Evolution of protease inhibitor resistance in HIV-1-infected patients failing protease inhibitor monotherapy as second-line therapy in low-income countries: an observational analysis within the EARNEST randomised trial

BACKGROUND: Limited viral load (VL) testing in HIV-infected individuals on treatment in low-income countries often results in late detection of treatment failure. The impact of remaining on failing second-line, protease inhibitor (PI) containing regimens is unclear. METHODS: We retrospectively tested VL from 2,164 stored plasma samples from 386 patients randomised to receive PI-monotherapy (ritonavir-boosted lopinavir, after initial PI+raltegravir induction) in the EARNEST trial. Protease genotypic resistance testing was performed in samples with VL>1000 copies/ml. We assessed evolution of drug resistance mutations from virological failure (confirmed VL>1000 copies/ml) until discontinuation of PI-monotherapy and examined associations using Poisson and linear mixed-effects models. RESULTS: 118 patients had a median 68(IQR 48-88) weeks on PI-monotherapy post-failure. At failure, 21/107(20%) had intermediate/high resistance to lopinavir. 40-48 weeks post-failure, 49/72(68%) and 36/71(51%) had intermediate/high-level resistance to lopinavir and atazanavir. Most remained susceptible to darunavir (12/72[17%] intermediate, no high resistance). Common PI mutations were M46I, I54V, and V82A. On average, 1.7(95% CI 1.5,2.0) PI mutations developed per year; this increased after the first mutation developed, but decreased with subsequent mutations (p<0.0001). Modest VL changes were mainly driven by non-adherence (p=0.006) and PI mutation development. I47A was associated with a larger increase in log₁₀ VL(+0.53[+0.18,+0.87], p=0.003) than other PI mutations (+0.15[+0.07,+0.23] p<0.001; heterogeneity p=0.05). CONCLUSION: Most develop intermediate/high-level lopinavir resistance within one year when lopinavir/ritonavir is exposed to sustained VL replication without protection from other drugs. Even in this extreme situation, annual VL testing (current WHO recommendation) would identify failure when most would still benefit from switching to darunavir

Transplanting the leafy liverwort Herbertus hutchinsiae : A suitable conservation tool to maintain oceanic-montane liverwort-rich heath?

Thanks to the relevant landowners and managers for permission to carry out the experiments, Chris Preston for helping to obtain the liverwort distribution records and the distribution map, Gordon Rothero and Dave Horsfield for advice on choosing experimental sites and Alex Douglas for statistical advice. Juliane Geyer’s help with fieldwork was greatly appreciated. This study was made possible by a NERC PhD studentship and financial support from the Royal Botanic Garden Edinburgh and Scottish Natural Heritage.Peer reviewedPostprin

Getting the right balance: insole design alters the static balance of people with diabetes and neuropathy

BACKGROUND: Over 1 in 3 older people with diabetes sustain a fall each year. Postural instability has been identified as independent risk factor for falls within people with Diabetic Peripheral Neuropathy (DPN). People with DPN, at increased risk of falls, are routinely required to wear offloading insoles, yet the impact of these insoles on postural stability and postural control is unknown. The aim of this study was to evaluate the effect of a standard offloading insole and its constituent parts on the balance in people with DPN. METHODS: A random sample of 50 patients with DPN were observed standing for 3 × 30 s, and stepping in response to a light, under five conditions presented in a random order; as defined by a computer program; 1) no insole, 2) standard diabetic: a standard offloading insole made from EVA/poron®, and three other insoles with one design component systematically altered 3) flat: diabetic offloading insole with arch fill removed, 4) low resilient memory: diabetic offloading insole with the cover substituted with low resilience memory V9, 5) textured: diabetic offloading insole with a textured PVC surface added (Algeos Ltd). After each condition participants self-rated perceived steadiness. RESULTS: Insole design effected static balance and balance perception, but not stepping reaction time in people with DPN. The diabetic and memory shaped insoles (with arch fill) significantly increased centre of pressure velocity (14 %, P = 0.006), (13 %, P = 0.001), and path length (14 %, P = 0.006), (13 %, P = 001), when compared to the no insole condition. The textured shaped and flat soft insole had no effect on static balance when compared to the no insole condition (P > 0.05). CONCLUSION: Insoles have an effect on static balance but not stepping reaction time. This effect is independent of neuropathy severity. The addition of a textured cover seems to counter the negative effect of an arch fill, even in participants with severe sensation loss. Static balance is unaffected by material softness or resilience. Current best practice of providing offloading insoles, with arch fill, to increase contact area and reduce peak pressure could be making people more unstable. Whilst flat, soft insoles maybe the preferable design option for those with poor balance. There is a need to develop an offloading insole that can reduce diabetic foot ulcer risk, without compromising balance

Locus Coeruleus as a vigilance centre for active inspiration and expiration in rats

Abstract At rest, inspiration is an active process while expiration is passive. However, high chemical drive (hypercapnia or hypoxia) activates central and peripheral chemoreceptors triggering reflex increases in inspiration and active expiration. The Locus Coeruleus contains noradrenergic neurons (A6 neurons) that increase their firing frequency when exposed to hypercapnia and hypoxia. Using recently developed neuronal hyperpolarising technology in conscious rats, we tested the hypothesis that A6 neurons are a part of a vigilance centre for controlling breathing under high chemical drive and that this includes recruitment of active inspiration and expiration in readiness for flight or fight. Pharmacogenetic inhibition of A6 neurons was without effect on resting and on peripheral chemoreceptors-evoked inspiratory, expiratory and ventilatory responses. On the other hand, the number of sighs evoked by systemic hypoxia was reduced. In the absence of peripheral chemoreceptors, inhibition of A6 neurons during hypercapnia did not affect sighing, but reduced both the magnitude and incidence of active expiration, and the frequency and amplitude of inspiration. These changes reduced pulmonary ventilation. Our data indicated that A6 neurons exert a CO2-dependent modulation of expiratory drive. The data also demonstrate that A6 neurons contribute to the CO2-evoked increases in the inspiratory motor output and hypoxia-evoked sighing

Zircon ages in granulite facies rocks: decoupling from geochemistry above 850 °C?

Granulite facies rocks frequently show a large spread in their zircon ages, the interpretation of which raises questions: Has the isotopic system been disturbed? By what process(es) and conditions did the alteration occur? Can the dates be regarded as real ages, reflecting several growth episodes? Furthermore, under some circumstances of (ultra-)high-temperature metamorphism, decoupling of zircon U–Pb dates from their trace element geochemistry has been reported. Understanding these processes is crucial to help interpret such dates in the context of the P–T history. Our study presents evidence for decoupling in zircon from the highest grade metapelites (> 850 °C) taken along a continuous high-temperature metamorphic field gradient in the Ivrea Zone (NW Italy). These rocks represent a well-characterised segment of Permian lower continental crust with a protracted high-temperature history. Cathodoluminescence images reveal that zircons in the mid-amphibolite facies preserve mainly detrital cores with narrow overgrowths. In the upper amphibolite and granulite facies, preserved detrital cores decrease and metamorphic zircon increases in quantity. Across all samples we document a sequence of four rim generations based on textures. U–Pb dates, Th/U ratios and Ti-in-zircon concentrations show an essentially continuous evolution with increasing metamorphic grade, except in the samples from the granulite facies, which display significant scatter in age and chemistry. We associate the observed decoupling of zircon systematics in high-grade non-metamict zircon with disturbance processes related to differences in behaviour of non-formula elements (i.e. Pb, Th, U, Ti) at high-temperature conditions, notably differences in compatibility within the crystal structure

The impact of food assistance on weight gain and disease progression among HIV-infected individuals accessing AIDS care and treatment services in Uganda

BACKGROUND: The evidence evaluating the benefits of programmatic nutrition interventions to HIV-infected individuals in developing countries, where there is a large overlap between HIV prevalence and malnutrition, is limited. This study evaluates the impact of food assistance (FA) on change in weight and disease progression as measured by WHO staging. METHODS: We utilize program data from The AIDS Support Organization (TASO) in Uganda to compare outcomes among FA recipients to a control group, using propensity score matching (PSM) methods among 14,481 HIV-infected TASO clients. RESULTS: FA resulted in a significant mean weight gain of 0.36 kg over one year period. This impact was conditional on anti-retroviral therapy (ART) receipt and disease stage at baseline. FA resulted in mean weight gain of 0.36 kg among individuals not receiving ART compared to their matched controls. HIV-infected individuals receiving FA with baseline WHO stage II and III had a significant weight gain (0.26 kg and 0.2 kg respectively) compared to their matched controls. Individuals with the most advanced disease at baseline (WHO stage IV) had the highest weight gain of 1.9 kg. The impact on disease progression was minimal. Individuals receiving FA were 2 percentage points less likely to progress by one or more WHO stage compared to their matched controls. There were no significant impacts on either outcome among individuals receiving ART. CONCLUSIONS: Given the widespread overlap of HIV and malnutrition in sub-Saharan Africa, FA programs have the potential to improve weight and delay disease progression, especially among HIV-infected individuals not yet on ART. Additional well designed prospective studies evaluating the impact of FA are urgently needed

Day-case open reduction for developmental dysplasia of the hip.

AIMS: Open reduction in developmental dysplasia of the hip (DDH) is regularly performed despite screening programmes, due to failure of treatment or late presentation. A protocol for open reduction of DDH has been refined through collaboration between surgical, anaesthetic, and nursing teams to allow same day discharge. The objective of this study was to determine the safety and feasibility of performing open reduction of DDH as a day case. METHODS: A prospectively collected departmental database was visited. All consecutive surgical cases of DDH between June 2015 and March 2020 were collected. Closed reductions, bilateral cases, cases requiring corrective osteotomy, and children with comorbidities were excluded. Data collected included demographics, safety outcome measures (blood loss, complications, readmission, reduction confirmation), and feasibility for discharge according to the Face Legs Activity Cry Consolidability (FLACC) pain scale. A satisfaction questionnaire was filled by the carers. Descriptive statistics were used for analysis. RESULTS: Out of 168 consecutive DDH cases, 16 patients fit the inclusion criteria (age range 10 to 26 months, 13 female). Intraoperative blood loss ranged from "minimal" to 120 ml, and there were no complications or readmissions. The FLACC score was 0 for all patients. The carers satisfaction questionnaire expressed high satisfaction from the experience with adequate information and support provided. CONCLUSION: Open reduction in DDH, without corrective osteotomy, is safe and feasible to be managed as a day case procedure. It requires a clear treatment pathway, analgesia, sufficient counselling, and communication with carers. It is even more important during the COVID-19 pandemic when reduced length of hospital stay is likely to be safer for both patient and their parents. Cite this article: Bone Joint Open 2021;2(4):271-277

New regulations regarding Postgraduate Medical Training in Spain: perception of the tutor's role in the Murcia Region

<p>Abstract</p> <p>Background</p> <p>Recently introduced regulatory changes have expanded the Tutor role to include their primary responsibility for Postgraduate Medical Training (PMT). However, accreditation and recognition of that role has been devolved to the autonomic regions. The opinions of the RT may be relevant to future decisions;</p> <p>Methods</p> <p>A comprehensive questionnaire, including demographic characteristics, academic and research achievement and personal views about their role, was sent to 201 RTs in the Murcia Region of Spain. The responses are described using median and interquartile ranges (IQR);</p> <p>Results</p> <p>There were 147 replies (response rate 73%), 69% male, mean age 45 ± 7 yrs. RTs perception of the residents' initial knowledge and commitment throughout the program was 5 (IQR 4-6) and 7 (IQR 5-8), respectively. As regards their impact on the PMT program, RTs considered that their own contribution was similar to that of senior residents. RTs perception of how their role was recognised was 5 (IQR 3-6). Only 16% did not encounter difficulties in accessing specific RT training programs. Regarding the RTs view of their various duties, supervision of patient care was accorded the greatest importance (64%) while the satisfactory completion of the PMT program and supervision of day-to-day activities were also considered important (61% and 59% respectively). The main RT requirements were: a greater professional recognition (97%), protected time (95%), specific RT training programs (95%) and financial recognition (86%);</p> <p>Conclusions</p> <p>This comprehensive study, reflecting the feelings of our RTs, provides a useful insight into the reality of their work and the findings ought to be taken into consideration in the imminent definitive regulatory document on PMT.</p

Similar Neural Activity during Fear and Disgust in the Rat Basolateral Amygdala

Much research has focused on how the amygdala processes individual affects, yet little is known about how multiple types of positive and negative affects are encoded relative to one another at the single-cell level. In particular, it is unclear whether different negative affects, such as fear and disgust, are encoded more similarly than negative and positive affects, such as fear and pleasure. Here we test the hypothesis that the basolateral nucleus of the amygdala (BLA), a region known to be important for learned fear and other affects, encodes affective valence by comparing neuronal activity in the BLA during a conditioned fear stimulus (fear CS) with activity during intraoral delivery of an aversive fluid that induces a disgust response and a rewarding fluid that induces a hedonic response. Consistent with the hypothesis, neuronal activity during the fear CS and aversive fluid infusion, but not during the fear CS and rewarding fluid infusion, was more similar than expected by chance. We also found that the greater similarity in activity during the fear- and disgust-eliciting stimuli was specific to a subpopulation of cells and a limited window of time. Our results suggest that a subpopulation of BLA neurons encodes affective valence during learned fear, and furthermore, within this subpopulation, different negative affects are encoded more similarly than negative and positive affects in a time-specific manner