Innovative partnerships to advance public health training in community-based academic residency programs

Collaborative partnerships between community-based academic residency training programs and schools of public health, represent an innovative approach to training future physician leaders in population management and public health. In Kaiser Permanente Northern California, development of residency-Masters in Public Health (MPH) tracks in the Internal Medicine Residency and the Pediatrics Residency programs, with MPH graduate studies completed at the University of California Berkeley School of Public Health, enables physicians to integrate clinical training with formal education in epidemiology, biostatistics, health policy, and disease prevention. These residency-MPH programs draw on more than 50 years of clinical education, public health training, and health services research - creating an environment that sparks inquiry and added value by developing skills in patient-centered care through the lens of population-based outcomes

Improved catalytic activity of ruthenium–arene complexes in the reduction of NAD+

A series of neutral Ru-II half-sandwich complexes of the type [(eta(6)-arene)Ru(N,N')Cl] where the arene is para-cymene (p-cym), hexamethylbenzene (hmb), biphenyl (bip), or benzene (bn) and N,N' is N-(2-aminoethyl) -4-(trifluoromethyl)benzenesulfonamide (TfEn), N-(2-aminoethyl)-4-toluenesulfonamide (TsEn), or N-(2-aminoethyl)-methylenesulfonamide (MsEn) were synthesized and characterized. X-ray crystal structures of [(p-cym)Ru(MsEn)Cl] (1), [(hmb)Ru(TsEn)Cl] (5), [(hmb)Ru(TfEn)Cl] (6), [(bip)Ru(MsEn)Cl] (7), and [(bip)Ru(TsEn)Cl] (8) have been determined. The complexes can regioselectively catalyze the transfer hydrogenation of NAD(+) to give 1,4-NADH in the presence of formate. The turnover frequencies (TOF) when the arene is varied decrease in the order bn > bip > p-cym > hmb for complexes with the same N,N' chelating ligand. The TOF decreased with variation in the N,N' chelating ligand in the order TfEn > TsEn > MsEn for a given arene. [(bn)Ru(TfEn)Cl] (12) was the most active, with a TOP of 10.4 h(-1). The effects of NAD(+) and formate concentration on the reaction rates were determined for [(p-cym)Ru(TsEn)Cl] (2). Isotope studies implicated the formation of [(arene)Ru(N,N')(H)] as the rate-limiting step. The coordination of formate and subsequent CO2 elimination to generate the hydride were modeled computationally by density functional theory (DFT). CO2 elimination occurs via a two-step process with the coordinated formate first twisting to present its hydrogen toward the metal center. The computed barriers for CO2 release for arene = benzene follow the order MsEn > TsEn > TfEn, and for the Ms En system the barrier followed bn < hmb, both consistent with the observed rates. The effect of methanol on transfer hydrogenation rates in aqueous solution was investigated. A study of pH dependence of the reaction in D2O gave the optimum pH* as 7.2 with a TOF of 1.58 h(-1) for 2. The series of compounds reported here show an improvement in the catalytic activity by an order of magnitude compared to the ethylenediamine analogues

A Comparison of Rectal Diazepam Gel and Placebo for Acute Repetitive Seizures

ABSTRACT Background Acute repetitive seizures are readily recognizable episodes involving increased seizure frequency. Urgent treatment is often required. Rectal diazepam gel is a promising therapy. Methods We conducted a randomized, doubleblind, parallel-group, placebo-controlled study of home-based treatment for acute repetitive seizures. Patients were randomly assigned to receive either rectal diazepam gel, at doses ranging from 0.2 to 0.5 mg per kilogram of body weight on the basis of age, or placebo. Children received one dose at the onset of acute repetitive seizures and a second dose four hours later. Adults received three doses — one dose at onset, and two more doses 4 and 12 hours after onset. Treatment was administered by a care giver, such as a parent, who had received special training. The number of seizures after the first dose was counted for 12 hours in children and for 24 hours in adults. Results Of 125 study patients (64 assigned to diazepam and 61 to placebo) with a history of acute repetitive seizures, 91 (47 children and 44 adults) were treated for an exacerbation of seizures during the study period. Diazepam treatment was superior to placebo with regard to the outcome variables related to efficacy: reduced seizure frequency (P\u3c0.001) and improved global assessment of treatment outcome by the care giver (frequency and severity of seizures and drug toxicity) (P\u3c0.001). Post hoc analysis showed diazepam to be superior to placebo in reducing seizure frequency in both children (P\u3c0.001) and adults (P=0.02), but only in children was it superior with regard to improvement in global outcome (P\u3c0.001). The time to the first recurrence of seizures after initial treatment was longer for the patients receiving diazepam (P\u3c0.001). Thirty-five patients reported at least one adverse effect of treatment; somnolence was the most frequent. Respiratory depression was not reported. Conclusions Rectal diazepam gel, administered at home by trained care givers, is an effective and welltolerated treatment for acute repetitive seizures. (N Engl J Med 1998;338:1869-75.

IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome

Expansion of the polyglutamine repeat within the protein Huntingtin (Htt) causes Huntington's disease, a neurodegenerative disease associated with aging and the accumulation of mutant Htt in diseased neurons. Understanding the mechanisms that influence Htt cellular degradation may target treatments designed to activate mutant Htt clearance pathways. We find that Htt is phosphorylated by the inflammatory kinase IKK, enhancing its normal clearance by the proteasome and lysosome. Phosphorylation of Htt regulates additional post-translational modifications, including Htt ubiquitination, SUMOylation, and acetylation, and increases Htt nuclear localization, cleavage, and clearance mediated by lysosomal-associated membrane protein 2A and Hsc70. We propose that IKK activates mutant Htt clearance until an age-related loss of proteasome/lysosome function promotes accumulation of toxic post-translationally modified mutant Htt. Thus, IKK activation may modulate mutant Htt neurotoxicity depending on the cell's ability to degrade the modified species

Diversity, structure and spatial distribution of megabenthic communities in Cap de Creus continental shelf and submarine canyon (NW Mediterranean)

The continental shelf and submarine canyon off Cap de Creus (NW Mediterranean) were declared a Site of Community Importance (SCI) within the Natura 2000 Network in 2014. Implementing an effective management plan to preserve its biological diversity and monitor its evolution through time requires a detailed character ization of its benthic ecosystem. Based on 60 underwater video transects performed between 2007 and 2013 (before the declaration of the SCI), we thoroughly describe the composition and structure of the main mega benthic communities dwelling from the shelf down to 400 m depth inside the submarine canyon. We then mapped the spatial distribution of the benthic communities using the Random Forest algorithm, which incor porated geomorphological and oceanographic layers as predictors, as well as the intensity of the bottom-trawling fishing fleet. Although the study area has historically been exposed to commercial fishing practices, it still holds a rich benthic ecosystem with over 165 different invertebrate (morpho)species of the megafauna identified in the video footage, which form up to 9 distinct megabenthic communities. The continental shelf is home to coral gardens of the sea fan Eunicella cavolini, sea pen and soft coral assemblages, dense beds of the crinoid Leptometra phalangium, diverse sponge grounds and massive aggregations of the brittle star Ophiothrix fragilis. The submarine canyon off Cap de Creus is characterized by a cold-water coral community dominated by the scleractinian coral Madrepora oculata, found in association with several invertebrate species including oysters, brachiopods and a variety of sponge species, as well as by a community dominated by cerianthids and sea urchins, mostly in sedimentary areas. The benthic communities identified in the area were then compared with habitats/biocenoses described in reference habitat classification systems that consider circalittoral and bathyal environments of the Mediterranean. The complex environmental setting characteristic of the marine area off Cap de Creus likely produces the optimal conditions for communities dominated by suspension- and filter-feeding species to develop. The uniqueness of this ecosystem and the anthropogenic pressures that it faces should prompt the development of effective management actions to ensure the long-term conservation of the benthic fauna representative of this marine area3,26

Cesarean section rate in Iran, multidimensional approaches for behavioral change of providers: a qualitative study

<p>Abstract</p> <p>Background</p> <p>The cesarean section rate has been steadily rising from 35% in 2000 to 40% in 2005 in Iran. The objective of this study was to identify barriers of reduce the cesarean section rate in Iran, as perceived by obstetricians and midwives as the main behavioral change target groups.</p> <p>Methods</p> <p>A qualitative study with purposive sampling was designed in which data were collected through in-depth interviews and document analyses. Hospitals were selected on the bases of being public and or private and their response to the ministry's C-section reduction interventions. The hospital director, obstetricians and midwives from each hospital were included in the study. The classification of barriers suggested by Grol and Wensing was used for the thematic analysis.</p> <p>Results</p> <p>After 26 in-depth interviews and document analyses, the barriers were identified as: financial, insurance and judicial problems at the <it>economic and political context </it>level; the type and ownership of hospitals, absence of an on call physician, absence of clear job-descriptions for obstetricians and midwives, too many interventions in the delivery process and shortage of human resources and facilities at the <it>organizational context </it>level; distrust and insufficient collaborations between obstetricians and midwives from macro to micro level at the <it>social context </it>level; attitudes toward complications of C-section, reduced capabilities of obstetricians, midwives and residents at the <it>individual professional </it>level; and finally, at the <it>innovation </it>level, vaginal delivery is time consuming, imposes high stress levels and is unpredictable.</p> <p>Conclusion</p> <p>Changing service providers' behavior is not possible through presentation of scientific evidence alone. A multi-level and multidisciplinary approach using behavior change theories is unavoidable. In future studies, the effect of the barriers should be determined to help policy makers recognize the most effective interventional package.</p

Race, ethnicity, community-level socioeconomic factors, and risk of COVID-19 in the United States and the United Kingdom

BACKGROUND: There is limited prior investigation of the combined influence of personal and community-level socioeconomic factors on racial/ethnic disparities in individual risk of coronavirus disease 2019 (COVID-19). METHODS: We performed a cross-sectional analysis nested within a prospective cohort of 2,102,364 participants from March 29, 2020 in the United States (US) and March 24, 2020 in the United Kingdom (UK) through December 02, 2020 via the COVID Symptom Study smartphone application. We examined the contribution of community-level deprivation using the Neighborhood Deprivation Index (NDI) and the Index of Multiple Deprivation (IMD) to observe racial/ethnic disparities in COVID-19 incidence. ClinicalTrials.gov registration: NCT04331509. FINDINGS: Compared with non-Hispanic White participants, the risk for a positive COVID-19 test was increased in the US for non-Hispanic Black (multivariable-adjusted odds ratio [OR], 1.32; 95% confidence interval [CI], 1.18–1.47) and Hispanic participants (OR, 1.42; 95% CI, 1.33–1.52) and in the UK for Black (OR, 1.17; 95% CI, 1.02–1.34), South Asian (OR, 1.39; 95% CI, 1.30–1.49), and Middle Eastern participants (OR, 1.38; 95% CI, 1.18–1.61). This elevated risk was associated with living in more deprived communities according to the NDI/IMD. After accounting for downstream mediators of COVID-19 risk, community-level deprivation still mediated 16.6% and 7.7% of the excess risk in Black compared to White participants in the US and the UK, respectively. INTERPRETATION: Our results illustrate the critical role of social determinants of health in the disproportionate COVID-19 risk experienced by racial and ethnic minorities. FUNDING: Please refer to the Funding section at the end of the article

Therapy-induced tumour secretomes promote resistance and tumour progression.

Drug resistance invariably limits the clinical efficacy of targeted therapy with kinase inhibitors against cancer. Here we show that targeted therapy with BRAF, ALK or EGFR kinase inhibitors induces a complex network of secreted signals in drug-stressed human and mouse melanoma and human lung adenocarcinoma cells. This therapy-induced secretome stimulates the outgrowth, dissemination and metastasis of drug-resistant cancer cell clones and supports the survival of drug-sensitive cancer cells, contributing to incomplete tumour regression. The tumour-promoting secretome of melanoma cells treated with the kinase inhibitor vemurafenib is driven by downregulation of the transcription factor FRA1. In situ transcriptome analysis of drug-resistant melanoma cells responding to the regressing tumour microenvironment revealed hyperactivation of several signalling pathways, most prominently the AKT pathway. Dual inhibition of RAF and the PI(3)K/AKT/mTOR intracellular signalling pathways blunted the outgrowth of the drug-resistant cell population in BRAF mutant human melanoma, suggesting this combination therapy as a strategy against tumour relapse. Thus, therapeutic inhibition of oncogenic drivers induces vast secretome changes in drug-sensitive cancer cells, paradoxically establishing a tumour microenvironment that supports the expansion of drug-resistant clones, but is susceptible to combination therapy

Neuropathology of 16p13.11 Deletion in Epilepsy

16p13.11 genomic copy number variants are implicated in several neuropsychiatric disorders, such as schizophrenia, autism, mental retardation, ADHD and epilepsy. The mechanisms leading to the diverse clinical manifestations of deletions and duplications at this locus are unknown. Most studies favour NDE1 as the leading disease-causing candidate gene at 16p13.11. In epilepsy at least, the deletion does not appear to unmask recessive-acting mutations in NDE1, with haploinsufficiency and genetic modifiers being prime candidate disease mechanisms. NDE1 encodes a protein critical to cell positioning during cortical development. As a first step, it is important to determine whether 16p13.11 copy number change translates to detectable brain structural alteration. We undertook detailed neuropathology on surgically resected brain tissue of two patients with intractable mesial temporal lobe epilepsy (MTLE), who had the same heterozygous NDE1-containing 800 kb 16p13.11 deletion, using routine histological stains and immunohistochemical markers against a range of layer-specific, white matter, neural precursor and migratory cell proteins, and NDE1 itself. Surgical temporal lobectomy samples from a MTLE case known not to have a deletion in NDE1 and three non-epilepsy cases were included as disease controls. We found that apart from a 3 mm hamartia in the temporal cortex of one MTLE case with NDE1 deletion and known hippocampal sclerosis in the other case, cortical lamination and cytoarchitecture were normal, with no differences between cases with deletion and disease controls. How 16p13.11 copy changes lead to a variety of brain diseases remains unclear, but at least in epilepsy, it would not seem to be through structural abnormality or dyslamination as judged by microscopy or immunohistochemistry. The need to integrate additional data with genetic findings to determine their significance will become more pressing as genetic technologies generate increasingly rich datasets. Detailed examination of brain tissue, where available, will be an important part of this process in neurogenetic disease specifically

Real-Time PCR Improves Helicobacter pylori Detection in Patients with Peptic Ulcer Bleeding

Background and aims: Histological and rapid urease tests to detect H. pylori in biopsy specimens obtained during peptic ulcer bleeding episodes (PUB) often produce false-negative results. We aimed to examine whether immunohistochemistry and real-time PCR can improve the sensitivity of these biopsies. Patients and Methods: We selected 52 histology-negative formalin-fixed paraffin-embedded biopsy specimens obtained during PUB episodes. Additional tests showed 10 were true negatives and 42 were false negatives. We also selected 17 histology-positive biopsy specimens obtained during PUB to use as controls. We performed immunohistochemistry staining and real-time PCR for 16S rRNA, ureA, and 23S rRNA for H. pylori genes on all specimens. Results: All controls were positive for H. pylori on all PCR assays and immunohistochemical staining. Regarding the 52 initially negative biopsies, all PCR tests were significantly more sensitive than immunohistochemical staining (p<0.01). Sensitivity and specificity were 55% and 80% for 16S rRNA PCR, 43% and 90% for ureA PCR, 41% and 80% for 23S rRNA PCR, and 7% and 100% for immunohistochemical staining, respectively. Combined analysis of PCR assays for two genes were significantly more sensitive than ureA or 23S rRNA PCR tests alone (p<0.05) and marginally better than 16S rRNA PCR alone. The best combination was 16S rRNA+ureA, with a sensitivity of 64% and a specificity of 80%. Conclusions: Real-time PCR improves the detection of H. pylori infection in histology-negative formalin-fixed paraffin-embedded biopsy samples obtained during PUB episodes. The low reported prevalence of H. pylori in PUB may be due to the failure of conventional tests to detect infection