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The iridium-catalyzed C-H borylation of diethyl phenylphosphonate results in nonselective mono and bisborylation to afford a near statistical mixture of 3-, 3,5- and 4-boryl substituted aryl phosphonates whereas 3-substituted aryl phosphonates undergo highly regioselective C-H borylation to afford the corresponding meta-phosphonate substituted arylboronic esters as the sole product; the resulting boronic esters were used as nucleophilic reagents in a subsequent palladium-catalyzed Suzuki–Miyaura cross-coupling to generate a range of biarylmonophosphonates. Gratifyingly, the Suzuki–Miyaura cross-coupling can be conducted without purifying the boronic ester which greatly simplifies the synthetic procedure.

We evaluated therapeutic TAT for a tertiary hospital in Western Kenya, using a time-motion study focusing specifically on common hematology and biochemistry orders. The aim was to determine significant bottlenecks in diagnostic testing processes at the institution. A total of 356 (155 hematology and 201 biochemistry) laboratory tests were fully tracked from the time of ordering to availability of results to care providers. The total therapeutic TAT for all tests was 21.5 ± 0.249 hours (95% CI). The therapeutic TAT for hematology was 20.3 ± 0.331 hours (95% CI) while that for biochemistry tests was 22.2 ± 0.346 hours (95% CI). Printing, sorting and dispatch of the printed results emerged as the most significant bottlenecks, accounting for up to 8 hours of delay (Hematology-8.3 ± 1.29 hours (95% CI), Biochemistry-8.5 ± 1.18 hours (95% CI)). Time of test orders affected TAT, with orders made early in the morning and those in the afternoon experiencing the most delays in TAT. Significant inefficiencies exist at multiple steps in the turnaround times for routine laboratory tests at a large referral hospital within an LMIC setting. Multiple opportunities exist to improve TAT and streamline processes around diagnostic testing in this and other similar settings.

Improving maternal nutrition practices during pregnancy is essential to save lives and improve health outcomes for both mothers and babies. This paper examines the maternal, household, and health service factors influencing maternal nutrition practices in the context of a large scale maternal, newborn, and child health (MNCH) program in Bangladesh. Data were from a household survey of pregnant (n = 600) and recently delivered women (n = 2,000). Multivariate linear and logistic regression analyses were used to examine the determinants of three outcomes: consumption of iron and folic acid (IFA) tablets, calcium tablets, and diverse diets. Women consumed 94 ± 68 IFA and 82 ± 66 calcium tablets (out of 180 as recommended) during pregnancy, and only half of them consumed an adequately diverse diet. Good nutrition knowledge was the key maternal factor associated with higher consumption of IFA (β = 32.5, 95% CI: 19.5, 45.6) and calcium tablets (β ~31.9, 95% CI: 20.9, 43.0) and diverse diet (OR = 1.8, 95% CI: 1.0-3.1), compared to poor knowledge. Women's self-efficacy in achieving the recommended practices and perception of enabling social norms were significantly associated with dietary diversity. At the household level, women who reported a high level of husband's support were more likely to consume IFA (β = 25.0, 95% CI: 18.0, 32.1) and calcium (β = 26.6, 95% CI: 19.4, 33.7) tablets and diverse diet (OR = 1.9, 95% CI: 1.2, 3.3), compared to those who received low support. Health service factors associated with higher intakes of IFA and calcium tablets were early and more prenatal care visits and receipt of free supplements. Combined exposure to several of these factors was attributed to the consumption of an additional 46 IFA and 53 calcium tablets and 17% higher proportions of women consuming diverse diets. Our study shows that improving knowledge, self-efficacy and perceptions of social norms among pregnant women, and increasing husbands' support, early registration in prenatal care, and provision of free supplements will largely improve maternal nutrition practices.

Severely burned and non-burned trauma patients are at risk for acute kidney injury (AKI). The study objective was to assess the theoretical performance of artificial intelligence (AI)/machine learning (ML) algorithms to augment AKI recognition using the novel biomarker, neutrophil gelatinase associated lipocalin (NGAL), combined with contemporary biomarkers such as N-terminal pro B-type natriuretic peptide (NT-proBNP), urine output (UOP), and plasma creatinine. Machine learning approaches including logistic regression (LR), k -nearest neighbor ( k -NN), support vector machine (SVM), random forest (RF), and deep neural networks (DNN) were used in this study. The AI/ML algorithm helped predict AKI 61.8 (32.5) hours faster than the Kidney Disease and Improving Global Disease Outcomes (KDIGO) criteria for burn and non-burned trauma patients. NGAL was analytically superior to traditional AKI biomarkers such as creatinine and UOP. With ML, the AKI predictive capability of NGAL was further enhanced when combined with NT-proBNP or creatinine. The use of AI/ML could be employed with NGAL to accelerate detection of AKI in at-risk burn and non-burned trauma patients.

In this study, a miniaturized biosensor based on permselective polymer layers (overoxidized polypyrrole (Ppy) and Nafion®) modified and enzyme (glutamate oxidase (GlutOx)) immobilized micro-platinum wire electrode for the detection of alanine aminotransferase (ALT) was fabricated. The proposed ALT biosensor was measured electrochemically by constant potential amperometry at +0.7 V vs. Ag/AgCl. The ALT biosensor provides fast response time (~5 s) and superior selectivity towards ALT against both negatively and positively charged species (e.g., ascorbic acid (AA) and dopamine (DA), respectively). The detection range of the ALT biosensor is found to be 10–900 U/L which covers the range of normal ALT levels presented in the serum and the detection limit and sensitivity are found to be 8.48 U/L and 0.059 nA/(U/L·mm2) (N = 10), respectively. We also found that one-day storage of the ALT biosensor at −20 °C right after the sensor being fabricated can enhance the sensor sensitivity (1.74 times higher than that of the sensor stored at 4 °C). The ALT biosensor is stable after eight weeks of storage at −20 °C. The sensor was tested in spiked ALT samples (ALT activities: 20, 200, 400, and 900 U/L) and reasonable recoveries (70%~107%) were obtained.

Embryonic aneuploidy from mis-segregation of chromosomes during meiosis causes pregnancy loss. Proper disjunction of homologous chromosomes requires the mismatch repair (MMR) genes MLH1 and MLH3 , essential in mice for fertility. Variants in these genes can increase colorectal cancer risk, yet the reproductive impacts are unclear. To determine if MLH1/3 single nucleotide polymorphisms (SNPs) in human populations could cause reproductive abnormalities, we use computational predictions, yeast two-hybrid assays, and MMR and recombination assays in yeast, selecting nine MLH1 and MLH3 variants to model in mice via genome editing. We identify seven alleles causing reproductive defects in mice including female subfertility and male infertility. Remarkably, in females these alleles cause age-dependent decreases in litter size and increased embryo resorption, likely a consequence of fewer chiasmata that increase univalents at meiotic metaphase I. Our data suggest that hypomorphic alleles of meiotic recombination genes can predispose females to increased incidence of pregnancy loss from gamete aneuploidy. Proper meiotic chromosome segregation requires mismatch repair genes MLH1 and MLH3 , of which variants occur in the human population. Here, the authors use computational predictions and yeast assays to select human MLH1/3 variants for modelling in mice, observing reproductive defects from abnormal levels of crossing over.

Each human genome carries tens of thousands of coding variants. The extent to which this variation is functional and the mechanisms by which they exert their influence remains largely unexplored. To address this gap, we leverage the ExAC database of 60,706 human exomes to investigate experimentally the impact of 2009 missense single nucleotide variants (SNVs) across 2185 protein-protein interactions, generating interaction profiles for 4797 SNV-interaction pairs, of which 421 SNVs segregate at > 1% allele frequency in human populations. We find that interaction-disruptive SNVs are prevalent at both rare and common allele frequencies. Furthermore, these results suggest that 10.5% of missense variants carried per individual are disruptive, a higher proportion than previously reported; this indicates that each individual’s genetic makeup may be significantly more complex than expected. Finally, we demonstrate that candidate disease-associated mutations can be identified through shared interaction perturbations between variants of interest and known disease mutations. Low frequency coding single-nucleotide variants (SNVs) are predicted to disproportionately affect protein function. Here, the authors evaluate 2,009 missense SNVs across 2,185 protein-protein interactions using yeast two-hybrid and protein complementation assays and find that disruptive SNVs often occur in disease-associated genes.

Despite recommendations supporting optimal breastfeeding, the number of women practicing exclusive breastfeeding (EBF) remains low, and few interventions have demonstrated implementation and impact at scale. Alive & Thrive was implemented over a period of 6 y (2009-2014) and aimed to improve breastfeeding practices through intensified interpersonal counseling (IPC), mass media (MM), and community mobilization (CM) intervention components delivered at scale in the context of policy advocacy (PA) in Bangladesh and Viet Nam. In Bangladesh, IPC was delivered through a large non-governmental health program; in Viet Nam, it was integrated into government health facilities. This study evaluated the population-level impact of intensified IPC, MM, CM, and PA (intensive) compared to standard nutrition counseling and less intensive MM, CM, and PA (non-intensive) on breastfeeding practices in these two countries. A cluster-randomized evaluation design was employed in each country. For the evaluation sample, 20 sub-districts in Bangladesh and 40 communes in Viet Nam were randomized to either the intensive or the non-intensive group. Cross-sectional surveys (n ~ 500 children 0-5.9 mo old per group per country) were implemented at baseline (June 7-August 29, 2010, in Viet Nam; April 28-June 26, 2010, in Bangladesh) and endline (June 16-August 30, 2014, in Viet Nam; April 20-June 23, 2014, in Bangladesh). Difference-in-differences estimates (DDEs) of impact were calculated, adjusting for clustering. In Bangladesh, improvements were significantly greater in the intensive compared to the non-intensive group for the proportion of women who reported practicing EBF in the previous 24 h (DDE 36.2 percentage points [pp], 95% CI 21.0-51.5, p < 0.001; prevalence in intensive group rose from 48.5% to 87.6%) and engaging in early initiation of breastfeeding (EIBF) (16.7 pp, 95% CI 2.8-30.6, p = 0.021; 63.7% to 94.2%). In Viet Nam, EBF increases were greater in the intensive group (27.9 pp, 95% CI 17.7-38.1, p < 0.001; 18.9% to 57.8%); EIBF declined (60.0% to 53.2%) in the intensive group, but less than in the non-intensive group (57.4% to 40.6%; DDE 10.0 pp, 95% CI -1.3 to 21.4, p = 0.072). Our impact estimates may underestimate the full potential of such a multipronged intervention because the evaluation lacked a \"pure control\" area with no MM or national/provincial PA. At-scale interventions combining intensive IPC with MM, CM, and PA had greater positive impacts on breastfeeding practices in Bangladesh and Viet Nam than standard counseling with less intensive MM, CM, and PA. To our knowledge, this study is the first to document implementation and impacts of breastfeeding promotion at scale using rigorous evaluation designs. Strategies to design and deliver similar programs could improve breastfeeding practices in other contexts. ClinicalTrials.gov NCT01678716 (Bangladesh) and NCT01676623 (Viet Nam).

A major challenge in medical genetics is to characterize variants of unknown significance (VUS). Doing so would help delineate underlying causes of disease and the design of customized treatments. Infertility has presented an especially difficult challenge with respect to not only determining if a given patient has a genetic basis, but also to identify the causative genetic factor(s). Though genome sequencing can identify candidate variants, in silico predictions of causation are not always sufficiently reliable so as to be actionable. Thus, experimental validation is crucial. Here, we describe the phenotype of mice containing a non-synonymous (proline-to-threonine at position 306) change in Spo11, corresponding to human SNP rs185545661. SPO11 is a topoisomerase-like protein that is essential for meiosis because it induces DNA double stranded breaks (DSBs) that stimulate pairing and recombination of homologous chromosomes. Although both male and female Spo11P306T/P306T mice were fertile, they had reduced sperm and oocytes, respectively. Spermatocyte chromosomes exhibited synapsis defects (especially between the X and Y chromosomes), elevated apoptotic cells, persistent markers of DSBs, and most importantly, fewer Type 1 crossovers that causes some chromosomes to have none. Spo11P306T/- mice were sterile and made fewer meiotic DSBs than Spo11+/- animals, suggesting that the Spo11P306T allele is a hypomorph and likely is delayed in making sufficient DSBs in a timely fashion. If the consequences are recapitulated in humans, it would predict phenotypes of premature ovarian failure, reduced sperm counts, and possible increased number of aneuploid gametes. These results emphasize the importance of deep phenotyping in order to accurately assess the impact of VUSs in reproduction genes. Summary Sentence Modeling of a rare SPO11 allele in mice demonstrates it causes defects that could impact fertility of affected people and their children.

With an incidence of ~1 in 800 births, Down syndrome (DS) is the most common chromosomal condition linked to intellectual disability worldwide. While the genetic basis of DS has been identified as a triplication of chromosome 21 (HSA21), the genes encoded from HSA21 that directly contribute to cognitive deficits remain incompletely understood. Here, we found that the HSA21-encoded chromatin effector, BRWD1 , was upregulated in neurons derived from iPS cells from an individual with Down syndrome and brain of trisomic mice. We showed that selective copy number restoration of Brwd1 in trisomic animals rescued deficits in hippocampal LTP, cognition and gene expression. We demonstrated that Brwd1 tightly binds the BAF chromatin remodeling complex, and that increased Brwd1 expression promotes BAF genomic mistargeting. Importantly, Brwd1 renormalization rescued aberrant BAF localization, along with associated changes in chromatin accessibility and gene expression. These findings establish BRWD1 as a key epigenomic mediator of normal neurodevelopment and an important contributor to DS-related phenotypes. The molecular mechanisms underlying deficits in Down syndrome remain unclear. Here, the authors show that copy number restoration of a chromatin remodeler in trisomic mice is sufficient to rescue epigenomic, physiological and cognitive deficits.