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1.
Am J Clin Nutr ; 2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-34982820

RESUMO

BACKGROUND: Newborn oil massage is a widespread practice. Vigorous massage with potentially harmful products and forced removal of vernix may disrupt skin barrier integrity. Hospitalized, very preterm infants treated with sunflower seed oil (SSO) have demonstrated improved growth but community-based data on growth and health outcomes are lacking. OBJECTIVE: We aimed to test whether SSO therapy enhances neonatal growth and reduces morbidity at population-level. DESIGN: We conducted an open-label, controlled trial in rural Uttar Pradesh, India, randomly allocating 276 village clusters equally to comparison (usual care) and intervention comprised of promotion of improved massage practices exclusively with SSO, using intention-to-treat and per-protocol mixed-effects regression analysis. RESULTS: We enrolled 13,478 and 13,109 newborn infants in demographically similar intervention and comparison arms, respectively. Adherence to exclusive SSO increased from 22.6% of intervention infants enrolled in the first study quartile to 37.2% in the last quartile. Intervention infants gained significantly more weight by 0.94 grams/kilogram/day (g/kg/d) [95% confidence interval (CI): 0.07, 1.82, p = 0.03] than comparison infants by intention-to-treat analysis. Restricted cubic spline regression revealed the largest benefits in weight gain (2-4 g/kg/day) occurred in infants <2000 g. Weight gain in intervention infants was higher by 1.31 g/kg/d (95% CI: 0.17, 2.46, p = 0.02) by per-protocol analysis. Morbidities were similar by intention-to-treat analysis but in per-protocol analysis rates of hospitalization and of any illness were reduced by 36% [odds ratio (OR): 0.64; 95% CI: 0.44, 0.94, p = 0.02] and 44% (OR: 0.56; 95% CI: 0.40, 0.77, p<0.001), respectively, in treated infants. CONCLUSIONS: SSO therapy improved neonatal growth, and reduced morbidities when applied exclusively, across the facility-community continuum of care at population-level. Further research is needed to improve demand for recommended therapy inside hospital as well as in community settings, and to confirm these results in other settings. Clinical Trial Registry: The trial was registered at the ISRCTN (ISRCTN38965585) and CTRI (CTRI/2014/12/005282) registries with WHO UTN # U1111-1158-4665.

2.
Indian J Surg Oncol ; 12(3): 472-476, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34658573

RESUMO

Head and neck cancers are one of the leading causes of morbidity and mortality in Indian population. Reconstruction and restoration of function are also of paramount importance in these patients. The aim of this study was to report outcomes for free flaps and pedicle flaps in patients with oral cavity cancers. A retrospective analysis of 628 patients with oral cavity cancers who underwent reconstruction with either free flaps or pedicle flaps during 2014-2020 was done. The median age of the cohort was 49 years. The free flap reconstruction was performed in 481 (76%) and pedicle flap in 147 (24%) patients. Among free and pedicle flaps, 27 (5.6%) and 3 (2.1%) respectively had major flap complications and 25 (5.1%) and 14 (9.9%) respectively had minor complications. CCI score > 4 was associated with higher events (p = 0.02) in free flap group. The outcomes of free flaps are similar in comparison to pedicle flaps in patients with oral cavity cancers. The higher CCI score is significantly associated with increased flap-related complications for the free flap group.

3.
PLoS Med ; 18(9): e1003680, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34582448

RESUMO

BACKGROUND: Hospitalized preterm infants with compromised skin barrier function treated topically with sunflower seed oil (SSO) have shown reductions in sepsis and neonatal mortality rate (NMR). Mustard oil and products commonly used in high-mortality settings may possibly harm skin barrier integrity and enhance risk of infection and mortality in newborn infants. We hypothesized that SSO therapy may reduce NMR in such settings. METHODS AND FINDINGS: This was a population-based, cluster randomized, controlled trial in 276 clusters in rural Uttar Pradesh, India. All newborn infants identified through population-based surveillance in the study clusters within 7 days of delivery were enrolled from November 2014 to October 2016. Exclusive, 3 times daily, gentle applications of 10 ml of SSO to newborn infants by families throughout the neonatal period were recommended in intervention clusters (n = 138 clusters); infants in comparison clusters (n = 138 clusters) received usual care, such as massage practice typically with mustard oil. Primary analysis was by intention-to-treat with NMR and post-24-hour NMR as the primary outcomes. Secondary analysis included per-protocol analysis and subgroup analyses for NMR. Regression analysis was adjusted for caste, first-visit weight, delivery attendant, gravidity, maternal age, maternal education, sex of the infant, and multiple births. We enrolled 13,478 (52.2% male, mean weight: 2,575.0 grams ± standard deviation [SD] 521.0) and 13,109 (52.0% male, mean weight: 2,607.0 grams ± SD 509.0) newborn infants in the intervention and comparison clusters, respectively. We found no overall difference in NMR in the intervention versus the comparison clusters [adjusted odds ratio (aOR) 0.96, 95% confidence interval (CI) 0.84 to 1.11, p = 0.61]. Acceptance of SSO in the intervention arm was high at 89.3%, but adherence to exclusive applications of SSO was 30.4%. Per-protocol analysis showed a significant 58% (95% CI 42% to 69%, p < 0.01) reduction in mortality among infants in the intervention group who were treated exclusively with SSO as intended versus infants in the comparison group who received exclusive applications of mustard oil. A significant 52% (95% CI 12% to 74%, p = 0.02) reduction in NMR was observed in the subgroup of infants weighing ≤1,500 g (n = 589); there were no statistically significant differences in other prespecified subgroup comparisons by low birth weight (LBW), birthplace, and wealth. No severe adverse events (SAEs) were attributable to the intervention. The study was limited by inability to mask allocation to study workers or participants and by measurement of emollient use based on caregiver responses and not actual observation. CONCLUSIONS: In this trial, we observed that promotion of SSO therapy universally for all newborn infants was not effective in reducing NMR. However, this result may not necessarily establish equivalence between SSO and mustard oil massage in light of our secondary findings. Mortality reduction in the subgroup of infants ≤1,500 g was consistent with previous hospital-based efficacy studies, potentially extending the applicability of emollient therapy in very low-birth-weight (VLBW) infants along the facility-community continuum. Further research is recommended to develop and evaluate therapeutic regimens and continuum of care delivery strategies for emollient therapy for newborn infants at highest risk of compromised skin barrier function. TRIAL REGISTRATION: ISRCTN Registry ISRCTN38965585 and Clinical Trials Registry-India (CTRI/2014/12/005282) with WHO UTN # U1111-1158-4665.

4.
Cancer Res ; 81(7): 1868-1882, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33531372

RESUMO

Cancer evolves from premalignant clones that adopt unusual cell states to achieve transformation. We previously pinpointed the oligodendrocyte precursor cell (OPC) as a cell of origin for glioma, but the early changes of mutant OPCs during premalignancy remained unknown. Using mice engineered for inducible Nf1-Trp53 loss in OPCs, we acutely isolated labeled mutant OPCs by laser-capture microdissection, determined global gene-expression changes by bulk RNA sequencing, and compared with cell-state fluctuations at the single-cell level by stochastic profiling, which uses RNA-sequencing measurements from random pools of 10 mutant cells. At 12 days after Nf1-Trp53 deletion, bulk differences were mostly limited to mitotic hallmarks and genes for ribosome biosynthesis, and stochastic profiling revealed a spectrum of stem-progenitor (Axl, Aldh1a1), proneural, and mesenchymal states as potential starting points for gliomagenesis. At 90 days, bulk sequencing detected few differentially expressed transcripts, whereas stochastic profiling revealed cell states for neurons and mural cells that do not give rise to glial tumors, suggesting cellular dead-ends for gliomagenesis. Importantly, mutant OPCs that strongly expressed key effectors of nonsense-mediated decay (Upf3b) and homology-dependent DNA repair (Rad51c, Slx1b, Ercc4) were identified along with DNA-damage markers, suggesting transcription-associated replication stress. Analysis of 10-cell transcriptomes at 90 days identified a locus of elevated gene expression containing an additional repair endonuclease (Mus81) and Rin1, a Ras-Raf antagonist and possible counterbalance to Nf1 loss, which was microdeleted or downregulated in gliomas at 150 days. These hidden cell-state variations uncover replication stress as a potential bottleneck that must be resolved for glioma initiation. SIGNIFICANCE: Profiling premalignant cell states in a mouse model of glioma uncovers regulatory heterogeneity in glioma cells-of-origin and defines a state of replication stress that precedes tumor initiation.See related articles by Singh and colleagues, p. 1840 and Schaff and colleagues, p. 1853.


Assuntos
Neoplasias da Mama , Glioma , Células Precursoras de Oligodendrócitos , Animais , Transformação Celular Neoplásica , Proteínas de Ligação a DNA , Endonucleases , Feminino , Glioma/genética , Humanos , Camundongos , Oligodendroglia , Proteínas de Ligação a RNA
5.
Cancer Res ; 81(7): 1840-1852, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33531373

RESUMO

The heterogeneous composition of solid tumors is known to impact disease progression and response to therapy. Malignant cells coexist in different regulatory states that can be accessed transcriptomically by single-cell RNA sequencing, but these methods have many caveats related to sensitivity, noise, and sample handling. We revised a statistical fluctuation analysis called stochastic profiling to combine with 10-cell RNA sequencing, which was designed for laser-capture microdissection (LCM) and extended here for immuno-LCM. When applied to a cohort of late-onset, early-stage luminal breast cancers, the integrated approach identified thousands of candidate regulatory heterogeneities. Intersecting the candidates from different tumors yielded a relatively stable set of 710 recurrent heterogeneously expressed genes (RHEG), which were significantly variable in >50% of patients. RHEGs were not strongly confounded by dissociation artifacts, cell-cycle oscillations, or driving mutations for breast cancer. Rather, RHEGs were enriched for epithelial-to-mesenchymal transition genes and, unexpectedly, the latest pan-cancer assembly of driver genes across cancer types other than breast. These findings indicate that heterogeneous transcriptional regulation conceivably provides a faster, reversible mechanism for malignant cells to evaluate the effects of potential oncogenes or tumor suppressors on cancer hallmarks. SIGNIFICANCE: Profiling intratumor heterogeneity of luminal breast carcinoma cells identifies a recurrent set of genes, suggesting sporadic activation of pathways known to drive other types of cancer.See related articles by Schaff and colleagues, p. 1853 and Sutcliffe and colleagues, p. 1868.


Assuntos
Neoplasias da Mama , Neoplasias Pulmonares , Mama , Neoplasias da Mama/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Oncogenes , Microambiente Tumoral
6.
Cancer Res ; 81(7): 1853-1867, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33531375

RESUMO

Small-cell lung cancers derive from pulmonary neuroendocrine cells, which have stem-like properties to reprogram into other cell types upon lung injury. It is difficult to uncouple transcriptional plasticity of these transformed cells from genetic changes that evolve in primary tumors or secondary metastases. Profiling of single cells is also problematic if the required sample dissociation activates injury-like signaling and reprogramming. Here we defined cell-state heterogeneities in situ through laser capture microdissection-based 10-cell transcriptomics coupled with stochastic-profiling fluctuation analysis. In labeled cells from a small-cell lung cancer mouse model initiated by neuroendocrine deletion of Rb1-Trp53, variations in transcript abundance revealed cell-to-cell differences in regulatory state in vitro and in vivo. Fluctuating transcripts in spheroid culture were partly shared among Rb1-Trp53-null models, and heterogeneities increased considerably when cells were delivered intravenously to colonize the liver. Colonization of immunocompromised animals drove a fractional appearance of alveolar type II-like markers and poised cells for paracrine stimulation from immune cells and hepatocytes. Immunocompetency further exaggerated the fragmentation of tumor states in the liver, yielding mixed stromal signatures evident in bulk sequencing from autochthonous tumors and metastases. Dozens of transcript heterogeneities recurred irrespective of biological context; their mapped orthologs brought together observations of murine and human small-cell lung cancer. Candidate heterogeneities recurrent in the liver also stratified primary human tumors into discrete groups not readily explained by molecular subtype but with prognostic relevance. These data suggest that heterotypic interactions in the liver and lung are an accelerant for intratumor heterogeneity in small-cell lung cancer. SIGNIFICANCE: These findings demonstrate that the single-cell regulatory heterogeneity of small-cell lung cancer becomes increasingly elaborate in the liver, a common metastatic site for the disease.See related articles by Singh and colleagues, p. 1840 and Sutcliffe and colleagues, p. 1868.


Assuntos
Neoplasias da Mama , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Animais , Feminino , Humanos , Pulmão , Neoplasias Pulmonares/genética , Camundongos , Recidiva Local de Neoplasia , Carcinoma de Pequenas Células do Pulmão/genética , Microambiente Tumoral
7.
BMJ Glob Health ; 5(9)2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32928798

RESUMO

BACKGROUND: Evidence-based practices that reduce childbirth-related morbidity and mortality are core processes to quality of care. In the BetterBirth trial, a matched-pair, cluster-randomised controlled trial of a coaching-based implementation of the WHO Safe Childbirth Checklist (SCC) in Uttar Pradesh, India, we observed a significant increase in adherence to practices, but no reduction in perinatal mortality. METHODS: Within the BetterBirth trial, we observed birth attendants in a subset of study sites providing care to labouring women to assess the adherence to individual and groups of practices. We observed care from admission to the facility until 1 hour post partum. We followed observed women/newborns for 7-day perinatal health outcomes. Using this observational data, we conducted a post-hoc, exploratory analysis to understand the relationship of birth attendants' practice adherence to perinatal mortality. FINDINGS: Across 30 primary health facilities, we observed 3274 deliveries and obtained 7-day health outcomes. Adherence to individual practices, containing supply preparation and direct provider care, varied widely (0·51 to 99·78%). We recorded 166 perinatal deaths (50·71 per 1000 births), including 56 (17·1 per 1000) stillbirths. Each additional practice performed was significantly associated with reduced odds of perinatal (OR: 0·82, 95% CI: 0·72, 0·93) and early neonatal mortality (OR: 0·78, 95% CI: 0·71, 0·85). Each additional practice as part of direct provider care was associated strongly with reduced odds of perinatal (OR: 0·73, 95% CI: 0·62, 0·86) and early neonatal mortality (OR: 0·67, 95% CI: 0·56, 0·80). No individual practice or single supply preparation was associated with perinatal mortality. INTERPRETATION: Adherence to practices on the WHO SCC is associated with reduced mortality, indicating that adherence is a valid indicator of higher quality of care. However, the causal relationships between practices and outcomes are complex. FUNDING: Bill & Melinda Gates Foundation. TRIAL REGISTRATION DETAILS: ClinicalTrials.gov: NCT02148952; Universal Trial Number: U1111-1131-5647.


Assuntos
Morte Perinatal , Mortalidade Perinatal , Parto Obstétrico , Prática Clínica Baseada em Evidências , Feminino , Humanos , Índia/epidemiologia , Recém-Nascido , Mortalidade Materna , Morte Perinatal/prevenção & controle , Gravidez
8.
J Family Med Prim Care ; 9(5): 2573-2576, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32754550

RESUMO

An iatrogenic injection abscess is usually easy to treat if caused by aerobic bacteria but some rapidly growing mycobacteria (RGM), namely, Mycobacterium fortuitum, M. chelonae, and M. abscessus are associated with postinjection abscess and may cause delayed wound healing. RGM can cause mild localized cellulitis or abscess to osteomyelitis following penetration injuries or unsafe injection practices. A 7-year-old girl was presented to pediatric surgery OPD with abscess formation over the right buttock. Incision and drainage from abscess were performed in OPD and pus sample was sent for aerobic bacterial culture and sensitivity. On gram stain plenty of pus cells with no microorganism were seen and growth on blood agar after 48 h of aerobic incubation at 37°C showed small off-white pinpoint, smooth butyrous waxy colonies. Smear prepared from blood agar showed uniformly stained short, slender, faintly stained gram-positive bacilli, for which acid-fast staining (1% and 20% H2SO4) was performed that showed acid-fast bacilli. The isolate was further identified by the molecular method and was confirmed to be Mycobacterium fortuitum by genotype Mycobacterium CM VER 1.0 (HAIN LIFESCIENCE, BioMerieux India Pvt. Ltd.).

9.
Mol Biol Cell ; 31(16): 1714-1725, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32614644

RESUMO

Epithelial tubules form critical structures in lung, kidney, and vascular tissues. However, the processes that control their morphogenesis and physiological expansion and contraction are not well understood. Here we examine the dynamic remodeling of epithelial tubes in vivo using a novel model system: the extracorporeal vasculature of Botryllus schlosseri, in which the disruption of the basement membrane triggers rapid, massive vascular retraction without loss of barrier function. We developed and implemented 3-D image analysis and virtual reconstruction tools to characterize the cellular morphology of the vascular wall in unmanipulated vessels and during retraction. In both control and regressed conditions, cells within the vascular wall were planar polarized, with an integrin- and curvature-dependent axial elongation of cells and a robust circumferential alignment of actin bundles. Surprisingly, we found no measurable differences in morphology between normal and retracting vessels under extracellular matrix (ECM) disruption. However, inhibition of integrin signaling through focal adhesion kinase inhibition caused disruption of cellular actin organization. Our results demonstrate that epithelial tubes can maintain tissue organization even during extreme remodeling events, but that the robust response to mechanical signals-such as the response to loss of vascular tension after ECM disruption-requires functional force sensing machinery via integrin signaling.


Assuntos
Células Epiteliais/metabolismo , Imageamento Tridimensional/métodos , Remodelação Vascular/fisiologia , Actinas/metabolismo , Animais , Membrana Basal/metabolismo , Citoesqueleto/metabolismo , Matriz Extracelular/metabolismo , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Proteína-Tirosina Quinases de Adesão Focal/fisiologia , Processamento de Imagem Assistida por Computador/métodos , Integrinas/fisiologia , Fenômenos Mecânicos , Mecanotransdução Celular/fisiologia , Morfogênese , Transdução de Sinais , Urocordados/metabolismo
10.
Indian J Surg Oncol ; 11(2): 316-320, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32523282

RESUMO

T4 b carcinoma of oral cavity has poor outcomes. The aim for analysis is to evaluate the clinical outcomes with infratemporal fossa clearance for stage T4b carcinoma of oral cavity. Fifty four patients out of maintained data of 528 patients of oral cavity carcinoma were evaluated for current retrospective analysis. All had T4b disease on imaging and underwent bite composite resection with ITF clearance. The median age of the cohort was 52 years. At last follow-up, 28 patients were alive. Twenty two patients had loco-regional recurrence (ITF recurrence 7), and 16 patients had distant metastasis. At median follow-up of 29 months, 2-year loco-regional control, DFS and OS were 52%, 54% and 54%, respectively. Perineural invasion, pathological tumour stage, node positive and ITF tissue involvement were associated with poor oncological outcomes. ITF clearance is feasible in clinical practice and provides curative option for this group.

11.
J Family Med Prim Care ; 9(3): 1407-1412, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32509624

RESUMO

Respiratory tract infections are the most common diseases that are associated with social burden for the patient. Western Rajasthan has cases of Cystic fibrosis due to migrant population. The dry and dusty environment has led to prevalence of silicosis and COPD. As per IDSA (2018) guidelines, patients attending Out-Patient Department do not need microbiological investigations for lower respiratory tract infections (LRTI) except for influenza and tuberculosis. Aims: This study was conducted to identify the bacterial aetiology of LRTI among patients who attended AIIMS, Jodhpur, and to ascertain the current scenario of bacterial susceptibility in respiratory tract infections in order to optimize empiric therapy in Hospitals ad community. Methods and Material: In total, 1,775 lower respiratory tract samples were received in Bacteriology Section of Microbiology Department (January 2017 to December 2018). Bartlett's criteria were stringently used to assess quality of specimen. Semiquantitative cultures were done for tracheal aspirate and bronchoalveolar lavage samples. Following culture, the isolated organisms were identified and antimicrobial sensitivity was performed according to CLSI. Results: Total 769 bacterial pathogens were isolated from 1,775 samples collected from cases of VAP, HAP, CAP, COPD, and cystic fibrosis. Pseudomonas species was the commonest isolate (31%), followed by Klebsiella pneumonia (21.3%), Acinetobacter species (17.5%), Escherichia coli (15.4%), and Staphylococcus aureus (5%). Others include Group A ß-hemolytic Streptococcus, Burkholderia cepacia complex, Stenotrophomonas maltophilia, and Nocardia. Gram-negative organisms showed increased resistance to routinely used antibiotics. Gram-positive organisms showed 100% susceptibility to vancomycin, linezolid, and clindamycin. Conclusions: Cotrimoxazole, ßL-ßLIs, aminoglycosides, and all second-line antibiotics tested were effective for treatment of RTIs.

13.
Med Mycol Case Rep ; 26: 38-41, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31667059

RESUMO

Basidiobolomycosis is an infection due to the fungus Basidiobolus ranarum, an environmental saprophyte found worldwide. We are reporting youngest case of Gastrointestinal Basidiobolomycosis (GIB) in a two month old boy from India. He presented with a mass in right iliac fossa with the signs of intestinal obstruction. Histopathology of the lesion showed broad aseptate hyphae. It disseminated to kidneys. Aspirate culture from nephrostomy yielded growth of B. ranarum. It is important to differentiate it from mucormycosis to institute right therapy. Culture remains the gold standard for its diagnosis.

14.
Health Policy Plan ; 34(8): 574-581, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31419287

RESUMO

In India, most women now delivery in hospitals or other facilities, however, maternal and neonatal mortality remains stubbornly high. Studies have shown that mistreatment causes delays in care-seeking, early discharge and poor adherence to post-delivery guidance. This study seeks to understand the variation of women's experiences in different levels of government facilities. This information can help to guide improvement planning. We surveyed 2018 women who gave birth in a representative set of 40 government facilities from across Uttar Pradesh (UP) state in northern India. Women were asked about their experiences of care, using an established scale for person-centred care. We asked questions specific to treatment and clinical care, including whether tests such as blood pressure, contraction timing, newborn heartbeat or vaginal exams were conducted, and whether medical assessments for mothers or newborns were done prior to discharge. Women delivering in hospitals reported less attentive care than women in lower-level facilities, and were less trusting of their providers. After controlling for a range of demographic attributes, we found that better access, higher clinical quality, and lower facility-level, were all significantly predictive of patient-centred care. In UP, lower-level facilities are more accessible, women have greater trust for the providers and women report being better treated than in hospitals. For the vast majority of women who will have a safe and uncomplicated delivery, our findings suggest that the best option would be to invest in improvements mid-level facilities, with access to effective and efficient emergency referral and transportation systems should they be needed.


Assuntos
Parto Obstétrico/estatística & dados numéricos , Serviços de Saúde Materna/estatística & dados numéricos , Satisfação do Paciente/estatística & dados numéricos , Qualidade da Assistência à Saúde/estatística & dados numéricos , Adulto , Instituições de Assistência Ambulatorial/estatística & dados numéricos , Parto Obstétrico/métodos , Parto Obstétrico/psicologia , Feminino , Hospitais Públicos/estatística & dados numéricos , Humanos , Índia , Cuidado do Lactente/estatística & dados numéricos , Recém-Nascido , Assistência Centrada no Paciente/estatística & dados numéricos , Inquéritos e Questionários
15.
Lancet Glob Health ; 7(8): e1088-e1096, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31303296

RESUMO

BACKGROUND: A coaching-based implementation of the WHO Safe Childbirth Checklist in Uttar Pradesh, India, improved adherence to evidence-based practices, but did not reduce perinatal mortality, maternal morbidity, or maternal mortality. We examined facility-level correlates of the outcomes, which varied widely across the 120 study facilities. METHODS: We did a post-hoc analysis of the coaching-based implementation of the WHO Safe Childbirth Checklist in Uttar Pradesh. We used multivariable modelling to identify correlations between 30 facility-level characteristics and each health outcome (perinatal mortality, maternal morbidity, or maternal mortality). To identify contexts in which the intervention might have had an effect, we then ran the models on data restricted to the period of intensive coaching and among patients not referred out of the facilities. FINDINGS: In the multivariable context, perinatal mortality was associated with only 3 of the 30 variables: female literacy at the district level, geographical location, and previous neonatal mortality. Maternal morbidity was only associated with geographical location. No facility-level predictors were associated with maternal mortality. Among facilities in the lowest tertile of birth volume (<95 births per month), our models estimated perinatal mortality was 17 (95% CI 11·7-24·8) per 1000 births in the intervention group versus 38 (31·6-44·8) per 1000 in the control group (p<0·0001). INTERPRETATION: Mortality was not directly associated with measured facility-level indicators but was associated with general risk factors. The absence of correlation between expected predictors and patient outcomes and the association between improved outcomes and the intervention in smaller facilities suggest a need for additional measures of quality of care that take into account complexity. FUNDING: Bill & Melinda Gates Foundation.


Assuntos
Lista de Checagem , Prática Clínica Baseada em Evidências , Fidelidade a Diretrizes , Parto , Organização Mundial da Saúde , Adulto , Análise por Conglomerados , Aconselhamento , Parto Obstétrico , Feminino , Humanos , Índia/epidemiologia , Recém-Nascido , Mortalidade Materna/tendências , Mortalidade Perinatal/tendências , Gravidez
16.
Sci Rep ; 9(1): 4836, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30894605

RESUMO

Single-cell transcriptomic methods classify new and existing cell types very effectively, but alternative approaches are needed to quantify the individual regulatory states of cells in their native tissue context. We combined the tissue preservation and single-cell resolution of laser capture with an improved preamplification procedure enabling RNA sequencing of 10 microdissected cells. This in situ 10-cell RNA sequencing (10cRNA-seq) can exploit fluorescent reporters of cell type in genetically engineered mice and is compatible with freshly cryoembedded clinical biopsies from patients. Through recombinant RNA spike-ins, we estimate dropout-free technical reliability as low as ~250 copies and a 50% detection sensitivity of ~45 copies per 10-cell reaction. By using small pools of microdissected cells, 10cRNA-seq improves technical per-cell reliability and sensitivity beyond existing approaches for single-cell RNA sequencing (scRNA-seq). Detection of low-abundance transcripts by 10cRNA-seq is comparable to random 10-cell groups of scRNA-seq data, suggesting no loss of gene recovery when cells are isolated in situ. Combined with existing approaches to deconvolve small pools of cells, 10cRNA-seq offers a reliable, unbiased, and sensitive way to measure cell-state heterogeneity in tissues and tumors.


Assuntos
Neoplasias/genética , Análise de Sequência de RNA/métodos , Animais , Biópsia/métodos , Linhagem Celular Tumoral , Perfilação da Expressão Gênica/métodos , Humanos , Camundongos , RNA/genética , RNA Citoplasmático Pequeno/genética , Reprodutibilidade dos Testes , Análise de Célula Única/métodos , Software , Transcriptoma/genética
17.
Curr Stem Cell Rep ; 3(3): 156-163, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29230380

RESUMO

Purpose of review: Recent advances in genomics and gene editing have expanded the range of model organisms to include those with interesting biological capabilities such as regeneration. Among these are the classic models of regeneration biology, the salamander. Although stimulating endogenous regeneration in humans likely is many years away, with advances in stem cell biology and biomedical engineering (e.g. bio-inspired materials), it is evident that there is great potential to enhance regenerative outcomes by approaching the problem from an engineering perspective. The question at this point is what do we need to engineer? Recent findings: The value of regeneration models is that they show us how regeneration works, which then can guide efforts to mimic these developmental processes therapeutically. Among these models, the Accessory Limb Model (ALM) was developed in the axolotl as a gain-of-function assay for the sequential steps that are required for successful regeneration. To date, this model has identified a number of proregenerative signals, including growth factor signaling associated with nerves, and signals associated with the extracellular matrix (ECM) that induce pattern formation. Summary: Identification of these signals through the use of models in highly regenerative vertebrates (e.g. the axolotl) offers a wide range of possible modifications for engineering bio-inspired, biomimetic materials to create a dynamic stem cell niche for regeneration and scar-free repair.

18.
Proc Natl Acad Sci U S A ; 114(17): E3434-E3443, 2017 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-28396387

RESUMO

Oncogenic PIK3CA mutations are found in a significant fraction of human cancers, but therapeutic inhibition of PI3K has only shown limited success in clinical trials. To understand how mutant PIK3CA contributes to cancer cell proliferation, we used genome scale loss-of-function screening in a large number of genomically annotated cancer cell lines. As expected, we found that PIK3CA mutant cancer cells require PIK3CA but also require the expression of the TCA cycle enzyme 2-oxoglutarate dehydrogenase (OGDH). To understand the relationship between oncogenic PIK3CA and OGDH function, we interrogated metabolic requirements and found an increased reliance on glucose metabolism to sustain PIK3CA mutant cell proliferation. Functional metabolic studies revealed that OGDH suppression increased levels of the metabolite 2-oxoglutarate (2OG). We found that this increase in 2OG levels, either by OGDH suppression or exogenous 2OG treatment, resulted in aspartate depletion that was specifically manifested as auxotrophy within PIK3CA mutant cells. Reduced levels of aspartate deregulated the malate-aspartate shuttle, which is important for cytoplasmic NAD+ regeneration that sustains rapid glucose breakdown through glycolysis. Consequently, because PIK3CA mutant cells exhibit a profound reliance on glucose metabolism, malate-aspartate shuttle deregulation leads to a specific proliferative block due to the inability to maintain NAD+/NADH homeostasis. Together these observations define a precise metabolic vulnerability imposed by a recurrently mutated oncogene.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases , Complexo Cetoglutarato Desidrogenase , Mutação , Proteínas de Neoplasias , Neoplasias , Animais , Linhagem Celular Tumoral , Ciclo do Ácido Cítrico/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Glicólise/genética , Humanos , Complexo Cetoglutarato Desidrogenase/biossíntese , Complexo Cetoglutarato Desidrogenase/genética , Camundongos , Camundongos Nus , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/enzimologia , Neoplasias/genética , Neoplasias/patologia
19.
Cell Rep ; 10(5): 755-770, 2015 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-25660025

RESUMO

Novel therapeutic approaches are urgently required for multiple myeloma (MM). We used a phenotypic screening approach using co-cultures of MM cells with bone marrow stromal cells to identify compounds that overcome stromal resistance. One such compound, BRD9876, displayed selectivity over normal hematopoietic progenitors and was discovered to be an unusual ATP non-competitive kinesin-5 (Eg5) inhibitor. A novel mutation caused resistance, suggesting a binding site distinct from known Eg5 inhibitors, and BRD9876 inhibited only microtubule-bound Eg5. Eg5 phosphorylation, which increases microtubule binding, uniquely enhanced BRD9876 activity. MM cells have greater phosphorylated Eg5 than hematopoietic cells, consistent with increased vulnerability specifically to BRD9876's mode of action. Thus, differences in Eg5-microtubule binding between malignant and normal blood cells may be exploited to treat multiple myeloma. Additional steps are required for further therapeutic development, but our results indicate that unbiased chemical biology approaches can identify therapeutic strategies unanticipated by prior knowledge of protein targets.

20.
J Org Chem ; 77(8): 4123-30, 2012 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-22480284

RESUMO

An intramolecular palladium(0)-mediated α-arylation of ketones applied to the synthesis of various substituted tetracyclic indoles is reported. Most significantly, the efficiency of the transformation was enhanced by the use of monoligated Pd(0) complexes. This methodology was extended to double α-arylation of ketones using one-pot reactions with either simultaneous addition or sequential addition of two aryl halides for producing aryl substituted tetracyclic indoles.


Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Indóis/química , Indóis/síntese química , Cetonas/química , Paládio/química , Catálise , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo
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