Pre-polycystic ovary syndrome and polymenorrhoea as new facets of polycystic ovary syndrome (PCOS): Evidences from a single centre data set.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is a complex disorder with diverse metabolic implications. Diagnosis typically relies on oligo-amenorrhoea (OA), hyperandrogenism (HA), and polycystic ovarian morphology (PCOM). However, the role of polymenorrhoea in PCOS remains understudied. Additionally, limited information exists regarding metabolic disturbances in women with partial PCOS phenotypes that do not meet diagnostic criteria. This extensive database aims to provide substantial evidence on the metabolic implications of polymenorrhoea and partial PCOS phenotypes. DESIGN: Prospective observational study. PATIENTS AND MEASUREMENTS: In this single-centre study, 6463 women with PCOS-like characteristics and 3142 age-matched healthy women were included. The study compared clinical (anthropometry, modified Ferriman Gallwey [mFG] score), hormonal (serum testosterone), and metabolic (plasma glucose, serum lipids, insulin) characteristics between women diagnosed with PCOS, those with partial PCOS phenotypes, and the healthy control group RESULTS: In all, 5174 women met Rotterdam criteria for PCOS diagnosis, while 737 were classified as Pre-PCOS, including HA (n = 538), OA (n = 121), or PCOM (n = 78). Common clinical features included oligomenorrhoea (75.5%), hirsutism (82.9%), obesity (27.2%), hypertension (1.6%), metabolic syndrome (19.6%), and diabetes mellitus (5.6%). Women diagnosed with PCOS, HA only, and OA only exhibited higher average body mass index, plasma glucose levels (both fasting and 2 h after the oral glucose tolerance test), and lipid fractions in comparison to those with PCOM and the healthy controls. However, indices of insulin resistance were similar among women with PCOS, HA, PCOM, and OA, albeit higher than in the healthy controls. The polymenorrhoea subgroup (5.9%) had lower BMI and serum testosterone, but similar mFG score, plasma glucose, insulin, and lipid levels as the oligomenorrhoea subgroup. CONCLUSION: The metabolic disturbances observed in Pre-PCOS women highlight the need to reassess diagnostic criteria. Including the polymenorrhoea subcategory in PCOS criteria is recommended due to similar metabolic dysfunctions as the oligomenorrhoea group.

Efficacy and safety of various oral regimens (three oral doses) and schedules (daily v. monthly) of cholecalciferol in North Indian adults with low vitamin D status: evidence from a randomised controlled trial.

Vitamin D (VD) deficiency (serum 25 hydroxy vitamin D (25(OH)D) concentration of < 20 ng/ml), in endemic proportions, demands a supplementation strategy with optimal dosing regimens. A randomised parallel-group, active-controlled trial was conducted among apparently healthy, VD-deficient subjects, aged 18-60 years who received 600 µg/d (Group A), 1000 µg/d (Group B), 2000 µg/d (Group C) and 60 000 µg/month (Group D) of oral cholecalciferol. The intervention was carried in two phases (I and II) of 12 weeks each, with same dose, separated by a washout phase of 12 weeks. Serum 25(OH)D, intact parathyroid hormones (iPTH), Ca, phosphorous (PO4), alkaline phosphatase (ALP) and spot urine Ca/Cr were measured at baseline, 12, 24 and 36 weeks following the intervention, and adverse events were recorded at each occurrence and at 12, 24 and 36 weeks. A statistically significant time-group interaction was found in serum 25(OH)D concentration (P < 0·05). Serum 25(OH)D concentration increased significantly from baseline to 12 weeks (P < 0·05) in all the groups with no change at 24 weeks but further increase at 36 weeks (P < 0·05). At the end of the study, Group C had maximum increment in serum 25(OH)D concentration, while as Groups C and D (95 %, and 90 %) had higher proportion of subjects VD sufficient than Groups A and B (65 % and 78 %) (P < 0·05). No significant time-dose interactions were observed in serum iPTH, Ca, PO4 and ALP or urine Ca/Cr ratio. Three subjects (two in Group C and one in Group D) developed transient hypercalciuria. Supplementation with daily 2000 µg or monthly 60 000 µg of oral cholecalciferol among adults seems optimal and safe.

Impact of Prevalent Dietary Pattern on Serum Vitamin B12 Status and Its Association With Inflammation Among Reproductive Age Women.

SCOPE: Association between vitamin B12 deficiency (VB12D) and dietary patterns being well documented has bearing on obstetrics and neonatal outcomes. However, relationship between VB12D and serum inflammatory markers (IMs), particularly in vegetarian diet and Polycystic ovary syndrome (PCOS), remains elusive. This cross-sectional study assesses VB12D and IMs among reproductive age women consuming different diets. METHODS AND RESULTS: Nonvegetarian (PCOS, n = 104; healthy, n = 148) and vegetarian women (PCOS n = 112; healthy, n = 186) are for evaluated clinical, biochemical, hormonal assessment, inflammatory, and four vitamin B 12 (VB12) markers. VB12D is defined by Fedosov's wellness quotient (4cB12). Using 4cB12, prevalence of VB12D is discerned in 54.4% (PCOS: 72.1%; healthy 36.5%) and 93.4% (PCOS: 95.9%; healthy: 91.9%) among nonvegetarians and vegetarians, respectively. Vegetarian PCOS women depict lowest median (interquartile range [IQR]) of serum B12 76.2(72.6) pg mL-1, holotranscobalamine (HTC) 37.9(11.3) and highest homocysteine (HCY) 40.32(6.0) µmol L-1, methylmalonic acid (MMA) 352.26(156.7) nmol L-1 with highest Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and IMs (Monocyte chemoattractant protein 1 (MCP-1), High sensitivity C-reactive protein (hs-CRP), Tumour Necrosis Factor alpha (TNF-α) and Interleukin 6 (IL-6)). Significant correlation of serum hs-CRP, TNF-α, and IL-6 with VB12 markers is observed. CONCLUSION: The VB12D is rampant among reproductive age women that gets exacerbated by PCOS or vegetarian diet. It is directly correlated with magnitude of proinflammatory markers. The results carry substantial implications for public health policies aimed at improving preconception maternal VB12 status for better future pregnancy and offspring outcomes.

Do Pleiotropic Effects of Spironolactone in Women with PCOS Make it More than an Anti-androgen? Evidence from a Systematic Review and Meta-analysis.

BACKGROUND: Spironolactone use as a treatment for hirsutism and other dermatological conditions among polycystic ovary syndrome (PCOS) and idiopathic hirsutism shows varied results. OBJECTIVE: This study thus summarizes the entire evidence to better define its impact on Ferriman-Gallwey (FG) score in addition to other derangements associated with PCOS. METHODS: PubMed, Embase, Scopus and bibliographies of relevant articles were searched. Randomized controlled trails (RCTs) investigating the efficacy of spironolactone in PCOS and idiopathic hirsutism were included. Pooled mean difference (MD) was calculated using random effects model and relevant subgroup analysis was done. Potential heterogeneity and publication bias was assessed. RESULTS: Of 1041 retrieved studies, 24 RCTs were included. Spironolactone (100 mg/daily) exhibited a significant reduction in FG score in idiopathic hirsutism compared to finasteride (MD: -2.43; 95% C.I: -3.29, -1.57) and cyproterone acetate (MD: -1.18; 95% C.I: -2.10, -0.26), however, no significant difference was found among PCOS subjects in comparison to flutamide and finasteride. A lower dose of spironolactone (50 mg/day) exhibited no significant difference relative to metformin on FG Score (MD: -0.61; 95% C.I: -1.76, 0.54, I2 = 57%), serum total testosterone (MD: -0.61; 95% C.I: -1.76, 0.54), I2 = 57% and HOMA-IR (MD: 1.03; 95% C.I: -1.22, 3.29), I2 = 60% among PCOS women. The main side effects reported by the studies were menstrual irregularity, mild nausea, vomiting and diarrhea. CONCLUSION: Spironolactone is well tolerated among idiopathic hirsute and PCOS women. The drug significantly improved hirsutism in the former group and shows a positive trend in the latter women, however, displays no effect on FSH, LH, menstrual cyclicity, BMI, and HOMA-IR in PCOS women.

A novel mutation in the KCNJ11 gene (p.Val36Glu), predisposes to congenital hyperinsulinemia.

The hypoglycemia induced by insulin hypersecretion in congenital hyperinsulinemia (CHI), a rare life-threatening condition can lead to irreversible brain damage in neonates. Inactivating mutations in the genes encoding KATP channel (ABCC8 and KCNJ11) as well as HNF4A, HNF1A, HADH, UCP2, and activating mutations in GLUD1, GCK, and SLC16A1 have been identified as causal. A 3-month-old male infant presenting tonic-clonic seizures and hyperinsulinemia was clinically assessed and subjected to genetic analysis. Besides the index patient, his parents were clinically investigated, and a detailed family history was also recorded. The laboratory investigations and the genetic test results of the parents were compared with the index patient. The biochemical and hormonal profile of the patient confirmed his suffering from CHI and did not respond to diazoxide treatment. The genetic testing revealed that the subject harbored a novel homozygous missense mutation in the KCNJ11 gene, (c.107T>A, p.Val36Glu.). The bioinformatic analysis revealed that valine is highly conserved and predicted that the variant allele (p.Val36Glu) is likely pathogenic and causal for CHI. Parents were heterozygous carriers and did not report any abnormal metabolic profile. Identification of such mutations is critical and likely to change the therapeutic interventions for such patients in the future.

Family history of menstrual irregularity or diabetes mellitus enhances the susceptibility to polycystic ovary syndrome among subjects harboring rs7903146 genetic variant of TCF7L2.

Purpose: TCF7L2 mediated Wnt signaling cascade regulates glucose homeostasis by orchestrating expression, processing, and hepatic clearance of insulin. Type 2 diabetes mellitus (T2DM) and polycystic ovary syndrome (PCOS) significantly overlap in pathophysiological features with insulin resistance as a central driver. While TCF7L2 is the most potent T2DM locus, studies on the association of TCF7L2 with PCOS are limited and inconclusive. Therefore, in addition to expression profiling, the association of TCF7L2 polymorphic variant rs7903146 with PCOS was evaluated. Methods: Using Rotterdam-2003 criteria for the diagnosis, 120 PCOS cases, and 120 age-matched controls were recruited. Subjects underwent clinical, biochemical, and hormonal assessment, followed by genotyping for rs7903146, carried out by PCR-RFLP and TCFL2 expression profiling by qRT-PCR. Genotype-phenotype correlation analysis was performed to evaluate any such associations. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were computed by conditional logistic regression. Results: Higher odds of developing PCOS were observed in the women having a family history (FH) of either T2DM (OR = 3.86, 95% CI:1.90 - 7.83), hirsutism (OR = 4.74. 95%CI: 1.91 - 17.21) or menstrual irregularities (MI) (OR = 3.07, 95%CI: 1.61 - 8.54). The genotypes of rs7903146 did not confer any risk for developing PCOS (OR = 0.46;95%CI: 0.15 - 2.03). However, the elevated risk was seen in the subjects who harbored the variant allele and had FH of either T2DM (OR = 6.71; 95%CI: 1.89 - 23.78) or MI (OR = 9.71; 95% CI:1.89 - 23.78). Conclusion: TCF7L2 polymorphic variant rs7903146 is not independently linked to PCOS risk, but modulates the risk in the subjects having a family history of either T2DM or MI. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-022-01050-y.

A systematic review of economic evaluations of treatment regimens in multiple myeloma.

BACKGROUND: The expansion of advanced expensive therapeutic innovations for Multiple Myeloma (MM) led to increased disclosure of economic evaluations. The present analysis systematically reviewed and appraised the reporting quality of economic evaluations in MM. METHODOLOGY: A comprehensive literature search in Ovid, MEDLINE(R), PubMed, and Cochrane libraries was conducted for studies published in the past decade. Two independent authors performed study selection and data extraction in a standardized form. Study methodological quality assessment was performed using 10-item Drummond's tool. RESULTS: Of potentially eligible 1150 retrieved studies, 17 met eligibility criteria. Six evaluations (35%) were in newly diagnosed MM and 11 (65%) in relapse refractory (RR) MM. Nine studies (53%) embraced the payer's perspective, five (29%) adopted health care system, one (6%) societal and two did not report. Six (35%) employed partitioned survival model, 4(24%) discrete event simulation, 4(24%) Markov model and 2(12%) used decision tree model. The methodological quality has improved significantly; 16 (94%) studies comprehended a well-defined question by affirming the analysis perspective and examined both costs and outcomes while 13 (71%) provided a comprehensive description of competing alternatives. CONCLUSION: The addition of novel drugs to the treatment armamentarium of MM is considerably cost-effective. The evaluations became more frequent, methodological quality has improved in the last decade.

Psychosocial morbidity profile in a community based sample of low back pain patients.

Low back pain (LBP) is a major health concern and is closely associated with psychosocial morbidity and diminished Health-related quality of life (HRQoL). This is minimally investigated in community-based samples of developing nations like India. This study is aimed to specifically investigate the exposure-outcome associations between LBP and burden of disability (Modified Oswestry questionnaire (MODQ)), psychological morbidities (Depression, Anxiety and Stress Scale (DASS-21)), and HRQoL (Short Form -12 version 2 (SF12V2). A Cross-sectional study using a community-based sample of LBP positive population was conducted. The range of treatment options sought was also collected. Chi-square tests and independent t-test were used to analyze the data. Of 1531 recruited participants, 871(57%) were identified as LBP positive of whom 60% were females. Mean (SD) of age and pain intensity of LBP patients was 33 (11) years and numeric rating scale4.2 (2.6) respectively. Two-third reported minimal/moderate disability. Mean (SD) scores of depression 11.87 (4.05), anxiety (8.32), stress 13.7 (5.98), physical and mental summary scores of SF-12v2 were 47.9 (7.4) and 42.2 (10.4). A multitude of remedial options was sought for the ailment. LBP causes significant disability and psychological morbidity among affected population. This may adversely affect their HRQoL and subsequently productivity. Acupuncture was a preferred treatment sought by Indian LBP patients.

Relative Efficacy and Safety of Pharmacotherapeutic Interventions for Diabetic Peripheral Neuropathy: A Systematic Review and Bayesian Network Meta-Analysis.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is a most common devitalizing complication of diabetes mellitus, which is primarily characterized by sensory loss, paresthesia, prickling, pain, or allodynia. OBJECTIVES: To evaluate the relative efficacy and safety of the interventions used in the DPN pain management and rank their order. STUDY DESIGN: A systematic review and Bayesian network meta-analysis (NMA). METHODS: Randomized, controlled trials were identified through a comprehensive, systematic literature exploration, primarily utilizing the PubMed, EMBASE, Ovid, and Cochrane Library databases. The efficacy and safety outcomes consist of the proportion of patients reporting either 30% or 50% pain reduction and overall withdrawal or withdrawal due to adverse drug events, respectively. Effect estimates from Bayesian NMA were presented as odds ratio (OR) with 95% credible intervals (CrI). Heterogeneity and convergence were assessed by using I2 and deviation information criteria. The risk of bias was evaluated by using Pedro Scale. RESULTS: A total of 3,246 potentially relevant trials were identified and screened, finally 43 trials consisting of 7,877 randomized patients met the inclusion criteria. Statistically significant treatment difference for 50% pain reduction was reported for duloxetine vs. placebo (OR: 2.50; CrI: 1.62-3.91), mirogabalin vs. placebo (OR: 3.25; CrI: 1.16-9.35), pregabalin vs. placebo (OR: 2.33; CrI: 1.69-3.27), duloxetine vs. carbamazepine (OR: 3.37; CrI: 1.07-10.90), mirogabalin vs. carbamazepine (OR: 4.39; CrI: 1.01-19.63), mirogabalin vs. lamotrigine (OR: 4.05: CrI: 1.07-15.77), pregabalin vs. lamotrigine (OR: 2.90, CrI: 1.19-7.22) and pregabalin vs. nortriptyline (OR: 4.10, CrI: 1.13-5.28). Nortriptyline reported the highest possibility of achieving 30% and 50% pain reduction. Sodium valproate and benztropine reported the highest probability of total withdrawals and withdrawals due to adverse drug events, respectively. LIMITATION: The different follow-up time of the included studies can result in the variation of intended results. CONCLUSION: Nortriptyline reported the advantage relative to other drugs in achieving 30% and 50% pain reduction from the baseline. Gabapentin reported a significance of 50% pain reduction relative to placebo.

Comparative short-term efficacy and safety of add-on anti-seizure medications in Dravet syndrome: An indirect treatment comparison.

PURPOSE: Although cannabidiol and fenfluramine have been recently approved by the US Food and Drug Administration (FDA) for seizures in children with Dravet syndrome (DS), the comparative efficacy and safety of these and stiripentol as an add-on therapy for DS has not been evaluated in head-to-head trials. The current study aimed to assess the comparative efficacy and safety of add-on anti-seizure medications in DS. METHODS: PubMed and EMBASE database search and a manual search was done using keywords; "antiepileptic", "Dravet syndrome" and "antiseizure". The primary efficacy outcome was ≥50% reduction in convulsive seizure frequency from baseline while the safety outcome was treatment-emergent adverse events (TEAEs). Frequentist approach were used for combining direct and indirect evidence and network plots prepared. The drugs were ranked based on p-scores obtained using the surface under the cumulative ranking (SUCRA). Heterogeneity across studies was calculated by I2 statistic and Q test. RESULTS: Five randomized controlled trials (RCTs) with 565 patients with DS (2-20 years) who received placebo or any of the three active interventions (stiripentol, cannabidiol, and fenfluramine) were included. Compared with placebo, all the three drugs were associated with a significant reduction in convulsive seizure frequency from baseline. Stiripentol had the highest probability ranking for ≥50% reduction in convulsive seizure frequency from baseline [OR: 20.2; 95% CI: 2.1-198.0] and for occurrence of any treatment emergent adverse events (TEAEs) [OR:53.9; 95% CI: 1.4 to 2079.8] followed by fenfluramine and cannabidiol. However, for serious TEAEs, the ranking order was stiripentol followed by cannabidiol and fenfluramine. The trial on stiripentol had limited sample size explaining the wide confidence intervals for the comparative outcomes. CONCLUSION: In this indirect comparison, fenfluramine and stiripentol hadd comparable efficacy but fenfluramine appeareded to be safer in terms of less frequent serious TEAEs. Cannabidiol had relatively lower efficacy and was associated with serious TEAEs. A head-to-head trial between stiripentol, cannabidiol and fenfluramine is the need of the hour.

Health-related quality of life in transplant eligible multiple myeloma patients with or without early ASCT in the real-world setting.

There is no comparative health-related quality of life (HR-QoL) data of transplant eligible (TE) multiple myeloma (MM) patients undergoing early autologous stem cell transplantation (ASCT) and those without in the era of novel drugs. This study prospectively evaluated the serial HR-QoL in TE-MM using the EORTC QLQ-C30 and MY20 questionnaires. Barring the transient worsening in QoL one-month after ASCT, there was a comparable improvement in most QoL domains in both early-ASCT and no-early ASCT cohorts. Post-early-ASCT patients had higher global health scores (71.9 vs. 60.8, p < .05) than no-early ASCT at 12-months. Patients belonging to lower socioeconomic status (SES) were more likely not to undergo ASCT than middle-high SES patients (38.6% vs. 74.5%, p < .05). While age, gender had no impact on QoL, performance status, staging, and induction therapy impacted QoL. This study shows that early ASCT maintains QoL and should be encouraged in all TE-MM patients.

Prevalence and Impact of Low Back Pain in a Community-Based Population in Northern India.

BACKGROUND: Low back pain (LBP) ranks first for disability and sixth for overall burden on world health, with an annual approximate cost of $135 billion. There are limited data on the prevalence and risk factors for LBP in developing countries, such as India. OBJECTIVES: To assess the prevalence, pain intensity, and quality of life (QOL) associated with LBP in northern India. STUDY DESIGN: Cross-sectional study. SETTINGS: Northern states of India. METHODS: Adult population of different strata of the community were interviewed. Lifetime, point, 1-year, and age standardized lifetime prevalence with 95% confidence intervals (CI) and QOL, and pain intensity using the Numeric Rating Scale (NRS-11) were determined. Binary logistic regression test was conducted to determine the predictors of LBP prevalence; odds ratio (OR) with 95% CI are presented. Significance level was set at P <= 0.05. RESULTS: A total of 1,531 patients were interviewed of whom 48% were men and mean (standard deviation [SD]) age was 32 (10) years. Lifetime, point, 1-year, and age standardized lifetime prevalence (95% CI) were 57% (54%-59%), 32% (30%-34%), 48% (46%-51%), and 59% (56%-62%), respectively. Average (SD) NRS-11 was 4.2 (2.6). Significant impact of LBP on sleep (24%), depression/psychological problems (24%), and social life (28%) were observed. Women (OR, 2.23; 95% CI, 1.80-2.77; P < 0.05), walking/lifting activity (OR, 1.362; 95% CI, 1.097-1.692; P < 0.05), and increasing age (OR, 1.03; 95% CI, 1.02-1.04; P < 0.05) were most significant positive predictors of LBP. LIMITATIONS: The progression of LBP could not be assessed in the enrolled patients. CONCLUSIONS: LBP is highly prevalent in India, adversely affecting QOL in respondents. This calls for action by health officials to plan prevention, education, and management programs in the society. KEY WORDS: Low back pain, pain intensity, prevalence, incidence, quality of life.

Development, validation and evaluation of a novel self-instructional module in patients with chronic non-specific low back pain.

BACKGROUND: Low back pain (LBP) is ranked highest in terms of disability-adjusted life-years lived. Patient education and self-management have shown to play a crucial role in the overall pain management. However, the literature on the same with respect to Indian context is still lacking. The study was aimed to develop, validate and assess the acceptability and effectiveness of self-instructional educational module among Indian chronic LBP (CLBP) patients. METHODS: A prospective single-arm open-label study was conducted in a pain clinic of a tertiary care public hospital in North India with 'Backcare booklet-self-instructional module (SIM)' as an intervention in patients with CLBP. SIM was developed with the intent to provide up-to-date evidence-based information in an easy understanding way to patients with CLBP. 132 patients were administered SIM with a single session of verbal explanation. Pain intensity (numeric rating scale [NRS]), disability, fear-avoidance belief Questionnaire (FABQ), quality of life (EQ5D) and knowledge level were assessed at baseline and after 3 months of intervention. Student's paired t-test and Chi-square test were used. Data were analysed using SPSS version 15.0. RESULTS: 120 patients successfully completed the 3 months' follow-up. Significant reductions were observed in pain intensity (76[12] vs 55 [15, P < 0.01); disability (51[14] vs 43 [10], P < 0.01); FABQ (46[12] vs 41 [10], P < 0.01); EQ5D (0.35 [0.27] vs 0.18 [0.26], P < 0.01). CONCLUSION: Backcare booklet as an intervention, along with usual pharmacological care is a cost-effective educational medium to promote self-management of CLBP in the clinical outpatient settings.