Visual cortical γ-aminobutyric acid and perceptual suppression in amblyopia.

In amblyopia, abnormal visual experience during development leads to an enduring loss of visual acuity in adulthood. Physiological studies in animal models suggest that intracortical GABAergic inhibition may mediate visual deficits in amblyopia. To better understand the relationship between visual cortical γ-aminobutyric acid (GABA) and perceptual suppression in persons with amblyopia (PWA), we employed magnetic resonance spectroscopy (MRS) to quantify GABA levels in both PWA and normally-sighted persons (NSP). In the same individuals, we obtained psychophysical measures of perceptual suppression for a variety of ocular configurations. In PWA, we found a robust negative correlation between the depth of amblyopia (the difference in visual acuity between the amblyopic and non-amblyopic eyes) and GABA concentration that was specific to visual cortex and was not observed in a sensorimotor cortical control region. Moreover, lower levels of visual cortical GABA were associated with weaker perceptual suppression of the fellow eye by the amblyopic eye and stronger suppression of the amblyopic eye by the fellow eye. Taken together, our findings provide evidence that intracortical GABAergic inhibition is an important component of the pathology of human amblyopia and suggest possible therapeutic interventions to restore vision in the amblyopic eye through enhancement of visual cortical GABAergic signaling in PWA.

72 weeks post-partum follow-up of dolutegravir versus efavirenz initiated in late pregnancy (DolPHIN-2): an open-label, randomised controlled study.

BACKGROUND: Late initiation of antiretrovirals in pregnancy is associated with increased risk of perinatal transmission and higher infant mortality. We report the final 72-week postpartum results for efficacy and safety of dolutegravir-based compared with efavirenz-based regimens in mothers and infants. METHODS: DolPHIN-2 was a randomised, open-label trial. Pregnant women in South Africa and Uganda aged at least 18 years, with untreated but confirmed HIV infection and an estimated gestation of at least 28 weeks, initiating antiretroviral therapy in third trimester were eligible for inclusion. Eligible women were randomly assigned (1:1) to receive either dolutegravir-based (50 mg dolutegravir, 300 mg tenofovir disoproxil fumarate, and either 200 mg emtricitabine in South Africa or 300 mg lamivudine in Uganda) or efavirenz-based (fixed dose combination 600 mg tenofovir disoproxil fumarate plus either emtricitabine in South Africa or lamivudine in Uganda) therapy. The primary efficacy outcome was the time to a viral load of less than 50 copies per mL measured at 6, 12, 24, 48, and 72 weeks postpartum with a Cox model adjusting for viral load and CD4 cell count. Safety endpoints were summarised by the number of women and infants with events. This trial is registered with ClinicalTrials.gov, NCT03249181. FINDINGS: Between Jan 23 and Aug 15, 2018, 280 women were screened for inclusion, of whom 268 (96%) women were randomly assigned: 133 (50%) to the efavirenz group and 135 (50%) to the dolutegravir group. 250 (93%; 125 [50%] in the efavirenz group and 125 [50%] in the dolutegravir group) women were included in the intention-to-treat analysis of efficacy. Median time to viral load of less than 50 copies per mL was 4·1 weeks (IQR 4·0-5·1) in the dolutegravir group compared with 12·1 weeks (10·7-13·3) in the efavirenz group (adjusted hazard ratio [HR] 1·93 [95% CI 1·5-2·5]). At 72 weeks postpartum, 116 (93%) mothers in the dolutegravir group and 114 (91%) in the efavirenz group had a viral load of less than 50 copies per mL. Of 57 (21%) mothers with a severe adverse event, three (2%) in the dolutegravir group and five (4%) in the efavirenz group were related to the drug (dolutegravir drug-related events were one woman each with suicidal ideation, suicide attempt, herpes zoster meningitis; efavirenz drug-related events were one woman each with suicide attempt and liver cirrhosis, and three people with drug-induced liver injury). Of 136 (56%) infants in whom severe adverse events were recorded, none were related to the study drugs. In addition to the three infant HIV infections detected at birth in the dolutegravir group that have been previously reported, an additional transmission in the efavirenz group occurred during breastfeeding despite optimal maternal viral suppression and serial negative infant tests in the first year of life. INTERPRETATION: Dolutegravir was safe and well tolerated, supporting updated WHO treatment recommendations in pregnant and breastfeeding women. Infant HIV transmissions can occur during breastfeeding despite persistently undetectable maternal viral load highlighting the need for continued infant testing. FUNDING: Unitaid.

Statistical Nonparametric fMRI Maps in the Analysis of Response Inhibition in Abstinent Individuals with History of Alcohol Use Disorder.

Inhibitory impairments may persist after abstinence in individuals with alcohol use disorder (AUD). Using traditional statistical parametric mapping (SPM) fMRI analysis, which requires data to satisfy parametric assumptions often difficult to satisfy in biophysical system as brain, studies have reported equivocal findings on brain areas responsible for response inhibition, and activation abnormalities during inhibition found in AUD persist after abstinence. Research is warranted using newer analysis approaches. fMRI scans were acquired during a Go/NoGo task from 30 abstinent male AUD and 30 healthy control participants with the objectives being (1) to characterize neuronal substrates associated with response inhibition using a rigorous nonparametric permutation-based fMRI analysis and (2) to determine whether these regions were differentially activated between abstinent AUD and control participants. A blood oxygen level dependent contrast analysis showed significant activation in several right cortical regions and deactivation in some left cortical regions during successful inhibition. The largest source of variance in activation level was due to group differences. The findings provide evidence of cortical substrates employed during response inhibition. The largest variance was explained by lower activation in inhibition as well as ventral attentional cortical networks in abstinent individuals with AUD, which were not found to be associated with length of abstinence, age, or impulsiveness.

Recommendations for effective documentation in regional anesthesia: an expert panel Delphi consensus project.

BACKGROUND AND OBJECTIVES: Documentation is important for quality improvement, education, and research. There is currently a lack of recommendations regarding key aspects of documentation in regional anesthesia. The aim of this study was to establish recommendations for documentation in regional anesthesia. METHODS: Following the formation of the executive committee and a directed literature review, a long list of potential documentation components was created. A modified Delphi process was then employed to achieve consensus amongst a group of international experts in regional anesthesia. This consisted of 2 rounds of anonymous electronic voting and a final virtual round table discussion with live polling on items not yet excluded or accepted from previous rounds. Progression or exclusion of potential components through the rounds was based on the achievement of strong consensus. Strong consensus was defined as ≥75% agreement and weak consensus as 50%-74% agreement. RESULTS: Seventy-seven collaborators participated in both rounds 1 and 2, while 50 collaborators took part in round 3. In total, experts voted on 83 items and achieved a strong consensus on 51 items, weak consensus on 3 and rejected 29. CONCLUSION: By means of a modified Delphi process, we have established expert consensus on documentation in regional anesthesia.

An Open Label, Adaptive, Phase 1 Trial of High-Dose Oral Nitazoxanide in Healthy Volunteers: An Antiviral Candidate for SARS-CoV-2.

Repurposing approved drugs may rapidly establish effective interventions during a public health crisis. This has yielded immunomodulatory treatments for severe coronavirus disease 2019 (COVID-19), but repurposed antivirals have not been successful to date because of redundancy of the target in vivo or suboptimal exposures at studied doses. Nitazoxanide is a US Food and Drug Administration (FDA) approved antiparasitic medicine, that physiologically-based pharmacokinetic (PBPK) modeling has indicated may provide antiviral concentrations across the dosing interval, when repurposed at higher than approved doses. Within the AGILE trial platform (NCT04746183) an open label, adaptive, phase I trial in healthy adult participants was undertaken with high-dose nitazoxanide. Participants received 1,500 mg nitazoxanide orally twice-daily with food for 7 days. Primary outcomes were safety, tolerability, optimum dose, and schedule. Intensive pharmacokinetic (PK) sampling was undertaken day 1 and 5 with minimum concentration (Cmin ) sampling on days 3 and 7. Fourteen healthy participants were enrolled between February 18 and May 11, 2021. All 14 doses were completed by 10 of 14 participants. Nitazoxanide was safe and with no significant adverse events. Moderate gastrointestinal disturbance (loose stools or diarrhea) occurred in 8 participants (57.1%), with urine and sclera discoloration in 12 (85.7%) and 9 (64.3%) participants, respectively, without clinically significant bilirubin elevation. This was self-limiting and resolved upon drug discontinuation. PBPK predictions were confirmed on day 1 but with underprediction at day 5. Median Cmin was above the in vitro target concentration on the first dose and maintained throughout. Nitazoxanide administered at 1,500 mg b.i.d. with food was safe with acceptable tolerability a phase Ib/IIa study is now being initiated in patients with COVID-19.

AGILE: a seamless phase I/IIa platform for the rapid evaluation of candidates for COVID-19 treatment: an update to the structured summary of a study protocol for a randomised platform trial letter.

BACKGROUND: There is an urgent unmet clinical need for the identification of novel therapeutics for the treatment of COVID-19. A number of COVID-19 late phase trial platforms have been developed to investigate (often repurposed) drugs both in the UK and globally (e.g. RECOVERY led by the University of Oxford and SOLIDARITY led by WHO). There is a pressing need to investigate novel candidates within early phase trial platforms, from which promising candidates can feed into established later phase platforms. AGILE grew from a UK-wide collaboration to undertake early stage clinical evaluation of candidates for SARS-CoV-2 infection to accelerate national and global healthcare interventions. METHODS/DESIGN: AGILE is a seamless phase I/IIa platform study to establish the optimum dose, determine the activity and safety of each candidate and recommend whether it should be evaluated further. Each candidate is evaluated in its own trial, either as an open label single arm healthy volunteer study or in patients, randomising between candidate and control usually in a 2:1 allocation in favour of the candidate. Each dose is assessed sequentially for safety usually in cohorts of 6 patients. Once a phase II dose has been identified, efficacy is assessed by seamlessly expanding into a larger cohort. AGILE is completely flexible in that the core design in the master protocol can be adapted for each candidate based on prior knowledge of the candidate (i.e. population, primary endpoint and sample size can be amended). This information is detailed in each candidate specific trial protocol of the master protocol. DISCUSSION: Few approved treatments for COVID-19 are available such as dexamethasone, remdesivir and tocilizumab in hospitalised patients. The AGILE platform aims to rapidly identify new efficacious and safe treatments to help end the current global COVID-19 pandemic. We currently have three candidate specific trials within this platform study that are open to recruitment. TRIAL REGISTRATION: EudraCT Number: 2020-001860-27 14 March 2020 ClinicalTrials.gov Identifier: NCT04746183  19 February 2021 ISRCTN reference: 27106947.

Effects of Upper Extremity Elevation on Intra-Cast Pressure and Digital Perfusion in a Fiberglass Short-Arm Cast Model.

The goal of this study was to determine the relationship of digital artery pressure to arm position and forearm skin surface pressure using a short-arm cast experimental setup, to ascertain the safest position for the injured casted upper extremity. A total of 27 volunteers were placed in bilateral short-arm fiber-glass casts with an empty 50-mL bladder bag under the cast and attached to a pressure transducer. Digital systolic pressure (Pdig), and skin surface pressure under the cast (Pskin) were assessed in 4 positions. Measurements were taken with and without 50 mL air in the bladder bag. A total of 54 forearms were evaluated. Both arm position and Pskin had a significant effect on Pdig (P<.001 for both), with increasing elevation leading to a decrease in Pdig (r=-0.50). The effect size of position on Pdig was large, whereas that of Pskin was small (partial eta-squared=0.371 and 0.028, respectively). Linear regression analysis of Pskin and Pdig with air in the neutral position yielded a moderate negative relationship with body mass index (r=-0.64, P<.001 for Pskin; r=0.49, P<.001 for Pdig) and wrist circumference (r=-0.66, P<.001 for Pskin; r=0.52, P<.001 for Pdig), without significant association with forearm length. For volunteers with short-arm fiberglass casts, increasing arm elevation had a large effect size on digital arterial pressure, whereas 50 mL simulated swelling had only a small effect size. Decreasing body mass index and forearm circumference correlated with increased skin surface pressure and decreased digital arterial pressure. These findings show that aggressive elevation of the injured limb may not be as desirable as previously believed. [Orthopedics. 2021;44(4):e487-e492.].

A pilot randomized-controlled trial evaluating the erector spinae plane block in thoracic and breast surgery.

PURPOSE: This pilot study evaluated the feasibility of investigating the effect of the erector spinae plane (ESP) block on the patient-centred outcomes of quality of recovery-15 (QoR-15), and brief pain inventory (BPI) in thoracic and breast surgery patients. METHODS: In this randomized-controlled pilot trial, 82 patients undergoing video-assisted thoracoscopic surgery (n = 77) and mastectomy (n = 5) received either continuous ESP block with ropivacaine (ropivacaine group) or the same procedure with 0.9% saline (saline group). All patients received surgical intercostal block (thoracic surgery) or local anesthetic infiltration (breast surgery). Feasibility as the primary outcome was evaluated on recruitment (three patients per week), catheter retention (above 90% at 24 hr), and patient attrition (less than 10%). Secondary outcomes comprised of QoR-15, BPI, and opioid consumption. RESULTS: Recruitment rate was 1.8 patients per week. Catheters were retained in 77 patients (94%) at 24 hr. At three months, five patients were lost to follow-up (6%). At 24 hr compared with baseline, the ropivacaine group had a smaller decline in QoR-15 score (median difference, 14; 95% confidence interval [CI], 2 to 26; P = 0.02) and a smaller increase in BPI global score (median difference, 14; 95% CI, 0 to 24; P = 0.048). There was no difference in opioid consumption (P = 0.08). CONCLUSIONS: In this pilot study, the target recruitment rate was not met, but catheter retention and patient attrition rates were both satisfactory. A definitive trial with QoR-15 as the primary outcome would require 300 study participants. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ID12618000701224); registered 30 April 2018.

RéSUMé: OBJECTIF: Cette étude pilote a évalué la faisabilité d'explorer l'effet d'un bloc du plan des muscles érecteurs du rachis sur des résultats centrés sur le patient, soit la qualité de récupération (QoR-15) et le Questionnaire concis de la douleur (QCD ou BPI 'Brief Pain Inventory'), chez les patients de chirurgie thoracique et mammaire. MéTHODE: Dans cette étude pilote randomisée contrôlée, 82 patients subissant une chirurgie thoracoscopique (n = 77) ou une mastectomie (n = 5) ont reçu soit un bloc continu du plan des muscles érecteurs du rachis avec de la ropivacaïne (groupe ropivacaïne), ou la même intervention avec une solution saline à 0,9 % (groupe salin). Tous les patients ont reçu un bloc intercostal chirurgical (chirurgie thoracique) ou une infiltration d'anesthésique local (chirurgie mammaire). La faisabilité a été évaluée par les critères de recrutement (trois patients par semaine), de la rétention du cathéter (plus de 90 % à 24 h), et du taux d'attrition des patients (moins de 10 %). Les critères d'évaluation secondaires comportaient la QoR-15, le QCD et la consommation d'opioïdes. RéSULTATS: Le taux de recrutement était de 1,8 patients par semaine. Les cathéters sont restés en place chez 77 patients (94 %) à 24 h. À trois mois, cinq patients ont été perdus au suivi (6 %). Après 24 h, par rapport aux valeurs de base, le groupe ropivacaïne présentait un déclin plus léger du score de QoR-15 (différence médiane, 14; intervalle de confiance [IC] 95 %, 2 à 26; P = 0,02) ainsi qu'une augmentation moindre du score global de QCD (différence médiane, 14; IC 95 %, 0 à 24; P = 0,048). Aucune différence n'a été observée en matière de consommation d'opioïdes (P = 0,08). CONCLUSION: Dans cette étude pilote, le taux de recrutement cible n'a pas été atteint, mais les taux de rétention des cathéters et d'attrition des patients étaient tous deux satisfaisants. Une étude définitive de la QoR-15 en tant que critère d'évaluation principal nécessiterait le recrutement de 300 participants. ENREGISTREMENT DE L'éTUDE: Australian New Zealand Clinical Trials Registry (ID12618000701224); enregistrée le 30 avril 2018.

Transient cholinergic enhancement does not significantly affect either the magnitude or selectivity of perceptual learning of visual texture discrimination.

Perceptual learning (PL), often characterized by improvements in perceptual performance with training that are specific to the stimulus conditions used during training, exemplifies experience-dependent cortical plasticity. An improved understanding of how neuromodulatory systems shape PL promises to provide new insights into the mechanisms of plasticity, and by extension how PL can be generated and applied most efficiently. Previous studies have reported enhanced PL in human subjects following administration of drugs that increase signaling through acetylcholine (ACh) receptors, and physiological evidence indicates that ACh sharpens neuronal selectivity, suggesting that this neuromodulator supports PL and its stimulus specificity. Here we explored the effects of enhancing endogenous cholinergic signaling during PL of a visual texture discrimination task. We found that training on this task in the lower visual field yielded significant behavioral improvement at the trained location. However, a single dose of the cholinesterase inhibitor donepezil, administered before training, did not significantly impact either the magnitude or the location specificity of texture discrimination learning compared with placebo. We discuss potential explanations for discrepant findings in the literature regarding the role of ACh in visual PL, including possible differences in plasticity mechanisms in the dorsal and ventral cortical processing streams.

Dolutegravir versus efavirenz in women starting HIV therapy in late pregnancy (DolPHIN-2): an open-label, randomised controlled trial.

BACKGROUND: Late initiation of HIV antiretroviral therapy (ART) in pregnancy is associated with not achieving viral suppression before giving birth and increased mother-to-child transmission of HIV. We aimed to investigate virological suppression before giving birth with dolutegravir compared with efavirenz, when initiated during the third trimester. METHODS: In this randomised, open-label trial, DolPHIN-2, we recruited pregnant women in South Africa and Uganda aged at least 18 years, with untreated but confirmed HIV infection and an estimated gestation of at least 28 weeks, initiating ART in third trimester. Participants were randomly assigned (1:1) to dolutegravir-based or efavirenz-based therapy. HIV viral load was measured 7 days and 28 days after antiretroviral initiation, at 36 weeks' gestation, and at the post-partum visit (0-14 days post partum). The primary efficacy outcome was a viral load of less than 50 copies per mL at the first post-partum visit, and the primary safety outcome was the occurrence of drug-related adverse events in mothers and infants until the post-partum visit. Longer-term follow-up of mothers and infants continues. This study is registered with ClinicalTrials.gov, NCT03249181. FINDINGS: Between Jan 23, and Aug 15, 2018, we randomly assigned 268 mothers to dolutegravir (135) or efavirenz (133). All mothers and their infants were included in the safety analysis, and 250 mothers (125 in the dolutegravir group, 125 in the efavirenz group) and their infants in efficacy analyses, by intention-to-treat analyses. The median duration of maternal therapy at birth was 55 days (IQR 33-77). 89 (74%) of 120 in the dolutegravir group had viral loads less than 50 copies per mL, compared with 50 (43%) of 117 in the efavirenz group (risk ratio 1·64, 95% CI 1·31-2·06). 30 (22%) of 137 mothers in the dolutegravir group reported serious adverse events compared with 14 (11%) of 131 in the efavirenz group (p=0·013), particularly surrounding pregnancy and puerperium. We found no differences in births less than 37 weeks and less than 34 weeks gestation (16·4% vs 3·3%, across both groups). Three stillbirths in the dolutegravir group and one in the efavirenz group were considered unrelated to treatment. Three infant HIV infections were detected, all in the dolutegravir group, and were considered likely to be in-utero transmissions. INTERPRETATION: Our data support the revision to WHO guidelines recommending the transition to dolutegravir in first-line ART for all adults, regardless of pregnancy or child-bearing potential. FUNDING: Unitaid.

Superb Microvascular Imaging Improves Detection of Vascularity in Indeterminate Renal Masses.

OBJECTIVES: Vascular assessment of indeterminate renal masses (iRMs) remains a crucial element of diagnostic imaging, as the presence of blood flow within renal lesions suggests malignancy. We compared the utility of Superb Microvascular Imaging (SMI; Canon Medical Systems, Tustin, CA), a novel Doppler technique, to standard color Doppler imaging (CDI) and power Doppler imaging (PDI) for the detection of vascularity within iRMs. METHODS: Patients undergoing contrast-enhanced ultrasound (CEUS) evaluations for iRMs first underwent a renal ultrasound examination with the following modes: CDI, PDI, color Superb Microvascular Imaging (cSMI), and monochrome Superb Microvascular Imaging (mSMI), using an Aplio i800 scanner with an i8CX1 transducer (Canon Medical Systems). After image randomization, each mode was assessed for iRM vascularity by 4 blinded readers on a diagnostic confidence scale of 1 to 5 (5 = most confident). The results were compared to CEUS as the reference standard. RESULTS: Forty-one patients with 50 lesions met inclusion criteria. Relative to the other 3 modalities, mSMI had the highest sensitivity (63.3%), whereas cSMI had the highest specificity (62.1%). Both cSMI and mSMI also had the highest diagnostic accuracy (0.678 and 0.680, respectively; both P < 0.001) compared to CDI (0.568) and PDI (0.555). Although the reader-reported confidence interval of mSMI (mean ± SD, 3.6 ± 1.1) was significantly lower than CDI (4.1 ± 1.0) and PDI (4.0 ± 1.0; P < 0.001), the confidence level of cSMI (4.1 ± 0.9) was not (P > 0.173). CONCLUSIONS: Preliminary data suggest that SMI is a potentially useful modality in detecting microvasculature in iRMs compared to standard Doppler techniques. Future studies should aim to compare the efficacy of both SMI and CEUS and to assess the ability of SMI to characterize malignancy in iRMs.

Reversing the Effects of a Peripheral Nerve Block with Normal Saline: A Randomised Controlled Trial.

OBJECTIVE: The objective of the present study was to determine whether or not the effects of peripheral nerve block can be reversed by flushing normal saline down a peripheral nerve block catheter following the completion of arteriovenous (AV) fistula surgery. METHODS: In the present study, 38 patients undergoing AV fistula surgery were recruited, and a brachial plexus block with a peripheral nerve catheter was established. Following surgery, the patients were randomised to either the control group or the washout group, where 10 mL of normal saline was flushed down the peripheral nerve catheter at 15-minute intervals for 1 h while the patients were in the postoperative recovery room. An observer blinded to the patient group allocation assessed motor and sensory functions in all patients at 15-minute intervals for 1 h, and pain scores were recorded. RESULTS: There was no difference in time to resolution of motor or sensory block in the two groups. The median changes in the motor score were 1.5 out of 10 for the control group and 2 for the washout group (p=0.95). The median changes in the sensory score were 3 out of 10 for the control group and 1 for the washout group (p=0.14). There were no differences in pain scores over the study period in either group (p=0.44). CONCLUSION: We were unable to show any useful improvement in block resolution with normal saline washout of supraclavicular or infraclavicular brachial plexus blocks following AV fistula surgery.