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Background Restrictions as a result of the COVID-19 pandemic have demanded an innovative approach to provide appropriate patient review. We have been running virtual cardiology clinics as per Health Service Executive guidance. Aims Our study aims to determine how virtual clinics change practice vs traditional clinics. Methods A retrospective cohort analysis was conducted on patients attending cardiology clinics in our hospital from 6 January to 13 March 2020 (‘traditional clinic’, n = 1644), compared with clinics during the COVID-19 outbreak, from 16 March to 22 April 2020 (‘virtual clinic’, n = 691), with the same medical staff. Results There was no difference in age (61 vs 60), case mix or new vs return appointments in virtual vs traditional clinics. There were similar rates of clinic participation, 71.8% vs 74.2%. A lower proportion of investigations (e.g. imaging) were booked in virtual (38.5%) vs traditional (55.7%) clinics, p

The COVID-19 (SARS-CoV-2) pandemic has changed the social environment in which people live and work, as well as the social systems they rely on.39,88 To contain the spread of coronavirus and to prepare for a dramatic increase in demand for limited hospital/medical facilities and resources, societies have enforced physical distancing measures. Consequently, there have been limitations on the use of public transportation, public spaces, and work, education, and recreational facilities. Furthermore, access to vital, but nonurgent, healthcare services (including pain management services) has been restricted. These changes have affected the way people connect with each other, manage their health and wellbeing, and fulfil their social roles. For some, these changes may present opportunities (eg, increased time with family, normalisation of flexible working, and reduced demand for travel). For others, however, these social changes can also represent significant threats to health and wellbeing. The negative impact of social changes prompted by the COVID-19 crisis may disproportionately affect individuals living with long-term painful conditions. Living with chronic pain can threaten an individuals' fundamental social needs for autonomy (agency or independence), belonging (social connection), and justice (fairness). In turn, for some, experiencing heightened social threat can maintain and exacerbate chronic pain.48 In this review, we draw attention to the potential for social and systemic changes associated with attempts to contain the spread of COVID-19 to precipitate, maintain, and exacerbate pain by increasing the social threats faced by individuals with chronic pain (Fig. ​(Fig.1).1). We also suggest strategies for mitigating the social impact of COVID-19 on those living with chronic pain, for instance by learning from the resilience demonstrated by people in pain who have found ways to deal with social threat. Finally, we suggest several time-critical, high-impact research questions for further investigation (Fig. 1). Open in a separate window Figure 1. Schematic representation of how the COVID 19 pandemic (A) exacerbates existing levels of social threat (B), thereby inducing several social challenges (C) for people with chronic pain, and ultimately increasing the risk for the development, maintenance, and exacerbation of chronic pain complaints (D). Possible protecting processes and interventions countering the effects of the pandemic are portrayed as well (E).

BackgroundChronic inflammation contributes to the pathogenesis of depression in persons with HIV (PWH). Neopterin, a biomarker of HIV-related immune activation that partially normalizes with antiretroviral therapy (ART), correlates with major depressive disorder (MDD) and subclinical depressive symptoms in persons without HIV and acutely infected, young PWH. The sensitivity of neopterin, however, to both lifetime and current depression is poorly understood in older PWH on suppressive ART.MethodsParticipants were 70 PWH and 35 persons without HIV (HIV-) who were at least 50 years old and completed standardized neurobehavioral and neuromedical assessments. Depressive symptoms in the past 2 weeks, measured with the Beck Depression Inventory-II (BDI-II), and lifetime MDD diagnoses, defined as meeting Diagnostic and Statistical Manual of Mental Disorders-IV criteria for a depressive episode at any point in one's lifetime, were separately modeled as a function of plasma neopterin levels in the full sample and by HIV serostatus.ResultsCompared with HIV- adults, PWH had higher neopterin levels (P < 0.001) and BDI-II scores (P < 0.01) and were more likely to have lifetime MDD (P < 0.01). Higher neopterin related to lifetime MDD, but only in PWH, even after controlling for clinically relevant comorbidities and treatment factors in logistic regression (odds ratio = 3.11, P = 0.002). Higher neopterin correlated with higher BDI-II scores in the full sample (rs = 0.25; P = 0.010), but not within either group (PWH: rs = 0.03, P = 0.819; HIV-: rs = 0.09, P = 0.588).ConclusionNeopterin was associated with lifetime MDD, but not current depressive symptoms in older PWH on suppressive ART. This may reflect a legacy of inflammation-related disruptions to amino acid metabolism and neurotransmitter synthesis, similar to prior observations. Identification of biopsychosocial and resilience factors underlying the null association between neopterin and current depression in older PWH is warranted.

Given the co-occurrence of memory impairment in HIV-associated neurocognitive disorders (HAND) and amnestic mild cognitive impairment/Alzheimer’s disease (aMCI/AD), biomarkers are needed that can disentangle these conditions among people with HIV (PWH). We assessed whether cerebrospinal fluid (CSF) markers of AD could help in this effort by determining their relationship to learning and memory deficits versus cognitive deficits more characteristic of HAND than aMCI/AD (processing speed and complex visual/motor coordination) among 31 older PWH. CSF amyloid-β(42.) phosphorylated-Tau, amyloid-β(40)/amyloid-β(42) and phosphorylated-Tau/amyloid-β(42) ratio related to learning/memory performance but not HAND-related deficits, suggesting that these biomarkers may have utility in disentangling aMCI/AD from HAND.

Purpose: Vitreous haze (VH) is a key marker of inflammation in uveitis but limited by its subjectivity. Optical coherence tomography (OCT) has potential as an objective, noninvasive method for quantifying VH. We test the hypotheses that OCT can reliably quantify VH and the measurement is associated with slit-lamp based grading of VH. \ud \ud Methods: In this prospective study, participants underwent three repeated OCT macular scans to evaluate the within-eye reliability of the OCT vitreous intensity (VI). Association between OCT VI and clinical findings (including VH grade, phakic status, visual acuity [VA], anterior chamber cells, and macular thickness) were assessed. \ud \ud Results: One hundred nineteen participants were included (41 healthy participants, 32 patients with uveitis without VH, and 46 patients with uveitis with VH). Within-eye test reliability of OCT VI was high in healthy eyes and in all grades of VH (intraclass correlation coefficient [ICC] > 0.79). Average OCT VI was significantly different between healthy eyes and uveitic eyes without and uveitic eyes with VH, and was associated with increasing clinical VH grade (P < 0.05). OCT VI was significantly associated with VA, whereas clinical VH grading was not. Cataract was also associated with higher OCT VI (P = 0.03). \ud \ud Conclusions: OCT VI is a fast, noninvasive, objective, and automated method for measuring vitreous inflammation. It is associated with clinician grading of vitreous inflammation and VA, however, it can be affected by media opacities. \ud \ud Translational Relevance: OCT imaging for quantifying vitreous inflammation shows high within-eye repeatability and is associated with clinical grading of vitreous haze. OCT measurements are also associated with visual acuity but may be affected by structures anterior to the acquisition window, such as lens opacity and other anterior segment changes.

Purpose The aim of this paper is to describe our experience with a virtual fracture management pathway in the setting of a paediatric trauma service. Methods All patients referred to the virtual fracture clinic service from the Paediatric Emergency Department (PED) were prospectively collected. Outcome data of interest (patients discharged, referred for urgent operative treatment, referred back to emergency department for further evaluation, referred for face-to-face clinical assessment and all patients who re-presented on an unplanned basis for further management of the index injury) were compiled and collated. Cost analysis was performed using established costing for a virtual fracture clinic within the Irish Healthcare System. Results There were a total of 3961 patients referred to the virtual fracture clinic from the PED. Of these, 70% (n = 2776) were discharged. In all, 26% (n = 1033) were referred to a face-to-face appointment. Of discharged patients, 7.5% (n = 207) required an unplanned face-to-face evaluation. A total of 0.1% (n = 3) subsequently required operative treatment relating to their index injury. Implementation of the virtual fracture clinic model generated calculated savings of €254 120. Conclusion This prospective evaluation has demonstrated that a virtual fracture clinic pathway for minor paediatric trauma is safe, effective and brings significant cost savings. Level of Evidence II

Gastro-oesophageal reflux (GOR) is a common physiological state in infants and young children, with gastro-oesophageal reflux disease (GORD) its pathological manifestation. Management of GOR/GORD requires elimination of possible underlying causes, parental reassurance, modification of feeding and symptom mitigation, monitoring, and referral to paediatricians if warning signs are present. Published clinical practice guidelines (CPGs) seek to support clinicians and improve management. This study aimed to measure the proportion of Australian GOR/GORD paediatric care that was in line with CPG recommendations. National and international CPGs for GOR/GORD were systematically identified and candidate indicators extracted; a Delphi process selected 32 indicators relevant to Australian paediatric care in 2012 and 2013. Medical records were identified in General Practices, the offices of general paediatricians, Emergency Departments and inpatient settings. Adherence to indicators was assessed by nine trained paediatric nurses undertaking retrospective medical record review. Medical records were reviewed in 115 healthcare sites; identifying 285 children, three-quarters aged infants at the first presentation was higher if they were healthy and thriving (86.9% adherence: 95% CI 86.0–96.8), intermediate if they had feeding refusal (73.1%: 95% CI 56.0–86.3) and lower if they presented with irritability and unexplained crying (58.8%: 95% CI 28.2–85.0). A guideline targeting Australian health professionals caring for infants and children with GOR/GORD is warranted, highlighting the importance of differential diagnostic testing and avoidance of acid-suppression medication in infants.

Tactile sensitivities are common in Autism Spectrum Conditions (autism). Psychophysically, slow, gentle stroking touch is typically rated as more pleasant than faster or slower touch. Vicarious ratings of social touch results in a similar pattern of velocity dependent hedonic ratings as directly felt touch. Here we investigated whether adults and childrens vicarious ratings vary according to autism diagnosis and self-reported autistic traits. Adults scoring high on the AQ rated stroking touch on the palm as less pleasant than a Low AQ group. However, in contrast to our hypothesis, we did not find any effect of autism diagnosis on childrens touch ratings despite parental reports highlighting significant somatosensory sensitivities. These results are discussed in terms of underpinning sensory and cognitive factors. Funding Agencies|Linkoping University; Leverhulme TrustLeverhulme Trust [RPG-2013-058]; Liverpool John Moores University PhD studentship

Background Memory impairment occurs in human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) and amnestic mild cognitive impairment (aMCI), the precursor to Alzheimer disease (AD). Methods are needed to distinguish aMCI-associated from HAND-associated impairment in people with HIV (PWH). We developed a neuropsychological method of identifying aMCI in PWH and tested this by relating AD neuropathology (β-amyloid, phospho-Tau) to aMCI versus HAND classification. Methods Seventy-four HIV-positive cases (aged 50−68 years) from the National NeuroAIDS Tissue Consortium had neurocognitive data within 1 year of death and data on β-amyloid and phospho-Tau pathology in frontal brain tissue. High aMCI risk was defined as impairment ( Results High aMCI risk was more common in HAND (69.0%) versus no HAND (37.5%) group. β-amyloid pathology was 4.75 times more likely in high versus low aMCI risk group. Phospho-Tau pathology did not differ between aMCI groups. Neither neuropathological feature differed by HAND status. Conclusions Amnestic mild cognitive impairment criteria that include recognition impairment may help to detect AD-like cognitive/biomarker profiles among PWH.

Background African Americans are disproportionally affected by HIV and have poorer rates of antiretroviral therapy (ART) adherence compared to other racial or ethnic groups in the United States. Factors associated with poor HIV disease outcomes are commonly associated with sociostructural barriers that prevent engagement with and retention in HIV care. SMS text messaging interventions to promote ART adherence among predominantly non-Hispanic White persons with HIV (PWH) have been shown to be efficacious; however, limited research has been devoted to culturally tailoring interventions for underrepresented racial/ethnic groups. Considering African Americans show poorer engagement along the HIV care continuum, we developed an individualized and culturally tailored two-way SMS text messaging intervention to improve ART adherence and associated virologic suppression among African American PWH. Objective In this paper we describe the protocol of a culturally tailored individualized Texting for Adherence Building (iTAB) intervention in a 24- to 48-week, single-arm study. Methods We developed a culturally tailored iTAB intervention, which we are implementing in a 24- to 48-week, single-arm study. Participants were recruited from the Family Health Centers of San Diego (FHCSD), a federally qualified health center. Patient inclusion criteria were (1) receiving care at the FHCSD, (2) living with HIV, (3) self-identification as Black, African American, or of African ancestry, (4) English speaking, (5) age 18 or older, (6) currently on ART, and (7) able to provide informed consent. Study enrollment began in November 2017 and closed in July 2019. A total of 90 participants from the FHCSD enrolled in the iTAB intervention, and we anticipate completing data collection in July 2020. Participants were assisted in individualizing and customizing their SMS text message preferences at the baseline study visit. Self-assessment measures are collected at baseline, interim, and final study visits. Problems related to sending/receiving SMS text messages and barriers to ART adherence are assessed at each interim study visit. The FHCSD staff monitors and tracks participants’ daily SMS text message responses to ART adherence reminders using a clinical dashboard. Results We hypothesize that the proportion of individuals achieving HIV virologic suppression (viral load Conclusions The iTAB intervention is a novel individualized two-way SMS text messaging intervention that has been culturally tailored for use among African Americans with HIV. We anticipate that iTAB will demonstrate efficacy in future randomized control trials and will be supportive of medication adherence among other populations facing health disparities. International Registered Report Identifier (IRRID) DERR1-10.2196/21592

With increasing effectiveness of antiretroviral therapy, people with HIV (PWH) are living longer and the prevalence of older PWH continues to increase. Accordingly, PWH are experiencing an increased burden of age-related comorbidities. With this shifting demographics, clinicians and researchers face additional challenges in how to identify, address, and manage the complex intersections of HIV- and aging-related conditions. Established in 2009, the International Workshop on HIV and Aging brings together clinicians and researchers in cross-disciplinary fields along with community advocates and PWH to address the multidisciplinary nature of HIV and aging. This article summarizes plenary talks from the 10th Annual International Workshop on HIV and Aging, which took place in New York City on October 10 and 11, 2019. Presentation topics included the following: the burdens of HIV-associated comorbidities, aging phenotypes, community engagement, and loneliness; these issues are especially important for older PWH, considering the current COVID-19 pandemic. We also discuss broad questions and potential directions for future research necessary to better understand the interaction between HIV and aging.

ObjectiveTo determine whether oxidative stress in virologically suppressed people with HIV (PWH) may contribute to or result from neurodegeneration, we measured 7,8-dihydro-8-oxoguanine (8-oxo-dG), a marker of DNA damage due to oxidative stress, and markers of age-related neurodegeneration, specifically, reduced levels of CSF Aβ-42, and elevated CSF total tau and neurofilament light (NFL).MethodsThis cross-sectional study prospectively enrolled participants at 6 US centers in the CNS HIV Antiretroviral Effects Research study. Inclusion criteria included HIV+ with a plasma level of HIV RNA ≤50 copies/mL. Exclusions included significant CNS confounding conditions. Measurements of total tau and Aβ-42 were performed by bead suspension array. NFL and 8-oxo-dG were measured using ELISA.ResultsParticipants were 53 PWH, mean age 55 (±9.3) years, 19% women, and 48% non-Hispanic White. Higher 8-oxo-dG correlated with markers of AD-related neurodegeneration including lower CSF Aβ-42 (r = −0.34; p = 0.012) and higher CSF NFL (r = 0.39; p = 0.0091) and total tau (r = 0.6696; p < 0.0001). Relationships remained after adjusting for demographic variables. Levels of protein carbonyls, a marker of protein oxidation, were not related to neurodegeneration markers.ConclusionsAmong virologically suppressed PWH, nucleic acid oxidation was associated with standard CSF biomarkers of neurodegeneration. Potential sources of oxidative stress in PWH include low-level HIV replication, inflammation, mitochondrial dysfunction, and specific antiretroviral drugs. Results suggest that the higher levels of oxidative stress among PWH may play a role in neurodegeneration.Classification of evidenceThis study provides Class II evidence that among virologically suppressed PWH, nucleic acid oxidation is associated with standard CSF biomarkers of neurodegeneration.

Background Daily activities have been associated with neurocognitive performance. However, much of this research has used in-person neuropsychological testing that requires participants to travel to a laboratory or clinic, which may not always be feasible and does not allow for the examination of real-time relationships between cognition and behavior. Thus, there is a need to understand the real-time relationship between activities in the real world and neurocognitive functioning to improve tracking of symptoms or disease states and aid in the early identification of neurocognitive deficits among at-risk individuals. Objective We used a smartphone-based ecological momentary cognitive assessment (EMCA) platform to examine real-time relationships between daily activities and neurocognitive performance (executive functioning and verbal learning) in the everyday environment of middle-aged and older adults with and without HIV. Methods A total of 103 adults aged 50-74 years (67 persons with HIV; mean age 59 years, SD 6.4) were recruited from the University of California, San Diego HIV Neurobehavioral Research Program and the San Diego community. Participants completed our EMCA protocol for 14 days. Participants reported their current daily activities 4 times per day; following 2 of the 4 daily ecological momentary assessment (EMA) surveys, participants were administered the mobile Color-Word Interference Test (mCWIT) and mobile Verbal Learning Test (mVLT), each once per day. Activities were categorized into cognitively stimulating activities, passive leisure activities, and instrumental activities of daily living (IADLs). We used multilevel modeling to examine the same-survey and lagged within-person and between-person effects of each activity type on mobile cognitive performance. Results On average, participants completed 91% of the EMA surveys, 85% of the mCWIT trials, and 80% of the mVLT trials, and they reported engaging in cognitively stimulating activities on 17% of surveys, passive leisure activities on 33% of surveys, and IADLs on 20% of surveys. Adherence and activity percentages did not differ by HIV status. Within-persons, engagement in cognitively stimulating activities was associated with better mCWIT performance (β=−1.12; P=.007), whereas engagement in passive leisure activities was associated with worse mCWIT performance (β=.94; P=.005). There were no lagged associations. At the aggregate between-person level, a greater percentage of time spent in cognitively stimulating activities was associated with better mean mVLT performance (β=.07; P=.02), whereas a greater percentage of time spent in passive leisure activities was associated with worse mean mVLT performance (β=−.07; P=.01). IADLs were not associated with mCWIT or mVLT performance. Conclusions Smartphones present unique opportunities for assessing neurocognitive performance and behavior in middle-aged and older adults’ own environment. Measurement of cognition and daily functioning outside of clinical settings may generate novel insights on the dynamic association of daily behaviors and neurocognitive performance and may add new dimensions to understanding the complexity of human behavior.

3-O-ethyl l-ascorbic acid (EA), an ether derivative of Vitamin C, is widely used in skincare formulations. Previously, we reported the effects of neat solvents on EA percutaneous absorption and observed that 0.6&ndash, 7.5% of the applied EA was delivered through the skin over 24 h. In this work, we designed complex formulations using combinations of solvents that may act synergistically and examined their impact on EA permeation in porcine skin in vitro under finite dose conditions. Binary combinations of propylene glycol (PG) with propylene glycol monolaurate (PGML) were effective in enhancing skin permeation of EA compared with individual solvents (p &lt, 0.05). Combining PGML with 1,2-hexanediol (HEX) did not result in significantly higher EA permeation compared with the neat solvents (p &gt, 0.05). Addition of the volatile solvent isopropyl alcohol (IPA) to PG solutions also did not improve EA skin delivery compared with neat PG. Ternary solvent systems containing PG:PGML were subsequently prepared by the addition of a lipophilic solvent, either isopropyl myristate (IPM), medium-chain triglycerides (MCT) or isostearyl isostearate (ISIS). The optimum vehicle, PG:PGML:IPM, promoted up to 70.9% skin delivery of EA. The PG:PGML:ISIS vehicles also promoted EA permeation across the skin, but to a significantly lesser extent than the IPM-containing vehicles. No enhancement of EA delivery was noted for the PG:PGML:MCT mixtures. These results will inform the development of targeted formulations for EA in the future.

Background Non-infectious uveitis represents a sub-type of intraocular inflammation often associated with disorders of immune dysregulation. If untreated, the intraocular inflammation may progress to severe visual impairment and blindness. Current treatment is heavily reliant on systemic corticosteroid, often at doses associated with severe side effects. There is a need for efficacious corticosteroid-sparing immunomodulatory therapy for these patients. Current immunomodulators include various immunosuppressants and biologics but mammalian target of rapamycin (mTOR) inhibitors (such as sirolimus and everolimus) may also be contenders for this role. The systematic review proposed here will evaluate the evidence for the use of sirolimus and everolimus in the context of non-infectious uveitis. Method/design Standard systematic review methodology will be used to identify, select and extract data from any comparative or non-comparative study of mTOR inhibitors in patients with non-infectious uveitis excluding case reports. Searches of bibliographic databases (MEDLINE, EMBASE, The Cochrane Library and CINAHL) and clinical trials registers will be performed, with no restriction on language or date of publication. Translation of non-English language articles will be undertaken where necessary. The primary outcome of interest will be uveitis activity as measured by vitreous haze. Secondary outcomes will include other pre-specified measures of uveitis activity (such as anterior chamber cells or central macular thickness) best corrected visual acuity, heath-related quality of life, requirement for concurrent treatment and adverse events. Risk of bias assessment will be performed appropriate to each study design. Study selection, data extraction and risk of bias assessment will be undertaken by two reviewers independently. Data will be grouped, tabulated and narratively synthesised. Meta-analysis will be undertaken where appropriate clinical and methodological homogeneity exists. The review will be published according to PRISMA guidance. Discussion Studies of various designs have investigated the clinical use of mTOR inhibitors for non-infectious uveitis, and a large international randomised controlled trail of sirolimus for non-infectious uveitis is due to report. The findings of this systematic review will help inform ophthalmologists and aid the improvement of treatment protocols for non-infectious uveitis with regard to the use of mTOR inhibitors. Systematic review registration PROSPERO CRD42017056390

The co-occurrence of HIV and alcohol use disorder (AUD) amplifies risk for neural injury and neurocognitive deficits. However, the substantial neurocognitive heterogeneity across HIV+/AUD+ individuals suggests inter-individual differences in vulnerability to the neurotoxicity of comorbid HIV/AUD. Genetic variation in alcohol dehydrogenase (ADH), which metabolizes ethanol, may contribute to inter-individual neurocognitive variability. We evaluated associations between five ADH single-nucleotide polymorphisms (SNPs) and neurocognition in men stratified by HIV and lifetime AUD status. Neurobehavioral assessments were administered to 153 men. Three-way ANOVAs examined the interaction of HIV, AUD, and ADH SNPs on global and domain-specific demographically corrected T scores. Follow-up ANCOVAs adjusted for age, estimated verbal IQ, depression, and remote non-alcohol substance use disorders. HIV/AUD groups differed globally and for verbal fluency, working memory, executive function, and processing speed T scores specifically, with HIV+/AUD+ exhibiting the poorest performance. ADH4 (rs1126671) was associated with large effects on working memory (d = - 1.16, p = .001) and executive function (d = - 0.77, p = .028) selectively in HIV+/AUD+, which remained significant in ANCOVA models. ADH1A (rs3819197) moderated the deleterious effects of HIV+/AUD+ on processing speed such that HIV+/AUD+ related to slower information processing in A allele carriers but not GG homozygotes (ps

Graphical abstract, l-ascorbic acid (AA), commonly known as vitamin C, has been widely used in topical formulations for many years as an antioxidant and anti-aging ingredient. However, the physicochemical properties of AA are not optimal for skin uptake and the molecule is also unstable, readily undergoing oxidation on exposure to air. The compound 3-o-ethyl-l-ascorbic acid (EA) has been developed as a stable vitamin C derivative and has been used in topical products. The aims of this work were to conduct a comprehensive characterisation of physicochemical properties of EA as well as to investigate the influence of various neat solvents on EA skin delivery. Nuclear magnetic resonance (NMR), mass spectroscopy, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were used to characterise the molecule. The pKa of the compound and the partition coefficient logP(o/w) were experimentally determined. A new HPLC method for analysis of the molecule was also developed and validated. A number of solvents for topical preparations were selected based on their wide use as excipients in topical formulations, their potential to act as skin penetration enhancers and their favourable safety profiles. The solubility and stability of EA was examined. Skin permeation of the molecule in full thickness porcine skin in vitro was investigated using Franz-type diffusion cells. The melting point, log P(o/w) value and pKa value of EA were determined to be 114.39 ± 0.5 °C, −1.07 ± 0.03 and 7.72 ± 0.01 respectively. Skin penetration of EA was evident for the following vehicles 1,2 hexanediol (HEX), glycerol (GLY), propylene glycol (PG), 1,2 pentanediol (1-2P), isopropyl alcohol (IPA), propylene glycol monolaurate (PGML) and propylene glycol monocaprylate (PGMC). Skin uptake but no permeation through the skin was observed for Transcutol® (TC) and dipropylene glycol (DiPG), while no penetration was observed for the solvents 1,5 pentanediol (1-5P) and tripropylene glycol (TriPG). The findings of the permeation experiments confirm the potential of simple formulations to deliver EA to the skin. Studies are ongoing to identify complex vehicles for synergistic enhancement of EA skin penetration. To our knowledge this is the first study to conduct a comprehensive characterization of EA and examine its skin uptake and permeation properties in porcine skin.

Background High‐resolution esophageal manometry (HREM), derived esophageal pressure topography metrics (EPT), integrated relaxation pressure (IRP), and distal latency (DL) are influenced by age and size. Combined pressure and intraluminal impedance also allow derivation of metrics that define distension pressure and bolus flow timing. We prospectively investigated the effects of esophageal length on these metrics to determine whether adjustment strategies are required for children. Methods Fifty‐five children (12.3 ± 4.5 years) referred for HREM, and 30 healthy adult volunteers (46.9 ± 3.8 years) were included. Studies were performed using the MMS system and a standardized protocol including 10 × 5 mL thin liquid bolus swallows (SBM kit, Trisco Foods) and analyzed via Swallow Gateway (http://www.swallowgateway.com). Esophageal distension pressures and swallow latencies were determined in addition to EGJ resting pressure and standard EPT metrics. Effects of esophageal length were examined using partial correlation, correcting for age. Adult‐derived upper limits were adjusted for length using the slopes of the identified linear equations. Key Results Mean esophageal length in children was 16.8 ± 2.8 cm and correlated significantly with age (r = 0.787, P = .000). Shorter length correlated with higher EGJ resting pressure and 4‐s integrated relaxation pressures (IRP), distension pressures, and shorter contraction latencies. Ten patients had an IRP above the adult upper limit. Adjustment for esophageal length reduced the number of patients with elevated IRP to three. Conclusions & Inferences We prospectively confirmed that certain EPT metrics, as well as potential useful adjunct pressure‐impedance measures such as distension pressure, are substantially influenced by esophageal length and require adjusted diagnostic thresholds specifically for children., Esophageal length has a significant impact on key esophageal pressure topography metrics and other novel metrics, such as bolus distension pressure (DP), which may be a useful adjunct measure of outflow obstruction. These effects must be considered in the pediatric setting.

Individuals with autism spectrum disorder (ASD) are often reported to exhibit an apparent indifference to pain or temperature. Leading models suggest that this behavior is the result of elevated perceptual thresholds for thermal stimuli, but data to support these assertions are inconclusive. An alternative proposal suggests that the sensory features of ASD arise from increased intra-individual perceptual variability. In this study, we measured method-of-limits warm and cool detection thresholds in 142 individuals (83 with ASD, 59 with typical development [TD], aged 7–54 years), testing relationships with diagnostic group, demographics, and clinical measures. We also investigated the relationship between detection thresholds and a novel measure of intra-individual (trial-to-trial) threshold variability, a putative index of “perceptual noise.” This investigation found no differences in thermal detection thresholds between individuals with ASD and typical controls, despite large differences between groups in sensory reactivity questionnaires and modest group differences in intra-individual variability. Lower performance IQ, male sex, and higher intra-individual variability in threshold estimates were the most significant predictors of elevated detection thresholds. Although no psychophysical measure was significantly correlated with questionnaire measures of sensory hyporeactivity, large intra-individual variability may partially explain the elevated psychophysical thresholds seen in a subset of the ASD population.

As pre-exposure prophylaxis (PrEP) effectiveness is strongly linked to adherence, we sought to determine if certain self-report measures could be used to inform objective PrEP adherence. We studied participants from the TAPIR study (a multicenter randomized study of daily text messages to support adherence to PrEP In At-Risk), a 48-week randomized controlled trial of HIV-uninfected men who have sex with men (MSM) randomized to receive text message to support adherence versus standard of care. Self-reported medication adherence was assessed using several validated measures modified for PrEP. Objective PrEP adherence was determined through dried blood spot (DBS) measurement of intracellular tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP). A summary of adherence was estimated using responses to the seven adherence items at weeks 12 and 48 using confirmatory factor analysis. Correlations between self-report questions and drug concentrations were estimated with Pearson's correlations for continuous outcomes and point-biserial correlations for dichotomous outcomes. Receiver operating characteristic (ROC) analyses were conducted to assess the performance of self-report measures in predicting protective or perfect TFV-DP concentrations. Of the 369 participants who completed week 12 or 48 visits, the mean age was 35 (standard deviation 9 years), with 79% White, 12% Black, and 29% Hispanic. Correlations between self-report measures of adherence (both individual items and the adherence factor) and quantifiable FTC-TP and continuous TFV-DP concentrations showed that all self-report measures were significantly associated with these objective measures. Compared to a summary measure of self-reported adherence, the 4-week percent taken question medication recall was the only self-report item similarly or more strongly associated with recent adherence and long-term protective and perfect adherence at weeks 12 and 48. ROC analysis also showed that 4-week percent taken question had a reasonable AUC (0.798 at week 12 and 0.758 at week 48) in predicting protective TFV-DP concentrations. All single-item self-report questions assessing PrEP adherence were significantly associated with biomarker quantification, with the 4-week percent taken question performing best. Therefore, in the absence of drug concentration measurements, a 4-week self-report percent taken question may be a good single-item measure of PrEP adherence.

Objectives:Methamphetamine (MA) dependence contributes to neurotoxicity and neurocognitive deficits. Although combined alcohol and MA misuse is common, how alcohol consumption relates to neurocognitive performance among MA users remains unclear. We hypothesized that alcohol and MA use would synergistically diminish neurocognitive functioning, such that greater reported alcohol consumption would exert larger negative effects on neurocognition among MA-dependent individuals compared to MA-nonusing persons.Methods:Eighty-seven MA-dependent (MA+) and 114 MA-nonusing (MA−) adults underwent neuropsychological and substance use assessments. Linear and logistic regressions examined the interaction between MA status and lifetime average drinks per drinking day on demographically corrected global neurocognitive T scores and impairment rates, controlling for recent alcohol use, lifetime cannabis use, WRAT reading performance, and lifetime depression.Results:MA+ displayed moderately higher rates of impairment and lower T scores compared to MA−. Lifetime alcohol use significantly interacted with MA status to predict global impairment (ORR = 0.70, p = .003) such that greater lifetime alcohol use increased likelihood of impairment in MA−, but decreased likelihood of impairment in MA+. Greater lifetime alcohol use predicted poorer global T scores among MA− (b = −0.44, p = .030) but not MA+ (b = 0.08, p = .586).Conclusions:Contrary to expectations, greater lifetime alcohol use related to reduced risk of neurocognitive impairment among MA users. Findings are supported by prior research identifying neurobiological mechanisms by which alcohol may attenuate stimulant-driven vasoconstriction and brain thermotoxicity. Replication and examination of neurophysiologic mechanisms underlying alcohol use in the context of MA dependence are warranted to elucidate whether alcohol confers a degree of neuroprotection.

Men who have sex with men (MSM) reporting higher HIV risk behavior over time are often more adherent to pre-exposure prophylaxis (PrEP), but it is unclear if recent risk behavior and partnership type affect long-term PrEP adherence. HIV-negative MSM and transgender women completing the 48-week randomized study TAPIR (Daily Text Messages to Support Adherence to PrEP in At-Risk for HIV Individuals) were included. At baseline and weeks 24 and 48, a modified Calculated Risk (mCalcR) Score estimated the likelihood of HIV seroconversion over 1 year based on reported condomless anal sex acts in the last month and current sexually transmitted infection. mCalcR scores were categorized as low, moderate, and high/very high risk. Partnership type was classified as no partner/single HIV-negative partner (no/single-), single HIV-positive partner (single+), or multiple partners of any serostatus (multi) in the past 3 months. PrEP adherence was measured by intracellular tenofovir-diphosphate (TFV-DP) levels. Among 313 individuals, there was no difference in mCalcR category from baseline to week 48. There was a significant change in partnership type, with no/single partnerships increasing from 0.5% to 9%. Participants with moderate and high/very risk had higher TFV-DP levels than the low-risk group. No/single participants had lower TFV-DP levels than those reporting single+ or multi. Although there was a shift toward lower-risk partnerships, HIV risk category remained stable over time. Individuals with riskier behaviors and partnerships had higher PrEP drug levels, suggesting continued motivation for and adherence to PrEP.

Purpose Femoral lengthening using a circular or mono-lateral frame is a commonly used technique. Fracture at the site of the regenerate bone is a major concern especially following removal of the external fixator. This aim of this study was to assess the rate of fracture of the regenerate bone in this single surgeon series of paediatric patients and determine potential risk factors. Methods Retrospective review of all the femoral lengthening performed by the senior author was performed. The medical and physiotherapy notes were reviewed. The gender, age at time of surgery, disease aetiology, total days in the external fixator and length of the new regenerate bone were recorded. Patients who sustained a regenerate fracture were identified. Results A total of 176 femoral lengthening procedures were performed on 108 patients. Eight regenerate fractures occurred in seven patients (4.5%). The mechanism of injury was a fall in five cases and during physiotherapy in three cases. The regenerate fracture occurred a median number of nine days following removal of frame. There was no significant difference between gender, age at time of surgery, total time in external fixator between those who sustained a regenerate fracture and those patients who did not. A significant difference was noted between the amount of lengthening between the ‘regenerate fracture group’ and the ‘no fracture group’ (50 mm vs 38 mm, respectively; p = 0.029). There was no association between disease aetiology and risk of regenerate fracture. Conclusions Femoral lengthening of more than 50 mm increases the risk of a fracture at the regenerate site regardless of the disease aetiology. We recommend avoidance of aggressive physiotherapy for the initial four weeks following external fixator removal.

The objective of this study was to examine differences in the levels of risky decision making and other frontal system behavior constructs in relation to self-initiated continuance of HIV pre-exposure prophylaxis (PrEP) and PrEP adherence outcomes among men who have sex with men (MSM) following completion of a clinical PrEP trial. At the last PrEP trial visit, study provided PrEP was discontinued and participants were navigated to the community for PrEP continuation. In this cross-sectional analysis, 84/187 (45%) MSM who completed a prospective observational post-PrEP trial follow-up visit at the University of California San Diego were included. PrEP adherence was measured using dried blood spot tenofovir diphosphate (TFV-DP) levels. Risky decision making was assessed using the Iowa Gambling Task (IGT) and the Balloon Analogue Risk Task (BART), while impulsivity/disinhibition, sensation seeking, and substance use were assessed via standardized self-report questionnaires. A total of 58/84 (69%) of MSM who completed the 12-month post-study visit continued PrEP. Of those, n = 46 (79%) reached TFV-DP levels associated with adequate adherence. Individuals who elected to continue PrEP 12months post-trial had riskier decision making on BART, but less impulsivity/disinhibition compared to individuals who did not continue PrEP. Neither risky decision making nor impulsivity/disinhibition/sensation seeking nor substance use correlated with PrEP adherence. Our findings suggest that those with risky decision making may have greater insight into their HIV risks, and therefore be more likely to continue to use PrEP. However, elevated impulsivity/disinhibition, indicative of greater neurobehavioral alterations, was negatively associated with PrEP continuance and is a potential target for future interventions to help people link to PrEP.

Franz cells are routinely used to measure in vitro skin permeation of actives and must be inert to the permeant under study. The aim of the present work was to develop and manufacture transparent Franz-type diffusion cells using 3D printing and test these using a range of model active compounds. The study also aims to identify the critical 3D printing parameters necessary for the process including object design, choice of printing resin, printout curing and post-curing settings and introduction of model coatings. Transparent Franz cells were constructed using an online computer aided design program and reproduced with different stereolithography 3D printers. The two acrylate-based resins used for the fabrication process were a commercially available product and a polymer synthesised in-house. Comparative studies between glass and 3D printed Franz cells were conducted with selected model actives: terbinafine hydrochloride (TBF), niacinamide (NIA), diclofenac free acid (DFA) and n-methyl paraben (MPB). In preliminary studies, MPB showed the lowest recovery when exposed to the receptor compartment of 3D printed cells. Consequently, in vitro permeation studies were carried out using only MPB with polydimethylsiloxane (PDMS) membrane. A decrease in the amounts of selected compounds was observed for transparent 3D printed Franz cells compared to glass cells. MPB showed the lowest recovery (53.8 ± 13.1%) when compared with NIA (74.9 ± 4.0%), TBF (81.5 ± 12.0%) and DFA (90.2 ± 12.9%) after 72 h. Permeation studies conducted using 3D printed transparent cells with PDMS membrane also showed a decrease in MPB recovery of 51.4 ± 3.7% for the commercial resin and 94.4 ± 3.5% for the polymer synthesised in-house, when compared to glass cells. Although hydrophobic coatings were subsequently applied to the 3D printed cells the same reduction in MPB concentration was observed in the receptor solution. Transparent Franz cells were successfully prepared using 3D printing and were observed to be robust and leak-proof. There are few resins currently available for preparation of transparent materials and incompatibilities between the actives investigated and the 3D printed cells were evident. Hydrophobic coatings applied as barriers to the printed materials did not prevent these interactions. This article is protected by copyright. All rights reserved. [Abstract copyright: This article is protected by copyright. All rights reserved.]

Grit and ambition are psychological factors that may protect neurocognitive function among persons living with HIV (PLWH). We examined associations between grit, ambition, premorbid verbal intellectual function, and current neurocognitive and everyday functioning among PLWH and persons without HIV (HIV-). 120 PLWH and 94 HIV- adults completed the Grit Scale (includes total score and consistency of interests and perseverance of effort subscales), ambition scale, and a comprehensive neurobehavioral battery. PLWH had lower grit scores than HIV- adults. The two groups did not differ on ambition. No relationship was observed between grit and cognition among HIV- adults. Among PLWH, however, higher perseverance of effort and more ambition was related to better global neurocognitive functioning, and higher grit, but not ambition, was related to independence in daily functioning. Longitudinal studies are needed to elucidate these relationships over time and examine whether grit or ambition have protective effects on cognitive outcomes among PLWH.

Higher levels of physical activity (PA) have been linked to better neurocognitive functioning in many populations. The current study examines the longitudinal association between PA and neurocognitive functioning among HIV-infected and HIV-uninfected persons. Community-dwelling adults (N = 291) self-reported level of PA and completed a comprehensive neuropsychological battery at two to four study visits (Mean follow-up time = 2.6 years). Participants were divided into three PA groups: "No PA" (no PA at any visit), "consistent PA" (PA at ≥50% of visits), and "inconsistent PA" (PA 50% of visits). A mixed effect model, adjusting for significant covariates showed that all PA groups had statistically significant, yet modest, neurocognitive decline over time; and, the consistent PA group began with, and maintained, significantly better neurocognitive function compared to the other two PA groups. This effect was evident among both HIV-uninfected and HIV-infected persons, despite the fact that HIV-infected persons showed lower baseline neurocognitive function. PA is a modifiable lifestyle behavior that may help to protect against neurocognitive impairment regardless of HIV status, however, given the proportion of HIV-infected individuals who evidence neurocognitive difficulties, a focus on increasing PA seems warranted.La actividad física (AF) ha sido asociada con un mejor funcionamiento neurocognitivo en varios grupos. Este estudio examinó la asociación longitudinal entre la AF y el funcionamiento neurocognitivo en personas con y sin infección del VIH. Adultos viviendo en la comunidad (N = 291) proporcionaron información acerca de sus niveles de AF y completaron una batería neuropsicológica exhaustiva. Los participantes completaron entre dos y cuatro visitas relacionadas con el estudio (tiempo de seguimiento promedio = 2,6 años) y fueron divididos en tres grupos de AF: “Ninguna AF” (Ninguna AF durante todas las visitas del estudio), “AF Consistente” (AF durante 50% o más de las visitas del estudio), y “AF Inconsistente” (AF durante menos del 50% de las visitas del estudio). Un modelo estadístico mixto, ajustando por el efecto de variables externas, indicó que hubo una reducción estadísticamente significativa, pero poco pronunciada, en el funcionamiento neurocognitivo en todos los grupos. Además, el grupo con AF Consistente demostró un mejor funcionamiento neurocognitivo en comparación con los otros dos grupos de AF al comienzo del estudio, el cual se mantuvo durante el seguimiento. A pesar de que las personas con VIH demostraron un funcionamiento neurocognitivo más bajo al comienzo del estudio que las personas sin VIH, el efecto de AF fue demostrado en los dos grupos. Es importante recalcar que la AF es un factor de vida modificable que podría proteger contra los daños neurocognitivos independientemente de si las personas tienen o no VIH. Dada la proporción de personas con VIH que demuestran problemas neurocognitivos relacionados con esta enfermedad, será importante enfocar los esfuerzos investigativos en desarrollar formas de incrementar la AF en este grupo de personas.

Two metabolites (M4 and M1b) in plasma and four metabolites (M4, M6, M1a and M1b) in faeces were detected through the human ADME study following a single oral administration of [14C]alectinib, a small-molecule anaplastic lymphoma kinase inhibitor, to healthy subjects. In the present study, M1a and M1b, which chemical structures had not been identified prior to the human ADME study, were identified as isomers of a carboxylate metabolite oxidatively cleaved at the morpholine ring. In faeces, M4 and M1b were the main metabolites, which shows that the biotransformation to M4 and M1b represents two main metabolic pathways for alectinib. In plasma, M4 was a major metabolite and M1b was a minor metabolite. The contribution to in vivo pharmacological activity of these circulating metabolites was assessed from their in vitro pharmacological activity and plasma protein binding. M4 had a similar cancer cell growth inhibitory activity and plasma protein binding to that of alectinib, suggesting its contribution to the antitumor activity of alectinib, whereas the pharmacological activity of M1b was insignificant.