Optimising health after early menopause.

The typical age at menopause is 50-51 years in high-income countries. However, early menopause is common, with around 8% of women in high-income countries and 12% of women globally experiencing menopause between the ages of 40 years and 44 years. Menopause before age 40 years (premature ovarian insufficiency) affects an additional 2-4% of women. Both early menopause and premature ovarian insufficiency can herald an increased risk of chronic disease, including osteoporosis and cardiovascular disease. People who enter menopause at younger ages might also experience distress and feel less supported than those who reach menopause at the average age. Clinical practice guidelines are available for the diagnosis and management of premature ovarian insufficiency, but there is a gap in clinical guidance for early menopause. We argue that instead of distinct age thresholds being applied, early menopause should be seen on a spectrum between premature ovarian insufficiency and menopause at the average age. This Series paper presents evidence for the short-term and long-term consequences of early menopause. We offer a practical framework for clinicians to guide diagnosis and management of early menopause, which considers the nature and severity of symptoms, age and medical history, and the individual's wishes and priorities to optimise their quality of life and short-term and long-term health. We conclude with recommendations for future research to address key gaps in the current evidence.

Application of Chiral Transfer Reagents to Improve Stereoselectivity and Yields in the Synthesis of the Antituberculosis Drug Bedaquiline.

Bedaquiline (BDQ) is an important drug for treating multidrug-resistant tuberculosis (MDR-TB), a worldwide disease that causes more than 1.6 million deaths yearly. The current synthetic strategy adopted by the manufacturers to assemble this molecule relies on a nucleophilic addition reaction of a quinoline fragment to a ketone, but it suffers from low conversion and no stereoselectivity, which subsequently increases the cost of manufacturing BDQ. The Medicines for All Institute (M4ALL) has developed a new reaction methodology to this process that not only allows high conversion of starting materials but also results in good diastereo- and enantioselectivity toward the desired BDQ stereoisomer. A variety of chiral lithium amides derived from amino acids were studied, and it was found that lithium (R)-2-(methoxymethyl)pyrrolidide, obtained from d-proline, results in high assay yield of the desired syn-diastereomer pair (82%) and with considerable stereocontrol (d.r. = 13.6:1, e.r. = 3.6:1, 56% ee), providing BDQ in up to a 64% assay yield before purification steps toward the final API. This represents a considerable improvement in the BDQ yield compared to previously reported conditions and could be critical to further lowering the cost of this life-saving drug.

Do contrasting socio-ecological conditions bring difference in premenstrual syndrome and its concomitants? A sedente-migrant comparative study from Eastern India.

OBJECTIVES: We asked in our research whether the premenstrual syndrome (PMS) and its concomitants, differ between "sedente" and "migrant" populations hailing from the same ethnic group, owing to their living in contrasting socio-ecological conditions. METHODS: A total of 501 Oraon adolescents (sedente: 200, migrant: 301) were studied. Data on PMS was reported retrospectively using a list of 29 standard symptoms. Principal component analysis (PCA) was applied on PMS. PCA, which resulted in six principal components (PC1 to PC6) were loaded with "behavioral and cognitive," "negative mood," "pain and fluid retention," "vestibular and breast tenderness," and "fatigue," and/or "gastrointestinal" symptoms. Step-wise hierarchical regression was applied using migration status (step 1), socio-demographic (step 2), menstrual (step 3), and nutritional and lifestyle variables (step 4) as concomitants for each principal component. RESULTS: Significantly, a greater number of migrants reported PMS but of milder intensity, unlike the sedentes. Significant sedente-migrant differences were found in the concomitants for PMS. Multivariate analyses showed differential socio-demographic (occupational, educational and wealth status, religion), nutritional (dietary carbohydrate protein and fat, tea intake, body mass index, percent body fat, waist hip ratio, fat mass index), menstrual (age at menarche, cycle length, dysmenorrhoea) and anemic status of the sedentes and the migrants were significantly associated with PMS. CONCLUSIONS: Sedente and migrant participants, despite hailing from the same ethnic group, sharply differed in the prevalence of PMS and its concomitants owing to their living in contrasting socio-ecological conditions.

Factors associated with the CVD risk factors and body fat pattern of postmenopausal Hindu caste and Lodha tribal populations living in India: An exploratory study.

BACKGROUND: Loss in ovarian function during mid-life results in adverse changes in the cardiovascular profile of women. The association between CVD risk factors and menopause differ cross-culturally since several modifiable factors play significant roles in explaining CVD mortality in addition to differences in endogenous estrogen. Very few of the studies from the Indian subcontinent have been concerned with the menopause-specific CVD risk factors, particularly among the tribal groups. Thus, we intended to study the variations in body fat pattern and CVD risk factors between Hindu caste and Lodha tribal postmenopausal women and how these risk factors were associated with differential socio-economic, reproductive and menstrual characteristics and lifestyle variables. The Lodha tribal populations is considered a Particularly Vulnerable Group (PVTG) in this country. METHODS: This cross-sectional study was conducted among the Bengali Hindu caste and Lodha tribal populations of the State of West Bengal, India covering three districts namely Howrah, Jhargram and East Midnapure. A total of 197 postmenopausal participants were recruited for this study (urban caste 69, rural caste 65 and rural Lodha 63). Data on blood glucose and total cholesterol levels, blood pressure, muscle mass, body fat distribution and sociodemographic, reproductive and menstrual history and lifestyle variables were collected following standard protocols. Analysis of variance (ANOVA) was applied to compare blood glucose, total cholesterol and blood pressure levels and body fat measures across the three populations. Stepwise multiple linear regression analysis was performed to find out the factors associated with CVD risk factors. The data were analyzed with the Statistical Package for Social Science version 20.0(IBM corporation, 2011). RESULTS: This cross-sectional comparison of women at midlife, though exploratory in nature showed significant differences in body fat pattern and CVD risk factors between caste and tribal groups owing to socioeconomic disparities and, differences in reproductive characteristics and lifestyle factors. CONCLUSION: The caste and tribal populations differed significantly in body fat pattern and CVD risk factors and in the factors associated with CVD risk suggesting interplay between menopause and modifiable factors in explaining CVD risk factors during mid-life.

Do maternal obstetric morbidity and its concomitants differ between sedente and migrant groups? The case of the Oraon populations of Eastern India.

The state of pregnancy and child birth is a stretch of intense vulnerability and incurs reproductive cost, which is governed within a specific socio-ecological context. We asked in our research whether the obstetric morbidities at three stages: antepartum, intrapartum and postpartum, and their concomitants differed significantly between sedente and migrant populations. 403 Oraon indigenous women [203 sedente and 200 migrants] living in Eastern India were selected. Data on socio-demographic, reproductive, maternal health care services and obstetric morbidities were collected using semi structured schedules. We applied Categorical Principal Component Analysis (CATPCA) on the first three variables; PC1 and PC4 were loaded with "socio-demographic and maternal health care services" and PC2 and PC3 loaded with "socio-demographic and reproductive" variables. We applied Poisson regression to examine the determinants of obstetric morbidities. Bivariate analyses showed significant (p ≤ 0.05) sedente-migrant differences in variables related to socio-demographic, reproductive, maternal health care and obstetric morbidities. Poisson regression showed migrants were more likely (p ≤ 0.001) to experience ante and intrapartum morbidities than the sedentes, after controlling the confounders. PC1, PC2 and PC3 could significantly (p ≤ 0.05) predict ante and intrapartum morbidities. For postpartum morbidities, barring the variables related to availing of maternal health care services at the time of child delivery and post delivery, neither migration status nor any of the PCs was a significant predictor. For example, participants who delivered their child in health institutions and had episiotomy and/or caesarean delivery (p ≤ 0.01); and those who availed first PNC within the 24 hours of delivery, stayed under medical supervision after delivery for more than 48 hours and received higher coverage of PNCs were more and less likely respectively (p ≤ 0.05) to have experienced postpartum morbidities. We conclude that the maternal obstetric morbidities and their concomitants differed between sedente and migrant Oraon populations owing to their living in differential socio-ecological contexts.

Pathways that determine the fertility of sedente and migrant Oraon populations of Eastern India: a structural equation modelling approach.

Within local socio-ecological context, the fertility determinants of a population are mediated through complex interrelated physiological and behavioural pathways. We aimed to find out the direct and indirect determinants of fertility of sedente and migrant Oraon populations using Structural Equation Model (SEM). Bivariate analysis showed significant (p ≤ 0.05) sedente-migrant differences in socio-demographic, reproductive, contraceptive, and reproductive and sexual decision-making variables. Results of SEM showed migration status, age at first conception, contraceptive preference and reproductive and sexual decision making have direct but negative association (p ≤ 0.05), and age of the participants, under-five mortality and preference for male child have direct but positive association with fertility (p ≤ 0.05). These variables are also associated with fertility through certain mediated pathways (p ≤ 0.05) like ages at first conception with contraceptive preferences, reproductive and sexual decision-making ability (positive), under-five mortality and desired family size (negative). Educational status of the spouses showed indirect association (p ≤ 0.05) with fertility through four pathways: (i) contraceptive preferences; (ii) reproductive and sexual decision-making ability; (iii) ages at first conception (positive); and (iv) desired family size (negative). Hence, sedente and migrant participants reflected a sharp difference in the determinants of fertility owing to differential local socio-ecological attributes.

Bioinspired Synthesis of Pinoxaden Metabolites Using a Site-Selective C-H Oxidation Strategy.

A bioinspired synthesis of Pinoxaden metabolites 2-5 is described herein. A site-selective C-H oxidation strategy validated by density functional theory (DFT) calculations was devised for preparing metabolites 2-4. Oxidation of the benzylic C-H bond in tertiary alcohol 7 using K2S2O8 and catalytic AgNO3 formed the desired metabolite 2 that enabled access to metabolites 3 and 4 in a single step. Unlike most metal/persulfate-catalyzed transformations reported for the C-C and C-O bond formation reactions wherein the metal acts as a catalyst, we propose that Ag(I)/K2S2O8 plays the role of an initiator in the oxidation of intermediate 7 to 2. Metabolite 2 was subjected to a ruthenium tetroxide-mediated C-H oxidation to form metabolites 3 and 4 as a mixture that were purified to isolate pure standards of these metabolites. Metabolite 5 was synthesized from readily available advanced intermediate 9 via a House-Meinwald-type rearrangement in one step using a base.

Facile and Scalable Methodology for the Pyrrolo[2,1-f][1,2,4]triazine of Remdesivir.

Pyrrolo[2,1-f][1,2,4]triazine (1) is an important regulatory starting material in the production of the antiviral drug remdesivir. Compound 1 was produced through a newly developed synthetic methodology utilizing simple building blocks such as pyrrole, chloramine, and formamidine acetate by examining the mechanistic pathway for the process optimization exercise. Triazine 1 was obtained in 55% overall yield in a two-vessel-operated process. This work describes the safety of the process, impurity profiles and control, and efforts toward the scale-up of triazine for the preparation of kilogram quantity.

Do vasomotor and genitourinary symptoms of menopause vary between sedente and migrant groups? A study on the Oraon tribal populations of Eastern India.

OBJECTIVES: Human reproductive characteristics are embedded within local ecological contexts. A shift in the local ecology is likely to offer challenges in reproductive outcome. We aimed to investigate sedente-migrant variation in experiencing vasomotor and genitourinary symptoms at perimenopausal and postmenopausal stages and its concomitants. METHODS: Four hundred Oraon tribal populations living in Eastern India (sedente [100 each from perimenopausal and postmenopausal groups] and migrants [100 each from perimenopausal and postmenopausal groups]) were studied. Data on vasomotor and genitourinary symptoms, socio-demographic and reproductive history, body compositions, lifestyle variables, and energy intake were compared between sedente and migrant independently for perimenopausal and postmenopausal groups. Principal component analysis (PCA) was used to identify the principal components (PCs) of menopausal symptoms. A two level multilevel linear regression was applied independently for perimenopausal and postmenopausal groups to identify the concomitants of menopausal symptoms and estimate sedente-migrant variance. RESULTS: Bivariate analysis showed significant (p ≤ .05) sedente-migrant differences in socio-demographic, reproductive, body composition, energy intake, and lifestyle variables and in some of the vasomotor and genitourinary symptoms. In multilevel analyses, random effect did not show significant heterogeneity between sedente and migrant groups in experiencing menopausal symptoms; however, fixed effect showed that region from which participants were recruited (Gram Panchayat [GP]) and individual level characteristics were concomitants (p ≤ .05) for menopausal symptoms, irrespective of menopausal status. CONCLUSION: Variability at GP levels and individual level characteristics of sedente and migrant groups predominantly determined menopausal symptoms of the study populations, but not the migration status.

Does menopausal status have an effect on body mass index and blood pressure?

Aim of the study was to understand the relationship of menopausal status with BMI and blood pressure. The study area was selected through multistage sampling technique covering six districts of West Bengal, a state located at the eastern part of India. 1400 participants were selected for the study. The participants were divided into four groups on the basis of menopausal status: early and late perimenopausal; early and late postmenopausal. Results shows that menopausal status was significantly associated with Body Mass Index (BMI) and Mean Arterial Pressure (MAP), after controlling the effect of covariates such as participants' age, reproductive behavior, diet and addiction to tobacco use.

Change in the Prevalence and Determinants of Consanguineous Marriages in India Between National Family and Health Surveys of 1992-1993 and 2015-2016.

This study aimed to determine the changing prevalence of consanguineous marriage in India between two national-level surveys. The primary hypothesis was whether region of residence and religious affiliation continue to play a significant role in determining consanguineous marriage even after controlling other potentially significant confounding variables. Data from the 81,781 and 85,851 ever-married women during the National Family and Health Surveys (NFHS) survey periods 1992-1993 (NFHS-1) and 2015-2016 (NFHS-4), respectively, were used in the analysis. Multinomial and binary logistic regression analyses examined determinants of consanguineous marriage types and of paternal and maternal first-cousin marriages, respectively. In both analyses a systematic model-building procedure was adopted. Altogether, four models were estimated. In the final model (model 4) of both the analyses, all respondent background characteristics (region of residence, religious affiliation, sociodemographic, household wealth) and years of survey were included. Although the overall prevalence of consanguineous marriage in India declined significantly (16%), it was not uniform across respondent background characteristics. The northern region of India (154%) showed a significant increase in consanguineous marriage, whereas eastern (31%), central (2.3%), northeastern (40%), and southern (8%) regions showed a significant decline. Significant declines in consanguineous marriage were found for Hindus (16%) and Muslims (29%); for Muslims of eastern (48%), central (29%), western (31%), and southern (27%) regions; and for Hindus in the western region (37%). Relative risk ratios estimated using multinomial logistic regression models suggest those living in the southern region show 9.55 (p < 0.001), 5.96 (p < 0.001), and 38.16 (p < 0.001) times more likelihood in the prevalence of first-cousin, second-cousin, and uncle-niece marriages, respectively, compared to the northern region after controlling all other confounding variables. Muslims also showed 3.76 (p < 0.001) and 2.91 (p < 0.001) times more likelihood in first-cousin and second-cousin marriages, respectively, compared to Hindus. Adjusted odds ratios (AORs) estimated using binary logistic regression models suggest those living in southern and northeastern regions were 1.25 (p < 0.001) and 1.36 (p < 0.05) times more likely, respectively, to marry a maternal first cousin compared to the northern region. The AOR estimates also show that Muslims were 1.11 (p < 0.01) times more likely to marry a maternal first cousin compared to Hindus. The authors conclude that, despite significant development in the socioeconomic condition of India during the postglobalization era (beginning in 1992-1993), region of residence and religious affiliation continue to play significant role in determining consanguineous marriage.

Prevalence and determinants of consanguineous marriage and its types in India: evidence from the National Family Health Survey, 2015-2016.

The aim of the present study was to estimate the prevalence and examine the determinants of consanguineous marriage types in India. Data for 456,646 ever-married women aged 15-49 years were analysed from the National Family Health Survey (NFHS)-4 conducted in 2015-16. The overall prevalence of consanguineous marriage was 9.9%; the South region (23%) and North-East region (3.1%) showed the highest and lowest prevalences, respectively. Muslims had a higher prevalence (15%) than Hindus (9%). The prevalence of first cousin marriage (8.7%) was more than that of second cousin (0.7%) and of uncle-niece marriages (0.6%). Women living in urban areas and in nuclear families, having a higher level of education and belonging to affluent families were less likely to marry their cousins (p < 0.01). Women living in the South region of the country were more likely to marry their cousins, as well as uncles (p < 0.001). Close scrutiny of the trends in the results (odds ratios) revealed no clear relationship between socioeconomic condition and consanguineous marriage. The study results suggest that religion and north-south regional dichotomy in culture largely determine consanguineous marriage rather than socioeconomic condition in India.

Dihydrochelerythrine and its derivatives: Synthesis and their application as potential G-quadruplex DNA stabilizing agents.

A convenient route was envisaged toward the synthesis of dihydrochelerythrine (DHCHL), 4 by intramolecular Suzuki coupling of 2-bromo-N-(2-bromobenzyl)-naphthalen-1-amine derivative 5 via in situ generated arylborane. This compound was converted to (±)-6-acetonyldihydrochelerythrine (ADC), 3 which was then resolved by chiral prep-HPLC. Efficiency of DHCHL for the stabilization of promoter quadruplex DNA structures and a comparison study with the parent natural alkaloid chelerythrine (CHL), 1 was performed. A thorough investigation was carried out to assess the quadruplex binding affinity by using various biophysical and biochemical studies and the binding mode was explained by using molecular modeling and dynamics studies. Results clearly indicate that DHCHL is a strong G-quadruplex stabilizer with affinity similar to that of the parent alkaloid CHL. Compounds ADC and DHCHL were also screened against different human cancer cell lines. Among the cancer cells, (±)-ADC and its enantiomers showed varied (15-48%) inhibition against human colorectal cell line HCT116 and breast cancer cell line MDA-MB-231 albeit low enantio-specificity in the inhibitory effect; whereas DHCHL showed 30% inhibition against A431 cell line only, suggesting the compounds are indeed cancer tissue specific.

Formal total syntheses of the (-)-salicylihalamides A and B from D-glucose and L-rhamnose.

[reaction: see text] Two formal total syntheses of the (-)-salicylihalamides, based on chiral pool approaches, are reported. D-glucose and L-rhamnose were used to prepare advanced intermediates 23 and 54, which can be converted in three or four steps, respectively, to the target compounds. The synthesis of 23 from a known D-glucose-derivative was accomplished in 12 steps and 17% overall yield, and the synthesis of 54 from a known L-rhamnose-derivative was done in nine steps and 6% overall yield. A key step in the synthesis was a ring-closing metathesis reaction to prepare the macrocyclic ring system. It was demonstrated that the phenolic protecting group was critical for inducing the preferential formation of the desired E isomer. It was further shown that the protecting group at the C13 hydroxyl group had no significant influence on the E:Z ratio during the ring-closing metathesis reaction.

Formal total synthesis of (+)-salicylihalamides A and B: a combined chiral pool and RCM strategy.

The formal total synthesis of the (+)-salicylihalamides A and B is detailed, utilizing a chiral pool approach to generate the three stereogenic centers and a ring-closing metathesis (RCM) for the formation of the macrocyclic ring structure. Starting from a known glucose-derived alcohol, the formal total synthesis was achieved in an efficient 13-step protocol in 26% overall yield. It was found that substitution at the remote phenolic group significantly influenced the ratio of the E- and Z-double bond products in the RCM step. The introduction of phenol protecting groups provided E-isomers preferentially and also enhanced the rates of the RCM reactions.

Enantiospecific formal total syntheses of (-)-salicylihalamides A and B from D-glucose and L-rhamnose.

[reaction: see text] Two formal chiral pool syntheses of the (-)-salicylihalamides A and B were achieved from commercially available 1,2,5,6-diacetone-d-glucose and l-rhamnose.