/ER are probably less likely to perceive an improvement in HMB compared to women having open hysterectomy (risk ratio (RR) 0.90, 95% confidence interval (CI) 0.84 to 0.95; 2 studies, 247 women; moderate-certainty evidence) and probably have a 13% risk of requiring further surgery for treatment failure (compared to 0 on the open hysterectomy group; 2 studies, 247 women; moderate-certainty evidence). Both treatments probably lead to similar quality of life at two years (mean difference (MD) -5.30, 95% CI -11.90 to 1.30; 1 study, 155 women; moderate-certainty evidence) and satisfaction rate at one year (RR 0.91, 95% CI 0.82 to 1.00; 1 study, 194 women; moderate-certainty evidence). There may be no difference in serious adverse events (RR 1.29, 95% CI 0.32 to 5.20; 2 studies, 247 women; low-certainty evidence). EA/ER probably reduces time to return to normal activity compared to open hysterectomy (MD -21.00 days, 95% CI -24.78 to -17.22; 1 study, 197 women; moderate-certainty evidence). Endometrial resection/ablation versus minimally invasive hysterectomy We found five trials. The proportion of women with perception of improvement in HMB at two years may be similar between groups (RR 0.97, 95% CI 0.90 to 1.04; 1 study, 79 women; low-certainty evidence). Blood loss may be higher in the EA/ER group when assessed using the Pictorial Blood Assessment Chart (MD 44.00, 95% CI 36.09 to 51.91; 1 study, 68 women; low-certainty evidence). Quality of life is probably lower in the EA/ER group compared to the minimally invasive hysterectomy group at two years according to the 36-item Short Form (SF-36) (MD -10.71, 95% CI -15.11 to -6.30; 2 studies, 145 women; moderate-certainty evidence) and Menorrhagia Multi-Attribute Scale (RR 0.82, 95% CI 0.70 to 0.95; 1 study, 616 women; moderate-certainty evidence). EA/ER probably increases the risk of further surgery for HMB compared to minimally invasive hysterectomy (RR 7.70, 95% CI 2.54 to 23.32; 4 studies, 922 women; moderate-certainty evidence) and treatments probably have similar rates of any serious adverse events (RR 0.75, 95% CI 0.35 to 1.59; 4 studies, 809 women; moderate-certainty evidence). Women with EA/ER are probably less likely to be satisfied with treatment at one year (RR 0.90, 95% CI 0.85 to 0.94; 1 study, 558 women; moderate-certainty evidence). We were unable to pool data for time to return to work or normal life because of extreme heterogeneity (99%); however, the three studies reporting this all had the same direction of effect favouring EA/ER. Endometrial resection/ablation versus unspecified route of hysterectomy We found three trials. EA/ER may lead to a lower perception of improvement in HMB compared to unspecified route of hysterectomy (RR 0.89, 95% CI 0.83 to 0.95; 2 studies, 403 women; low-certainty evidence). Although EA/ER may lead to similar quality of life using the SF-36 General Health Perception at two years' follow-up (MD -1.90, 95% CI -8.67 to 4.87; 1 study, 209 women; low-certainty evidence), the proportion of women with improvement in general health at one year may be lower (RR 0.85, 95% CI 0.77 to 0.95; 1 study, 185 women; low-certainty evidence). EA/ER probably has a risk of 5.4% of requiring further surgery for treatment failure (compared to 0 with total hysterectomy; 2 studies, 374 women; moderate-certainty evidence) and reduces the proportion of women with any serious adverse event (RR 0.21, 95% CI 0.06 to 0.80; 2 studies, 374 women; moderate-certainty evidence). Both treatments probably lead to a similar satisfaction rate at one year' follow-up (RR 0.96, 95% CI 0.88 to 1.04; 3 studies, 545 women; moderate-certainty evidence). EA/ER may lead to shorter time to return to normal activity (MD -18.90 days, 95% CI -24.63 to -13.17; 1 study, 172 women; low-certainty evidence). AUTHORS' CONCLUSIONS: Endometrial resection/ablation (EA/ER) offers an alternative to hysterectomy as a surgical treatment for HMB. Effectiveness varies with EA/ER compared to different hysterectomy approaches. The perception of improvement in HMB with EA/ER is probably lower compared to open and unspecified route of hysterectomy, but may be similar compared to minimally invasive. Quality of life with EA/ER is probably similar to open and unspecified route of hysterectomy, but lower compared to minimally invasive hysterectomy. Further surgery for treatment failure is probably more likely with EA/ER compared to all routes of hysterectomy. Satisfaction rates also vary. EA/ER probably has a similar rate of satisfaction compared to open and unspecified route of hysterectomy, but a lower rate of satisfaction compared to minimally invasive hysterectomy. The proportion having any serious adverse event appears similar in all groups, but specific adverse events did reported difference between EA/ER and different routes. We were unable to draw conclusions about the time to return to normal activity, but the direction of effect suggests it is likely to be shorter with EA/ER.

Progestogen-releasing intrauterine systems for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) impacts the quality of life of otherwise healthy women. The perception of HMB is subjective and management depends upon, among other factors, the severity of the symptoms, a woman's age, her wish to get pregnant, and the presence of other pathologies. Heavy menstrual bleeding was classically defined as greater than or equal to 80 mL of blood loss per menstrual cycle. Currently the definition is based on the woman's perception of excessive bleeding which is affecting her quality of life. The intrauterine device was originally developed as a contraceptive but the addition of progestogens to these devices resulted in a large reduction in menstrual blood loss: users of the levonorgestrel-releasing intrauterine system (LNG-IUS) reported reductions of up to 90%. Insertion may, however, be regarded as invasive by some women, which affects its acceptability. OBJECTIVES: To determine the effectiveness, acceptability and safety of progestogen-releasing intrauterine devices in reducing heavy menstrual bleeding. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL (from inception to June 2019); and we searched grey literature and for unpublished trials in trial registers. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in women of reproductive age treated with LNG-IUS devices versus no treatment, placebo, or other medical or surgical therapy for heavy menstrual bleeding. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed risk of bias and conducted GRADE assessments of the certainty of evidence. MAIN RESULTS: We included 25 RCTs (2511 women). Limitations in the evidence included risk of attrition bias and low numbers of participants. The studies compared the following interventions. LNG-IUS versus other medical therapy The other medical therapies were norethisterone acetate, medroxyprogesterone acetate, oral contraceptive pill, mefenamic acid, tranexamic acid or usual medical treatment (where participants could choose the oral treatment that was most suitable). The LNG-IUS may improve HMB, lowering menstrual blood loss according to the alkaline haematin method (mean difference (MD) 66.91 mL, 95% confidence interval (CI) 42.61 to 91.20; 2 studies, 170 women; low-certainty evidence); and the Pictorial Bleeding Assessment Chart (MD 55.05, 95% CI 27.83 to 82.28; 3 studies, 335 women; low-certainty evidence). We are uncertain whether the LNG-IUS may have any effect on women's satisfaction up to one year (RR 1.28, 95% CI 1.01 to 1.63; 3 studies, 141 women; I² = 0%, very low-certainty evidence). The LNG-IUS probably leads to slightly higher quality of life measured with the SF-36 compared with other medical therapy if (MD 2.90, 95% CI 0.06 to 5.74; 1 study: 571 women; moderate-certainty evidence) or with the Menorrhagia Multi-Attribute Scale (MD 13.40, 95% CI 9.89 to 16.91; 1 trial, 571 women; moderate-certainty evidence). The LNG-IUS and other medical therapies probably give rise to similar numbers of women with serious adverse events (RR 0.91, 95% CI 0.63 to 1.30; 1 study, 571 women; moderate-certainty evidence). Women using other medical therapy are probably more likely to withdraw from treatment for any reason (RR 0.49, 95% CI 0.39 to 0.60; 1 study, 571 women, moderate-certainty evidence) and to experience treatment failure than women with LNG-IUS (RR 0.34, 95% CI 0.26 to 0.44; 6 studies, 535 women; moderate-certainty evidence). LNG-IUS versus endometrial resection or ablation (EA) Bleeding outcome results are inconsistent. We are uncertain of the effect of the LNG-IUS compared to EA on rates of amenorrhoea (RR 1.21, 95% CI 0.85 to 1.72; 8 studies, 431 women; I² = 21%; low-certainty evidence) and hypomenorrhoea (RR 0.98, 95% CI 0.73 to 1.33; 4 studies, 200 women; low-certainty evidence) and eumenorrhoea (RR 0.55, 95% CI 0.30 to 1.00; 3 studies, 160 women; very low-certainty evidence). We are uncertain whether both treatments may have similar rates of satisfaction with treatment at 12 months (RR 0.95, 95% CI 0.85 to 1.07; 5 studies, 317 women; low-certainty evidence). We are uncertain if the LNG-IUS compared to EA has any effect on quality of life, measured with SF-36 (MD -14.40, 95% CI -22.63 to -6.17; 1 study, 33 women; very low-certainty evidence). Women with the LNG-IUS compared with EA are probably more likely to have any adverse event (RR 2.06, 95% CI 1.44 to 2.94; 3 studies, 201 women; moderate-certainty evidence). Women with the LNG-IUS may experience more treatment failure compared to EA at one year follow up (persistent HMB or requirement of additional treatment) (RR 1.78, 95% CI 1.09 to 2.90; 5 studies, 320 women; low-certainty evidence); or requirement of hysterectomy may be higher at one year follow up (RR 2.56, 95% CI 1.48 to 4.42; 3 studies, 400 women; low-certainty evidence). LNG-IUS versus hysterectomy We are uncertain whether the LNG-IUS has any effect on HMB compared with hysterectomy (RR for amenorrhoea 0.52, 95% CI 0.39 to 0.70; 1 study, 75 women; very low-certainty evidence). We are uncertain whether there is difference between LNG-IUS and hysterectomy in satisfaction at five years (RR 1.01, 95% CI 0.94 to 1.08; 1 study, 232 women; low-certainty evidence) and quality of life (SF-36 MD 2.20, 95% CI -2.93 to 7.33; 1 study, 221 women; low-certainty evidence). Women in the LNG-IUS group may be more likely to have treatment failure requiring hysterectomy for HMB at 1-year follow-up compared to the hysterectomy group (RR 48.18, 95% CI 2.96 to 783.22; 1 study, 236 women; low-certainty evidence). None of the studies reported cost data suitable for meta-analysis. AUTHORS' CONCLUSIONS: The LNG-IUS may improve HMB and quality of life compared to other medical therapy; the LNG-IUS is probably similar for HMB compared to endometrial destruction techniques; and we are uncertain if it is better or worse than hysterectomy. The LNG-IUS probably has similar serious adverse events to other medical therapy and it is more likely to have any adverse events than EA.

Interventions commonly available during pandemics for heavy menstrual bleeding: an overview of Cochrane Reviews.

BACKGROUND: Within the context of heavy menstrual bleeding, pandemics impact upon women's assessment and treatment by healthcare providers. OBJECTIVES: To summarise the evidence from Cochrane Reviews evaluating interventions for heavy menstrual bleeding that are commonly available during pandemics. METHODS: We sought published Cochrane Reviews, evaluating interventions that can continue during pandemics for women with heavy menstrual bleeding with no known underlying cause. We identified Cochrane Reviews by searching the Cochrane Database of Systematic Reviews in June 2020. The primary outcome was menstrual bleeding. Secondary outcomes included quality of life, patient satisfaction, side effects, and serious adverse events. We undertook the selection of systematic reviews, data extraction, and quality assessment in duplicate. We resolved any disagreements by discussion. We assessed review quality using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) 2 tool, and the certainty of the evidence for each outcome using GRADE methods. MAIN RESULTS: We included four Cochrane Reviews, with 11 comparisons, data from 44 randomised controlled trials (RCTs), and 3196 women. We assessed all the reviews to be high quality. Non-steroidal anti-inflammatory drugs (NSAIDs) NSAIDs may be more effective in reducing heavy menstrual bleeding than placebo (mean difference (MD) -124 mL per cycle, 95% confidence interval (CI) -186 to -62 mL per cycle; 1 RCT, 11 women; low-certainty evidence). Mefenamic acid may be similar to naproxen (MD 21 mL per cycle, 95% CI -6 to 48 mL per cycle; 2 RCTs, 61 women; low-certainty evidence), and NSAIDs may be similar to combined hormonal contraceptives for heavy menstrual bleeding (MD 25 mL per cycle, 95% CI -22 to 73 mL per cycle; 1 RCT, 26 women; low-certainty evidence). NSAIDs may be be less effective in reducing menstrual bleeding than antifibrinolytics (relative risk (RR) 0.70, 95% CI 0.58 to 0.85; 2 RCTs, 161 women; low-certainty evidence). We are uncertain whether NSAIDs reduce menstrual blood loss more than short-cycle progestogens (RR 0.80, 95% CI 0.49 to 1.32; 1 RCT 32 women; very low-certainty evidence). Antifibrinolytics Antifibrinolytics appear to be more effective in reducing heavy menstrual bleeding than placebo (MD -53 mL per cycle, 95% CI -63 to -44 mL per cycle; 4 RCTs, 565 women; moderate-certainty evidence). Antifibrinolytics may be similar to placebo on the incidence of side effects (RR 1.05, 95% CI 0.93 to 1.18; 1 RCT, 297 women; low-certainty evidence), and they are probably similar on the incidence of serious adverse events (thrombotic events; RR 0.10, 95% CI 0.00 to 2.46; 2 RCT, 468 women; moderate-certainty evidence). Antifibrinolytics may be more effective in reducing heavy menstrual bleeding than short-cycle progestogen (MD -111 mL per cycle, 95% CI -178 mL to -44 mL per cycle; 1 RCT, 46 women; low-certainty evidence). We are uncertain whether antifibrinolytics are similar to short-cycle progestogens on quality of life (RR 1.67, 95% CI 0.76 to 3.64; 1 RCT, 44 women; very low-certainty evidence), patient satisfaction (RR 0.91, 95% CI 0.59 to 1.39; 1 RCT, 42 women; very low-certainty evidence), or side effects (RR 0.85, 95% CI 0.65 to 1.12; 3 RCTs, 211 women; very low-certainty evidence). We are uncertain whether antifibrinolytics are more effective in reducing heavy menstrual bleeding when compared with long-cycle progestogen (MD -9 points per cycle, 95% CI -30 to 12 points per cycle; 2 RCTs, 184 women; low-certainty evidence). Antifibrinolytics may increase self-reported improvement in menstrual bleeding when compared with long-cycle medroxyprogesterone acetate (RR 1.32, 95% CI 1.08 to 1.61; 1 RCT, 94 women; low-certainty evidence). Antifibrinolytics may be similar to long-cycle progestogens on quality of life (MD 5, 95% CI -2.49 to 12.49; 1 RCT, 90 women; low-certainty evidence). We are uncertain whether antifibrinolytics are similar to long-cycle progestogens on side effects (RR 0.58, 95% CI 0.33 to 1.00; 2 RCTs, 184 women; very low-certainty evidence). There were no trials comparing antifibrinolytics to combined hormonal contraceptives. Combined hormonal contraceptives Combined hormonal contraceptives appear to be more effective for heavy menstrual bleeding than placebo or no treatment (RR 13.25, 95% CI 2.94 to 59.64; 2 RCTs, 363 women; moderate-certainty evidence). Combined hormonal contraceptives are probably similar to placebo on the incidence of side effects (RR 1.53, 95% CI 0.90 to 2.60; 2 RCTs, 411 women; moderate-certainty evidence). Progestogens There were no trials comparing progestogens to placebo. Limitations in the evidence included risk of bias in the primary RCTs, inconsistency between the primary RCTs, and imprecision in effect estimates. AUTHORS' CONCLUSIONS: There is moderate-certainty evidence that antifibrinolytics and combined hormonal contraceptives reduce heavy menstrual bleeding compared with placebo. There is low-certainty evidence that NSAIDs reduce heavy menstrual bleeding compared with placebo. There is low-certainty evidence that antifibrinolytics are more effective in reducing heavy menstrual bleeding when compared with NSAIDs and short-cycle progestogens, but we are unable to draw conclusions about the effects of antifibrinolytics compared to long-cycle progestogens, on low-certainty evidence.

Non-steroidal anti-inflammatory drugs for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) is an important cause of ill health in premenopausal women. Although surgery is often used as a treatment, a range of medical therapies are also available. Non-steroidal anti-inflammatory drugs (NSAIDs) reduce prostaglandin levels, which are elevated in women with excessive menstrual bleeding and also may have a beneficial effect on dysmenorrhoea. OBJECTIVES: To determine the effectiveness, safety and tolerability of NSAIDs in achieving a reduction in menstrual blood loss (MBL) in women of reproductive years with HMB. SEARCH METHODS: We searched, in April 2019, the Cochrane Gynaecology and Fertility specialised register, Cochrane Central Register of Studies Online (CENTRAL CRSO), MEDLINE, Embase, PsycINFO, the clinical trial registries and reference lists of articles. SELECTION CRITERIA: The inclusion criteria were randomised comparisons of individual NSAIDs or combined with other medical therapy with each other, placebo or other medical treatments in women with regular heavy periods measured either objectively or subjectively and with no pathological or iatrogenic (treatment-induced) causes for their HMB. DATA COLLECTION AND ANALYSIS: We identified 19 randomised controlled trials (RCTs) (759 women) that fulfilled the inclusion criteria for this review and two review authors independently extracted data. We estimated odds ratios (ORs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes from the data of nine trials. We described in data tables the results of the remaining seven cross-over trials with data unsuitable for pooling, one trial with skewed data, and one trial with missing variances. One trial had no data available for analysis. MAIN RESULTS: As a group, NSAIDs were more effective than placebo at reducing HMB but less effective than tranexamic acid, danazol or the levonorgestrel-releasing intrauterine system (LNG IUS). Treatment with danazol caused a shorter duration of menstruation and more adverse events than NSAIDs, but this did not appear to affect the acceptability of treatment, based on trials from 1980 to 1990. However, currently danazol is not a usual or recommended treatment for HMB. There was no clear evidence of difference between NSAIDs and the other treatments (oral luteal progestogen, ethamsylate, an older progesterone-releasing intrauterine system and the oral contraceptive pill (OCP), but most studies were underpowered. There was no evidence of a difference between the individual NSAIDs (naproxen and mefenamic acid) in reducing HMB. The evidence quality ranged from low to moderate, the main limitations being risk of bias and imprecision. AUTHORS' CONCLUSIONS: NSAIDs reduce HMB when compared with placebo, but are less effective than tranexamic acid, danazol or LNG IUS. However, adverse events are more severe with danazol therapy. In the limited number of small studies suitable for evaluation, there was no clear evidence of a difference in efficacy between NSAIDs and other medical treatments such as oral luteal progestogen, ethamsylate, OCP or the older progesterone-releasing intrauterine system.

Endometrial resection and ablation versus hysterectomy for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) is an important cause of ill health in women of reproductive age, causing them physical problems, social disruption and reducing their quality of life. Medical therapy has traditionally been first-line therapy. Surgical treatment of HMB often follows failed or ineffective medical therapy. The definitive treatment is hysterectomy, but this is a major surgical procedure with significant physical and emotional complications, as well as social and economic costs. Less invasive surgical techniques, such as endometrial resection and ablation, have been developed with the purpose of improving menstrual symptoms by removing or ablating the entire thickness of the endometrium. OBJECTIVES: To compare the effectiveness, acceptability and safety of techniques of endometrial destruction by any means versus hysterectomy by any means for the treatment of heavy menstrual bleeding. SEARCH METHODS: Electronic searches for relevant randomised controlled trials (RCTs) targeted-but were not limited to-the following: the Cochrane Gynaecology and Fertility Group's specialised register, CENTRAL via the Cochrane Register of Studies Online (CRSO), MEDLINE, Embase, PsycINFO, and the ongoing trial registries. We made attempts to identify trials by examining citation lists of review articles and guidelines and by performing handsearching. Searches were performed in 1999, 2007, 2008, 2013 and on 10 December 2018. SELECTION CRITERIA: Any RCTs that compared techniques of endometrial resection or ablation (by any means) with hysterectomy (by any technique) for the treatment of heavy menstrual bleeding in premenopausal women. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, extracted data and assessed trials for risk of bias. MAIN RESULTS: We identified nine RCTs that fulfilled our inclusion criteria for this review. For two trials, the review authors identified multiple publications that assessed different outcomes at different postoperative time points for the same women. No included trials used third generation techniques.Clinical measures of improved bleeding symptoms and satisfaction rates were observed in women who had undergone hysterectomy compared to endometrial ablation. A slightly lower proportion of women who underwent endometrial ablation perceived improvement in bleeding symptoms at one year (risk ratio (RR) 0.89, 95% confidence interval (CI) 0.85 to 0.93; 4 studies, 650 women, I² = 31%; low-quality evidence), at two years (RR 0.92, 95% CI 0.86 to 0.99; 2 studies, 292 women, I² = 53%) and at four years (RR 0.93, 95% CI 0.88 to 0.99; 2 studies, 237 women, I² = 79%). Women in the endometrial ablation group also showed improvement in pictorial blood loss assessment chart compared to their baseline (PBAC) score at one year (MD 24.40, 95% CI 16.01 to 32.79; 1 study, 68 women; moderate-quality evidence) and at two years (MD 44.00, 95% CI 36.09 to 51.91; 1 study, 68 women). Repeat surgery resulting from failure of the initial treatment was more likely to be needed after endometrial ablation than after hysterectomy at one year (RR 16.17, 95% CI 5.53 to 47.24; 927 women; 7 studies; I2 = 0%), at two years (RR 34.06, 95% CI 9.86 to 117.65; 930 women; 6 studies; I2 = 0%), at three years (RR 22.90, 95% CI 1.42 to 370.26; 172 women; 1 study) and at four years (RR 36.32, 95% CI 5.09 to 259.21;197 women; 1 study). The satisfaction rate was lower amongst those who had endometrial ablation at two years after surgery (RR 0.87, 95% CI 0.80 to 0.95; 4 studies, 567 women, I² = 0%; moderate-quality evidence), and no evidence of clear difference was reported between post-treatment satisfaction rates in groups at other follow-up times (1 and 4 years).Most adverse events, both major and minor, were more likely after hysterectomy during hospital stay. Women who had an endometrial ablation were less likely to experience sepsis (RR 0.19, 95% CI 0.12 to 0.31; participants = 621; studies = 4; I2 = 62%), blood transfusion (RR 0.20, 95% CI 0.07 to 0.59; 791 women; 5 studies; I2 = 0%), pyrexia (RR 0.17, 95% CI 0.09 to 0.35; 605 women; 3 studies; I2 = 66%), vault haematoma (RR 0.11, 95% CI 0.04 to 0.34; 858 women; 5 studies; I2 = 0%) and wound haematoma (RR 0.03, 95% CI 0.00 to 0.53; 202 women; 1 study) before hospital discharge. After discharge from hospital, the only difference that was reported for this group was a higher rate of infection (RR 0.27, 95% CI 0.13 to 0.58; 172 women; 1 study).Recovery time was shorter in the endometrial ablation group, considering hospital stay, time to return to normal activities and time to return to work; we did not, however, pool these data owing to high heterogeneity. Some outcomes (such as a woman's perception of bleeding and proportion of women requiring further surgery for HMB), generated a low GRADE score, suggesting that further research in these areas is likely to change the estimates. AUTHORS' CONCLUSIONS: Endometrial resection and ablation offers an alternative to hysterectomy as a surgical treatment for heavy menstrual bleeding. Both procedures are effective, and satisfaction rates are high. Although hysterectomy offers permanent and immediate relief from heavy menstrual bleeding, it is associated with a longer operating time and recovery period. Hysterectomy also has higher rates of postoperative complications such as sepsis, blood transfusion and haematoma (vault and wound). The initial cost of endometrial destruction is lower than that of hysterectomy but, because retreatment is often necessary, the cost difference narrows over time.

Cyclical progestogens for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) is a menstrual blood loss perceived by women as excessive that affects the health of women of reproductive age, interfering with their physical, emotional, social and material quality of life. Whilst abnormal menstrual bleeding may be associated with underlying pathology, in the present context, HMB is defined as excessive menstrual bleeding in the absence of other systemic or gynaecological disease. The first-line therapy is usually medical, avoiding possibly unnecessary surgery. Of the wide variety of medications used to reduce HMB, oral progestogens were originally the most commonly prescribed agents. This review assesses the effectiveness of two different types and regimens of oral progestogens in reducing ovulatory HMB.This is the update of a Cochrane review last updated in 2007, and originally named "Effectiveness of cyclical progestagen therapy in reducing heavy menstrual bleeding" (1998). OBJECTIVES: To determine the effectiveness, safety and tolerability of oral progestogen therapy taken either during the luteal phase (short cycle) or for a longer course of 21 days per cycle (long cycle), in achieving a reduction in menstrual blood loss in women of reproductive age with HMB. SEARCH METHODS: In January 2019 we searched Cochrane Gynaecology and Fertility's specialized register, CENTRAL, MEDLINE, Embase, CINAHL and PsycInfo. We also searched trials registers, other sources of unpublished or grey literature and reference lists of retrieved trials. We also checked citation lists of review articles to identify trials. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing different treatments for HMB that included cyclical oral progestogens were eligible. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed trials for risk of bias and extracted data. We contacted trial authors for clarification of methods or additional data when necessary. We only assessed adverse events if they were separately measured in the included trials. We compared cyclical oral progestogen in different regimens and placebo or other treatments. Our primary outcomes were menstrual blood loss and satisfaction with treatment; the secondary outcomes were number of days of bleeding, quality of life, compliance and acceptability of treatment, adverse events and costs. MAIN RESULTS: This review identified 15 randomized controlled trials (RCTs) with 1071 women in total. Most of the women knew which treatment they were receiving, which may have influenced their judgements about menstrual blood loss and satisfaction. Other aspects of trial quality varied among trials.We did not identify any RCTs comparing progestogen treatment with placebo. We assessed comparisons between oral progestogens and other medical therapies separately according to different regimens.Short-cycle progestogen therapy during the luteal phase (medroxyprogesterone acetate or norethisterone for 7 to 10 days, from day 15 to 19) was inferior to other medical therapy, including tranexamic acid, danazol and the progestogen-releasing intrauterine system (Pg-IUS (off of the market since 2001)), releasing 60 mcg of progesterone daily, with respect to reduction of menstrual blood loss (mean difference (MD) 37.29, 95% confidence interval (CI) 17.67 to 56.91; I2 = 50%; 6 trials, 145 women). The rate of satisfaction and the quality of life with treatment was similar in both groups. The number of bleeding days was greater on the short cycle progestogen group compared to other medical treatments. Adverse events (such as gastrointestinal symptoms and weight gain) were more likely with danazol when compared with progestogen treatment. We note that danazol is no longer in general use for treating HMB.Long-cycle progestogen therapy (medroxyprogesterone acetate or norethisterone), from day 5 to day 26 of the menstrual cycle, is also inferior to the levonorgestrel-releasing intrauterine system (LNG-IUS), releasing tranexamic acid and ormeloxifene, but may be similar to the combined vaginal ring with respect to reduction of menstrual blood loss (MD 16.88, 95% CI 10.93 to 22.84; I2 = 87%; 4 trials, 355 women). A higher proportion of women taking norethisterone found their treatment unacceptable compared to women having Pg-IUS (Peto odds ratio (OR) 0.12, 95% CI 0.03 to 0.40; 1 trial, 40 women). However, the adverse effects of breast tenderness and intermenstrual bleeding were more likely in women with the LNG-IUS. No trials reported on days of bleeding or quality of life for this comparison.The evidence supporting these findings was limited by low or very low gradings of quality; thus, we are uncertain about the findings and there is a potential that they may change if we identify other trials. AUTHORS' CONCLUSIONS: Low- or very low-quality evidence suggests that short-course progestogen was inferior to other medical therapy, including tranexamic acid, danazol and the Pg-IUS with respect to reduction of menstrual blood loss. Long cycle progestogen therapy (medroxyprogesterone acetate or norethisterone) was also inferior to the LNG-IUS, tranexamic acid and ormeloxifene, but may be similar to the combined vaginal ring with respect to reduction of menstrual blood loss.

Combined hormonal contraceptives for heavy menstrual bleeding.

BACKGROUND: Menorrhagia or heavy menstrual bleeding (HMB) is an excessive blood loss that impairs a woman's quality of life, either physical, emotional, social or material. It is benign and not associated with pregnancy or any other gynaecological or systemic disease. Medical treatments used to reduce excessive menstrual blood loss (MBL) include prostaglandin synthetase inhibitors, antifibrinolytics, oral contraceptive pills, and other hormones. The combined oral contraceptive pill (COCP) is claimed to have a variety of beneficial effects, inducing a regular shedding of a thinner endometrium and inhibiting ovulation, thus having the effect of both treating HMB and providing contraception. More recently, a contraceptive vaginal ring (CVR) has been trialled to investigate whether this treatment can provide similar benefits to COCP while lessening hormonal systemic exposure. This review is an update of a review which originally focused on COCP alone. The scope of the review has been widened to consider other types of delivery of combined hormonal contraceptives for reduction of MBL. OBJECTIVES: To determine the efficacy of combined hormonal contraceptives (pills, vaginal ring or patch) compared with other medical therapies, placebo, or no therapy in the treatment of HMB. A secondary objective was to compare the COCP with the CVR. SEARCH METHODS: We searched the Gynecology and Fertility Group trials register, MEDLINE, Embase, CENTRAL, CINAHL and PsycINFO (search dates: Oct 1996, May 2002, June 2004, April 2006, June 2009, July 2017 and September 2018) for all randomised controlled trials (RCTs) of COCP and CVR for the treatment of HMB. We also searched trial registers and the reference lists of retrieved studies for additional trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of the use of COCP or CVR compared with no treatment, placebo, or other medical therapies for women with HMB and regular menstrual cycles. DATA COLLECTION AND ANALYSIS: All assessments of trial quality and data extraction were performed unblinded by at least two review authors. Our primary review outcomes were treatment success, menstrual bleeding (assessed objectively, semi-objectively or subjectively), and participant satisfaction with treatment. Secondary outcomes were adverse events, quality of life, and haemoglobin level. MAIN RESULTS: We identified eight RCTs involving 805 participants. Two trials comparing COCP with placebo were considered to be moderate quality and the remaining studies were low to very low quality, mainly because of serious risk of bias from lack of blinding and concerns over precision.COCP versus placeboCOCP, with a step-down oestrogen and step-up progestogen regimen, improved response to treatment (return to menstrual 'normality') (OR 22.12, 95% CI 4.40 to 111.12; 2 trials; 363 participants; I2 = 50%; moderate-quality evidence), and lowered MBL (OR 5.15, 95% CI 3.16 to 8.40; 2 trials; 339 participants; I2 = 0%; moderate-quality evidence) when compared to placebo. The results suggested that, if the chance of 'successful' treatment was 3% in women taking placebo, then COCP increased this chance from 12% to 77% in women with unacceptable HMB. Minor adverse events, in particular breast pain, were more common with COCP. No study in this comparison reported semi-objectively assessed MBL or participant satisfaction with treatment.COCP versus other medical treatmentsNon-steroidal anti-inflammatory drugs (NSAIDs)There was insufficient evidence to determine whether the COCP reduced MBL when compared to NSAIDs (mefenamic acid and naproxen). No study in this comparison reported semi-objectively assessed MBL, subjectively assessed MBL, participant satisfaction with treatment or adverse events.Levonorgestrel-releasing intrauterine system (LNG IUS)The LNG IUS was more effective than COCP in reducing MBL (OR 0.21, 95% CI 0.09 to 0.48; 2 trials; 151 participants; I2 = 0%; low-quality evidence) but it was not clear whether satisfaction with treatment or adverse effects varied according to which treatment was used. No study in this comparison reported semi-objectively assessed MBL or subjectively assessed MBL.Contraceptive vaginal ring (CVR) versus other medical treatmentsCOCP COCP was compared with CVR in two trials. There were discrepancies between some of the findings and there was no evidence of a benefit for one treatment compared to the other for response to treatment, MBL or participant satisfaction with treatment. There was a greater likelihood of nausea with COCP. No study in this comparison reported objectively assessed MBL or subjectively assessed MBL.ProgestogensCVR was compared to long course progestogens in one trial. It is possible that CVR increased the odds of satisfaction; but we are uncertain whether CVR improved MBL. The evidence was based on small numbers of participants and was very low quality, so definitive conclusions could not be reached. No study in this comparison reported objectively assessed MBL, subjectively assessed MBL, or adverse events. AUTHORS' CONCLUSIONS: Moderate-quality evidence suggests that the combined oral contraceptive pill over six months reduces HMB in women with unacceptable HMB from 12% to 77% (compared to 3% in women taking placebo). When compared with other medical options for HMB, COCP was less effective than the LNG IUS. Limited evidence suggested that COCP and CVR had similar effects. There was insufficient evidence to determine comparative efficacy of combined hormonal contraceptives with NSAIDs, or long course progestogens.

Endometrial resection and ablation techniques for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) is a significant health problem in premenopausal women; it can reduce their quality of life and can cause social disruption and physical problems such as iron deficiency anaemia. First-line treatment has traditionally consisted of medical therapy (hormonal and non-hormonal), but this is not always successful in reducing menstrual bleeding to acceptable levels. Hysterectomy is a definitive treatment, but it is more costly and carries some risk. Endometrial ablation may be an alternative to hysterectomy that preserves the uterus. Many techniques have been developed to 'ablate' (remove) the lining of the endometrium. First-generation techniques require visualisation of the uterus with a hysteroscope during the procedure; although it is safe, this procedure requires specific technical skills. Newer techniques for endometrial ablation (second- and third-generation techniques) have been developed that are quicker than previous approaches because they do not require hysteroscopic visualisation during the procedure. OBJECTIVES: To compare the efficacy, safety, and acceptability of endometrial destruction techniques to reduce heavy menstrual bleeding (HMB) in premenopausal women. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase, CINAHL, and PsycInfo (from inception to May 2018). We also searched trials registers, other sources of unpublished or grey literature, and reference lists of retrieved studies, and we made contact with experts in the field and with pharmaceutical companies that manufacture ablation devices. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing different endometrial ablation or resection techniques for women reporting HMB without known uterine pathology, other than fibroids outside the uterine cavity and smaller than 3 centimetres, were eligible. Outcomes included improvement in HMB and in quality of life, patient satisfaction, operative outcomes, complications, and the need for further surgery, including hysterectomy. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed trials for risk of bias, and extracted data. We contacted study authors for clarification of methods or for additional data. We assessed adverse events only if they were separately measured in the included trials. We undertook comparisons with individual techniques as well as an overall comparison of first- and second-generation ablation methods. MAIN RESULTS: We included in this update 28 studies (4287 women) with sample sizes ranging from 20 to 372. Most studies had low risk of bias for randomisation, attrition, and selective reporting. Less than half of these studies had adequate allocation concealment, and most were unblinded. Using GRADE, we determined that the quality of evidence ranged from moderate to very low. We downgraded evidence for risk of bias, imprecision, and inconsistency.Overall comparison of second-generation versus first-generation (i.e. gold standard hysteroscopic ablative) techniques revealed no evidence of differences in amenorrhoea at 1 year and 2 to 5 years' follow-up (risk ratio (RR) 0.99, 95% confidence interval (CI) 0.78 to 1.27; 12 studies; 2145 women; I² = 77%; and RR 1.16, 95% CI 0.78 to 1.72; 672 women; 4 studies; I² = 80%; very low-quality evidence) and showed subjective improvement at 1 year follow-up based on a Pictorial Blood Assessment Chart (PBAC) (< 75 or acceptable improvement) (RR 1.03, 95% CI 0.98 to 1.09; 5 studies; 1282 women; I² = 0%; and RR 1.12, 95% CI 0.97 to 1.28; 236 women; 1 study; low-quality evidence). Study results showed no difference in patient satisfaction between second- and first-generation techniques at 1 year follow-up (RR 1.01, 95% CI 0.98 to 1.04; 11 studies; 1750 women; I² = 36%; low-quality evidence) nor at 2 to 5 years' follow-up (RR 1.02, 95% CI 0.93 to 1.13; 672 women; 4 studies; I² = 81%).Compared with first-generation techniques, second-generation endometrial ablation techniques were associated with shorter operating times (mean difference (MD) -13.52 minutes, 95% CI -16.90 to -10.13; 9 studies; 1822 women; low-quality evidence) and more often were performed under local rather than general anaesthesia (RR 2.8, 95% CI 1.8 to 4.4; 6 studies; 1434 women; low-quality evidence).We are uncertain whether perforation rates differed between second- and first-generation techniques (RR 0.32, 95% CI 0.10 to 1.01; 1885 women; 8 studies; I² = 0%).Trials reported little or no difference between second- and first-generation techniques in requirement for additional surgery (ablation or hysterectomy) at 1 year follow-up (RR 0.72, 95% CI 0.41 to 1.26; 6 studies: 935 women; low-quality evidence). At 5 years, results showed probably little or no difference between groups in the requirement for hysterectomy (RR 0.85, 95% CI 0.59 to 1.22; 4 studies; 758 women; moderate-quality evidence). AUTHORS' CONCLUSIONS: Approaches to endometrial ablation have evolved from first-generation techniques to newer second- and third-generation approaches. Current evidence suggests that compared to first-generation techniques (endometrial laser ablation, transcervical resection of the endometrium, rollerball endometrial ablation), second-generation approaches (thermal balloon endometrial ablation, microwave endometrial ablation, hydrothermal ablation, bipolar radiofrequency endometrial ablation, endometrial cryotherapy) are of equivalent efficacy for heavy menstrual bleeding, with comparable rates of amenorrhoea and improvement on the PBAC. Second-generation techniques are associated with shorter operating times and are performed more often under local rather than general anaesthesia. It is uncertain whether perforation rates differed between second- and first-generation techniques. Evidence was insufficient to show which second-generation approaches were superior to others and to reveal the efficacy and safety of third-generation approaches versus first- and second-generation techniques.

Niemann-Pick disease A or B in four pediatric patients and SMPD1 mutation carrier frequency in the Mexican population.

INTRODUCTION AND OBJECTIVES: Niemann-Pick disease type A (NPD-A) and B (NPD-B) are lysosomal storage diseases with a birth prevalence of 0.4-0.6/100,000. They are caused by a deficiency in acid sphingomyelinase, an enzyme encoded by SMPD1. We analyzed the phenotype and genotype of four unrelated Mexican patients, one with NPD-A and three with NPD-B. PATIENTS AND METHODS: Four female patients between 1 and 7 years of age were diagnosed with NPD-A or NPD-B by hepatosplenomegaly, among other clinical characteristics, and by determining the level of acid sphingomyelinase enzymatic activity and sequencing of the SMPD1 gene. Additionally, a 775bp amplicon of SMPD1 (from 11:6393835_6394609, including exons 5 and 6) was analyzed by capillary sequencing in a control group of 50 unrelated healthy Mexican Mestizos. RESULTS: An infrequent variant (c.1343A>G p.Tyr448Cys) was observed in two patients. One is the first NPD-A homozygous patient reported with this variant and the other a compound heterozygous NPD-B patient with the c.1829_1831delGCC p.Arg610del variant. Another compound heterozygous patient had the c.1547A>G p.His516Arg variant (not previously described in affected individuals) along with the c.1805G>A p.Arg602His variant. A new c.1263+8C>T pathogenic variant was encountered in a homozygous state in a NPD-B patient. Among the healthy control individuals there was a heterozygous carrier for the c.1550A>T (rs142787001) pathogenic variant, but none with the known pathogenic variants in the 11:6393835_6394609 region of SMPD1. CONCLUSIONS: The present study provides further NPD-A or B phenotype-genotype correlations. We detected a heterozygous carrier with a pathogenic variant in 1/50 healthy Mexican mestizos.

Spatio-temporal distribution of vertically transmitted dengue viruses by Aedes aegypti (Diptera: Culicidae) from Arroyo Naranjo, Havana, Cuba.

OBJECTIVE: To study the distribution of vertical transmission of dengue viruses in field-collected Aedes aegypti larvae in the municipality of Arroyo Naranjo in Havana, Cuba. METHODS: Aedes aegypti larvae and pupae were collected monthly between September 2013 and July 2014 in the seven Municipal Health Areas of Arroyo Naranjo. Pools formed of 30-55 larvae were examined through PCR and sequencing to detect the presence of each serotype. RESULTS: We analysed 111 pools of larvae and pupae (4102 individuals) of which 37 tested positive for at least one DENV. More than one DENV type was observed in 10 of the 37 positive pools. Infected pools were detected every month, except in January, suggesting a sustained circulation of DENV in the vector populations. DENV-1 and DENV-3 were the most frequent and dispersed, though all four DENV types were detected. Nucleotide sequencing from positive pools confirmed RT-PCR results for DENV-1 (genotype V), DENV-3 (genotype III) and DENV-4 (genotype II). DENV-2 was detected by RT-PCR but could not be confirmed by nucleotide sequencing. CONCLUSION: Our study of the distribution of natural vertical transmission of dengue virus types highlights extrinsic virus activity patterns in the area and could be used as a new surveillance tool.

Prospective comparative multi-centre study on imported Plasmodium ovale wallikeri and Plasmodium ovale curtisi infections.

BACKGROUND: Few previous retrospective studies suggest that Plasmodium ovale wallikeri seems to have a longer latency period and produces deeper thrombocytopaenia than Plasmodium ovale curtisi. Prospective studies were warranted to better assess interspecies differences. METHODS: Patients with imported P. ovale spp. infection diagnosed by thick or thin film, rapid diagnostic test (RDT) or polymerase chain reaction (PCR) were recruited between March 2014 and May 2017. All were confirmed by DNA isolation and classified as P. o. curtisi or P. o. wallikeri using partial sequencing of the ssrRNA gene. Epidemiological, analytical and clinical differences were analysed by statistical methods. RESULTS: A total of 79 samples (35 P. o. curtisi and 44 P. o. wallikeri) were correctly genotyped. Males predominate in wallikeri group (72.7%), whereas were 48.6% in curtisi group. Conversely, 74.3% of curtisi group were from patients of African ethnicity, whilst 52.3% of Caucasians were infected by P. o. wallikeri. After performing a multivariate analysis, more thrombocytopaenic patients (p = 0.022), a lower number of platelets (p = 0.015), a higher INR value (p = 0.041), and shorter latency in Caucasians (p = 0.034) were significantly seen in P. o. wallikeri. RDT sensitivity was 26.1% in P. o. curtisi and 42.4% in P. o. wallikeri. Nearly 20% of both species were diagnosed only by PCR. Total bilirubin over 3 mg/dL was found in three wallikeri cases. Two patients with curtisi infection had haemoglobin under 7 g/dL, one of them also with icterus. A wallikeri patient suffered from haemophagocytosis. Chemoprophylaxis failed in 14.8% and 35% of curtisi and wallikeri patients, respectively. All treated patients with various anti-malarials which included artesunate recovered. Diabetes mellitus was described in 5 patients (6.32%), 4 patients of wallikeri group and 1 curtisi. CONCLUSIONS: Imported P. o. wallikeri infection may be more frequent in males and Caucasians. Malaria caused by P. o. wallikeri produces more thrombocytopaenia, a higher INR and shorter latency in Caucasians and suggests a more pathogenic species. Severe cases can be seen in both species. Chemoprophylaxis seems less effective in P. ovale spp. infection than in P. falciparum, but any anti-malarial drug is effective as initial treatment. Diabetes mellitus could be a risk factor for P. ovale spp. infection.

Acquisition of Uropygial Gland Microbiome by Hoopoe Nestlings.

Mutualistic symbioses between animals and bacteria depend on acquisition of appropriate symbionts while avoiding exploitation by non-beneficial microbes. The mode of acquisition of symbionts would determine, not only the probability of encountering but also evolutionary outcomes of mutualistic counterparts. The microbiome inhabiting the uropygial gland of the European hoopoe (Upupa epops) includes a variety of bacterial strains, some of them providing antimicrobial benefits. Here, the mode of acquisition and stability of this microbiome is analyzed by means of Automated rRNA Intergenic Spacer Analysis and two different experiments. The first experiment impeded mothers' access to their glands, thus avoiding direct transmission of microorganisms from female to offspring secretions. The second experiment explored the stability of the microbiomes by inoculating glands with secretions from alien nests. The first experiment provoked a reduction in similarity of microbiomes of mother and nestlings. Interestingly, some bacterial strains were more often detected when females had not access to their glands, suggesting antagonistic effects among bacteria from different sources. The second experiment caused an increase in richness of the microbiome of receivers in terms of prevalence of Operational Taxonomic Units (OTUs) that reduced differences in microbiomes of donors and receivers. That occurred because OTUs that were present in donors but not in receivers incorporated to the microbiome of the latter, which provoked that cross-inoculated nestlings got similar final microbiomes that included the most prevalent OTUs. The results are therefore consistent with a central role of vertical transmission in bacterial acquisition by nestling hoopoes and support the idea that the typical composition of the hoopoe gland microbiome is reached by the incorporation of some bacteria during the nestling period. This scenario suggests the existence of a coevolved core microbiome composed by a mix of specialized vertically transmitted strains and facultative symbionts able to coexist with them. The implications of this mixed mode of transmission for the evolution of the mutualism are discussed.

The Microbiome of the Uropygial Secretion in Hoopoes Is Shaped Along the Nesting Phase.

Microbial symbiont acquisition by hosts may determine the effectiveness of the mutualistic relationships. A mix of vertical and horizontal transmission may be advantageous for hosts by allowing plastic changes of microbial communities depending on environmental conditions. Plasticity is well known for gut microbiota but is poorly understood for other symbionts of wild animals. We here explore the importance of environmental conditions experienced by nestling hoopoes (Upupa epops) during the late nesting phase determining microbiota in their uropygial gland. In cross-fostering experiments of 8 days old nestlings, "sibling-sibling" and "mother-offspring" comparisons were used to explore whether the bacterial community naturally established in the uropygial gland of nestlings could change depending on experimental environmental conditions (i.e., new nest environment). We found that the final microbiome of nestlings was mainly explained by nest of origin. Moreover, cross-fostered nestlings were more similar to their siblings and mothers than to their stepsiblings and stepmothers. We also detected a significant effect of nest of rearing, suggesting that nestling hoopoes acquire most bacterial symbionts during the first days of life but that the microbiome is dynamic and can be modified along the nestling period depending on environmental conditions. Estimated effects of nest of rearing, but also most of those of nest of origin are associated to environmental characteristics of nests, which are extended phenotypes of parents. Thus, natural selection may favor the acquisition of appropriated microbial symbionts for particular environmental conditions found in nests.

Defenses against keratinolytic bacteria in birds living in radioactively contaminated areas.

Microorganisms have shaped the evolution of a variety of defense mechanisms against pathogenic infections. Radioactivity modifies bacterial communities and, therefore, bird hosts breeding in contaminated areas are expected to adapt to the new bacterial environment. We tested this hypothesis in populations of barn swallows (Hirundo rustica) from a gradient of background radiation levels at Chernobyl and uncontaminated controls from Denmark. Investment in defenses against keratinolytic bacteria was measured from feather structure (i.e., susceptibility to degradation) and uropygial secretions. We studied degradability of tail feathers from areas varying in contamination in laboratory experiments using incubation of feathers with a feather-degrading bacterium, Bacillus licheniformis, followed by measurement of the amount of keratin digested. The size of uropygial glands and secretion amounts were quantified, followed by antimicrobial tests against B. licheniformis and quantification of wear of feathers. Feathers of males, but not of females, from highly contaminated areas degraded at a lower rate than those from medium and low contamination areas. However, feathers of both sexes from the Danish populations showed little evidence of degradation. Individual barn swallows from the more contaminated areas of Ukraine produced the largest uropygial secretions with higher antimicrobial activity, although wear of feathers did not differ among males from different populations. In Denmark, swallows produced smaller quantities of uropygial secretion with lower antimicrobial activity, which was similar to swallow populations from uncontaminated areas in Ukraine. Therefore, barn swallows breeding in contaminated areas invested more in all defenses against keratinolytic bacteria than in uncontaminated areas of Ukraine and Denmark, although they had similar levels of feather wear. Strong natural selection exerted by radioactivity may have selected for individuals with higher defense capacity against bacterial infections during the 30 years since the Chernobyl disaster.