Efficacy of recurrent transcutaneous magnetic stimulation in the treatment of diabetic peripheral neuropathy: Multicenter randomized trial.

AIMS: Transcutaneous magnetic stimulation (TCMS) is successful in decreasing pain in several neurologic conditions. This multicenter parallel double-blind phase II clinical trial is a follow-up to a pilot study that demonstrated pain relief in patients with diabetic peripheral neuropathy (DPN) treated with TCMS. METHODS: Thirty-four participants with confirmed DPN and baseline pain score ≥ 5 were randomized to treatment at two sites. Participants were treated with either TCMS (n = 18) or sham (n = 16) applied to each foot once a week for four weeks. Pain scores using the Numeric Pain Rating Scale after 10 steps on a hard floor surface and answers to Patient-Reported Outcomes Measurement Information System pain questions were recorded by participants daily for 28 days. RESULTS: Thirty-one participants completed the study and were analyzed. Average pain scores decreased from baseline in both the groups. The difference in pain scores between TCMS and sham treatments was -0.55 for morning, -0.13 for evening, and -0.34 overall, below the pre-determined clinically relevant difference of -2. Moderate adverse events that resolved spontaneously were experienced in both treatment arms. CONCLUSION: In this two-arm trial, TCMS failed to demonstrate a significant benefit over sham in patient reported pain suggesting a substantial placebo effect in our previous pilot study. TRIAL REGISTRATION: TCMS for the Treatment of Foot Pain Caused By Diabetic Neuropathy, https://clinicaltrials.gov/ct2/show/NCT03596203, ID-NCT03596203.

Vitamin D Supplementation and Prevention of Type 2 Diabetes.

BACKGROUND: Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown. METHODS: We randomly assigned adults who met at least two of three glycemic criteria for prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level, 5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of vitamin D3 or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508. RESULTS: A total of 2423 participants underwent randomization (1211 to the vitamin D group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (95% confidence interval, 0.75 to 1.04; P = 0.12). The incidence of adverse events did not differ significantly between the two groups. CONCLUSIONS: Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D3 supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, NCT01942694.).

Intensifying Treatment Beyond Monotherapy in Type 2 Diabetes Mellitus: Where Do Newer Therapies Fit?

PURPOSE OF REVIEW: Guidelines for a standard second diabetes medication for the treatment of type 2 diabetes (T2DM) have yet to be established. The rapid increase in the number of newer therapies available makes the choice more difficult. Thus, we reviewed clinical trial evidence evaluating newer therapies available for treatment intensification beyond monotherapy. RECENT FINDINGS: Head-to-head studies comparing newer therapies versus traditional (i.e., sulfonylurea) approaches consistently find lower incidence of hypoglycemia and weight gain with newer therapies. Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter 2 (SGLT2) inhibitors demonstrate high glycemic efficacy, while merits of dipeptidyl peptidase-4 (DPP-4) inhibitors include their tolerability. Secondary effects (weight loss, cardiovascular outcomes, renal function) are of growing interest with newer therapies. Choices for treatment intensification in T2DM diabetes are numerous. Understanding the comparative evidence of newer treatment choices, as provided in this review, may help guide clinical decision making.

High-grade pancreatic intraepithelial lesions: prevalence and implications in pancreatic neoplasia.

BACKGROUND: High-grade pancreatic intraepithelial neoplasia (PanIN-3), a precursor of pancreatic ductal adenocarcinoma (PDAC), is not universally detected in resected pancreatic neoplasms. We sought to determine the prevalence and prognostic relevance of PanIN-3 lesions in primary surgical resections of PDACs and intraductal papillary mucinous neoplasms (IPMNs). METHODS: A retrospective review of a tertiary care center pathology database (1/2000-6/2014) was performed. Demographics, imaging, pathology, disease-recurrence, and survival data were reviewed. RESULTS: A total of 458 patients who underwent primary pancreatic resection were included. "PanIN-3" lesions were found in 74 (16.2%) patients who either had PDAC (n=67) or main duct (MD)-IPMN (n=7). Among IPMN-MDs, PanIN-3 lesions were exclusively found in those with pathological evidence of chronic pancreatitis. For PDACs, the median overall survival (OS) for pancreata with PanIN-3 lesions was significantly better than those without (OS 1.12 years, inter-quartile range [IQR] 0.72, 2.05 years vs OS 0.86 years, IQR 0.64, 1.60 years respectively; P=0.04). Multivariate Cox regression analysis demonstrated that the presence of PanIN-3 lesions was associated with a reduced risk of death (HR=0.43; 95% CI: 0.23-0.82; P=0.01). CONCLUSIONS: Following primary resection of pancreatic adenocarcinoma, the lower survival observed in patients without PanIN-3 lesions might suggest a state of complete or accelerated transformation. Further investigations are necessary to validate these findings that might impact disease prognosis and management.

Process-oriented evaluation of an international faculty development program for Asian developing countries: a qualitative study.

BACKGROUND: Non-English-speaking developing countries in Southeast Asia have been provided only limited opportunities for faculty development in the education of health professions. Although there exist a few programs that have been shown to be effective, they are frequently presented with few explanations on how and why the programs work due to their outcome-oriented nature. This study explores the process of the Lee Jong-Wook Fellowship for Health Professional Education, an international faculty development program designed for capacity building of educators of health professions in Southeast Asian developing countries. METHODS: Fellows were from Cambodia, Myanmar, and Laos. Qualitative data were collected from two types of semi-structured interviews - group and individual. Thematic analysis was conducted to explore the factors related to the effectiveness of the program, framed by four components of faculty development, which included context, facilitators, program, and participants. RESULTS: From the thematic analysis, the authors identified a total of 12 themes in the four components of faculty development. In the context domain, the resource-poor setting, a culture that puts emphasis on hierarchy and seniority, and educational environment depending on individual commitment rather than broad consensus emerged as key factors. In the facilitators domain, their teaching methods and materials, mutual understanding between teacher and learner, and collaboration between facilitators mainly influenced the learning during the fellowship. In the program domain, the key advantages of the fellowship program were its applicability to the workplace of the fellows and enough allowed time for practice and reflection. Finally, in the participants domain, Fellows valued their heterogeneity of composition and recognized cognitive as well as non-cognitive attributes of the participants as essential. CONCLUSIONS: This process-oriented evaluation reveals the diverse factors that contributed to achieving the intended outcomes of the fellowship. Although much evidence from best practices in faculty development are still valid, the findings suggest that the selection strategies, learning environment, and English communication should be given more consideration when organizing a program targeting these people and cultures. A comprehensive understanding of the process would contribute to developing tailored strategies for educators of health professions in developing countries in similar settings.

A case of orbital dirofilariasis in New York.

A 39-year-old female presented with a 5-day history of left inferonasal periocular swelling and associated intermittent itching. Ophthalmologic examination demonstrated a 4 × 8 mm subcutaneous painless mass localized anterior to the medial left lower orbital rim. An excision of the mass was performed, and pathology revealed Dirofilaria. The patient improved over the 3 months of postoperative follow-up. Although several human cases of pulmonary dirofilariasis have been reported in the United States, periocular dirofilariasis has been rarely reported in the United States. The case report is in compliance with the Health Insurance Portability and Accountability Act.

Live-cell fluorescence imaging to investigate the dynamics of plant cell death during infection by the rice blast fungus Magnaporthe oryzae.

BACKGROUND: Plant cell death plays important roles during plant-pathogen interactions. To study pathogen-induced cell death, there is a need for cytological tools that allow determining not only host cell viability, but also cellular events leading to cell death with visualization of pathogen development. Here we describe a live cell imaging method to provide insights into the dynamics of cell death in rice (Oryza sativa). This method uses live-cell confocal microscopy of rice sheath cells mechanically damaged or invaded by fluorescently-tagged Magnaporthe oryzae together with fluorescent dyes fluorescein diacetate (FDA) and propidium iodide (PI). FDA stains the cytoplasm of live cells exclusively, thus also visualizing the vacuole, whereas PI stains nuclei of dead cells. RESULTS: We first demonstrated that confocal microscopy of rice leaf sheaths stained with FDA and PI discriminated between live cells and mechanically-killed cells. FDA-derived fluorescein was confined to the cytoplasm of live cells, indicating the intact vacuolar and plasma membranes. We also observed previously unreported fluorescein patterns in mechanically damaged cells. These patterns include: (1) homogeneous distribution of fluorescein in the increased area of the cytoplasm due to the shrunken vacuole; (2) the increase of the fluorescein intensity; and (3) containment of the brighter fluorescein signal only in affected cells likely due to closure of plasmodesmata. We refer to these as novel fluorescein patterns in this study. Simultaneous imaging of fluorescently-tagged M. oryzae (red) and FDA staining (green) in rice cells revealed characteristic features of the hemibiotrophic interaction. That is, newly invaded cells are alive but subsequently become dead when the fungus spreads into neighbor cells, and biotrophic interfacial complexes are associated with the host cytoplasm. This also revealed novel fluorescein patterns in invaded cells. Time-lapse imaging suggested that the FDA staining pattern in the infected host cell progressed from typical cytoplasmic localization (live cell with the intact vacuole), to novel patterns (dying cell with closed plasmodesmata with the shrunken or ruptured vacuole), to lack of fluorescence (dead cell). CONCLUSION: We have developed a method to visualize cellular events leading to host cell death during rice blast disease. This method can be used to compare and contrast host cell death associated with disease resistance and susceptibility in rice-M. oryzae and other host-pathogen interactions.

Mortality in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).

OBJECTIVE: We report mortality outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) among people with type 2 diabetes diagnosed within 10 years and no recent history of cardiovascular events or cancer. RESEARCH DESIGN AND METHODS: Overall mortality rates and major causes of death were assessed over an average of 5 years of follow-up. Cause of death was adjudicated centrally by a committee masked to treatment assignment. We examined baseline covariates and the 10-year Framingham Risk Score for associations. RESULTS: Mortality rate was low (0.59 per 100 participant-years). Participants who died during follow-up were likely to be older, be male, have a history of hypertension, have a history of smoking, and have moderate albuminuria. The two most common underlying causes of death were "cardiovascular-cause" (a composite of underlying causes) (38.6%) and cancer (26.8%). There were no differences by treatment group. CONCLUSIONS: Among people with diabetes of relatively short duration, cause of death was varied. Attention to health risks beyond cardiovascular diseases is warranted.

GAD65Abs Are Not Associated With Beta-Cell Dysfunction in Patients With T2D in the GRADE Study.

Context: Autoantibodies directed against the 65-kilodalton isoform of glutamic acid decarboxylase (GAD65Abs) are markers of autoimmune type 1 diabetes (T1D) but are also present in patients with Latent Autoimmune Diabetes of Adults and autoimmune neuromuscular diseases, and also in healthy individuals. Phenotypic differences between these conditions are reflected in epitope-specific GAD65Abs and anti-idiotypic antibodies (anti-Id) against GAD65Abs. We previously reported that 7.8% of T2D patients in the GRADE study have GAD65Abs but found that GAD65Ab positivity was not correlated with beta-cell function, glycated hemoglobin (HbA1c), or fasting glucose levels. Context: In this study, we aimed to better characterize islet autoantibodies in this T2D cohort. This is an ancillary study to NCT01794143. Methods: We stringently defined GAD65Ab positivity with a competition assay, analyzed GAD65Ab-specific epitopes, and measured GAD65Ab-specific anti-Id in serum. Results: Competition assays confirmed that 5.9% of the patients were GAD65Ab positive, but beta-cell function was not associated with GAD65Ab positivity, GAD65Ab epitope specificity or GAD65Ab-specific anti-Id. GAD65-related autoantibody responses in GRADE T2D patients resemble profiles in healthy individuals (low GAD65Ab titers, presence of a single autoantibody, lack of a distinct epitope pattern, and presence of anti-Id to diabetes-associated GAD65Ab). In this T2D cohort, GAD65Ab positivity is likely unrelated to the pathogenesis of beta-cell dysfunction. Conclusion: Evidence for islet autoimmunity in the pathophysiology of T2D beta-cell dysfunction is growing, but T1D-associated autoantibodies may not accurately reflect the nature of their autoimmune process.

Sacral colpopexy versus transvaginal mesh colpopexy in obese patients.

OBJECTIVES: Obesity can predispose women to pelvic organ prolapse and can also affect the success of pelvic organ prolapse surgery. The purpose of this study was to compare the postoperative anatomical outcomes following sacral colpopexy (SC) and transvaginal mesh colpopexy in a group of obese women with pelvic organ prolapse. METHODS: We conducted a retrospective cohort study of obese women who underwent SC (n = 56) or transvaginal mesh colpopexy (n = 35). Follow-up ranged from 6 to 12 months. Preoperative, perioperative, and postoperative variables were compared using Student t, Mann-Whitney U, and Fisher exact tests, and by analysis of covariance. RESULTS: The women in the SC group had significantly higher mean apical vaginal measurements (P < 0.05), and significantly fewer stage II recurrences than women in the transvaginal mesh colpopexy group. There were no significant differences between the groups for other postoperative outcomes, including mesh erosion, recurrent prolapse symptoms, dyspareunia, and surgical satisfaction (P > 0.05). CONCLUSION: In these 91 obese patients with pelvic organ prolapse, SC resulted in better anatomical outcomes than transvaginal mesh colpopexy. However, the two procedures had similar outcomes with regard to recurrent symptoms and surgical satisfaction.

Objectifs : L'obésité peut prédisposer les femmes au prolapsus des organes pelviens et peut également affecter la réussite de la chirurgie visant à rectifier ce dernier. Cette étude avait pour objectif de comparer, chez un groupe de femmes obèses présentant un prolapsus des organes pelviens, les issues anatomiques postopératoires constatées à la suite d'une colpopexie sacrée (CS) à celles qui sont constatées à la suite d'une colpopexie par treillis transvaginal. Méthodes : Nous avons mené une étude de cohorte rétrospective portant sur des femmes obèses qui ont subi une CS (n = 56) ou une colpopexie par treillis transvaginal (n = 35). Le suivi a été d'une durée allant de six à douze mois. Les variables préopératoires, périopératoires et postopératoires ont été comparées au moyen des tests t de Student, U de Mann­Whitney et exact de Fisher, ainsi qu'au moyen d'une analyse de covariance. Résultats : Les femmes du groupe « CS ¼ présentaient des mesures vaginales apicales moyennes considérablement plus élevées (P < 0,05) et des récurrences de stade II considérablement moins fréquentes que les femmes du groupe « colpopexie par treillis transvaginal ¼. Aucune différence significative n'a été constatée entre les groupes en ce qui concerne d'autres issues postopératoires, y compris l'érosion du treillis, les symptômes récurrents de prolapsus, la dyspareunie et la satisfaction chirurgicale (P > 0,05). Conclusion : Chez ces 91 patientes obèses présentant un prolapsus des organes pelviens, la CS s'est soldée en de meilleures issues anatomiques que la colpopexie par treillis transvaginal. Toutefois, ces deux interventions ont obtenu des issues similaires pour ce qui est des symptômes récurrents et de la satisfaction chirurgicale.