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The gut microbiome may be a mediator between obesity and health outcomes. However, it is unclear how intentional weight loss changes the gut microbiota and intestinal permeability. We aimed to systematically review and quantify this association. We searched Medline, Embase, CINAHL, Cochrane databases, and trial registries until June 2020 (PROSPERO: CRD42020205292). We included trials of weight loss interventions (energy-restricted diets, pharmacotherapy, bariatric surgery) reporting on the microbiome. Two reviewers independently completed screening, extraction, and risk assessment with the ROBINS-I tool. Pooled standardized mean differences (SMDs) were obtained from random-effects meta-analyses. Forty-seven trials with 1,916 participants (81% female) and a median follow-up of 6 months (range: 2–24) were included. Based on imprecise evidence but with fairly consistent direction of effect, weight loss was associated with a statistically significant increase in α-diversity [SMD: 0.4 (95% CI: 0.2, 0.6], p

Gram-negative bacteria are responsible for an increasing number of deaths from antibiotic resistant infections.(1,2) The bacterial natural product, colistin, is considered the last line of defense against a number of Gram-negative pathogens. The recent global spread of the plasmid-borne mobilized colistin resistance gene mcr-1 (phosphoethanolamine (PEtN) transferase) threatens colistin’s utility.(3) Bacterial-derived antibiotics often appear in nature as collections of similar structures that are encoded by evolutionarily related biosynthetic gene clusters (BGCs). This structural diversity is, at least in part, likely a response to the development of natural resistance, which often mechanistically mimics clinical resistance. Here, we proposed that a solution to mcr-1 mediated resistance might have evolved among naturally occurring colistin congeners. Our search of sequenced bacterial genomes identified a BGC that was predicted to encode the most structurally divergent colistin congener described to-date. Chemical synthesis of this structure produced macolacin, which is active against Gram-negative pathogens containing mcr-1 as well as intrinsically resistant pathogens with chromosomally encoded PEtN transferase genes. These include extremely drug resistant (XDR) Acinetobacter baumannii and intrinsically colistin resistant Neisseria gonorrhoeae which, due to a lack of effective treatment options, are considered among the highest level Gram-negative threats.(4) In a mouse neutropenic infection model, a biphenyl analog of macolacin proved to be effective against colistin resistant XDR A. baumannii, thus providing a new naturally inspired and easily produced therapeutic lead for combating colistin resistant pathogens.

Background Current TB treatment for children is not optimized to provide adequate drug levels in TB lesions. Dose optimization of first-line antituberculosis drugs to increase exposure at the site of disease could facilitate more optimal treatment and future treatment-shortening strategies across the disease spectrum in children with pulmonary TB. Objectives To determine the concentrations of first-line antituberculosis drugs at the site of disease in children with intrathoracic TB. Methods We quantified drug concentrations in tissue samples from 13 children, median age 8.6 months, with complicated forms of pulmonary TB requiring bronchoscopy or transthoracic surgical lymph node decompression in a tertiary hospital in Cape Town, South Africa. Pharmacokinetic models were used to describe drug penetration characteristics and to simulate concentration profiles for bronchoalveolar lavage, homogenized lymph nodes, and cellular and necrotic lymph node lesions. Results Isoniazid, rifampicin and pyrazinamide showed lower penetration in most lymph node areas compared with plasma, while ethambutol accumulated in tissue. None of the drugs studied was able to reach target concentration in necrotic lesions. Conclusions Despite similar penetration characteristics compared with adults, low plasma exposures in children led to low site of disease exposures for all drugs except for isoniazid.

Competency in psychodynamic psychotherapy is a requirement for residency training in psychiatry. However, for a variety of reasons, learning psychodynamic psychotherapy is difficult for residents. In this article, we share our experience in an elective in Transference-Focused Psychotherapy (TFP), a manualized treatment for severe personality disorders. Originally, this elective was conceptualized as an advanced component of training, offering specialized training in treating a subgroup of patients with severe personality disorders with a specific type of psychodynamic psychotherapy. However, contrary to the expectations of the residents and the training director, the elective in TFP strengthened understanding of core components of basic psychodynamic psychotherapy with all patients, not just those with severe personality disorders. We discuss various challenges in learning psychodynamic psychotherapy and how TFP served to address them. Two case vignettes illustrate several key points.

Candida species are a part of the human microbiome and can cause systemic infection upon immune suppression. Candida glabrata infections are increasing and have greater rates of antifungal resistance than other species. Here, we present a C. glabrata gastrointestinal (GI) colonization model to explore whether colonized yeast exposed to caspofungin, an echinocandin antifungal, develop characteristic resistance mutations and, upon immunosuppression, breakthrough causing systemic infection. Daily therapeutic dosing (5 mg/kg of body weight) of caspofungin resulted in no reduction in fecal burdens, organ breakthrough rates similar to control groups, and resistance rates (0 to 10%) similar to those reported clinically. Treatment with 20 mg/kg caspofungin initially reduced burdens, but a rebound following 5 to 9 days of treatment was accompanied by high levels of resistance ( FKS1 / FKS2 mutants). Although breakthrough rates decreased in this group, the same FKS mutants were recovered from organs. In an attempt to negate drug tolerance that is critical for resistance development, we cotreated mice with daily caspofungin and the chitin synthase inhibitor nikkomycin Z. The largest reduction (3 log) in GI burdens was obtained within 3 to 5 days of 20 mg/kg caspofungin plus nikkomycin treatment. Yet, echinocandin resistance, characterized by a novel Fks1-L630R substitution, was identified following 5 to 7 days of treatment. Therapeutic caspofungin plus nikkomycin treatment left GI burdens unchanged but significantly reduced organ breakthrough rates (20%; P < 0.05). Single-dose pharmacokinetics demonstrated low levels of drug penetration into the GI lumen posttreatment with caspofungin. Overall, we show that C. glabrata echinocandin resistance can arise within the GI tract and that resistant mutants can readily disseminate upon immunosuppression.

There is clear evidence for the positive motor outcomes of patients with Parkinson’s Disease (PD) undergoing deep brain stimulation (DBS) of the subthalamic nucleus (STN). 1 However, data for unintended neuropsychiatric effects of this procedure are accumulating. 2–7 Certain subsets of patients may be more likely to experience these adverse outcomes following implantation, but these are not yet clearly described. 2– 4,8 We report a case of a 51year-old Hispanic male with early-onset PD who became abruptly psychotic, apathetic, and cognitively impaired following DBS. The case draws attention to the still unanswered question of how to select patients who may be at risk for neuropsychiatric complications associated with this therapy.

During space missions, such as the prospective Mars mission, crew labor time is a strictly limited resource. The diet for such a mission (based on crops grown in a bioregenerative life support system) will require astronauts to prepare their meals essentially from raw ingredients. Time spent on food processing and preparation is time lost for other purposes. Recipe design and diet planning for a space mission should therefore incorporate the time required to prepare the recipes as a critical factor. In this study, videotape analysis of an experienced chef was used to develop a database of recipe preparation time. The measurements were highly consistent among different measurement teams. Data analysis revealed a wide variation between the active times of different recipes, underscoring the need for optimization of diet planning. Potential uses of the database developed in this study are discussed and illustrated in this work.

The renal biopsies of ten women with preeclampsia without other underlying renal disease were examined in detail using light and electron microscopy and immunofluorescence. Characteristic preeclamptic glomerular lesions with endocapillary cell swelling, subendothelial and mesangial deposits, and mesangial interposition were detected in each patient. Juxtaglomerular regions were not prominent and were poorly granulated on light microscopy; ultra-structurally, they showed myoepithelioid cells with sparse renin granulation and considerable heterogeneity of granule size and density in association with relatively meagre granular endoplasmic reticulum and Golgi profiles. These morphologic findings suggest that, in patients with clinical and renal biopsy evidence of preeclampsia, there is no significant stimulation of the renin–angiotensin system.