Apparent Insulin Deficiency in an Adult African Population With New-Onset Type 2 Diabetes

Identifying patients with new-onset type 2 diabetes who have insulin deficiency can aid in timely insulin replacement therapy. In this study, we measured fasting C-peptide concentration to assess endogenous insulin secretion and determine the prevalence and characteristics of patients with insulin deficiency in adult Ugandan patients with confirmed type 2 diabetes at presentation.MethodsAdult patients with new-onset diabetes were recruited from seven tertiary hospitals in Uganda. Participants who were positive for the three islet autoantibodies were excluded. Fasting C-peptide concentrations were measured in 494 adult patients, and insulin deficiency was defined as a fasting C-peptide concentration <0.76 ng/ml. The socio-demographic, clinical, and metabolic characteristics of participants with and without insulin deficiency were compared. Multivariate analysis was performed to identify independent predictors of insulin deficiency.ResultsThe median (IQR) age, glycated haemoglobin (HbA1c), and fasting C-peptide of the participants was 48 (39-58) years,10.4 (7.7-12.5) % or 90 (61-113) mmol/mol, and 1.4 (0.8-2.1) ng/ml, respectively. Insulin deficiency was present in 108 (21.9%) participants. Participants with confirmed insulin deficiency were more likely to be male (53.7% vs 40.4%, p=0.01), and had a lower body mass index or BMI [p<0.001], were less likely to be hypertensive [p=0.03], had reduced levels of triglycerides, uric acid, and leptin concentrations [p<0.001]), but higher HbA1c concentration (p=0.004). On multivariate analysis, BMI (AOR 0.89, 95% CI 0.85-0.94, p<0.001), non-HDLC (AOR 0.77, 95% CI 0.61-0.97, p=0.026), and HbA1c concentrations (AOR 1.08, 95% CI 1.00-1.17, p=0.049) were independent predictors of insulin deficiency.ConclusionInsulin deficiency was prevalent in this population, occurring in about 1 in every 5 patients. Participants with insulin deficiency were more likely to have high HbA1c and fewer markers of adiposity and metabolic syndrome. These features should increase suspicion of insulin deficiency and guide targeted testing and insulin replacement therapy

Apparent Insulin Deficiency in an Adult African Population With New-Onset Type 2 Diabetes

Identifying patients with new-onset type 2 diabetes who have insulin deficiency can aid in timely insulin replacement therapy. In this study, we measured fasting C-peptide concentration to assess endogenous insulin secretion and determine the prevalence and characteristics of patients with insulin deficiency in adult Ugandan patients with confirmed type 2 diabetes at presentation. METHODS: Adult patients with new-onset diabetes were recruited from seven tertiary hospitals in Uganda. Participants who were positive for the three islet autoantibodies were excluded. Fasting C-peptide concentrations were measured in 494 adult patients, and insulin deficiency was defined as a fasting C-peptide concentration <0.76 ng/ml. The socio-demographic, clinical, and metabolic characteristics of participants with and without insulin deficiency were compared. Multivariate analysis was performed to identify independent predictors of insulin deficiency. RESULTS: The median (IQR) age, glycated haemoglobin (HbA1c), and fasting C-peptide of the participants was 48 (39-58) years,10.4 (7.7-12.5) % or 90 (61-113) mmol/mol, and 1.4 (0.8-2.1) ng/ml, respectively. Insulin deficiency was present in 108 (21.9%) participants. Participants with confirmed insulin deficiency were more likely to be male (53.7% vs 40.4%, p=0.01), and had a lower body mass index or BMI [p<0.001], were less likely to be hypertensive [p=0.03], had reduced levels of triglycerides, uric acid, and leptin concentrations [p<0.001]), but higher HbA1c concentration (p=0.004). On multivariate analysis, BMI (AOR 0.89, 95% CI 0.85-0.94, p<0.001), non-HDLC (AOR 0.77, 95% CI 0.61-0.97, p=0.026), and HbA1c concentrations (AOR 1.08, 95% CI 1.00-1.17, p=0.049) were independent predictors of insulin deficiency. CONCLUSION: Insulin deficiency was prevalent in this population, occurring in about 1 in every 5 patients. Participants with insulin deficiency were more likely to have high HbA1c and fewer markers of adiposity and metabolic syndrome. These features should increase suspicion of insulin deficiency and guide targeted testing and insulin replacement therapy

A Recirculating Eddy Promotes Subsurface Particle Retention in an Antarctic Biological Hotspot

Palmer Deep Canyon is one of the biological hotspots associated with deep bathymetric features along the Western Antarctic Peninsula. The upwelling of nutrient-rich Upper Circumpolar Deep Water to the surface mixed layer in the submarine canyon has been hypothesized to drive increased phytoplankton biomass productivity, attracting krill, penguins and other top predators to the region. However, observations in Palmer Deep Canyon lack a clear in-situ upwelling signal, lack a physiological response by phytoplankton to Upper Circumpolar Deep Water in laboratory experiments, and surface residence times that are too short for phytoplankton populations to reasonably respond to any locally upwelled nutrients. This suggests that enhanced local upwelling may not be the mechanism that links canyons to increased biological activity. Previous observations of isopycnal doming within the canyon suggested that a subsurface recirculating feature may be present. Here, using in-situ measurements and a circulation model, we demonstrate that the presence of a recirculating eddy may contribute to maintaining the biological hotspot by increasing the residence time at depth and retaining a distinct layer of biological particles. Neutrally buoyant particle simulations showed that residence times increase to upwards of 175 days with depth within the canyon during the austral summer. In-situ particle scattering, flow cytometry, and water samples from within the subsurface eddy suggest that retained particles are detrital in nature. Our results suggest that these seasonal, retentive features of Palmer Deep Canyon are important to the establishment of the biological hotspot

Understanding the manifestation of diabetes in sub Saharan Africa to inform therapeutic approaches and preventive strategies: a narrative review.

BACKGROUND: Globally, the burden of diabetes mellitus has increased to epidemic proportions. Estimates from the International Diabetes Federation predict that the greatest future increase in the prevalence of diabetes mellitus will occur in Africa. METHODS: This article reviews literature on the manifestation of diabetes in adult patients in sub-Saharan Africa highlighting the distinct phenotypes, plausible explanations for this unique manifestation and the clinical significance of comprehensively defining and understanding the African diabetes phenotype. RESULTS: There are few studies on the manifestation or phenotype of diabetes in Africa. The limited data available suggests that, compared to the Western world, the majority of patients with diabetes in Africa are young and relatively lean in body size. In addition, hyperglycaemia in most cases is characterised by a significantly blunted acute first phase of insulin secretion in response to an oral or intravenous glucose load and pancreatic beta cell secretory dysfunction, rather than peripheral insulin resistance predominates. Genetic and environmental factors like chronic infections/inflammation, early life malnutrition and epigenetic modifications are thought to contribute to these distinct differences in manifestation. CONCLUSIONS: While published data is limited, there appears to be distinct phenotypes of diabetes in sub-Saharan Africa. Large and more detailed studies are needed especially among newly diagnosed patients to fully characterize diabetes in this region. This will further improve the understanding of manifestation of diabetes and guide the formulation of optimal therapeutic approaches and preventive strategies of the condition on the continent

Total Joint Arthroplasty in HIV-Positive Patients in Malawi: Outcomes from the National Arthroplasty Registry of the Malawi Orthopaedic Association.

In this observational study, we describe the medium-term outcomes of total joint arthroplasty (TJA) in human immunodeficiency virus (HIV)-positive patients in Malawi, a low-income country. With a high prevalence of HIV and increasing arthroplasty rates in low and middle-income countries, understanding the outcomes of TJA in this unique cohort of patients is essential to ensure that surgical practice is evidence-based. Data for all HIV-positive patients who had TJA from January 2005 to March 2020 were extracted from the National Arthroplasty Registry of the Malawi Orthopaedic Association (NARMOA). From January 2005 to March 2020, a total of 102 total hip arthroplasties (THAs) and 20 total knee arthroplasties (TKAs) were performed in 97 patients who were HIV-positive and without hemophilia or a history of intravenous drug use. The mean length of follow-up was 4 years and 3 months (range, 6 weeks to 15 years) in the THA group and 4 years and 9 months (range, 6 weeks to 12 years) in the TKA group. The mean patient age was 50 years (range, 21 to 76 years) and 64 years (range, 48 to 76 years) at the time of THA and TKA, respectively. The primary indication for THA was osteonecrosis (66 hips). In the THA group, the mean preoperative Oxford Hip Score and Harris hip score were 14.0 (range, 2 to 33) and 29.4 (range, 1 to 64), respectively, and improved to 46.6 (range, 23 to 48) and 85.0 (range, 28 to 91) postoperatively. The primary indication for TKA was osteoarthritis (19 knees). The mean preoperative Oxford Knee Score was 14.9 (range, 6 to 31) and increased to 46.8 (range, 40 to 48) postoperatively. In patients who underwent THA, there was 1 deep infection (1 of 102 procedures), and 6 patients developed aseptic loosening (6 of 102). There was 1 postoperative superficial infection following TKA (1 of 20 procedures), and 1 patient developed aseptic loosening (1 of 20). Postoperative 6-week mortality among all patients was zero. To our knowledge this is the largest medium-term follow-up of HIV-positive patients, without hemophilia or a history of intravenous drug use, who have had TJA in a low-income country. This study demonstrated good medium-term results among HIV-positive patients undergoing TJA, low complication rates, and improvements in patient-reported outcome measures. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence

New Models for Wolf-Rayet and O Star Populations in Young Starbursts

Using the latest stellar evolution models, theoretical stellar spectra, and a compilation of observed emission line strengths from Wolf-Rayet (WR) stars, we construct evolutionary synthesis models for young starbursts. We explicitly distinguish between the various WR subtypes (WN, WC, WO), and we treat O and Of stars separately. We provide detailed predictions of UV and optical emission line strengths for both the WR stellar lines and the major nebular hydrogen and helium emission lines, as a function of several input parameters related to the starburst episode. We also derive the theoretical frequency of WR-rich starbursts. We then discuss: nebular HeII 4686 emission, the contribution of WR stars to broad Balmer line emission, techniques used to derive the WR and O star content from integrated spectra, and explore the implications of the formation of WR stars through mass transfer in close binary systems in instantaneous bursts. The observational features predicted by our models allow a detailed quantitative determination of the massive star population in a starburst region (particularly in so-called "WR galaxies") from its integrated spectrum and provide a means of deriving the burst properties (e.g., duration, age) and the parameters of the initial mass function of young starbursts. (Abridged abstract)Comment: Accepted by ApJ Supplements. LaTeX using aasmp4, psfigs macros. 49 pages including 23 figures. Paper (full, or text/figures separated) and detailed model results available at http://www.stsci.edu/ftp/science/starburst/sv97.htm

Advancing Tests of Relativistic Gravity via Laser Ranging to Phobos

Phobos Laser Ranging (PLR) is a concept for a space mission designed to advance tests of relativistic gravity in the solar system. PLR's primary objective is to measure the curvature of space around the Sun, represented by the Eddington parameter $\gamma$, with an accuracy of two parts in $10^7$, thereby improving today's best result by two orders of magnitude. Other mission goals include measurements of the time-rate-of-change of the gravitational constant, $G$ and of the gravitational inverse square law at 1.5 AU distances--with up to two orders-of-magnitude improvement for each. The science parameters will be estimated using laser ranging measurements of the distance between an Earth station and an active laser transponder on Phobos capable of reaching mm-level range resolution. A transponder on Phobos sending 0.25 mJ, 10 ps pulses at 1 kHz, and receiving asynchronous 1 kHz pulses from earth via a 12 cm aperture will permit links that even at maximum range will exceed a photon per second. A total measurement precision of 50 ps demands a few hundred photons to average to 1 mm (3.3 ps) range precision. Existing satellite laser ranging (SLR) facilities--with appropriate augmentation--may be able to participate in PLR. Since Phobos' orbital period is about 8 hours, each observatory is guaranteed visibility of the Phobos instrument every Earth day. Given the current technology readiness level, PLR could be started in 2011 for launch in 2016 for 3 years of science operations. We discuss the PLR's science objectives, instrument, and mission design. We also present the details of science simulations performed to support the mission's primary objectives.Comment: 25 pages, 10 figures, 9 table

Modeling of miRNA and Drug Action in the EGFR Signaling Pathway

MicroRNAs have gained significant interest due to their widespread occurrence and diverse functions as regulatory molecules, which are essential for cell division, growth, development and apoptosis in eukaryotes. The epidermal growth factor receptor (EGFR) signaling pathway is one of the best investigated cellular signaling pathways regulating important cellular processes and its deregulation is associated with severe diseases, such as cancer. In this study, we introduce a systems biological model of the EGFR signaling pathway integrating validated miRNA-target information according to diverse studies, in order to demonstrate essential roles of miRNA within this pathway. The model consists of 1241 reactions and contains 241 miRNAs. We analyze the impact of 100 specific miRNA inhibitors (anit-miRNAs) on this pathway and propose that the embedded miRNA-network can help to identify new drug targets of the EGFR signaling pathway and thereby support the development of new therapeutic strategies against cancer

Synthetic lethality: a framework for the development of wiser cancer therapeutics

The challenge in medical oncology has always been to identify compounds that will kill, or at least tame, cancer cells while leaving normal cells unscathed. Most chemotherapeutic agents in use today were selected primarily for their ability to kill rapidly dividing cancer cells grown in cell culture and in mice, with their selectivity determined empirically during subsequent animal and human testing. Unfortunately, most of the drugs developed in this way have relatively low therapeutic indices (low toxic dose relative to the therapeutic dose). Recent advances in genomics are leading to a more complete picture of the range of mutations, both driver and passenger, present in human cancers. Synthetic lethality provides a conceptual framework for using this information to arrive at drugs that will preferentially kill cancer cells relative to normal cells. It also provides a possible way to tackle 'undruggable' targets. Two genes are synthetically lethal if mutation of either gene alone is compatible with viability but simultaneous mutation of both genes leads to death. If one is a cancer-relevant gene, the task is to discover its synthetic lethal interactors, because targeting these would theoretically kill cancer cells mutant in the cancer-relevant gene while sparing cells with a normal copy of that gene. All cancer drugs in use today, including conventional cytotoxic agents and newer 'targeted' agents, target molecules that are present in both normal cells and cancer cells. Their therapeutic indices almost certainly relate to synthetic lethal interactions, even if those interactions are often poorly understood. Recent technical advances enable unbiased screens for synthetic lethal interactors to be undertaken in human cancer cells. These approaches will hopefully facilitate the discovery of safer, more efficacious anticancer drugs that exploit vulnerabilities that are unique to cancer cells by virtue of the mutations they have accrued during tumor progression

Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism

SummaryWe have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6–12.0, p = 2.4 × 10-7). We estimate there are 130–234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1