Persistent cervical cancer disparities among American Indian/Alaska Native women: a systematic scoping review exploring the state of the science in this population.

PURPOSE: American Indian/Alaska Native (AI/AN) populations experience significantly higher incidence and mortality rates of cervical cancer. The objective of this systematic scoping review is to characterize the volume and nature of research being conducted specific to the AI/AN population regarding cervical cancer and related clinical themes. METHODS: This scoping review was conducted in collaboration with the Pacific Northwest Evidence-based Practice Center. Search strategies identified eligible publications from 1990 through 4 February 2022. Two reviewers independently abstracted study data, including clinical area, number of participants and percent inclusion of AI/AN, intervention or risk factor, outcomes reported, Indian Health Service (IHS) Region, and funding source. We used published algorithms to assess study design. RESULTS: Database searches identified 300 unique citations. After full-text evaluation of 129 articles, 78 studies and 9 secondary publications were included (total of 87). Approximately 74% of studies were observational in design, with cross-sectional methodology accounting for 42.7% of all included studies. The most common clinical theme was cervical cancer screening. The most common intervention/exposure was risk factor, typically race (AI/AN compared with other groups) (69%). For studies with documented funding sources, 67% were funded by the US Government. CONCLUSION: Of the small number of publications identified, the majority are funded through government agencies, are descriptive and/or cross-sectional studies that are hypothesis generating in nature, and fail to represent the diversity of the AI/AN populations in the US. This systematic scoping review highlights the paucity of rigorous research being conducted in a population suffering from a greater burden of disease.

Treatment of Non-Metastatic Muscle-Invasive Bladder Cancer: AUA/ASCO/SUO Guideline (2017; Amended 2020, 2024).

PURPOSE: Although representing approximately 25% of patients diagnosed with bladder cancer, muscle-invasive bladder cancer (MIBC) carries a significant risk of death that has not significantly changed in decades. Increasingly, clinicians and patients recognize the importance of multidisciplinary collaborative efforts that take into account survival and quality of life concerns. This guideline provides a risk-stratified, clinical framework for the management of muscle-invasive urothelial bladder cancer. METHODOLOGY/METHODS: In 2024, the MIBC guideline was updated through the AUA amendment process in which newly published literature is reviewed and integrated into previously published guidelines in an effort to maintain currency. The amendment allowed for the incorporation of additional literature released since the previous 2020 amendment. The updated search gathered literature from May 2020 to November 2023. This review identified 3739 abstracts, of which 46 met inclusion criteria.When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions. RESULTS: Updates were made regarding neoadjuvant/adjuvant chemotherapy, radical cystectomy, pelvic lymphadenectomy, multi-modal bladder preserving therapy, and future directions. Further revisions were made to the methodology and reference sections as appropriate. CONCLUSIONS: This guideline seeks to improve clinicians' ability to evaluate and treat patients with MIBC based on currently available evidence. Future studies will be essential to further support or refine these statements to improve patient care.

Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline: 2024 Amendment.

PURPOSE: The purpose of this American Urological Association (AUA)/Society of Urologic Oncology (SUO) guideline amendment is to provide a useful reference on the effective evidence-based treatment strategies for non-muscle invasive bladder cancer (NMIBC). MATERIALS AND METHODS: In 2023, the NMIBC guideline was updated through the AUA amendment process in which newly published literature is reviewed and integrated into previously published guidelines in an effort to maintain currency. The amendment allowed for the incorporation of additional literature released since the previous 2020 amendment. The updated search gathered literature from July 2019 to May 2023. This review identified 1918 abstracts, of which 75 met inclusion criteria.When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) in support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions. RESULTS: Updates were made to statements on variant histologies, urine markers after diagnosis of bladder cancer, intravesical therapy, BCG maintenance, enhanced cystoscopy, and future directions. Further revisions were made to the methodology and reference sections as appropriate. CONCLUSIONS: This guideline seeks to improve clinicians' ability to evaluate and treat patients with NMIBC based on currently available evidence. Future studies will be essential to further support or refine these statements to improve patient care.

Screening and Supplementation for Iron Deficiency and Iron Deficiency Anemia During Pregnancy: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: In 2015 the US Preventive Services Task Force (USPSTF) found insufficient evidence to assess the balance of benefits and harms of routine screening and supplementation for iron deficiency anemia during pregnancy. Objective: To update the 2015 review on screening for iron deficiency anemia, in addition to iron deficiency during pregnancy, to inform the USPSTF. Data Sources: Ovid MEDLINE and Cochrane databases through May 24, 2023; surveillance through May 24, 2024. Study Selection: Randomized clinical trials of iron supplementation, screening effectiveness, treatment, and harms; observational studies of screening. Data Extraction and Synthesis: Dual review of abstracts, full-text articles, study quality, and data abstraction. Data were pooled using a random-effects model. Main Outcomes and Measures: Maternal and infant clinical outcomes, hematologic indices, and harms. Results: Seventeen trials (N = 24 023) on maternal iron supplementation were included. Iron supplementation was associated with decreased risk of maternal iron deficiency anemia at term (4 trials, n = 2230; 8.6% vs 19.8%; relative risk, 0.40 [95% CI, 0.26-0.61]; I2 = 20.5%) and maternal iron deficiency at term (6 trials, n = 2361; 46% vs 70%; relative risk, 0.47 [95% CI, 0.33-0.67]; I2 = 81.9%) compared with placebo or no iron supplement. There were no statistically significant differences in maternal quality of life, rates of gestational diabetes, maternal hemorrhage, hypertensive disorders of pregnancy, cesarean delivery, preterm birth, infant low birth weight, or infants small for gestational age for maternal iron supplementation compared with placebo or no supplementation. Harms of iron supplementation included transient gastrointestinal adverse effects. No studies evaluated the benefits or harms of screening for iron deficiency or iron deficiency anemia during pregnancy. Data on the association between iron status and health outcomes, such as hypertensive disorders of pregnancy and preterm birth, were very limited. Conclusions and Relevance: Routine prenatal iron supplementation reduces the incidence of iron deficiency and iron deficiency anemia during pregnancy, but evidence on health outcomes is limited or indicates no benefit. No studies addressed screening for iron deficiency or iron deficiency anemia during pregnancy. Research is needed to understand the association between changes in maternal iron status measures and health outcomes.

Telehealth Strategies for the Delivery of Maternal Health Care : A Rapid Review.

BACKGROUND: Telehealth strategies to supplement or replace in-person maternity care may affect maternal health outcomes. PURPOSE: To conduct a rapid review of the effectiveness and harms of telehealth strategies for maternal health care given the recent expansion of telehealth arising from the COVID-19 pandemic, and to produce an evidence map. DATA SOURCES: Systematic searches of MEDLINE, the Cochrane Library, CINAHL, Embase, and Scopus for English-language studies (January 2015 to April 2022). STUDY SELECTION: Randomized controlled trials (RCTs) and observational studies of maternal care telehealth strategies versus usual care. DATA EXTRACTION: Dual data extraction and risk-of-bias assessment of studies, with disagreements resolved through consensus. DATA SYNTHESIS: 28 RCTs and 14 observational studies (n = 44 894) were included. Maternal telehealth interventions supplemented in-person care for most studies of mental health and diabetes during pregnancy, primarily resulting in similar, and sometimes better, clinical and patient-reported outcomes versus usual care. Supplementing in-person mental health care with phone- or web-based platforms or mobile applications resulted in similar or better mental health outcomes versus in-person care. A reduced-visit prenatal care schedule using telehealth to replace in-person general maternity care for low-risk pregnancies resulted in similar clinical outcomes and higher patient satisfaction versus usual care. Overall, telehealth strategies were heterogeneous and resulted in similar obstetric and patient satisfaction outcomes. Few studies addressed disparities, health equity, or harms. LIMITATIONS: Interventions varied, and evidence was inadequate for some clinical outcomes. CONCLUSION: Replacing or supplementing in-person maternal care with telehealth generally results in similar, and sometimes better, clinical outcomes and patient satisfaction compared with in-person care. The effect on access to care, health equity, and harms is unclear. PRIMARY FUNDING SOURCE: Patient-Centered Outcomes Research Institute. (PROSPERO: CRD42021276347).

Updates to Recurrent Uncomplicated Urinary Tract Infections in Women: AUA/CUA/SUFU Guideline.

PURPOSE: In 2019 the American Urological Association (AUA) released the evidence-based guideline "Recurrent Uncomplicated Urinary Tract Infections in Women: AUA/CUA/SUFU Guideline." Information supporting the guideline came from a 2019 systematic evidence review prepared for the AUA by the Pacific Northwest Evidence-based Practice Center (EPC). The AUA used evidence found for 11 Key Questions (Appendix C) in the EPC's report to derive 16 Guideline Statements. In 2021 the EPC conducted an Update Literature Review (ULR) assessing abstracts from new studies published since the 2019 systematic review. The AUA asked the EPC to further assess a subset of studies included in the ULR report, to support potential changes to the 2019 guideline. MATERIALS/METHODS: A systematic-review utilized research from the Oregon Health & Science University. Pacific Northwest EPC was used to update the 2019 AUA Guideline on rUTI in women with new evidence published through 2021. RESULTS: Updates were made to reflect changes in literature since 2019. Updates include recent publications on antibiotic prophylaxis, non-antibiotic prophylaxis, and estrogen therapy. CONCLUSION: The presence of rUTI is crucial to the health of patients and its effects must be considered for the welfare of society. This document will undergo updating as the knowledge regarding current treatments and future treatment options continues to expand. .

Screening for Hepatitis B Virus Infection in Nonpregnant Adolescents and Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: A 2014 review for the US Preventive Services Task Force (USPSTF) found antiviral therapy for hepatitis B virus (HBV) infection associated with improved intermediate outcomes, although evidence on clinical outcomes was limited. Objective: To update the 2014 HBV screening review in nonpregnant adolescents and adults to inform the USPSTF. Data Sources: Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Ovid MEDLINE (2014 to August 2019); with surveillance through July 24, 2020. Study Selection: Randomized clinical trials (RCTs) on screening and antiviral therapy; cohort studies on screening, antiviral therapy clinical outcomes, and the association between achieving intermediate outcomes after antiviral therapy and clinical outcomes. Data Extraction and Synthesis: One investigator abstracted data; a second investigator checked accuracy. Two investigators independently assessed study quality. Random-effects profile likelihood meta-analysis was performed. Results: Thirty trials and 20 cohort studies, with a total of 94 168 participants, were included. No study directly evaluated the effects of screening for HBV infection vs no screening on clinical outcomes such as mortality, hepatocellular carcinoma, or cirrhosis. Screening strategies that focused on risk factors such as ever having immigrated from high-prevalence countries and demographic and behavioral risk factors would identify nearly all HBV infection cases. In 1 study (n = 21 008), only screening immigrants from high-prevalence countries would miss approximately two-thirds of infected persons. Based on 18 trials (n = 2972), antiviral therapy compared with placebo or no treatment was associated with greater likelihood of achieving intermediate outcomes, such as virologic suppression and hepatitis B e-antigen (HBeAg) or hepatitis B surface antigen loss or seroconversion; the numbers needed to treat ranged from 2.6 for virologic suppression to 17 for HBeAg seroconversion. Based on 12 trials (n = 4127), first-line antiviral therapies were at least as likely as nonpreferred therapies to achieve intermediate outcomes. Based on 16 trials (n = 4809), antiviral therapy might be associated with improved clinical outcomes, but data were sparse and imprecise. Nine cohort studies (n = 3893) indicated an association between achieving an intermediate outcome following antiviral therapy and improved clinical outcomes but were heterogeneous (hazard ratios ranged from 0.07 to 0.87). Antiviral therapy was associated with higher risk of withdrawal due to adverse events vs placebo or no antiviral therapy. Conclusions and Relevance: There was no direct evidence for the clinical benefits and harms of HBV screening vs no screening. Antiviral therapy for HBV infection was associated with improved intermediate outcomes and may improve clinical outcomes.

Comparative effectiveness and harms of long-acting insulins for type 1 and type 2 diabetes: A systematic review and meta-analysis.

AIM: To review evidence comparing benefits and harms of long-acting insulins in patients with type 1 and 2 diabetes. METHODS: MEDLINE and two Cochrane databases were searched during February 2018. Two authors selected studies meeting inclusion criteria and assessed their quality. Comparative studies of adult or paediatric patients with diabetes treated with insulin degludec, detemir or glargine were included. Meta-analysis was used to combine results of similar studies, and the I2 statistic calculated to assess statistical heterogeneity. RESULTS: Of 2534 citations reviewed, 70 studies met the inclusion criteria. No statistically significant differences in HbA1c were seen between any two insulins or formulations. Hypoglycaemia was less probable with degludec than with glargine, including nocturnal hypoglycaemia in type 1 (rate ratio 0.68, 95% CI 0.56-0.81) and type 2 diabetes (rate ratio 0.73, 95% CI 0.65-0.82), and severe hypoglycaemia in type 2 diabetes (relative risk 0.72, 95% CI 0.54-0.96). Patients with type 2 diabetes had higher rates of withdrawal because of adverse events when treated with detemir compared with glargine (relative risk 2.1, 95% CI 1.4-3.3). Adults taking detemir gained about 1 kg less body weight than those taking degludec (type 1) or glargine (type 2). CONCLUSIONS: No differences in glycaemic control were seen between insulin degludec, detemir and glargine. Hypoglycaemia was less probable with degludec than glargine, and patients taking detemir gained less body weight than those given degludec or glargine. In type 2 diabetes, withdrawals as a result of adverse events were more probable with detemir than glargine.

Updating the evidence on drugs to treat overactive bladder: a systematic review.

INTRODUCTION: Overactive bladder (OAB) is a common condition, increasing with age and affecting quality of life. While numerous OAB drugs are available, persistence is low. We evaluated evidence published since 2012 to determine if newer drugs provided better efficacy and harm profiles. METHODS: We searched MEDLINE and the Cochrane Library from 2012 to September 2018 using terms for included drugs and requested information from manufacturers of included drugs. We performed dual review of all systematic review processes, evaluated study quality, and conducted meta-analyses using random effects models. RESULTS: In addition to 31 older studies, we included 20 trials published since 2012 (N = 16,478; 4 good, 11 fair, and 5 poor quality). Where statistical differences were found, they were clinically small (reductions of < 0.5 episodes/day). Solifenacin plus mirabegron improved efficacy outcomes over monotherapy with either drug, but significantly increased constipation compared with solifenacin and dry mouth compared with mirabegron. Solifenacin reduced incontinence over mirabegron and tolterodine and urgency episodes over tolterodine. Mirabegron did not differ from tolterodine in efficacy but had significantly lower incidence of dry mouth than solifenacin or tolterodine. Fesoterodine showed significant improvements but also anticholinergic effects vs. tolterodine. Oxybutynin, solifenacin, and tolterodine had similar efficacy, but dry mouth led to greater discontinuation with oxybutynin. Blurred vision, cardiac arrhythmia, and dizziness were uncommon. CONCLUSION: New evidence confirms small, but clinically uncertain, differences among monotherapies and also between combination and monotherapy, regardless of statistical significance. While drugs mainly differed in incidence of dry mouth or constipation, none provided improved efficacy without increased harms.

Extreme background-rejection techniques for the ELROI optical satellite license plate.

The extremely low-resource optical identifier (ELROI) is a concept for an autonomous, low-power optical "license plate" that can be attached to anything that goes into space. ELROI uses short, omnidirectional flashes of laser light to encode a unique ID number that can be read by a small ground telescope using a photon-counting sensor and innovative extreme background-rejection techniques. ELROI is smaller and lighter than a typical radio beacon, low-power enough to run on its own small solar cell, and can safely operate for the entire orbital lifetime of a satellite or debris object. The concept has been validated in ground tests, and orbital prototypes are scheduled for launch in 2018 and beyond. In this paper, we focus on the details of the encoding scheme and data analysis that allow a milliwatt optical signal to be read from orbit. We describe the techniques of extreme background-rejection needed to achieve this, including spectral filtering and temporal filtering using a period- and phase-recovery algorithm, and discuss the requirements for an error-correcting code to encode the ID number. Worked examples with both simulated and experimental (long-range ground test) data illustrate the methods used. We present these techniques to describe a new optical communication concept, and to encourage others to consider observing and analyzing our upcoming test flights.

Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer in Women: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Pathogenic mutations in breast cancer susceptibility genes BRCA1 and BRCA2 increase risks for breast, ovarian, fallopian tube, and peritoneal cancer in women; interventions reduce risk in mutation carriers. Objective: To update the 2013 US Preventive Services Task Force review on benefits and harms of risk assessment, genetic counseling, and genetic testing for BRCA1/2-related cancer in women. Data Sources: Cochrane libraries; MEDLINE, PsycINFO, EMBASE (January 1, 2013, to March 6, 2019, for updates; January 1, 1994, to March 6, 2019, for new key questions and populations); reference lists. Study Selection: Discriminatory accuracy studies, randomized clinical trials (RCTs), and observational studies of women without recently diagnosed BRCA1/2-related cancer. Data Extraction and Synthesis: Data on study methods, setting, population characteristics, eligibility criteria, interventions, numbers enrolled and lost to follow-up, outcome ascertainment, and results were abstracted. Two reviewers independently assessed study quality. Main Outcomes and Measures: Cancer incidence and mortality; discriminatory accuracy of risk assessment tools for BRCA1/2 mutations; benefits and harms of risk assessment, genetic counseling, genetic testing, and risk-reducing interventions. Results: For this review, 103 studies (110 articles; N = 92 712) were included. No studies evaluated the effectiveness of risk assessment, genetic counseling, and genetic testing in reducing incidence and mortality of BRCA1/2-related cancer. Fourteen studies (n = 43 813) of 8 risk assessment tools to guide referrals to genetic counseling demonstrated moderate to high accuracy (area under the receiver operating characteristic curve, 0.68-0.96). Twenty-eight studies (n = 8060) indicated that genetic counseling was associated with reduced breast cancer worry, anxiety, and depression; increased understanding of risk; and decreased intention for testing. Twenty studies (n = 4322) showed that breast cancer worry and anxiety were higher after testing for women with positive results and lower for others; understanding of risk was higher after testing. In 8 RCTs (n = 54 651), tamoxifen (relative risk [RR], 0.69 [95% CI, 0.59-0.84]; 4 trials), raloxifene (RR, 0.44 [95% CI, 0.24-0.80]; 2 trials), and aromatase inhibitors (RR, 0.45 [95% CI, 0.26-0.70]; 2 trials) were associated with lower risks of invasive breast cancer compared with placebo; results were not specific to mutation carriers. Mastectomy was associated with 90% to 100% reduction in breast cancer incidence (6 studies; n = 2546) and 81% to 100% reduction in breast cancer mortality (1 study; n = 639); oophorectomy was associated with 69% to 100% reduction in ovarian cancer (2 studies; n = 2108); complications were common with mastectomy. Conclusions and Relevance: Among women without recently diagnosed BRCA1/2-related cancer, the benefits and harms of risk assessment, genetic counseling, and genetic testing to reduce cancer incidence and mortality have not been directly evaluated by current research.

Loss of the Yeast SR Protein Npl3 Alters Gene Expression Due to Transcription Readthrough.

Yeast Npl3 is a highly abundant, nuclear-cytoplasmic shuttling, RNA-binding protein, related to metazoan SR proteins. Reported functions of Npl3 include transcription elongation, splicing and RNA 3' end processing. We used UV crosslinking and analysis of cDNA (CRAC) to map precise RNA binding sites, and strand-specific tiling arrays to look at the effects of loss of Npl3 on all transcripts across the genome. We found that Npl3 binds diverse RNA species, both coding and non-coding, at sites indicative of roles in both early pre-mRNA processing and 3' end formation. Tiling arrays and RNAPII mapping data revealed 3' extended RNAPII-transcribed RNAs in the absence of Npl3, suggesting that defects in pre-mRNA packaging events result in termination readthrough. Transcription readthrough was widespread and frequently resulted in down-regulation of neighboring genes. We conclude that the absence of Npl3 results in widespread 3' extension of transcripts with pervasive effects on gene expression.

Conditional inactivation of the DNA damage response gene Hus1 in mouse testis reveals separable roles for components of the RAD9-RAD1-HUS1 complex in meiotic chromosome maintenance.

The RAD9-RAD1-HUS1 (9-1-1) complex is a heterotrimeric PCNA-like clamp that responds to DNA damage in somatic cells by promoting DNA repair as well as ATR-dependent DNA damage checkpoint signaling. In yeast, worms, and flies, the 9-1-1 complex is also required for meiotic checkpoint function and efficient completion of meiotic recombination; however, since Rad9, Rad1, and Hus1 are essential genes in mammals, little is known about their functions in mammalian germ cells. In this study, we assessed the meiotic functions of 9-1-1 by analyzing mice with germ cell-specific deletion of Hus1 as well as by examining the localization of RAD9 and RAD1 on meiotic chromosomes during prophase I. Hus1 loss in testicular germ cells resulted in meiotic defects, germ cell depletion, and severely compromised fertility. Hus1-deficient primary spermatocytes exhibited persistent autosomal γH2AX and RAD51 staining indicative of unrepaired meiotic DSBs, synapsis defects, an extended XY body domain often encompassing partial or whole autosomes, and an increase in structural chromosome abnormalities such as end-to-end X chromosome-autosome fusions and ruptures in the synaptonemal complex. Most of these aberrations persisted in diplotene-stage spermatocytes. Consistent with a role for the 9-1-1 complex in meiotic DSB repair, RAD9 localized to punctate, RAD51-containing foci on meiotic chromosomes in a Hus1-dependent manner. Interestingly, RAD1 had a broader distribution that only partially overlapped with RAD9, and localization of both RAD1 and the ATR activator TOPBP1 to the XY body and to unsynapsed autosomes was intact in Hus1 conditional knockouts. We conclude that mammalian HUS1 acts as a component of the canonical 9-1-1 complex during meiotic prophase I to promote DSB repair and further propose that RAD1 and TOPBP1 respond to unsynapsed chromatin through an alternative mechanism that does not require RAD9 or HUS1.

Polymorphisms in folate-metabolizing enzymes and response to 5-fluorouracil among patients with stage II or III rectal cancer (INT-0144; SWOG 9304).

BACKGROUND: Recurrence and toxicity occur commonly among patients with rectal cancer who are treated with 5-fluorouracil (5-FU). The authors hypothesized that genetic variation in folate-metabolizing genes could play a role in interindividual variability. The objective of the current study was to evaluate the associations between genetic variants in folate-metabolizing genes and clinical outcomes among patients with rectal cancer treated with 5-FU. METHODS: The authors investigated 8 functionally significant polymorphisms in 6 genes (methylenetetrahydrofolate reductase [MTHFR] [C677T, A1298C], SLC19A1 [G80A], SHMT1 [C1420T], dihydrofolate reductase [DHFR] [Del19bp], TS 1494del,and TSER) involved in folate metabolism in 745 patients with TNM stage II or III rectal cancer enrolled in a phase 3 adjuvant clinical trial of 3 regimens of 5-FU and radiotherapy (INT-0144 and SWOG 9304). RESULTS: There were no statistically significant associations noted between polymorphisms in any of the genes and overall survival, disease-free survival (DFS), and toxicity in the overall analyses. Nevertheless, there was a trend toward worse DFS among patients with the variant allele of MTHFR C677T compared with wild-type, particularly in treatment arm 2, in which patients with the MTHFR C677T TT genotype had worse overall survival (hazards ratio, 1.76; 95% confidence interval, 1.06-2.93 [P = .03]) and DFS (hazards ratio, 1.84; 95% confidence interval, 1.12-3.03 [P = .02]) compared with those with homozygous wild-type. In addition, there was a trend toward reduced hematological toxicity among patients with variants of SLC19A1 G80A in treatment arm 1 (P for trend, .06) and reduced esophagitis/stomatitis noted among patients with variants of TSER in treatment arm 3 (P for trend, .06). CONCLUSIONS: Genetic variability in folate-metabolizing enzymes was found to be associated only to a limited degree with clinical outcomes among patients with rectal cancer treated with 5-FU.

Combined corticosteroid and long-acting beta2-agonist in one inhaler versus placebo for chronic obstructive pulmonary disease.

BACKGROUND: Both long-acting beta2-agonists (LABA) and inhaled corticosteroids (ICS) have been recommended in guidelines for the treatment of chronic obstructive pulmonary disease (COPD). Their coadministration in a combination inhaler may facilitate adherence to medication regimens and improve efficacy. OBJECTIVES: To determine the efficacy and safety of combined ICS and LABA for stable COPD in comparison with placebo. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials, reference lists of included studies and manufacturers' trial registries. The date of the most recent search was June 2013. SELECTION CRITERIA: We included randomised and double-blind studies of at least four weeks' duration. Eligible studies compared combined ICS and LABA preparations with placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study risk of bias and extracted data. Dichotomous data were analysed as fixed-effect odds ratios (OR) or rate ratios (RR) with 95% confidence intervals (95% CI), and continuous data as mean differences with 95% confidence intervals. MAIN RESULTS: Nineteen studies met the inclusion criteria (with 10,400 participants randomly assigned, lasting between 4 and 156 weeks, mean 42 weeks). Studies used three different combined preparations (fluticasone/salmeterol, budesonide/formoterol or mometasone/formoterol). The studies were generally at low risk of bias for blinding but at unclear or high risk for attrition bias because of participant dropouts. Compared with placebo, both fluticasone/salmeterol and budesonide/formoterol reduced the rate of exacerbations. Mometasone/formoterol reduced the number of participants experiencing one or more exacerbation. Pooled analysis of the combined therapies indicated that exacerbations were less frequent when compared with placebo (Rate Ratio 0.73; 95% CI 0.69 to 0.78, 7 studies, 7495 participants); the quality of this evidence when GRADE criteria were applied was rated as moderate. Participants included in these trials had on average one or two exacerbations per year, which means that treatment with combined therapy would lead to a reduction of one exacerbation every two to four years in these individuals. An overall reduction in mortality was seen, but this outcome was dominated by the results of one study (TORCH) of fluticasone/salmeterol. Generally, deaths in the smaller, shorter studies were too few to contribute to the overall estimate. Further longer studies on budesonide/formoterol and mometasone/formoterol are required to clarify whether this is seen more widely. When a baseline risk of death of 15.2% from the placebo arm of TORCH was used, the three-year number needed to treat for an additional beneficial outcome (NNTB) with fluticasone/salmeterol to prevent one extra death was 42 (95% CI 24 to 775). All three combined treatments led to statistically significant improvement in health status measurements, although the mean differences observed are relatively small in relation to the minimum clinically important difference. Furthermore, symptoms and lung function assessments favoured combined treatments. An increase in the risk of pneumonia was noted with combined inhalers compared with placebo treatment (OR 1.62, 95% CI 1.36 to 1.94), and the quality of this evidence was rated as moderate, but no dose effect was seen. The three-year NNTH for one extra case of pneumonia was 17, based on a 12.3% risk of pneumonia in the placebo arm of TORCH. Fewer participants withdrew from the combined treatment arms for adverse events or lack of efficacy. AUTHORS' CONCLUSIONS: Combined inhaler therapy led to around a quarter fewer COPD exacerbations than were seen with placebo. A significant reduction in all-cause mortality was noted, but this outcome was dominated by one trial (TORCH), emphasising the need for further trials of longer duration. Increased risk of pneumonia is a concern; however, this did not translate into increased exacerbations, hospitalisations or deaths. Current evidence does not suggest any major differences between inhalers in terms of effects, but nor is the evidence strong enough to demonstrate that all are equivalent. To permit firmer conclusions about the effects of combined therapy, more data are needed, particularly in relation to the profile of adverse events and benefits in relation to different formulations and doses of inhaled ICS. Head-to-head comparisons are necessary to determine whether one combined inhaler is better than the others.

The innate antiviral factor APOBEC3G targets replication of measles, mumps and respiratory syncytial viruses.

The cytidine deaminase APOBEC3G (apolipoprotein B mRNA-editing enzyme-catalytic polypeptide 3G; A3G) exerts antiviral activity against retroviruses, hepatitis B virus, adeno-associated virus and transposable elements. We assessed whether the negative-strand RNA viruses measles, mumps and respiratory syncytial might be affected by A3G, and found that their infectivity was reduced by 1-2 logs (90-99 %) in A3G overexpressing Vero cells, and in T-cell lines expressing A3G at physiological levels. Viral RNA was co-precipitated with HA-tagged A3G and could be amplified by RT-PCR. Interestingly, A3G reduced viral transcription and protein expression in infected cells by 50-70 %, and caused an increased mutation frequency of 0.95 mutations per 1000 nt in comparison to the background level of 0.22/1000. The observed mutations were not specific for A3G [cytidine to uridine (C→U) or guanine to adenine (G→A) hypermutations], nor specific for ADAR (adenosine deaminase acting on RNA, A→G and U→C transitions, with preference for next neighbour-nucleotides U = A>C>G). In addition, A3G mutants with inactivated catalytic deaminase (H257R and E259Q) were inhibitory, indicating that the deaminase activity is not required for the observed antiviral activity. In combination, impaired transcription and increased mutation frequencies are sufficient to cause the observed reduction in viral infectivity and eliminate virus replication within a few passages in A3G-expressing cells.

APOBEC-mediated viral restriction: not simply editing?

The APOBEC family of cytidine deaminases inhibit the mobility of diverse retroviruses, retrotransposons and other viruses. Initial reports proposed that these effects were due to the DNA editing capabilities of these enzymes; however, many recent studies have provided evidence suggesting that APOBEC proteins can inhibit these elements by several mechanisms, including editing-dependent and editing-independent processes. Investigating these modes of action and the potential contribution that each one makes to the antiviral activities of various APOBEC proteins is vital if we are to understand how APOBEC proteins protect host genomes from invading nucleic acids.

Management of tuberculosis infection in Victorian children: A retrospective clinical audit of factors affecting treatment completion.

BACKGROUND: Tuberculosis preventive treatment (TPT) is strongly recommended for children following infection with Mycobacterium tuberculosis because of their high risk of progression to active tuberculosis, including severe disseminated disease. We describe the implementation of TPT for children and adolescents with evidence of tuberculosis infection (TBI) at Victoria's largest children's hospital and examine factors affecting treatment completion. METHODS: We conducted a retrospective clinical audit of all children and adolescents aged <18 years diagnosed with latent TBI at the Royal Children's Hospital, Melbourne, between 2010 and 2016 inclusive. The primary outcome was treatment completion, defined as completing TPT to within one month of a target duration for the specified regimen (for instance, at least five months of a six-month isoniazid course), confirmed by the treating clinician. Factors associated with treatment adherence were evaluated by univariate and multivariate analysis. RESULTS: Of 402 participants with TBI, 296 (74%) met the criteria for treatment "complete". The most common TPT regimen was six months of daily isoniazid (377, 94%). On multivariate logistic regression analysis, treatment completion was more likely among children and adolescents who had refugee health screening performed (OR 2.31, 95%CI 1.34-4.00) or who were also treated for other medical conditions (OR 1.67 95%CI 1.0-2.85), and less likely among those who experienced side-effects (OR 0.32, 95%CI 0.11-0.94). However, TPT was generally well tolerated with side-effects reported in 15 participants (3.7%). CONCLUSION: Identification of factors associated with TPT completion and deficiencies in the existing care pathway have informed service provision changes to further improve outcomes for Victorian children and adolescents with TBI.

Gender-responsive social protection post-COVID-19.

Investment in gender-responsive social protection systems and evidence is key to a more equal future post-COVID-19.