Selected and shared hematological responses to apnea in elite human free-divers and northern elephant seals (Mirounga angustirostris).

Despite elite, human free-divers achieving incredible feats in competitive free-diving, there has yet to be a study that compares consummate divers, (i.e. northern elephant seals) to highly conditioned free-divers (i.e., elite, competitive free-diving humans). Herein, we compare these two diving models and suggest that hematological traits detected in seals reflect species-specific specializations, while hematological traits shared between the two species are fundamental mammalian characteristics. Arterial blood samples were analyzed in elite, human, free-divers (n=14) during a single, maximal volitional apnea and in juvenile northern elephant seals (n=3) during rest-associated apnea. Humans and elephant seals had comparable apnea durations (~6.5 mins) and end-apneic arterial PO2 (humans: 40.4±3.0mmHg (mean±SE), seals: 27.1±5.9mmHg; p=0.2). Despite similar increases in arterial PCO2 (humans: 33±5%, seals: 16.3±5%; P=0.2), only humans experienced reductions in pH from baseline (humans: 7.45±0.01, seal: 7.39±0.02) to end apnea (humans: 7.37±0.01, seals: 7.38±0.02; p<0.0001). Hemoglobin P50 was greater in humans compared to elephant seals (29.9±1.5 and 28.7±0.6mmHg, respectively; p=0.046). Elephant seals overall had higher COHb levels (5.9±2.6%) compared to humans (0.8±1.2%; p<0.0001); however, following apnea, COHb was reduced in seals (baseline: 6.1±0.3%, end-apnea: 5.6±0.3%), but was slightly elevated in humans (baseline: 0.7±0.1%, end-apnea: 0.9±0.1%; p<0.0002, both comparisons). Our data indicate that during static apnea, seals have reduced hemoglobin P50, greater pH buffering, and increased COHb levels. The differences in hemoglobin P50 is likely due to the differences in the physiological environment between the two species during apnea, whereas enhanced pH buffering and higher COHb may represent traits selected for in elephant seals.

Shining a light on cerebral autoregulation: Are we anywhere near the truth?

The near-infrared spectroscopy (NIRS)-derived cerebral oximetry index (COx) has become popularized for non-invasive neuromonitoring of cerebrovascular function in post-cardiac arrest patients with hypoxic-ischemic brain injury (HIBI). We provide commentary on the physiologic underpinnings and assumptions of NIRS and the COx, potential confounds in the context of HIBI, and the implications for the assessment of cerebral autoregulation.

Severe hypoxaemic hypercapnia compounds cerebral oxidative-nitrosative stress during extreme apnoea: Implications for cerebral bioenergetic function.

We examined the extent to which apnoea-induced extremes of oxygen demand/carbon dioxide production impact redox regulation of cerebral bioenergetic function. Ten ultra-elite apnoeists (six men and four women) performed two maximal dry apnoeas preceded by normoxic normoventilation, resulting in severe end-apnoea hypoxaemic hypercapnia, and hyperoxic hyperventilation designed to ablate hypoxaemia, resulting in hyperoxaemic hypercapnia. Transcerebral exchange of ascorbate radicals (by electron paramagnetic resonance spectroscopy) and nitric oxide metabolites (by tri-iodide chemiluminescence) were calculated as the product of global cerebral blood flow (by duplex ultrasound) and radial arterial (a) to internal jugular venous (v) concentration gradients. Apnoea duration increased from 306 ± 62 s during hypoxaemic hypercapnia to 959 ± 201 s in hyperoxaemic hypercapnia (P ≤ 0.001). Apnoea generally increased global cerebral blood flow (all P ≤ 0.001) but was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose (P = 0.015-0.044). This was associated with a general net cerebral output (v > a) of ascorbate radicals that was greater in hypoxaemic hypercapnia (P = 0.046 vs. hyperoxaemic hypercapnia) and coincided with a selective suppression in plasma nitrite uptake (a > v) and global cerebral blood flow (P = 0.034 to <0.001 vs. hyperoxaemic hypercapnia), implying reduced consumption and delivery of nitric oxide consistent with elevated cerebral oxidative-nitrosative stress. In contrast, we failed to observe equidirectional gradients consistent with S-nitrosohaemoglobin consumption and plasma S-nitrosothiol delivery during apnoea (all P ≥ 0.05). Collectively, these findings highlight a key catalytic role for hypoxaemic hypercapnia in cerebral oxidative-nitrosative stress. KEY POINTS: Local sampling of blood across the cerebral circulation in ultra-elite apnoeists determined the extent to which severe end-apnoea hypoxaemic hypercapnia (prior normoxic normoventilation) and hyperoxaemic hypercapnia (prior hyperoxic hyperventilation) impact free radical-mediated nitric oxide bioavailability and global cerebral bioenergetic function. Apnoea generally increased the net cerebral output of free radicals and suppressed plasma nitrite consumption, thereby reducing delivery of nitric oxide consistent with elevated oxidative-nitrosative stress. The apnoea-induced elevation in global cerebral blood flow was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose. Cerebral oxidative-nitrosative stress was greater during hypoxaemic hypercapnia compared with hyperoxaemic hypercapnia and coincided with a lower apnoea-induced elevation in global cerebral blood flow, highlighting a key catalytic role for hypoxaemia. This applied model of voluntary human asphyxia might have broader implications for the management and treatment of neurological diseases characterized by extremes of oxygen demand and carbon dioxide production.

Intravenous Ganaxolone: Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability in Healthy Adults.

Ganaxolone, a neuroactive steroid anticonvulsant that modulates both synaptic and extrasynaptic γ-aminobutyric acid type A (GABAA ) receptors, is in development for treatment of status epilepticus (SE) and rare epileptic disorders, and has been approved in the United States for treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder in patients ≥2 years old. This phase 1 study in 36 healthy volunteers evaluated the pharmacokinetics, pharmacodynamics, and safety of intravenous ganaxolone administered as a (i) single bolus, (ii) infusion, and (iii) bolus followed by continuous infusion. After a single bolus over 2 minutes (20 mg) or 5 minutes (10 or 30 mg), ganaxolone was detected in plasma with a median Tmax of 5 minutes, whereas a 60-minute infusion (10 or 30 mg) or a bolus (6 mg over 5 minutes) followed by infusion (20 mg/h) for 4 hours achieved a median Tmax of approximately 1 and 3 hours, respectively. Cmax was dose and administration-time dependent, ranging from 73.8 ng/mL (10 mg over 5 minutes) to 1240 ng/mL (30 mg over 5 minutes). Bolus doses above 10 mg of ganaxolone markedly influenced the bispectral index score with a rapid decline; smaller changes occurred on the Modified Observer's Assessment of Alertness/Sedation scale and in quantitative electroencephalogram. Most adverse events were of mild severity, with 2 events of moderate severity; none were reported as serious. No effects on systemic hemodynamics or respiratory functions were reported. Overall, ganaxolone was generally well tolerated at the doses studied and demonstrated pharmacokinetic and pharmacodynamic properties suitable to treat SE.

Intense exercise at high altitude causes platelet loss across the brain in humans.

Platelets are known primarily for their role in blood clotting; however, it is becoming clear that they play diverse roles beyond that of haemostasis. Exercise has been shown to activate platelets and stimulate neurogenesis, neuroplasticity and improve cognitive function, highlighting a potentially powerful link between platelet function and brain health. Despite this clear link between platelets and the brain, very little is known about the behaviour of platelets through the cerebral circulation in humans. We examined platelet concentration across the brain in exercising humans at sea level (340 m) and high altitude (6-8 days at 3800 m; a stimulus known to modify platelet function). During intense exercise at sea level, platelet concentration increased similarly by 27 ± 17% in the arterial and internal jugular venous circulations (exercise: P < 0.001, interaction: P = 0.262), indicating no uptake or release of platelets into/from the brain. At high altitude, resting platelet concentrations were similar to sea level values in both the arterial and jugular venous circulations (P = 0.590); however, intense exercise at high altitude caused a 31 ± 35% decrease in platelet concentration across the brain (P = 0.016). This divergent response across the brain was not observed in any other haematological or metabolic variables. These data highlight a unique situation where the combination of intense exercise and high altitude hypoxia cause a decrease in platelet concentration across the cerebral circulation. The physiological implications and mechanisms that might influence platelet function across the brain during exercise at high altitude remain to be established. KEY POINTS: Platelets are known primarily for their role in blood clotting; however, it is becoming clear that they play diverse roles beyond that of haemostasis. Exercise has been shown to activate platelets, which in turn stimulate neurogenesis, neuroplasticity and improve cognitive function, highlighting a powerful link between platelet function and brain health. At sea level, platelet concentration in blood going into and out of the brain was similar at rest, during maximal exercise and in recovery from exercise. During maximal exercise at high altitude, platelet concentration was 31% lower in the blood exiting the brain; the final destination of these platelets is unknown. The physiological implications and mechanisms that might influence platelet function across the cerebral circulation during exercise at high altitude remain to be established.

Artificial intelligence-supported diabetic retinopathy screening in Tanzania: rationale and design of a randomised controlled trial.

INTRODUCTION: Globally, diabetic retinopathy (DR) is a major cause of blindness. Sub-Saharan Africa is projected to see the largest proportionate increase in the number of people living with diabetes over the next two decades. Screening for DR is recommended to prevent sight loss; however, in many low and middle-income countries, because of a lack of specialist eye care staff, current screening services for DR are not optimal. The use of artificial intelligence (AI) for DR screening, which automates the grading of retinal photographs and provides a point-of-screening result, offers an innovative potential solution to improve DR screening in Tanzania. METHODS AND ANALYSIS: We will test the hypothesis that AI-supported DR screening increases the proportion of persons with true referable DR who attend the central ophthalmology clinic following referral after screening in a single-masked, parallel group, individually randomised controlled trial. Participants (2364) will be randomised (1:1 ratio) to either AI-supported or the standard of care DR screening pathway. Participants allocated to the AI-supported screening pathway will receive their result followed by point-of-screening counselling immediately after retinal image capture. Participants in the standard of care arm will receive their result and counselling by phone once the retinal images have been graded in the usual way (typically after 2-4 weeks). The primary outcome is the proportion of persons with true referable DR attending the central ophthalmology clinic within 8 weeks of screening. Secondary outcomes, by trial arm, include the proportion of persons attending the central ophthalmology clinic out of all those referred, sensitivity and specificity, number of false positive referrals, acceptability and fidelity of AI-supported screening. ETHICS AND DISSEMINATION: The London School of Hygiene & Tropical Medicine, Kilimanjaro Christian Medical Centre and Tanzanian National Institute of Medical Research ethics committees have approved the trial. The results will be submitted to peer-reviewed journals for publication. TRIAL REGISTRATION NUMBER: ISRCTN18317152.

Differentiating stages of functional vision loss from glaucoma using the Disc Damage Likelihood Scale and cup:disc ratio.

BACKGROUND: Glaucoma staging is critical for treatment planning but has rarely been tested in severe/end-stage disease. We compared the performance of the Disc Damage Likelihood Scale (DDLS) and cup:disc ratio (CDR) using a functional glaucoma staging system (GSS) as the reference standard. METHODS: Post hoc analysis of a randomised controlled trial at the Eye Department of Kilimanjaro Christian Medical Centre, Tanzania. Eligible participants (aged ≥18 years) with open-angle glaucoma, intraocular pressure (IOP) of >21 mm Hg, were randomised to timolol 0.5% eye drops or selective laser trabeculoplasty. Fundoscopy established vertical and horizontal CDRs and DDLS. Visual acuity and static visual fields were graded (GSS). The study used area under the receiver operating characteristic (AROC) curves and Spearman's rank correlation coefficients to compare staging systems. Logistic regression with generalised estimating equations determined risk factors of functional severe/end-stage glaucoma. RESULTS: 382 eyes (201 participants) were evaluated; 195 (51%) had severe or end-stage glaucoma; mean IOP was 26.7 (SD 6.9) mm Hg. DDLS yielded an AROC of 0.90 (95% CI 0.87 to 0.93), vertical cup:disc ratio (vCDR) of 0.88 (95% CI 0.85 to 0.91, p=0.048) for identifying severe/end-stage disease. Correlation coefficients comparing GSS to DDLS and vCDRs were 0.73 and 0.71, respectively. Advanced structural stages, vision impairment, higher IOP and less financial resources were risk factors of functional severe/end-stage glaucoma. CONCLUSION: This study indicates that both structural staging systems can differentiate severe/end-stage glaucoma from less severe disease, with a moderate advantage of DDLS over CDR. Clinical examination of the optic disc plays an important role in addition to functional assessment when managing severe/end-stage glaucoma.

A pilot study to assess the feasibility of a remotely monitored high-intensity interval training program prior to allogeneic hematopoietic stem cell transplantation.

INTRODUCTION: Although allogeneic hematopoietic stem cell transplantation (HCT) can be a curative therapy for hematologic disorders, it is associated with treatment-related complications and losses in cardiorespiratory fitness and physical function. High-intensity interval training (HIIT) may be a practical way to rapidly improve cardiorespiratory fitness and physical function in the weeks prior to HCT. The primary aim of this study was to assess the feasibility of implementing a pre-HCT home-based HIIT intervention. The secondary aim was to evaluate pre to post changes in cardiorespiratory fitness and physical function following the intervention. METHODS: This was a single-arm pilot study with patients who were scheduled to undergo allogeneic HCT within six months. Patients were instructed to complete three 30-minute home-based HIIT sessions/week between the time of study enrollment and sign-off for HCT. Sessions consisted of a 5-minute warm-up, 10 high and low intervals performed for one minute each, and a 5-minute cool-down. Prescribed target heart rates (HR) for the high- and low-intensity intervals were 80-90% and 50-60% of HR reserve, respectively. Heart rates during HIIT were captured via an Apple Watch and were remotely monitored. Feasibility was assessed via retention, session adherence, and adherence to prescribed interval number and intensities. Paired t-tests were used to compare changes in fitness (VO2peak) and physical function [Short Physical Performance Battery (SPPB), 30-second sit to stand, and six-minute walk test (6MWT)] between baseline and sign-off. Pearson correlations were used to determine the relationship between intervention length and changes in cardiorespiratory fitness or functional measures. RESULTS: Thirteen patients (58.8±11.6 years) participated in the study, and nine (69.2%) recorded their training sessions throughout the study. Median session adherence for those nine participants was 100% (IQR: 87-107). Adherence to intervals was 92% and participants met or exceeded prescribed high-intensity HR on 68.8±34.8% of intervals. VO2peak improved from baseline to sign-off (14.6±3.1 mL/kg/min to 17.9±3.3 mL/kg/min; p<0.001). 30-second sit to stand and SPPB chair stand scores significantly improved in adherent participants. Improvements in 30-second sit to stand (13.8±1.5 to 18.3±3.3 seconds) and 6MWT (514.4±43.2 to 564.6±19.3) exceeded minimal clinically important improvements established in other chronic disease populations, representing the minimum improvement considered meaningful to patients. CONCLUSIONS: Findings demonstrate that implementing a pre-HCT home-based remotely monitored HIIT program is feasible and may provide benefits to cardiorespiratory fitness and physical function.

Trachoma risk factors in Oromia Region, Ethiopia.

BACKGROUND: Trachoma, the leading infectious cause of blindness, is caused by the bacterium Chlamydia trachomatis (Ct). Despite enormous disease control efforts and encouraging progress, trachoma remains a significant public health problem in 44 countries. Ethiopia has the greatest burden of trachoma worldwide, however, robust data exploring transmission risk factors and the association between socio-economic status is lacking from some regions. This is the first study to investigate these factors in this South-Eastern region of Oromia, Ethiopia. METHODOLOGY/PRINCIPAL FINDINGS: A total of 1211 individuals were enrolled from 247 households in Shashemene Rural district in Oromia Region between 11th April and 25th June 2018, of whom 628 (51.9%) were female and 526 (43.4%) were children aged 1-9 years. Three standardised ophthalmic nurses examined each participant for the presence of active trachoma using the WHO simplified trachoma grading system. Conjunctival swab samples were collected from the upper tarsal conjunctiva of the left eye of each participant. Ct was detected using quantitative PCR. Risk factor data were collected through structured interviews and direct observations. Clinical signs of trachomatous inflammation-follicular among children aged 1-9 (TF1-9) were observed in at least one eye of 106/526 (20.2%) and trachomatous inflammation-intense among children aged 1-9 (TI1-9) were observed in at least one eye of 10/526 (1.9%). We detected Ct by PCR in 23 individuals, of whom 18 (78.3%) were in children aged 1-9 years. Among the 106 children aged 1-9 years with TF, 12 (11.3%) were Ct PCR positive and among 20 children aged 1-9 years with TI, 4 (20.0%) were Ct PCR positive. In a multivariable model, adjusting for household clustering, active trachoma was associated with younger age, the poorest households (aOR = 2.56, 95% CI 1.21-5.51), presence of flies on the face (aOR = 2.87, 95% CI 1.69-6.46), and ocular discharge (aOR = 1.89, 95% CI 1.03-3.24). Pre-school children face washing more than once a day had lower odds of having active trachoma (aOR = 0.59, 95% CI 0.19-0.84). The same was true for washing children's clothing at least once per week (aOR = 0.27, 95% CI 0.33-1.02). CONCLUSION/SIGNIFICANCE: Younger age, personal hygiene in this age group (presence of ocular and nasal discharges, infrequent washing of faces and clothing) and fly-eye contacts are potential risk factors for trachoma in this setting, suggesting that hygiene interventions and environmental improvements are required to suppress transmission to ensure sustained reduction in disease burden Further studies are needed to evaluate these interventions for trachoma control and elimination. Trachoma remains a disease associated with lower socio-economic status, emphasising the need for continued implementation of control measures in addition to poverty reduction interventions in this region.

Artificial intelligence for diabetic retinopathy in low-income and middle-income countries: a scoping review.

Diabetic retinopathy (DR) is a leading cause of blindness globally. There is growing evidence to support the use of artificial intelligence (AI) in diabetic eye care, particularly for screening populations at risk of sight loss from DR in low-income and middle-income countries (LMICs) where resources are most stretched. However, implementation into clinical practice remains limited. We conducted a scoping review to identify what AI tools have been used for DR in LMICs and to report their performance and relevant characteristics. 81 articles were included. The reported sensitivities and specificities were generally high providing evidence to support use in clinical practice. However, the majority of studies focused on sensitivity and specificity only and there was limited information on cost, regulatory approvals and whether the use of AI improved health outcomes. Further research that goes beyond reporting sensitivities and specificities is needed prior to wider implementation.

Improvement studies for equitable and evidence-based innovation: an overview of the 'IM-SEEN' model.

BACKGROUND: Health inequalities are ubiquitous, and as countries seek to expand service coverage, they are at risk of exacerbating existing inequalities unless they adopt equity-focused approaches to service delivery. MAIN TEXT: Our team has developed an equity-focused continuous improvement model that reconciles prioritisation of disadvantaged groups with the expansion of service coverage. Our new approach is based on the foundations of routinely collecting sociodemographic data; identifying left-behind groups; engaging with these service users to elicit barriers and potential solutions; and then rigorously testing these solutions with pragmatic, embedded trials. This paper presents the rationale for the model, a holistic overview of how the different elements fit together, and potential applications. Future work will present findings as the model is operationalised in eye-health programmes in Botswana, India, Kenya, and Nepal. CONCLUSION: There is a real paucity of approaches for operationalising equity. By bringing a series of steps together that force programme managers to focus on groups that are being left behind, we present a model that can be used in any service delivery setting to build equity into routine practice.

Hemoglobin and cerebral hypoxic vasodilation in humans: Evidence for nitric oxide-dependent and S-nitrosothiol mediated signal transduction.

Cerebral hypoxic vasodilation is poorly understood in humans, which undermines the development of therapeutics to optimize cerebral oxygen delivery. Across four investigations (total n = 195) we investigated the role of nitric oxide (NO) and hemoglobin-based S-nitrosothiol (RSNO) and nitrite (NO2-) signaling in the regulation of cerebral hypoxic vasodilation. We conducted hemodilution (n = 10) and NO synthase inhibition experiments (n = 11) as well as hemoglobin oxygen desaturation protocols, wherein we measured cerebral blood flow (CBF), intra-arterial blood pressure, and in subsets of participants trans-cerebral release/uptake of RSNO and NO2-. Higher CBF during hypoxia was associated with greater trans-cerebral RSNO release but not NO2-, while NO synthase inhibition reduced cerebral hypoxic vasodilation. Hemodilution increased the magnitude of cerebral hypoxic vasodilation following acute hemodilution, while in 134 participants tested under normal conditions, hypoxic cerebral vasodilation was inversely correlated to arterial hemoglobin concentration. These studies were replicated in a sample of polycythemic high-altitude native Andeans suffering from excessive erythrocytosis (n = 40), where cerebral hypoxic vasodilation was inversely correlated to hemoglobin concentration, and improved with hemodilution (n = 6). Collectively, our data indicate that cerebral hypoxic vasodilation is partially NO-dependent, associated with trans-cerebral RSNO release, and place hemoglobin-based NO signaling as a central mechanism of cerebral hypoxic vasodilation in humans.

Antimicrobial resistance in topical treatments for microbial keratitis: protocol for a systematic review and meta-analysis.

INTRODUCTION: There is evidence for increased resistance against the antimicrobials used to treat keratitis. This review aims to provide global and regional prevalence estimates of antimicrobial resistance in corneal isolates and the range of minimum inhibitory concentrations (MIC) with their associated resistance breakpoints. METHODS AND ANALYSIS: We report this protocol following Preferred Reporting Items for Systematic Review and Meta-Analyses Protocols guidelines. We will conduct an electronic bibliographic search in MEDLINE, EMBASE, Web of Science and the Cochrane Library. Eligible studies will report in any language data for the resistance or MIC for antimicrobials against bacterial, fungal or amoebic organisms isolated from suspected microbial keratitis. Studies that only report on viral keratitis will not be included. There will be no time restrictions on the date of publication. Screening for eligible studies, assessment of risk of bias and data extraction will be conducted by two reviewers independently, using predefined inclusion criteria and prepiloted data extraction forms. We will resolve disagreements between the reviewers by discussion and, if required, a third (senior) reviewer will arbitrate. We will assess the risk of bias using a tool validated in prevalence studies. The certainty of the evidence will be assessed using the Grades of Recommendation, Assessment, Development and Evaluation approach. Pooled proportion estimates will be calculated using a random-effects model. Heterogeneity will be assessed using the I2 statistic. We will explore differences between Global Burden of Disease regions and temporal trends. ETHICS APPROVAL AND DISSEMINATION: Ethics approval is not required as this is a protocol for a systematic review of published data. The findings of this review will be published in an open-access, peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42023331126.

The Impact of Simulation-Based Trabeculectomy Training on Resident Core Surgical Skill Competency.

PRCIS: Simulation-based surgical education shows a positive, immediate, and sustained impact on core surgical skill competency in trabeculectomy among resident ophthalmologists in training. PURPOSE: To measure the impact of trabeculectomy, surgical simulation training on core surgical skill competency in resident ophthalmologists. MATERIALS AND METHODS: This is a post hoc analysis of the GLAucoma Simulated Surgery trial, which is a multicenter, multinational randomized controlled trial. Resident ophthalmologists from 6 training centers in sub-Saharan Africa (in Kenya, Uganda, Tanzania, Zimbabwe, and South Africa) were recruited according to the inclusion criteria of having performed zero surgical trabeculectomies and assisted in <5. Participants were randomly assigned to intervention and control arms using allocation concealment. The intervention was a 1-week intensive trabeculectomy surgical simulation course. Outcome measures were mean surgical competency scores in 8 key trabeculectomy surgical skills (scleral incision, scleral flap, releasable suturing, conjunctival suturing, sclerostomy, tissue handling, fluidity, and speed), using a validated scoring tool. RESULTS: Forty-nine residents were included in the intention-to-treat analysis. Baseline characteristics were balanced between arms. Median baseline surgical competency scores were 2.88/16 [interquartile range (IQR): 1.75-4.17] and 3.25/16 (IQR: 1.83-4.75) in the intervention and control arms, respectively. At primary intervention, median scores increased to 11.67/16 (IQR: 9.58-12.63) and this effect was maintained at 3 months and 1 year ( P =0.0001). Maximum competency scores at primary intervention were achieved in the core trabeculectomy skills of releasable suturing (n=17, 74%), scleral flap formation (n=16, 70%), and scleral incision (n=15, 65%) compared with scores at baseline. CONCLUSIONS: This study demonstrates the positive impact of intensive simulation-based surgical education on core trabeculectomy skill development. The rapid and sustained effect of resident skill acquisition pose strong arguments for its formal integration into ophthalmic surgical education.

Cerebral O2 and CO2 transport in isovolumic haemodilution: Compensation of cerebral delivery of O2 and maintenance of cerebrovascular reactivity to CO2.

This study investigated the influence of acute reductions in arterial O2 content (CaO2) via isovolumic haemodilution on global cerebral blood flow (gCBF) and cerebrovascular CO2 reactivity (CVR) in 11 healthy males (age; 28 ± 7 years: body mass index; 23 ± 2 kg/m2). Radial artery and internal jugular vein catheters provided measurement of blood pressure and gases, quantification of cerebral metabolism, cerebral CO2 washout, and trans-cerebral nitrite exchange (ozone based chemiluminescence). Prior to and following haemodilution, the partial pressure of arterial CO2 (PaCO2) was elevated with dynamic end-tidal forcing while gCBF was measured with duplex ultrasound. CVR was determined as the slope of the gCBF response and PaCO2. Replacement of ∼20% of blood volume with an equal volume of 5% human serum albumin (Alburex® 5%) reduced haemoglobin (13.8 ± 0.8 vs. 11.3 ± 0.6 g/dL; P < 0.001) and CaO2 (18.9 ± 1.0 vs 15.0 ± 0.8 mL/dL P < 0.001), elevated gCBF (+18 ± 11%; P = 0.002), preserved cerebral oxygen delivery (P = 0.49), and elevated CO2 washout (+11%; P = 0.01). The net cerebral uptake of nitrite (11.6 ± 14.0 nmol/min; P = 0.027) at baseline was abolished following haemodilution (-3.6 ± 17.9 nmol/min; P = 0.54), perhaps underpinning the conservation of CVR (61.7 ± 19.0 vs. 69.0 ± 19.2 mL/min/mmHg; P = 0.23). These findings demonstrate that the cerebrovascular responses to acute anaemia in healthy humans are sufficient to support the maintenance of CVR.

Performance and Resource Requirements of In-Person, Voice Call, and Automated Telephone-Based Socioeconomic Data Collection Modalities for Community-Based Health Programs: A Systematic Review.

Importance: Gathering data on socioeconomic status (SES) is a prerequisite for health programs that aim to improve equity. There is a lack of evidence on which approaches offer the best combination of reliability, cost, and acceptability. Objective: To compare the performance of different approaches to gathering data on SES in community health programs. Data Sources: A search of the Cochrane Library, MEDLINE, Embase, Global Health, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform, and OpenGrey from 1999 to June 29, 2021, was conducted, with no language limits. Google Scholar was also searched and the reference lists of included articles were checked to identify further studies. The search was performed on June 29, 2021. Study Selection: Any empirical study design was eligible if it compared 2 or more modalities to elicit SES data from the following 3 categories: in-person, voice call, or automated telephone-based systems. Data Extraction and Synthesis: Two reviewers independently screened titles, abstracts, and full-text articles and extracted data. They also assessed the risk of bias using Cochrane tools and assessed the certainty of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation approach. Findings were synthesized thematically without meta-analysis. Main Outcomes and Measures: Response rate, equivalence, time, costs, and acceptability to patients and health care professionals. Results: The searches returned 3943 records. The 11 included studies reported data on 14 036 individuals from 7 countries, collecting data on 11 socioeconomic domains using 2 or more of the following modes: in-person surveys, computer-assisted telephone interviews (CATIs), and 2 types of automated data collection: interactive voice response calls (IVRs) and web surveys. Response rates were greater than 80% for all modes except IVRs. Equivalence was high across all modes (Cohen κ > 0.5). There were insufficient data to make robust time and cost comparisons. Patients reported high levels of acceptability providing data via IVRs, web surveys, and CATIs. Conclusions and Relevance: Selecting an appropriate and cost-effective modality to elicit SES data is an important first step toward advancing equitable effective service coverage. This systematic review did not identify evidence that remote and automated data collection modes differed from human-led and in-person approaches in terms of reliability, cost, or acceptability.

Viral suppression and self-reported ART adherence after 3 years of universal testing and treatment in the HPTN 071 (PopART) community-randomised trial in Zambia and South Africa: a cross-sectional analysis.

BACKGROUND: In 2014, UNAIDS set the target that 90% of individuals on antiretroviral therapy (ART) be virally suppressed. Here, we use data from the HPTN 071 (PopART) trial to report whether the introduction of universal testing and treatment has affected viral suppression or treatment adherence among individuals who self-reported they were taking ART, and identify risk factors for these outcomes. METHODS: This was a cross-sectional study nested within the randomly selected population cohort of the PopART trial. The trial took place in 21 communities in Zambia and South Africa. Analyses included 3570 HIV-positive participants who were seen at the second follow-up visit in 2016-17 and who self-reported that they were currently taking ART. Viral suppression was defined as HIV RNA of less than 400 copies per mL from a blood sample collected during the cohort visit, and ART adherence was measured using self-reporting (reported as no missed pills in last 7 days). Prevalences of these outcomes were compared across three trial arms using a two-stage approach suitable for clustered data. Each arm consisted of seven communities, with one arm receiving a combination HIV prevention package including immediate ART initiation, one receiving a combination HIV prevention package excluding immediate ART initiation and one arm receving standard of care. Risk factors for each of the outcomes were assessed using logistic regression. FINDINGS: Among the 3570 participants who self-reported that they were currently on ART, 416 (11·7%) of 3554 were not virally suppressed (16 were missing viral suppression status) and 345 (9·7%) of 3566 reported being non-adherent to ART (four were missing adherence status). The proportion not virally suppressed was higher in communities in South Africa (195 [16·4%] of 1191) than in Zambia (221 [9·4%] of 2363). There was no evidence that the prevalence of the outcomes differed between trial arms. There was evidence that men, younger individuals, individuals who reported participating in harmful alcohol use, and those who reported internalised stigma were more likely to be non-adherent, and not virally suppressed. INTERPRETATION: The results assuaged concerns that early ART initiation in a universal testing and treatment setting could lead to reduced adherence and viral suppression. FUNDING: US National Institute of Allergy and Infectious Diseases (which is a part of the National Institutes of Health), the International Initiative for Impact Evaluation with support from the Bill & Melinda Gates Foundation, US President's Emergency Plan for AIDS Relief, and Medical Research Council UK.

Projected outcomes of universal testing and treatment in a generalised HIV epidemic in Zambia and South Africa (the HPTN 071 [PopART] trial): a modelling study.

BACKGROUND: The long-term impact of universal home-based testing and treatment as part of universal testing and treatment (UTT) on HIV incidence is unknown. We made projections using a detailed individual-based model of the effect of the intervention delivered in the HPTN 071 (PopART) cluster-randomised trial. METHODS: In this modelling study, we fitted an individual-based model to the HIV epidemic and HIV care cascade in 21 high prevalence communities in Zambia and South Africa that were part of the PopART cluster-randomised trial (intervention period Nov 1, 2013, to Dec 31, 2017). The model represents coverage of home-based testing and counselling by age and sex, delivered as part of the trial, antiretroviral therapy (ART) uptake, and any changes in national guidelines on ART eligibility. In PopART, communities were randomly assigned to one of three arms: arm A received the full PopART intervention for all individuals who tested positive for HIV, arm B received the intervention with ART provided in accordance with national guidelines, and arm C received standard of care. We fitted the model to trial data twice using Approximate Bayesian Computation, once before data unblinding and then again after data unblinding. We compared projections of intervention impact with observed effects, and for four different scenarios of UTT up to Jan 1, 2030 in the study communities. FINDINGS: Compared with standard of care, a 51% (95% credible interval 40-60) reduction in HIV incidence is projected if the trial intervention (arms A and B combined) is continued from 2020 to 2030, over and above a declining trend in HIV incidence under standard of care. INTERPRETATION: A widespread and continued commitment to UTT via home-based testing and counselling can have a substantial effect on HIV incidence in high prevalence communities. FUNDING: National Institute of Allergy and Infectious Diseases, US President's Emergency Plan for AIDS Relief, International Initiative for Impact Evaluation, Bill & Melinda Gates Foundation, National Institute on Drug Abuse, and National Institute of Mental Health.

Whole-cell vaccine candidates induce a protective response against virulent Acinetobacter baumannii.

Acinetobacter baumannii causes multi-system diseases in both nosocomial settings and a pre-disposed general population. The bacterium is not only desiccation-resistant but also notoriously resistant to multiple antibiotics and drugs of last resort including carbapenem, colistin, and sulbactam. The World Health Organization has categorized carbapenem-resistant A. baumannii at the top of its critical pathogen list in a bid to direct urgent countermeasure development. Several early-stage vaccines have shown a range of efficacies in healthy mice, but no vaccine candidates have advanced into clinical trials. Herein, we report our findings that both an ionizing γ-radiation-inactivated and a non-ionizing ultraviolet C-inactivated whole-cell vaccine candidate protects neutropenic mice from pulmonary challenge with virulent AB5075, a particularly pathogenic isolate. In addition, we demonstrate that a humoral response is sufficient for this protection via the passive immunization of neutropenic mice.

Diagnosis of Fungal Keratitis in Low-Income Countries: Evaluation of Smear Microscopy, Culture, and In Vivo Confocal Microscopy in Nepal.

Clinically diagnosing fungal keratitis (FK) is challenging; diagnosis can be assisted by investigations including in vivo confocal microscopy (IVCM), smear microscopy, and culture. The aim of this study was to estimate the sensitivity in detecting fungal keratitis (FK) using IVCM, smear microscopy, and culture in a setting with a high prevalence of FK. In this cross-sectional study nested within a prospective cohort study, consecutive microbial keratitis (MK) patients attending a tertiary-referral eye hospital in south-eastern Nepal between June 2019 and November 2020 were recruited. IVCM and corneal scrapes for smear microscopy and culture were performed using a standardised protocol. Smear microscopy was performed using potassium hydroxide (KOH), Gram stain, and calcofluor white. The primary outcomes were sensitivities with 95% confidence intervals [95% CI] for IVCM, smear microscopy and culture, and for each different microscopy stain independently, to detect FK compared to a composite referent. We enrolled 642 patients with MK; 468/642 (72.9%) were filamentous FK, 32/642 (5.0%) were bacterial keratitis and 64/642 (10.0%) were mixed bacterial-filamentous FK, with one yeast infection (0.16%). No organism was identified in 77/642 (12.0%). Smear microscopy had the highest sensitivity (90.7% [87.9-93.1%]), followed by IVCM (89.8% [86.9-92.3%]) and culture (75.7% [71.8-79.3%]). Of the three smear microscopy stains, KOH had the highest sensitivity (85.3% [81.9-88.4%]), followed by Gram stain (83.2% [79.7-86.4%]) and calcofluor white (79.1% [75.4-82.5%]). Smear microscopy and IVCM were the most sensitive tools for identifying FK in our cohort. In low-resource settings we recommend clinicians perform corneal scrapes for microscopy using KOH and Gram staining. Culture remains an important tool to diagnose bacterial infection, identify causative fungi and enable antimicrobial susceptibility testing.