Inherited loss-of-function mutations in BRCA1 and BRCA2 and other tumor suppressor genes predispose to ovarian carcinomas, but the overall burden of disease due to inherited mutations is not known. ...Using targeted capture and massively parallel genomic sequencing, we screened for germ-line mutations in 21 tumor suppressor genes in genomic DNA from women with primary ovarian, peritoneal, or fallopian tube carcinoma. Subjects were consecutively enrolled at diagnosis and not selected for age or family history. All classes of mutations, including point mutations and large genomic deletions and insertions, were detected. Of 360 subjects, 24% carried germ-line loss-of-function mutations: 18% in BRCA1 or BRCA2 and 6% in BARD1, BRIP1, CHEK2, MRE11A, MSH6, NBN, PALB2, RAD50, RAD51C, or TP53. Six of these genes were not previously implicated in inherited ovarian carcinoma. Primary carcinomas were generally characterized by genomic loss of normal alleles of the mutant genes. Of women with inherited mutations, >30% had no family history of breast or ovarian carcinoma, and >35% were 60 y or older at diagnosis. More patients with ovarian carcinoma carry cancer-predisposing mutations and in more genes than previously appreciated. Comprehensive genetic testing for inherited carcinoma is warranted for all women with ovarian, peritoneal, or fallopian tube carcinoma, regardless of age or family history. Clinical genetic testing is currently done gene by gene, with each test costing thousands of dollars. In contrast, massively parallel sequencing allows such testing for many genes simultaneously at low cost.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Breast Cancer Type 1 Susceptibility Protein (BRCA1)-deficient cells have compromised DNA repair and are sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. Despite initial responses, the ...development of resistance limits clinical efficacy. Mutations in the BRCA C-terminal (BRCT) domain of BRCA1 frequently create protein products unable to fold that are subject to protease-mediated degradation. Here, we show HSP90-mediated stabilization of a BRCT domain mutant BRCA1 protein under PARP inhibitor selection pressure. The stabilized mutant BRCA1 protein interacted with PALB2-BRCA2-RAD51, was essential for RAD51 focus formation, and conferred PARP inhibitor as well as cisplatin resistance. Treatment of resistant cells with the HSP90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin reduced mutant BRCA1 protein levels and restored their sensitivity to PARP inhibition. Resistant cells also acquired a TP53BP1 mutation that facilitated DNA end resection in the absence of a BRCA1 protein capable of binding CtIP. Finally, concomitant increased mutant BRCA1 and decreased 53BP1 protein expression occur in clinical samples of BRCA1 -mutated recurrent ovarian carcinomas that have developed resistance to platinum. These results provide evidence for a two-event mechanism by which BRCA1 -mutant tumors acquire anticancer therapy resistance.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The rapid urbanization of Kenya has led to an increase in the growth of informal settlements. There are challenges with access to maternal, newborn, and child health (MNCH) services and higher ...maternal mortality rates in settlements. The Kuboresha Afya Mitaani (KAM) study aimed to improve access to MNCH services. We evaluate one component of the KAM study, PROMPTS (Promoting Mothers through Pregnancy and Postpartum), an innovative digital health intervention aimed at improving MNCH outcomes. PROMPTS is a two-way AI-enabled SMS-based platform that sends messages to pregnant and postnatal mothers based on pregnancy stage, and connects mothers with a clinical help desk to respond and refer urgent cases in minutes.
PROMPTS was rolled out in informal settlements in Mathare and Kawangware in Nairobi County. The study adopted a pre-post intervention design, comparing baseline and endline population outcomes (1,416 participants, Baseline = 678, Endline = 738). To further explore PROMPTS's effect, outcomes were compared between endline participants enrolled and not enrolled in PROMPTS (738 participants). Outcomes related to antenatal (ANC) and postnatal (PNC) service uptake and knowledge were assessed using univariate and multivariate linear and logistic regression.
Between baseline and enldine, mothers were 1.85 times more likely to report their babies and 1.88 times more likely to report themselves being checked by a provider post-delivery. There were improvements in moms and babies receiving care on time. 45% of the 738 endline participants were enrolled in the PROMPTS program, with 87% of these participants sending at least one message to the system. Enrolled mothers were 2.28 times more likely to report completing four or more ANC visits relative to unenrolled mothers. Similarly, enrolled mothers were 4.20 times more likely to report their babies and 1.52 times more likely to report themselves being checked by a provider post-delivery compared to unenrolled mothers.
This research demonstrates that a digital health tool can be used to improve care-seeking and knowledge levels among pregnant and postnatal women in informal settlements. Additional research is needed to refine and target solutions amongst those that were less likely to enroll in PROMPTS and to further drive improved MNCH outcomes amongst this population.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
Background
Children and women in urban informal settlements have fewer choices to access quality maternal and newborn health care. Many facilities serving these communities are ...under-resourced and staffed by fewer providers with limited access to skills updates. We sought to increase provider capacity by equipping them with skills to provide general and emergency obstetric and newborn care in 24 facilities serving two informal settlements in Nairobi. We present evidence of the combined effect of mentorship using facility-based mentors who demonstrate skills, support skills drills training, and provide practical feedback to mentees and a self-guided online learning platform with easily accessible EmONC information on providers’ smart phones.
Methods
We used mixed methods research with before and after cross-sectional provider surveys conducted at baseline and end line. During end line, 18 in-depth interviews were conducted with mentors and mentees who were exposed, and providers not exposed to the intervention to explore effectiveness and experience of the intervention on quality maternal health services.
Results
Results illustrated marked improvement from ability to identify antepartum hemorrhage (APH), postpartum hemorrhage (PPH), manage retained placenta, ability to identify and manage obstructed labour, Pre-Eclampsia and Eclampsia (PE/E), puerperal sepsis, and actions taken to manage conditions when they present. Overall, out of 95 elements examined there were statistically significant improvements of both individual scores and overall scores from 29/95 at baseline (30.5%) to 44.3/95 (46.6%) during end line representing a 16- percentage point increase (p > 0.001). These improvements were evident in public health facilities representing a 17.3% point increase (from 30.9% at baseline to 48.2% at end line, p > 0.001). Similarly, providers working in private facilities exhibited a 15.8% point increase in knowledge from 29.7% at baseline to 45.5% at end line (p = 0.0001).
Conclusion
This study adds to the literature on building capacity of providers delivering Maternal and Newborn Health (MNH) services to women in informal settlements. The complex challenges of delivering MNH services in informal urban settings where communities have limited access require a comprehensive approach including ensuring access to supplies and basic equipment. Nevertheless, the combined effects of the self-guided online platform and mentorship reinforces EmONC knowledge and skills. This combined approach is more likely to improve provider competency, and skills as well as improving maternal and newborn health outcomes.
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IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, UL, UM, UPUK, VSZLJ
Diabetes among individuals with low BMI (<19 kg/m2) has been recognized for >60 years as a prevalent entity in low- and middle-income countries (LMICs) and was formally classified as ..."malnutrition-related diabetes mellitus" by the World Health Organization (WHO) in 1985. Since the WHO withdrew this category in 1999, our objective was to define the metabolic characteristics of these individuals to establish that this is a distinct form of diabetes.
State-of-the-art metabolic studies were used to characterize Indian individuals with "low BMI diabetes" (LD) in whom all known forms of diabetes were excluded by immunogenetic analysis. They were compared with demographically matched groups: a group with type 1 diabetes (T1D), a group with type 2 diabetes (T2D), and a group without diabetes. Insulin secretion was assessed by C-peptide deconvolution. Hepatic and peripheral insulin sensitivity were analyzed with stepped hyperinsulinemic-euglycemic pancreatic clamp studies. Hepatic and myocellular lipid contents were assessed with 1H-nuclear magnetic resonance spectroscopy.
The total insulin secretory response was lower in the LD group in comparison with the lean group without diabetes and the T2D group. Endogenous glucose production was significantly lower in the LD group than the T2D group (mean ± SEM 0.50 ± 0.1 vs. 0.84 ± 0.1 mg/kg · min, respectively; P < 0.05). Glucose uptake was significantly higher in the LD group in comparison with the T2D group (10.1 ± 0.7 vs. 4.2 ± 0.5 mg/kg · min; P < 0.001). Visceral adipose tissue and hepatocellular lipids were significantly lower in LD than in T2D.
These studies are the first to demonstrate that LD individuals in LMICs have a unique metabolic profile, suggesting that this is a distinct entity that warrants further investigation.
There is limited data on personal exposure to fine particulate matter (PM 2.5 ) for mothers in informal settlements in Africa. Identifying and characterizing the sources of exposure to PM 2.5 for ...this population is key to finding potential solutions for mitigating air pollution exposures. As part of the USAID-funded Kuboresha Afya Mitaani Urban Maternal, Newborn and Child Health project in Nairobi, Kenya, this study aimed to (1) characterize and map environments that contribute to fine particulate matter (PM 2.5 ) exposure for mothers and infants and (2) determine which factors drive exposure to PM 2.5 . Mothers were enrolled and measured for 24 hours with PM 2.5 monitors and GPS loggers in two informal settlements in Nairobi (Dagoretti and Starehe), with complete data received from 73 participants. Two ambient PM 2.5 monitors were also installed in each of the respective communities. Time-activity surveys were administered following the monitoring period. Mean daily exposures were 39.9 and 45.5 µg m −3 in Dagoretti and Starehe, respectively, with 60% of samples exceeding the annual WHO Annual Interim-1 Target of 35 µg m −3 . Normal daily activities such as sleeping, resting, running errands, and visiting with friends constituted over three-quarters of exposure sampling time. These activities were not associated with elevated PM 2.5 exposures, and generally tracked diurnal ambient patterns (morning and evening peaks). Personal exposures, however, did peak higher than ambient in the evenings when cooking was most common, and cooking with wood or charcoal was associated with higher PM 2.5 personal exposures (daily mean of 54.2 µg m −3 n = 16, compared to 40.3 µg m −3 for those who used gas, liquid fuels or electricity n = 57). These results suggest that transitioning households to cleaner fuels, such as electricity, LPG, or ethanol, would be the most promising intervention that could rapidly reduce exposures of mothers in informal settlements where biomass use is common. At the same time, larger-scale sectoral efforts are needed to bring ambient PM 2.5 concentrations, and thus the overall population exposures, closer to WHO guidelines.
There is limited data on personal exposure to fine particulate matter (PM
2.5
) for mothers in informal settlements in Africa. Identifying and characterizing the sources of exposure to PM
2.5
for ...this population is key to finding potential solutions for mitigating air pollution exposures. As part of the USAID-funded Kuboresha Afya Mitaani Urban Maternal, Newborn and Child Health project in Nairobi, Kenya, this study aimed to (1) characterize and map environments that contribute to fine particulate matter (PM
2.5
) exposure for mothers and infants and (2) determine which factors drive exposure to PM
2.5
. Mothers were enrolled and measured for 24 hours with PM
2.5
monitors and GPS loggers in two informal settlements in Nairobi (Dagoretti and Starehe), with complete data received from 73 participants. Two ambient PM
2.5
monitors were also installed in each of the respective communities. Time-activity surveys were administered following the monitoring period. Mean daily exposures were 39.9 and 45.5 µg m
−3
in Dagoretti and Starehe, respectively, with 60% of samples exceeding the annual WHO Annual Interim-1 Target of 35 µg m
−3
. Normal daily activities such as sleeping, resting, running errands, and visiting with friends constituted over three-quarters of exposure sampling time. These activities were not associated with elevated PM
2.5
exposures, and generally tracked diurnal ambient patterns (morning and evening peaks). Personal exposures, however, did peak higher than ambient in the evenings when cooking was most common, and cooking with wood or charcoal was associated with higher PM
2.5
personal exposures (daily mean of 54.2 µg m
−3
n
= 16, compared to 40.3 µg m
−3
for those who used gas, liquid fuels or electricity
n
= 57). These results suggest that transitioning households to cleaner fuels, such as electricity, LPG, or ethanol, would be the most promising intervention that could rapidly reduce exposures of mothers in informal settlements where biomass use is common. At the same time, larger-scale sectoral efforts are needed to bring ambient PM
2.5
concentrations, and thus the overall population exposures, closer to WHO guidelines.
Maternal PM
2.5
exposures in informal settlements in Nairobi exceeded WHO air quality targets, with low-quality cooking fuel use identified as the most important non-ambient source.
Abstract Objective RAD51D , a gene in the Fanconi Anemia–BRCA homologous recombination pathway, has recently been shown to harbor germline mutations responsible for ovarian carcinoma in multiply ...affected families. We aimed to extend these results to ovarian carcinoma in the general population. Methods We sequenced RAD51D in germline DNA from 360 individuals with primary ovarian, peritoneal or fallopian tube carcinoma who were not selected for age of cancer onset or family history. We also sequenced RAD51D in 459 probands from 226 high risk breast cancer families who were wild type for 21 breast and ovarian cancer genes. Results Of 360 cases, three (0.8%) carried loss-of-function mutations in RAD51D . All three subjects had ovarian carcinoma; one was also diagnosed with a synchronous endometrial carcinoma. Only one of the three subjects had a family history of breast or ovarian cancer. Combined with previous data for this series, 23.9% of women with unselected ovarian, fallopian tube, or peritoneal carcinoma carried a germline loss-of-function mutation in any of 13 tumor suppressor genes. Among the 449 women and 10 men with familial breast cancer, none carried a loss of function mutation in RAD51D. Conclusions These data support the previous observation that loss-of-function mutations in RAD51D predispose to ovarian carcinoma but not to breast carcinoma. We conclude that inherited ovarian cancer is highly heterogeneous genetically, and that approximately one in four ovarian carcinoma patients carry a germline mutation in a known tumor suppressor gene that confers high risk.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Aim Fasting surrogate measures of insulin sensitivity are increasingly used in research and clinical practice. To assess the reliability of these measures, we aimed to evaluate multiple ...fasting surrogate measures simultaneously in non-diabetic subjects in comparison with the euglycemic hyperinsulinemic clamp study. Methods Sixteen normoglycemic male South Indian subjects were studied. After an overnight fast, blood samples were collected for glucose, insulin and lipid profile measurements, and stepped euglycemic hyperinsulinemic clamp studies were performed on all subjects. Steady state glucose infusion rates (M value) during low and high insulin phases of the clamp were calculated. Correlation of M value with surrogate markers of insulin sensitivity was performed. Predictive accuracy of surrogate indices was measured in terms of Root Mean Squared Error (RMSE) and leave-one-out cross-validation-type RMSE of prediction using a calibration model. Results M values showed a strong and significant correlation (p < 0.01) with the following surrogate markers: Fasting insulin (r = − 0.714), Fasting glucose to insulin ratio (FGIR, r = 0.747) and Raynaud index (r = 0.714). FGIR had a significantly lower RMSE when compared with HOMA-IR and QUICKI. Conclusions Among the surrogate measures, FGIR had the strongest correlation with M values. FGIR was also the most accurate surrogate measure, as assessed by the calibration model.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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