AIDS-defining illnesses at initial diagnosis of HIV in a large Guatemalan cohort

AbstractBackgroundAnecdotal evidence suggests that a high proportion of patients diagnosed with HIV in Guatemala present with AIDS. There remain limited data on the epidemiology of AIDS-defining illnesses (ADIs) in Central America.MethodsWe conducted a retrospective cohort study of all patients living with HIV at the largest HIV clinic in Guatemala. Charts were analyzed for clinical and demographic data. Presence of an ADI was assessed by US Centers for Disease Control definitions; patients who presented with an ADI were compared with those without ADI using descriptive statistics.ResultsOf 3686 patients living with HIV, 931 (25.3%) had an ADI at HIV diagnosis, 748 (80.3%) of whom had CD4 counts lower than 200 cells/mm3. Those with ADIs were more likely to be male (67.5% vs 54.6%; P &amp;lt; .0001) and heterosexual (89.4% vs 85.0%; P = .005). The most common ADIs were Mycobacterium tuberculosis (55.0%), Pneumocystis jirovecii pneumonia (13.7%), esophageal candidiasis (13.4%), and histoplasmosis (11.4%). Histoplasmosis and HIV wasting syndrome were both more common among rural patients.ConclusionsIn this large Guatemalan cohort of patients currently living with HIV, a significant portion presented with an ADI. These data inform the most common ADIs diagnosed among survivors, show that histoplasmosis is more commonly diagnosed in rural patients, and suggest that HIV wasting syndrome may reflect missed histoplasmosis diagnoses.</jats:sec

How to measure response diversity

The insurance effect of biodiversity—that diversity enhances and stabilises aggregate ecosystem properties—is mechanistically underlain by inter- and intraspecific trait variation in organismal responses to environmental change. This variation, termed response diversity, is therefore a potentially critical determinant of ecological stability. However, response diversity has yet to be widely quantified, possibly due to difficulties in its measurement. Even when it has been measured, approaches have varied.Here, we review methods for measuring response diversity and from them distil a methodological framework for quantifying response diversity from experimental and/or observational data, which can be practically applied in lab and field settings across a range of taxa.Previous empirical studies on response diversity most commonly invoke functional response traits as proxies aimed at capturing functional responses to the environment. Our approach, which is based on environment-dependent functional responses to any biotic or abiotic environmental variable, is conceptually simple and robust to any form of environmental response, including nonlinear responses. Given its derivation from empirical data on functional responses, this approach should more directly reflect response diversity than the trait-based approach dominant in the literature.By capturing even subtle inter- or intraspecific variation in environmental responses, and environment-dependencies in response diversity, we hope this framework will motivate tests of the diversity-stability relationship from a new perspective, and provide an approach for mapping, monitoring, and conserving this critical dimension of biodiversity

How to measure response diversity

The insurance effect of biodiversity—that diversity stabilises aggregate ecosystem properties—is mechanistically underlain by inter‐ and intraspecific trait variation in organismal responses to the environment. This variation, termed response diversity, is therefore a potentially critical determinant of ecological stability. However, response diversity has yet to be widely quantified, possibly due to difficulties in its measurement. Even when it has been measured, approaches have varied. Here, we review methods for measuring response diversity and from them distil a methodological framework for quantifying response diversity from experimental and/or observational data, which can be practically applied in laboratory and field settings across a range of taxa. Previous empirical studies on response diversity most commonly invoke response traits as proxies aimed at capturing species' ecological responses to the environment. Our approach, which is based on environment‐dependent ecological responses to any biotic or abiotic environmental variable, is conceptually simple and robust to any form of environmental response, including nonlinear responses. Given its derivation from empirical data on species' ecological responses, this approach should more directly reflect response diversity than the trait‐based approach dominant in the literature. By capturing even subtle inter‐ or intraspecific variation in environmental responses, and environment dependencies in response diversity, we hope this framework will motivate tests of the diversity–stability relationship from a new perspective, and provide an approach for mapping, monitoring and conserving this critical dimension of biodiversity

The Application of Reversible Intramolecular Sulfonamide Ligation to Modulate Reactivity in Organometallic Ruthenium(II) Diamine Complexes

Metallation of biomacromolecular species forms the basis for the anticancer activity of many metallodrugs. A major limitation of these compounds is that their reactivity is indiscriminate and can, in principle, occur in healthy tissue as well as cancerous tissue, potentially leading to side effects in vivo. Here we present pH-dependent intramolecular coordination of an arene-tethered sulfonamide functionality in organometallic ruthenium(II) ethylenediamine complexes as a route to controlling the coordination environment about the central metal atom. Through variation of the sulfonamide R group and the length of the tether linking it to the arene ligand the acidity of the sulfonamide NH group, and hence the pH-region over which regulation of metal coordination occurs, can be modulated. Intramolecular sulfonamide ligation controlled the reactivity of complex 4 within the physiologically relevant pH-region, rendering it more reactive towards 5?-GMP in mildly acidic pH-conditions typical of tumour tissue compared to the mildly alkaline pH-conditions typical of healthy tissue. However, the activation of 4 by ring-opening of the chelate was found to be a slow process relative to the timescale of typical cell culture assays and members of this series of complexes were found not to be cytotoxic towards the HT-29 cell line. These complexes provide the basis for the development of analogues of increased potency where intramolecular sulfonamide ligation regulates reactivity and therefore cytotoxicity in a pH-dependent, and potentially, tissue-dependent manner

Spatio-temporal ecology of sympatric felids on Borneo. Evidence for resource partitioning?

Niche differentiation, the partitioning of resources along one or more axes of a species’ niche hyper-volume, is widely recognised as an important mechanism for sympatric species to reduce interspecific competition and predation risk, and thus facilitate co-existence. Resource partitioning may be facilitated by behavioural differentiation along three main niche dimensions: habitat, food and time. In this study, we investigate the extent to which these mechanisms can explain the coexistence of an assemblage of five sympatric felids in Borneo. Using multi-scale logistic regression, we show that Bornean felids exhibit differences in both their broad and fine-scale habitat use. We calculate temporal activity patterns and overlap between these species, and present evidence for temporal separation within this felid guild. Lastly, we conducted an all-subsets logistic regression to predict the occurrence of each felid species as a function of the co-occurrence of a large number of other species and showed that Bornean felids co-occurred with a range of other species, some of which could be candidate prey. Our study reveals apparent resource partitioning within the Bornean felid assemblage, operating along all three niche dimension axes. These results provide new insights into the ecology of these species and the broader community in which they live and also provide important information for conservation planning for this guild of predators

A low-cost, portable optical explosive-vapour sensor

This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under agreement no 284747. IDWS acknowledges a Royal Society Wolfson Research Merit Award. Data supporting this research can be found at http://dx.doi.org/10.17630/5868c89a-7019-4897-9c54-24ccc551a6e6.Humanitarian demining requires a broad range of methodologies and instrumentation for reliable identification of landmines, antipersonnel mines, and other explosive remnants of war (ERWs). Optical sensing methods are ideal for this purpose due to advantages in sensitivity, time-of-response and small form factor. In this work we present a portable photoluminescence-based sensor for nitroaromatic vapours based on the conjugated polymer Super Yellow integrated into an instrument comprising an excitation LED, photodiode, Arduino microprocessor and pumping mechanics for vapour delivery. The instrument was shown to be sensitive to few-ppb concentrations of explosive vapours under laboratory conditions, and responds to simulated buried landmine vapour. The results indicate that a lightweight, easy-to-operate, lowcost and highly-sensitive optical sensor can be readily constructed for landmine and ERW detection in the field, with potential to aid worldwide efforts in landmine mitigation.PostprintPeer reviewe

Case Report Tacrolimus Toxicity due to Biliary Obstruction in a Combined Kidney and Liver Transplant Recipient

The immunosuppressant tacrolimus has a narrow therapeutic window, necessitating therapeutic drug monitoring to maintain efficacy and minimise toxicity. There are very few reports examining the impact of impaired biliary excretion on tacrolimus blood levels or toxicity. We report the case of a 26-year-old combined liver and kidney transplant recipient, who developed acute biliary obstruction leading to tacrolimus toxicity with very high blood tacrolimus levels. Despite a careful evaluation, no alternative cause was found for her acute kidney injury, and her kidney function returned to previous baseline within several days following treatment of the biliary obstruction and temporary withdrawal of tacrolimus

An Update on Hepatorenal Syndrome

Hepatorenal syndrome (HRS) is one of the many potential causes of acute kidney injury (AKI) in patients with decompensated liver disease. HRS is associated with poor prognosis and represents the end-stage of a sequence of reductions in renal perfusion induced by progressively severe hepatic injury. The pathophysiology of HRS is complex with multiple mechanisms interacting simultaneously, although HRS is primarily characterised by renal vasoconstriction. A recently revised diagnostic criteria and management algorithm for AKI has been developed for patients with cirrhosis, allowing physicians to commence treatment promptly. Vasopressor therapy and other general management, such as antibiotic prophylaxis, need to be initiated whilst patients are assessed for eligibility for transplantation. Liver transplantation remains the treatment of choice for HRS but is limited by organ shortage. Other management options, such as transjugular intrahepatic portosystemic shunt, renal replacement therapy and molecular absorbent recirculating system, may provide short-term benefit for patients not responding to medical therapy whilst awaiting transplantation. Clinicians need to be aware of the pathophysiology and management principles of HRS to provide quality care for patients with multi-organ failure

Backbone modification of a polypeptide drug alters duration of action in vivo

because of protease-catalyzed degradation. We used PTHR1 signaling to evaluate a strategy for creating active and biostable backbone-modified analogs of the well-known agonist PTH(1-34). PTH is an 84-residue protein that controls key physiological processes, including the maintenance of extracellular levels of calcium and phosphate and bone homeostasis 1 . PTH(1-34) matches full-length PTH in potency and efficacy at PTHR1 and is the active ingredient in the osteoporosis drug teriparatide (Forteo). As with many other peptide-based therapeutics, PTH(1-34) has a short half-life in the bloodstream (&lt;30 min) 2 . Therapeutic effects for osteoporosis treatment appear to be maximized by pulsatile rather than continuous exposure to PTH(1-34), but the optimal exposure cycle is unclear 3 . We generated new analogs of PTH(1-34) by replacing selected α-amino acid residues with homologous β-amino acid residues, an unconventional approach that alters the backbone but can maintain the natural side chain complement. The results show that this technically straightforward strategy can provide hormone analogs that display native-like receptor activation potencies and prolonged residency in the bloodstream. The C-terminal portion of PTH(1-34) forms an α-helix upon binding to the receptor, but the bioactive conformation of the N-terminal segment is unknown. The backbone-modification strategy described here is based on previous studies showing that α-helical segments Systematic modification of the backbone of bioactive polypeptides through b-amino acid residue incorporation could provide a strategy for generating molecules with improved drug properties, but such alterations can result in lower receptor affinity and potency. Using an agonist of parathyroid hormone receptor-1 (PTHR1), a G protein-coupled receptor in the B-family, we present an approach for a→b residue replacement that enables both high activity and improved pharmacokinetic properties in vivo. involved in protein-recognition processes can be mimicked by oligomers containing mixtures of α and β residues 4,5 . Other types of unnatural oligomers, such as peptides composed of D-α-amino acid residues 6 , peptoids 7 and β-peptides 8 , have been explored for functional mimicry of bioactive α-helices; however, none of these alternative molecular scaffolds allows faithful mimicry of a long α-helix 5 , as required for potent analogs of PTH. In previous studies, PTH analogs containing one to three β-residue replacements were used to probe local conformational requirements, and many of these replacements caused profound declines in agonist activity We prepared all four PTH(1-34) analogs containing five α→β 3 replacements in an αααβ pattern 13 within the C-terminal region (A5-D5 in PTHR1 has two distinct functional states: RG, which forms when the intracellular portion contacts G αS (a heterotrimeric G-protein responsible for activating adenylate cyclase upon receptor activation); and R 0 , which forms independent of G αS 15,16 . An agonist&apos;s affinity for the RG state correlates with PTHR1 activation potency, whereas R 0 affinity correlates with the duration of some in vivo response