A high‐quality homology model for the human dopamine transporter validated for drug design purposes

The human dopamine transporter (hDAT) plays many vital functions within the central nervous system and is thus targeted by many pharmaceutical agents. Dopamine‐related therapies are in current development for individuals with dopamine‐related disorders including depression, Parkinson's disease, and psychostimulant addictions such as cocaine abuse. Yet, most efforts to develop new dopamine therapies are within costly structure–activity relationship studies. Through structure‐based drug design techniques, the binding site of hDAT can be utilized to develop novel selective and potent dopamine therapies at reduced costs. However, no structural models of hDAT specifically validated for rational drug design purposes currently exist. Here, using the Drosophila dopamine transporter as a template, a homology model for the hDAT was developed and validated. The model was able to reproduce experimental binding modes with great accuracy, was able to rank inhibitors in the correct order of increasing potency with an R² value of 0.81 for the test set, and it also outperformed other published hDAT models. Thus, the model can be used reliably in structure‐based drug design projects.     

HbA1c Change and Diabetic Retinopathy During GLP-1 Receptor Agonist Cardiovascular Outcome Trials: A Meta-analysis and Meta-regression

BACKGROUNDLong-term glycemic control reduces retinopathy risk, but transient worsening can occur with glucose control intensification. Glucagon-like peptide 1 receptor agonists (GLP-1RA) lower glucose, but the long-term impact on retinopathy is unknown. GLP-1RA cardiovascular outcome trials (CVOTs) provide long-term follow-up, allowing examination of retinopathy outcomes.PURPOSETo examine the associations between retinopathy, HbA_1c, systolic blood pressure (SBP), and weight in GLP-1RA CVOTs.DATA SOURCESSystematic review identified six placebo-controlled GLP-1RA CVOTs reporting prespecified retinopathy outcomes.STUDY SELECTIONPublished trial reports were used as the primary data sources.DATA EXTRACTIONHbA_1c, SBP, and weight data throughout follow-up by treatment group were extracted.DATA SYNTHESISRandom-effects model meta-analysis showed no association between GLP-1RA treatment and retinopathy (odds ratio [OR] 1.10; 95% CI 0.93, 1.30), with high heterogeneity between studies (I² = 52.2%; Q statistic P = 0.063). Univariate meta-regression showed an association between retinopathy and average HbA_1c reduction during the overall follow-up (slope = 0.77, P = 0.007), but no relationship for SBP or weight. Sensitivity analyses for HbA_1c showed a relationship at 3 months (P = 0.006) and 1 year (P = 0.002). A 0.1% (1.09 mmol/mol) increase in HbA_1c reduction was associated with 6%, 14%, or 8% increased Ln(OR) for retinopathy at the 3-month, 1-year, and overall follow-up, respectively.LIMITATIONSCVOTs were not powered to assess retinopathy outcomes and differed in retinopathy-related criteria and methodology. The median follow-up of 3.4 years is short compared with the onset of retinopathy.CONCLUSIONSHbA_1c reduction was significantly associated with increased retinopathy risk in meta-regression for GLP-1RA CVOTs. The magnitude of HbA_1c reduction was correlated with retinopathy risk in people with diabetes and additional cardiovascular risk factors, but the long-term impact of improved glycemic control on retinopathy was unmeasured in these studies. Retinopathy status should be assessed when intensifying glucose-lowering therapy.     

Outcomes of Prehospital Chemical Sedation With Ketamine Versus Haloperidol and Benzodiazepine or Physical Restraint Only

Objective: The goal of this study is to describe complications and outcomes of prehospital ketamine use for agitation as compared to other methods of physical or chemical restraint such as haloperidol plus benzodiazepine or physical restraint only. Methods: We conducted a single-center retrospective review of patient encounters in which restraint was administered in the prehospital setting. At the beginning of our study window, only physical restraint was available to paramedics managing agitated patients but subsequently, haloperidol and benzodiazepines were introduced, followed by ketamine 2 years later. By comparing patients before and after each transition, we divided subjects into 3 cohorts based on restraint type: physical restraint, haloperidol plus benzodiazepine, and ketamine. Demographic data were collected, and outcome measures included intubation rate, need for additional physical or chemical restraint, emergency department (ED) length of stay, need for hospital admission, and employee injury. Results: Of 214 subjects included in the study, 95 patients were administered ketamine, 68 received haloperidol and benzodiazepine, and 51 were physically restrained. Eleven of the patients (11.6%) who received ketamine were intubated. Compared to patients who received haloperidol plus benzodiazepine, patients who received ketamine were more likely to be intubated (odds ratio [OR]?=?8.77, 95% confidence interval [CI], 1.10–69.68) and were more likely to require additional chemical restraint when compared to haloperidol/benzodiazepine or physical restraint only (OR =2.94, 95% CI, 1.49–5.80, and OR =2.15, 95% CI, 1.07–4.31, respectively). There were no differences between the 2 chemical sedation groups in terms of ED length of stay or hospital admission rate. Conclusions: This study demonstrates a lower intubation rate in patients administered ketamine than prior literature in association with a lower weight-based dosing regimen. Ketamine use was correlated with a higher frequency of intubation and a greater need for additional chemical restraint when compared with other restraint modalities, though exogenous factors such as provider preference may have impacted this result. There was no difference in ED length of stay or admission rate between the ketamine and haloperidol plus benzodiazepine groups. Further prospective study is needed to determine whether there is a subset of patients for whom ketamine would be beneficial compared to other therapies.     

Optical transfer diagnosis differentiating benign and malignant pigmented lesions in a simulated primary care practice

The incidence of the type of skin cancer called melanoma is on the rise. The detection of melanoma can be difficult, particularly for clinicians who have limited training (compared to dermatologists who specialize in skin) in telling the difference between normal moles (nevi) and melanomas. The noninvasive optical transfer diagnosis (OTD) method is a technology designed to assist in the screening of lesions (e.g. moles) that might be melanomas. In this study, from the U.S.A., U.K. and Norway, the authors took images using OTD and then analysed 712 pigmented lesions (which could be moles or melanomas). Of them, 415 were harmless, or ‘benign’, and 297 were suspicious when examined by specialists using a magnifier called a dermatoscope. After image capture, all of the suspicious moles were biopsied and the tissue samples were examined under the miscroscope. Of the suspicious lesions, 80 proved to be cancer on biopsy (64 melanomas, and 16 other types of skin cancer). OTD misdiagnosed 1 of the 80 cancerous lesions as benign. If verified in further studies, particularly in actual primary care settings, it is likely that the use of OTD technology could help doctors reduce the number of referrals to dermatologists, excision (surgical removal of the lesion), or biopsy, and reduce costs. Further studies are planned for screening patients in the primary care (e.g. GP) setting, with comparisons of OTD results to the gold standards of pathology or dermoscopy.     

A clinical trial with an interim analysis

We consider a fixed-sample parallel-group clinical trial with an interim analysis that tests H0:mu x = mu y against H1:mu x less than mu y. If we do not reject at the interim analysis, then the probability of making a type I error by rejecting H0 in favour of H2:mu x greater than mu y and the power at the final analysis are not appreciably affected by performing the interim analysis for certain relevant critical regions.     

Isoxazolo[3,4-d]pyridazinones and analogues as Leishmania mexicana PDE inhibitors

A series of isoxazolopyridazinones and analogues has been prepared and evaluated as Leishmania mexicana phosphodiesterase (PDE) inhibitors. Some of the synthesized compounds showed a moderate PDE inhibitory activity at 100 microM and preliminary structure-activity relationships were discussed.     

Pulmonary alveolar microlithiasis: clinical and radiological course of three cases according to conventional radiology and HRCT. A hypothesis for radiological classification

Pulmonary alveolar microlithiasis (PAM) is a rare chronic disease of unknown etiology and pathogenesis. The disease is characterized by the diffuse presence in the alveoli of minute calcific deposits known as microliths. In most cases patients have mild clinical symptoms, contrasting with the severe radiographic appearance: this is a typical feature that should raise the suspicion of PAM. The first to describe the clinical and radiographic aspects of the disease, as well as the first case series, was the radiologist Sosman. In recent years, high resolution computed tomography (HRCT) has made it possible to define the extent and severity of the disease more precisely, and has demonstrated calcifications in anatomical sites that could not be shown by conventional radiology. The present paper describes the radiological evolution of the disease, and suggests a classification based on the radiographic and HRCT follow-up of the three clinical cases: two young patients followed up for 24 and 11 years and one elderly man who is still alive and is the PAM case with the longest survival since diagnosis, over 50 years, to be reported in the international literature.     

Revisión sistemática de los métodos predictores de la funcionalidad del trasplante renal

Context

Kidney transplantation from donors with expanded criteria has increased the pool of kidneys at the cost of a higher risk of short and long-term graft dysfunction. The main issue lies in determining which kidneys will offer acceptable function and survival compared with the risk represented by surgery and subsequent immunosuppression.