RESUMO
Oxidative phosphorylation, the combined activities of the electron transport chain (ETC) and ATP synthase, has emerged as a valuable target for antibiotics to treat infection with Mycobacterium tuberculosis and related pathogens. In oxidative phosphorylation, the ETC establishes a transmembrane electrochemical proton gradient that powers ATP synthesis. Monitoring oxidative phosphorylation with luciferase-based detection of ATP synthesis or measurement of oxygen consumption can be technically challenging and expensive. These limitations reduce the utility of these methods for characterization of mycobacterial oxidative phosphorylation inhibitors. Here, we show that fluorescence-based measurement of acidification of inverted membrane vesicles (IMVs) can detect and distinguish between inhibition of the ETC, inhibition of ATP synthase, and nonspecific membrane uncoupling. In this assay, IMVs from Mycobacterium smegmatis are acidified either through the activity of the ETC or ATP synthase, the latter modified genetically to allow it to serve as an ATP-driven proton pump. Acidification is monitored by fluorescence from 9-amino-6-chloro-2-methoxyacridine, which accumulates and quenches in acidified IMVs. Nonspecific membrane uncouplers prevent both succinate- and ATP-driven IMV acidification. In contrast, the ETC Complex III2IV2 inhibitor telacebec (Q203) prevents succinate-driven acidification but not ATP-driven acidification, and the ATP synthase inhibitor bedaquiline prevents ATP-driven acidification but not succinate-driven acidification. We use the assay to show that, as proposed previously, lansoprazole sulfide is an inhibitor of Complex III2IV2, whereas thioridazine uncouples the mycobacterial membrane nonspecifically. Overall, the assay is simple, low cost, and scalable, which will make it useful for identifying and characterizing new mycobacterial oxidative phosphorylation inhibitors.
Assuntos
Antibacterianos , Descoberta de Drogas , Mycobacterium tuberculosis , Fosforilação Oxidativa , Trifosfato de Adenosina/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Complexo III da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Descoberta de Drogas/métodosRESUMO
INTRODUCTION: Although outcome disparities by race have been identified in colorectal cancer, these patterns are challenging to explain using variables that are commonly available in databases. In a single institution serving a diverse community, length of stay (LOS) varies by race following elective oncologic colectomy. We investigated previously unexplored variables that may explain the relationship between race and LOS following elective resection of colorectal neoplasms. METHODS: Retrospective, single institution cohort study from January 2015 to December 2020 for adult patients undergoing elective colorectal cancer resections. Baseline demographic variables and intraoperative factors were analyzed for changes in LOS following elective colorectal resection. Additional retrospective chart review was carried out to determine household member composition and distance from home to hospital. Bivariate analysis was conducted to determine which variables should be included in multivariable analyses. All analyses were conducted using SAS Academic. RESULTS: Most patients (n = 383) were Asian (40%), Black (12%), or Hispanic (26%). Race and LOS were associated with age (P = 0.001 and P < 0.001 for race and LOS, respectively), American Society of Anesthesiologists class (P = 0.004 and P < 0.001), enhanced recovery after surgery protocols (P = 0.006 and P < 0.001), household members (P = 0.009 and P = 0.002), and discharge disposition (P = 0.049 and P < 0.001). In multivariable analysis, household members (P = 0.021) independently remained associated with LOS after controlling for race (P = 0.008) and discharge disposition (P < 0.001). CONCLUSIONS: Household member composition varies with LOS, suggesting that level of support at home may influence decisions regarding discharge disposition, which lead to differences in LOS.
Assuntos
Colectomia , Neoplasias Colorretais , Procedimentos Cirúrgicos Eletivos , Disparidades em Assistência à Saúde , Tempo de Internação , Humanos , Masculino , Tempo de Internação/estatística & dados numéricos , Feminino , Colectomia/estatística & dados numéricos , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Procedimentos Cirúrgicos Eletivos/estatística & dados numéricos , Neoplasias Colorretais/cirurgia , Neoplasias Colorretais/etnologia , Disparidades em Assistência à Saúde/estatística & dados numéricos , Disparidades em Assistência à Saúde/etnologia , Fatores Sociodemográficos , Adulto , Recuperação Pós-Cirúrgica Melhorada , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: This study aimed to determine the effect of Enhanced Recovery After Surgery (ERAS) protocols on the weekend effect after elective colectomies. METHODS: This was a retrospective study on all elective colorectal surgeries at a single institution in New York City between January 1, 2015, and December 31, 2020. The length of stay (LOS) by day of the week of surgery and the effect of ERAS using univariable and multivariable analyses were compared. RESULTS: A total of 605 patients were included in the study. Of note, 41 cases were performed on Mondays, 197 cases were performed on Tuesdays, 45 cases were performed on Wednesdays, 187 cases were performed on Thursdays, and 135 cases were performed on Fridays. Univariate analysis showed that, for patients who did not undergo ERAS, Monday and Tuesday were significantly associated with decreased LOS (P < .001). For patients who underwent ERAS, there was no statistically significant difference in LOS (P = .06) when operated on early in the week vs later. After controlling for age, race/ethnicity, comorbidities, complications, functional health status, operation type, duration of surgery, presence of ostomy, and albumin level, adhering to the ERAS protocol was significantly associated with a shorter LOS (P < .001). CONCLUSION: Our study demonstrated that ERAS can mitigate the weekend effect on LOS. ERAS protocols may provide more structure to the expected hospital course and allow patients to reach recovery milestones earlier, facilitating discharge even by covering teams.
Assuntos
Colectomia , Procedimentos Cirúrgicos Eletivos , Recuperação Pós-Cirúrgica Melhorada , Tempo de Internação , Humanos , Tempo de Internação/estatística & dados numéricos , Feminino , Estudos Retrospectivos , Masculino , Colectomia/métodos , Colectomia/efeitos adversos , Pessoa de Meia-Idade , Idoso , Fatores de Tempo , Cidade de Nova Iorque , Complicações Pós-Operatórias/epidemiologiaRESUMO
BACKGROUND: Appendectomy is the gold standard for simple appendicitis. During the coronavirus-19 pandemic, it was estimated that appendectomies in the United States decreased by 24%. We aimed to describe trends in acute appendicitis management at a center located in one of the largest epicenters of the pandemic. METHODS: This is a retrospective cohort study in a single institution located in Queens, New York, of patients who presented with acute appendicitis. A pre-COVID time period, March-June 2019, was compared to peak-COVID, March-June 2020, and late-COVID, March-June 2021. RESULTS: Of the 382 patients admitted with appendicitis during the time periods, 164 were admitted pre-COVID. Appendicitis presentations decreased by 44% during peak-COVID and 23% in late-COVID. Patients were younger during peak-COVID compared to pre-COVID (39 vs 34 years old, P = .036). Incidence of complicated appendicitis in pre-, peak-, and late-COVID was equivalent (41% vs 46% vs 45%) and operative management was similar (85% vs 76% vs 79%). Non-operative patients had shorter lengths of stay (pre- vs peak-COVID: 4.6 vs 2.9 days, P = .006). Readmission rates were similar between the cohorts across time periods. CONCLUSIONS: During peak-COVID, there was a significant decrease in presentation of acute appendicitis but clinical presentation and outcomes remained similar between the cohorts. Patients who were managed non-operatively may be discharged earlier without increased rates of readmissions.
Assuntos
Apendicite , COVID-19 , Humanos , Adulto , COVID-19/epidemiologia , Cidade de Nova Iorque/epidemiologia , Apendicite/diagnóstico , Apendicite/epidemiologia , Apendicite/cirurgia , Pandemias , Estudos Retrospectivos , Doença AgudaRESUMO
Intellectual and developmental disabilities result from abnormal nervous system development. Over a 1,000 genes have been associated with intellectual and developmental disabilities, driving continued efforts toward dissecting variant functionality to enhance our understanding of the disease mechanism. This report identified two novel variants in CC2D1A in a cohort of four patients from two unrelated families. We used multiple model systems for functional analysis, including Xenopus, Drosophila, and patient-derived fibroblasts. Our experiments revealed that cc2d1a is expressed explicitly in a spectrum of ciliated tissues, including the left-right organizer, epidermis, pronephric duct, nephrostomes, and ventricular zone of the brain. In line with this expression pattern, loss of cc2d1a led to cardiac heterotaxy, cystic kidneys, and abnormal CSF circulation via defective ciliogenesis. Interestingly, when we analyzed brain development, mutant tadpoles showed abnormal CSF circulation only in the midbrain region, suggesting abnormal local CSF flow. Furthermore, our analysis of the patient-derived fibroblasts confirmed defective ciliogenesis, further supporting our observations. In summary, we revealed novel insight into the role of CC2D1A by establishing its new critical role in ciliogenesis and CSF circulation.
Assuntos
Cílios , Ciliopatias , Deficiência Intelectual , Humanos , Animais , Deficiência Intelectual/genética , Masculino , Cílios/metabolismo , Feminino , Ciliopatias/genética , Ciliopatias/metabolismo , Fibroblastos/metabolismo , Mutação , Rim/metabolismo , Encéfalo/metabolismo , Linhagem , Xenopus , Líquido Cefalorraquidiano/metabolismoRESUMO
Purpose of Review: Obese breast cancer patients have poorer outcomes compared to non-obese patients. The intent of this review is to discuss recent studies and analyses regarding the status of the obesity epidemic and its effect on breast cancer incidence and outcomes. Subsequently, we will introduce a program implemented at a New York City hospital to reduce the morbidity and mortality of breast cancer patients with obesity. Recent Findings: The prevalence of obesity among adult Americans is 42%, spanning all racial and socioeconomic groups. Importantly, obesity is associated with multiple chronic diseases including cancer. Among breast cancer patients, obesity is linked to higher mortality and poorer clinical outcomes, including but not limited to distant recurrence and secondary malignancies. Summary: Current treatment of breast cancer patients does not address the link between obesity and poorer prognosis. Here, we presentâ¯a general strategy for reducing the morbidity and mortality of obese breast cancer patients by addressing the obesity epidemic. Supplementary Information: The online version contains supplementary material available at 10.1007/s12609-022-00460-4.