A structure-function analysis shows SARS-CoV-2 BA.2.86 balances antibody escape and ACE2 affinity.

BA.2.86, a recently described sublineage of SARS-CoV-2 Omicron, contains many mutations in the spike gene. It appears to have originated from BA.2 and is distinct from the XBB variants responsible for many infections in 2023. The global spread and plethora of mutations in BA.2.86 has caused concern that it may possess greater immune-evasive potential, leading to a new wave of infection. Here, we examine the ability of BA.2.86 to evade the antibody response to infection using a panel of vaccinated or naturally infected sera and find that it shows marginally less immune evasion than XBB.1.5. We locate BA.2.86 in the antigenic landscape of recent variants and look at its ability to escape panels of potent monoclonal antibodies generated against contemporary SARS-CoV-2 infections. We demonstrate, and provide a structural explanation for, increased affinity of BA.2.86 to ACE2, which may increase transmissibility.

A Narrative Review of Health Status and Healthcare Delivery in the Oil and Gas Industry: Impacts on Employees, Employers, and Local Communities.

Workers in the oil and gas industry are exposed to numerous health risks, ranging from poor health behaviours to the possibility of life-threatening injuries. Determining the most appropriate models of healthcare for the oil and gas industry is difficult, as strategies must be acceptable to multiple stakeholders, including employees, employers, and local communities. The purpose of this review was to broadly explore the health status and needs of workers in the oil and gas industry and healthcare delivery models relating to primary care and emergency responses. Database searches of PubMed, EMBASE, CINAHL, PsycINFO, and Scopus were conducted, as well as grey literature searches of Google, Google Scholar, and the International Association of Oil and Gas Producers website. Resource-sector workers, particularly those in 'fly-in fly-out' roles, are susceptible to poor health behaviours and a higher prevalence of mental health concerns than the general population. Evidence is generally supportive of organisation-led behaviour change and mental health-related interventions. Deficiencies in primary care received while on-site may lead workers to inappropriately use local health services. For the provision of emergency medical care, telehealth and telemedicine lead to favourable outcomes by improving patient health status and satisfaction and reducing the frequency of medical evacuations.

CD4+ and CD8+ T cells and antibodies are associated with protection against Delta vaccine breakthrough infection: a nested case-control study within the PITCH study.

IMPORTANCE: Defining correlates of protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine breakthrough infection informs vaccine policy for booster doses and future vaccine designs. Existing studies demonstrate humoral correlates of protection, but the role of T cells in protection is still unclear. In this study, we explore antibody and T cell immune responses associated with protection against Delta variant vaccine breakthrough infection in a well-characterized cohort of UK Healthcare Workers (HCWs). We demonstrate evidence to support a role for CD4+ and CD8+ T cells as well as antibodies against Delta vaccine breakthrough infection. In addition, our results suggest a potential role for cross-reactive T cells in vaccine breakthrough.

Establishing SARS-CoV-2 membrane protein-specific antibodies as a valuable serological target via high-content microscopy.

The prevalence and strength of serological responses mounted toward SARS-CoV-2 proteins other than nucleocapsid (N) and spike (S), which may be of use as additional serological markers, remains underexplored. Using high-content microscopy to assess antibody responses against full-length StrepTagged SARS-CoV-2 proteins, we found that 85% (166/196) of unvaccinated individuals with RT-PCR confirmed SARS-CoV-2 infections and 74% (31/42) of individuals infected after being vaccinated developed detectable IgG against the structural protein M, which is higher than previous estimates. Compared with N antibodies, M IgG displayed a shallower time-dependent decay and greater specificity. Sensitivity for SARS-CoV-2 seroprevalence was enhanced when N and M IgG detection was combined. These findings indicate that screening for M seroconversion may be a good approach for detecting additional vaccine breakthrough infections and highlight the potential to use HCM as a rapidly deployable method to identify the most immunogenic targets of newly emergent pathogens.

Landscape experiments unlock relationships among habitat loss, fragmentation, and patch-size effects.

Habitat loss is often considered the greatest near-term threat to biodiversity, while the impact of habitat fragmentation remains intensely debated. A key issue of this debate centers on the problem of scale-landscape or patch-at which to assess the consequences of fragmentation. Yet patterns are often confounded across scales, and experimental designs that could solve this scaling problem remain scarce. We conducted two field experiments in 30 experimental landscapes in which we manipulated habitat loss, fragmentation, and patch size for a community of four insect herbivores that specialize on the cactus Opuntia. In the first experiment, we destroyed 2088 Opuntia patches in either aggregated or random patterns and compared the relative effects of landscape-scale loss and fragmentation to those of local patch size on species occurrence. This experiment focused on manipulating the relative separation of remaining patches, where we hypothesized that aggregated loss would disrupt dispersal more than random loss, leading to lower occurrence. In the second experiment, we destroyed 759 Opuntia patches to generate landscapes that varied in patch number and size for a given amount of habitat loss and assessed species occurrence. This experiment focused on manipulating the subdivision of remaining habitat, where we hypothesized that an increase in the number of patches for a given amount of loss would lead to negative effects on occurrence. For both, we expected that occurrence would increase with patch size. We find strong evidence for landscape-scale effects of habitat fragmentation, with aggregated loss and a larger number of patches for a given amount of habitat loss leading to a lower frequency of patches occupied in landscapes. In both experiments, occurrence increased with patch size, yet interactions of patch size and landscape-scale loss and fragmentation drove species occurrence in patches. Importantly, the direction of effects were consistent across scales and effects of patch size were sufficient to predict the effects of habitat loss and fragmentation across entire landscapes. Our experimental results suggest that changes at both the patch and landscape scales can impact populations, but that a long-standing pattern-the patch-size effect-captures much of the key variation shaping patterns of species occurrence.

Rapid escape of new SARS-CoV-2 Omicron variants from BA.2-directed antibody responses.

In November 2021, Omicron BA.1, containing a raft of new spike mutations, emerged and quickly spread globally. Intense selection pressure to escape the antibody response produced by vaccines or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection then led to a rapid succession of Omicron sub-lineages with waves of BA.2 and then BA.4/5 infection. Recently, many variants have emerged such as BQ.1 and XBB, which carry up to 8 additional receptor-binding domain (RBD) amino acid substitutions compared with BA.2. We describe a panel of 25 potent monoclonal antibodies (mAbs) generated from vaccinees suffering BA.2 breakthrough infections. Epitope mapping shows potent mAb binding shifting to 3 clusters, 2 corresponding to early-pandemic binding hotspots. The RBD mutations in recent variants map close to these binding sites and knock out or severely knock down neutralization activity of all but 1 potent mAb. This recent mAb escape corresponds with large falls in neutralization titer of vaccine or BA.1, BA.2, or BA.4/5 immune serum.

Evolution of long-term vaccine-induced and hybrid immunity in healthcare workers after different COVID-19 vaccine regimens.

BACKGROUND: Both infection and vaccination, alone or in combination, generate antibody and T cell responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the maintenance of such responses-and hence protection from disease-requires careful characterization. In a large prospective study of UK healthcare workers (HCWs) (Protective Immunity from T Cells in Healthcare Workers [PITCH], within the larger SARS-CoV-2 Immunity and Reinfection Evaluation [SIREN] study), we previously observed that prior infection strongly affected subsequent cellular and humoral immunity induced after long and short dosing intervals of BNT162b2 (Pfizer/BioNTech) vaccination. METHODS: Here, we report longer follow-up of 684 HCWs in this cohort over 6-9 months following two doses of BNT162b2 or AZD1222 (Oxford/AstraZeneca) vaccination and up to 6 months following a subsequent mRNA booster vaccination. FINDINGS: We make three observations: first, the dynamics of humoral and cellular responses differ; binding and neutralizing antibodies declined, whereas T and memory B cell responses were maintained after the second vaccine dose. Second, vaccine boosting restored immunoglobulin (Ig) G levels; broadened neutralizing activity against variants of concern, including Omicron BA.1, BA.2, and BA.5; and boosted T cell responses above the 6-month level after dose 2. Third, prior infection maintained its impact driving larger and broader T cell responses compared with never-infected people, a feature maintained until 6 months after the third dose. CONCLUSIONS: Broadly cross-reactive T cell responses are well maintained over time-especially in those with combined vaccine and infection-induced immunity ("hybrid" immunity)-and may contribute to continued protection against severe disease. FUNDING: Department for Health and Social Care, Medical Research Council.

A delicate balance between antibody evasion and ACE2 affinity for Omicron BA.2.75.

Variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have caused successive global waves of infection. These variants, with multiple mutations in the spike protein, are thought to facilitate escape from natural and vaccine-induced immunity and often increase in affinity for ACE2. The latest variant to cause concern is BA.2.75, identified in India where it is now the dominant strain, with evidence of wider dissemination. BA.2.75 is derived from BA.2 and contains four additional mutations in the receptor-binding domain (RBD). Here, we perform an antigenic and biophysical characterization of BA.2.75, revealing an interesting balance between humoral evasion and ACE2 receptor affinity. ACE2 affinity for BA.2.75 is increased 9-fold compared with BA.2; there is also evidence of escape of BA.2.75 from immune serum, particularly that induced by Delta infection, which may explain the rapid spread in India, where where there is a high background of Delta infection. ACE2 affinity appears to be prioritized over greater escape.

Evolution of long-term hybrid immunity in healthcare workers after different COVID-19 vaccination regimens: a longitudinal observational cohort study

Both infection and vaccination, alone or in combination, generate antibody and T cell responses against SARSCoV2. However, the maintenance of such responses, and hence protection from disease, requires careful characterisation. In a large prospective study of UK healthcare workers (Protective immunity from T cells in Healthcare workers (PITCH), within the larger SARSCoV2 immunity and reinfection evaluation (SIREN) study) we previously observed that prior infection impacted strongly on subsequent cellular and humoral immunity induced after long and short dosing intervals of BNT162b2 (Pfizer/BioNTech) vaccination. Here, we report longer follow up of 684 HCWs in this cohort over 6-9 months following two doses of BNT162b2 or AZD1222 (Oxford/AstraZeneca) vaccination and up to 6 months following a subsequent mRNA booster vaccination. We make three observations: Firstly, the dynamics of humoral and cellular responses differ; binding and neutralising antibodies declined whereas T and memory B cell responses were maintained after the second vaccine dose. Secondly, vaccine boosting restored IgG levels, broadened neutralising activity against variants of concern including omicron BA.1, BA.2 and BA.5, and boosted T cell responses above the 6 month level post dose 2. Thirdly, prior infection maintained its impact driving larger as well as broader T cell responses compared with never-infected people, a feature maintained until 6 months after the third dose. In conclusion, broadly cross-reactive T cell responses are well maintained over time, especially in those with combined vaccine and infection-induced immunity (hybrid immunity), and may contribute to continued protection against severe disease.

Towards a unified framework for connectivity that disentangles movement and mortality in space and time.

Predicting connectivity, or how landscapes alter movement, is essential for understanding the scope for species persistence with environmental change. Although it is well known that movement is risky, connectivity modelling often conflates behavioural responses to the matrix through which animals disperse with mortality risk. We derive new connectivity models using random walk theory, based on the concept of spatial absorbing Markov chains. These models decompose the role of matrix on movement behaviour and mortality risk, can incorporate species distribution to predict the amount of flow, and provide both short- and long-term analytical solutions for multiple connectivity metrics. We validate the framework using data on movement of an insect herbivore in 15 experimental landscapes. Our results demonstrate that disentangling the roles of movement behaviour and mortality risk is fundamental to accurately interpreting landscape connectivity, and that spatial absorbing Markov chains provide a generalisable and powerful framework with which to do so.

Safety issues associated with dietary management in patients with hepatic glycogen storage disease.

INTRODUCTION: Hepatic glycogen storage diseases (GSDs) are a group of inherited disorders of carbohydrate metabolism for which dietary management is the cornerstone. Safety and acute complications associated with dietary management have been poorly documented. We hypothesized that safety issues and complications associated with dietary management are prevalent amongst patients with these ultra-rare disorders. METHODS: A questionnaire was developed consisting of 40 questions and was distributed via eight GSD patient organizations from multiple countries. Respondents were (caregivers of) patients with self-reported hepatic GSD. RESULTS: 249 GSD patients from 26 countries responded with a median age of 14.8 years (range: 0.5-66.1). Although management was considered safe by 71% of patients, 51% reported at least one acute complication associated with dietary management, with a total number of 425 reported complications. Most frequently reported causes were: not waking up by an alarm clock (n = 70), forgetting a meal (n = 57) and infections (n = 43). Most frequently reported complications were: hypoglycemia (n = 112), hospital admissions (n = 79) and drowsiness (n = 74). Most complications occurred before the age of 12 years (82%; 637/774 total number of reported events) and during night time (63%; 340/536). Only 61% (152/249) of the GSD patients reported using a written emergency protocol. CONCLUSIONS: Safety issues and complications associated with dietary management are prevalently reported by (caregivers of) 249 GSD patients. A discrepancy has been observed between the patient's perspective on safety of dietary management and occurrence of complications as a result of dietary management.

Clinical and biochemical heterogeneity between patients with glycogen storage disease type IA: the added value of CUSUM for metabolic control.

OBJECTIVE: To study heterogeneity between patients with glycogen storage disease type Ia (GSD Ia), a rare inherited disorder of carbohydrate metabolism caused by the deficiency of glucose-6-phosphatase (G6Pase). STUDY DESIGN: Descriptive retrospective study of longitudinal clinical and biochemical data and long-term complications in 20 GSD Ia patients. We included 11 patients with homozygous G6PC mutations and siblings from four families carrying identical G6PC genotypes. To display subtle variations for repeated triglyceride measurements with respect to time for individual patients, CUSUM-analysis graphs were constructed. RESULTS: Patients with different homozygous G6PC mutations showed important differences in height, BMI, and biochemical parameters (i.e., lactate, uric acid, triglyceride, and cholesterol concentrations). Furthermore, CUSUM-analysis predicts and displays subtle changes in longitudinal blood triglyceride concentrations. Siblings in families also displayed important differences in biochemical parameters (i.e., lactate, uric acid, triglycerides, and cholesterol concentrations) and long-term complications (i.e., liver adenomas, nephropathy, and osteopenia/osteoporosis). CONCLUSIONS: Differences between GSD Ia patients reflect large clinical and biochemical heterogeneity. Heterogeneity between GSD Ia patients with homozygous G6PC mutations indicate an important role of the G6PC genotype/mutations. Differences between affected siblings suggest an additional role (genetic and/or environmental) of modifying factors defining the GSD Ia phenotype. CUSUM-analysis can facilitate single-patient monitoring of metabolic control and future application of this method may improve precision medicine for patients both with GSD and remaining inherited metabolic diseases.

The stable isotope ketoisocaproic acid breath test as a measure of hepatic decarboxylation capacity: a quantitative analysis in normal subjects after oral and intravenous administration.

BACKGROUND AND AIMS: There is no generally accepted kinetic evaluation method for the stable isotope [(13)C]ketoisocaproic acid (KIC) breath test. Differences found in the results between women and men are contradictory. METHODS: Oral and intravenous breath tests using 1 mg/kg stable isotope-labelled KIC were performed in healthy male and female volunteers. A power exponential function was fitted to the mass spectrometric data of breath (13)CO(2) enrichment, allowing mathematical analysis of time-to-peak-excretion, half-excretion time, percent label recovery and parameters describing the shape of the curve. Body composition was determined using bioelectrical impedance analysis. RESULTS: After oral administration, total label recovery after 3 h was about 22% and was not different between men (n=7) and women (n=8). The time to maximal label excretion was 0.67 +/- 0.12 h in men and 0.9 +/- 0.32 h in women (P=0.028) and the excretion curve showed an initially slower rise in women compared with men. Adjusting for lean body mass or body water abrogated the sex differences. Total label recovery after intravenous administration was about 9%, suggesting that the substrate was rapidly catabolized in the muscle compartment after intravenous administration. CONCLUSIONS: The modified power exponential function described allows standardized estimates of the KIC breath test results. When corrected for body composition, there are no differences in breath test results between men and women. The comparison between oral and intravenous results provides robust evidence that the KIC breath test measures predominantly hepatic and not muscle decarboxylation and is thus a highly specific liver function test.

Efficacy and Safety of Remacemide versus Carbamazepine in Newly Diagnosed Epilepsy: Comparison by Sequential Analysis.

An international trial comparing remacemide hydrochloride with carbamazepine was undertaken in newly diagnosed epilepsy using a novel double-blind, parallel group, double triangular sequential design. Patients with two or more partial or generalized tonic-clonic seizures in the previous year were randomized to 600 mg daily of remacemide or carbamazepine. Subsequent dosage adjustments were allowed while maintaining the blind. The trial completed 20 months after initiation following the second interim analysis. Efficacy data on 449 patients showed carbamazepine to be significantly more effective than remacemide in preventing seizure recurrence (P = 0.003). Median time to first seizure after titration, the primary endpoint, was 112 days for remacemide and 306 days with carbamazepine. Time to second, third, and fourth seizures after randomization all significantly favored carbamazepine. Remacemide was shown unequivocally to be inferior to carbamazepine in this patient population. This study also establishes carbamazepine as a proven treatment for use in subsequent active control comparative trials.

Accommodative esotropia: an unrecognized cause of hemifacial spasm in children.

Pediatric hemifacial spasm can be a sign of an intracranial tumor. We examined two females, ages 2 and 6 years, who presented with hemifacial spasm as an early sign of accommodative esotropia. Initial ophthalmologic examination disclosed high hyperopia without detectable esotropia. Both children developed an intermittent esotropia over the following month. In the first child, the hemifacial spasm resolved concurrent with the onset of amblyopia. In the second child, spectacle correction produced immediate cessation of the spasms. In both children, squinting to avoid diplopia produced an overflow facial movement that manifested as hemifacial spasm. Accommodative esotropia should be considered in the differential diagnosis of pediatric hemifacial spasm.

Divergence insufficiency.

PURPOSE: Divergence insufficiency is an unusual form of strabismus with esotropia and diplopia only at distance and single binocular vision at near. This retrospective case series describes the diagnosis and treatment of 7 patients and differentiates this clinical entity from other conditions. METHODS: Seven healthy patients aged 9 to 41 years who developed acquired esotropia only at distance were treated with unilateral or bilateral medical rectus recession. RESULTS: All patients had resolution of diplopia, although one patient initially treated with unilateral medial rectus recession required a second recession of the other medial rectus muscle. CONCLUSIONS: Divergence insufficiency is a distinct clinical entity in otherwise healthy patients, which can be successfully treated by unilateral or bilateral medial rectus recession.

A new approach to electrical safety testing of electromedical equipment.

The "New Approach" to electrical safety testing in Sir Charles Gairdner Hospital (SCGH) is based on the results and experience we have obtained in carrying out such tests for a period of over twenty years. Until recently our testing was carried out according to the annual procedures as described in Standards Australia recommendations. Test protocol changes have, however, now been made since it seemed from our records that we had been carrying out testing to an extent not justified by our test results. The paper describes the safety testing programme now in place at SCGH. This programme has resulted in substantial reduction in the testing time without, in our opinion, compromises in safety. The main elements in electromedical equipment test procedures are:- Acceptance tests In-Service tests Tests after repair We have found that the main consumer of time in electrical safety testing, aside from the test procedure itself, is gaining access to the equipment. This can be particularly difficult in areas where equipment is in constant use, e.g. in CCU, ICU, Renal Dialysis, Operating Theatres, etc. We have developed an earth integrity meter for the purpose of checking medical equipment without the need to disconnect it from the mains supply or from the patient. By means of this device, together with our new testing protocol, access problems have been largely eliminated.

[Regional anesthesia by the caudal route in adults. Apropos of 56 caudal blocks]. / Anesthésie régionale par voie caudale chez l'adulte. A propos de 56 blocs caudaux.

Caudal anaesthesia was described in 1901 but is now essentially used for paediatric surgery. From their experience of 56 caudal blocks in adult patients scheduled for pelvic surgery or endoscopy, the authors discuss the value of this technique. The anatomical and physiological basis and the main guidelines of caudal anaesthesia are recalled through some references.