DFFR: A New Method for High-Throughput Recalibration of Automatic Force-Fields for Drugs

We present drug force-field recalibration (DFFR), a new method for refining of automatic force-fields used to represent small drugs in docking and molecular dynamics simulations. The method is based on fine-tuning of torsional terms to obtain ensembles that reproduce observables derived from reference data. DFFR is fast and flexible and can be easily automatized for a high-throughput regime, making it useful in drug-design projects. We tested the performance of the method in a few model systems and also in a variety of druglike molecules using reference data derived from: (i) density functional theory coupled to a self-consistent reaction field (DFT/SCRF) calculations on highly populated conformers and (ii) enhanced sampling quantum mechanical/molecular mechanics (QM/MM) where the drug is reproduced at the QM level, while the solvent is represented by classical force-fields. Extension of the method to include other sources of reference data is discussed

Anthropology, Brokerage and Collaboration in the development of a Tongan Public Psychiatry: Local Lessons for Global Mental Health

The Global Mental Health (GMH) movement has revitalised questions of the translatability of psychiatric concepts and the challenges of community engagement in countries where knowledge of the biomedical basis for psychiatric diagnosis is limited or challenged by local cultural codes. In Tonga, the local psychiatrist Dr Puloka has successfully established a publicly accessible psychiatry that has raised admission rates for serious mental illness and addressed some of the stigma attached to diagnosis. On the basis of historical analysis and ethnographic fieldwork with healers, doctors and patients since 1998, this article offers an ethnographic contextualization of the development and reception of three key interventions during the 1990s inspired by traditional healing and reliant on the translation of psychiatric terms and diagnosis. Dr Puloka’s use of medical anthropological and transcultural psychiatry research informed a community engaged brokerage between the implications of psychiatric nosologies and local needs. As such it reveals deficiencies in current polarised positions on the GMH project and offers suggestions to address current challenges of the Global Mental Health movement

DNA structure directs positioning of the mitochondrial genome packaging protein Abf2p

The mitochondrial genome (mtDNA) is assembled into nucleo-protein structures termed nucleoids and maintained differently compared to nuclear DNA, the involved molecular basis remaining poorly understood. In yeast (Saccharomyces cerevisiae), mtDNA is a similar to 80 kbp linear molecule and Abf2p, a double HMG-box protein, packages and maintains it. The protein binds DNA in a non-sequence-specific manner, but displays a distinct 'phased-binding' at specific DNA sequences containing poly-adenine tracts (A-tracts). We present here two crystal structures of Abf2p in complex with mtDNA-derived fragments bearing A-tracts. Each HMG-box of Abf2p induces a 90. bend in the contacted DNA, causing an overall U-turn. Together with previous data, this suggests that U-turn formation is the universal mechanism underlying mtDNA compaction induced by HMG-box proteins. Combining this structural information with mutational, biophysical and computational analyses, we reveal a unique DNA binding mechanism for Abf2p where a characteristic N-terminal flag and helix are crucial for mtDNA maintenance. Additionally, we provide the molecular basis for A-tract mediated exclusion of Abf2p binding. Due to high prevalence of Atracts in yeast mtDNA, this has critical relevance for nucleoid architecture. Therefore, an unprecedented A-tract mediated protein positioning mechanism regulates DNA packaging proteins in the mitochondria, and in combination with DNA-bending and U-turn formation, governs mtDNA compaction

Microperimetry and Optical Coherence Tomography Changes in Type-1 Diabetes Mellitus without Retinopathy

Background: We aimed to measure and correlate inner retinal layer (IRL) thickness and macular sensitivity by optical coherence tomography (OCT) and by microperimetry, respectively, in type 1 diabetes mellitus patients (DM1) without diabetic retinopathy (DR). Methods: Fifty-one DM1 patients and 81 age-matched healthy subjects underwent measurement of the axial length (AL), retinal thickness in the macular ETDRS areas by swept source (SS)-OCT and macular sensitivity by microperimeter. Results: The total retinal and IRL thicknesses were thicker in the DM1 group (p < 0.05) in practically all ETDRS areas, and they had a generalized decrease in sensitivity (p < 0.05) in 9 areas between both groups. There was a significant negative correlation between retinal sensitivity and age in all areas and in visual acuity (VA) in 5 out of the 9 areas for DM1 patients. Only a mild negative correlation was observed between retinal sensitivity in the 5 degrees nasal inner (5NI) area and in IRL thickness in the temporal inner (TI) area (-0.309 with p = 0.029) in the DM1 group. Conclusion: Aging and disease evolution in DM1 patients without DR signs generate a decrease in retinal sensitivity. There was a direct relationship between retinal sensitivity and macular thickness in the DM1 group

NEONATAL SEPSIS: ANTIBIOTIC SENSITIVITY &amp; RESISTANCE PATTERN OF COMMONLY ISOLATED PATHOGENS IN A NEONATAL INTENSIVE CARE

Neonatal bacterial sepsis is one of the major causes of morbidity and mortality in neonates. Bacterial pathogens and drug resistance are different in hospitals of each country. In this study we identified bacterial pathogens and its sensitivity and resistance pattern for various antibiotics in the neonatal intensive care unit (NICU) in Amrita Institute of Medical Sciences (AIMS), kochi during September 2011 to April 2012. A total of 150 newborns admitted in the NICU with symptoms/signs of bacteremia/septicemia or developed sepsis during their stay in NICU were included in the study. 57 (38%) out of 150 patients admitted during the study period had proven sepsis confirmed by positive blood culture. Gram negative organisms accounted for 87.72 % of all positive cultures. Among the culture positive specimens, Klebsiella pneumoniae (45.61 %) and Coagulase Oxidase Negative Staphylococcus (CoNS) (12.28%) were the commonly isolated gram negative and gram positive organism respectively

Development and validation of a risk score for chronic kidney disease in HIV infection using prospective cohort data from the D:A:D study.

Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice

Structural and functional findings in patients with moderate diabetic retinopathy

Purpose: To evaluate structural and functional ocular changes in patients with type 2 diabetes mellitus (DM2) and moderate diabetic retinopathy (DR) without apparent diabetic macular edema (DME) assessed by optical coherence tomography (OCT) and microperimetry. Methods: This was a single-center cross-sectional descriptive study for which 75 healthy controls and 48 DM2 patients with moderate DR were included after applying exclusion criteria (one eye per patient was included). All eyes underwent a complete ophthalmic examination (axial length, macular imaging with swept-source OCT, and MAIA microperimetry). Macular thicknesses, ganglion cell complex (GCC) thicknesses, and central retinal sensitivity were compared between groups, and the relationships between the OCT and microperimetry parameters were evaluated. Results: Macular thickness was similar in both groups (242.17 ± 35.0 in the DM2 group vs 260.64 ± 73.9 in the control group). There was a diminution in the parafoveal area thickness in the DM2 group in the GCC complex. Retinal sensitivity was reduced in all sectors in the DM2 group. The central global value was 24.01 ± 5.7 in the DM2 group and 27.31 ± 2.7 in the control group (p < 0.001). Macular integrity was 80.89 ± 26.4 vs 64.70 ± 28.3 (p < 0.001) and total mean threshold was 23.90 ± 4.9 vs 26.48 ± 2.6 (p < 0.001) in the DM2 and control group, respectively. Moderate correlations were detected between the central sector of MAIA microperimetry and retina total central thickness (- 0.347; p = 0.0035). Age, visual acuity, and hemoglobin A1c levels also correlated with retinal sensitivity. Conclusion: Macular GCC thickness and central retinal sensitivity were reduced in patients with moderate DR without DME, suggesting the presence of macular neurodegeneration.[Figure not available: see fulltext.] © 2021, The Author(s)

Tracheostomy in patients with long-term mechanical ventilation: a survey.

BACKGROUND: Tracheostomy is increasingly performed in intensive care units (ICU), with many patients transferred to respiratory ICU (RICU). Indications/timing for closing tracheostomy are discussed. AIM AND METHOD: We report results of a one-year survey evaluating: 1) clinical characteristics, types of tracheostomy, complications in patients admitted to Italian RICU in 2006; 2) clinical criteria and systems for performing decannulation, and outcome of patients undergoing tracheostomy (number decannulated; number non-decannulated/non-ventilated; number non-decannulated/ventilated; dead/lost patients). RESULTS: 22/32 RICUs replied. There were 846 admissions of 719 patients (Mean age 64,3 (+/-14.2) years, 489 (68%) males). Causes of admission were: acute respiratory failure with underlying chronic co-morbidities 176 (24.4%); exacerbation of Chronic Obstructive Pulmonary Disease 222 (34.4%); neuromuscular diseases 200 (27.8%); surgical patients 77 (10.7%); thoracic dysmorphism 28 (3.8%); obstructive sleep apnea syndrome 16 (2.2%). Percutaneous tracheostomies were 65.9%. Major complications after tracheostomy were 2%. 427 tracheostomies were evaluated for decannulation: 96 (22.5%) were closed; 175 patients (41%) were discharged with home mechanical ventilation; 114 patients (26.5%) maintained the tracheostomy despite weaning from mechanical ventilation and 42 patients (10%) died or lost. The clinical criteria chosen for decannulation were: stability of respiratory conditions, effective cough, underlying diseases and ability to swallow. The systems for evaluating feasibility of decannulation were: closure of tracheostomy tube; laryngo-tracheoscopy; use of tracheal button and down-sizing. CONCLUSIONS: There were few major complications of tracheostomy. A substantial proportion of patients maintain the tracheostomy despite not requiring mechanical ventilation. There was no agreement on indications and systems for closing tracheostom