Immunological imprinting shapes the specificity of human antibody responses against SARS-CoV-2 variants.

The spike glycoprotein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to accumulate substitutions, leading to breakthrough infections of vaccinated individuals. It remains unclear if exposures to antigenically distant SARS-CoV-2 variants can overcome memory B cell biases established by initial SARS-CoV-2 encounters. We determined the specificity and functionality of antibody and B cell responses following exposure to BA.5 and XBB variants in individuals who received ancestral SARS-CoV-2 mRNA vaccines. BA.5 exposures elicited antibody responses that targeted epitopes conserved between the BA.5 and ancestral spike. XBB exposures also elicited antibody responses that primarily targeted epitopes conserved between the XBB.1.5 and ancestral spike. However, unlike BA.5, a single XBB exposure elicited low frequencies of XBB.1.5-specific antibodies and B cells in some individuals. Pre-existing cross-reactive B cells and antibodies were correlated with stronger overall responses to XBB but weaker XBB-specific responses, suggesting that baseline immunity influences the activation of variant-specific SARS-CoV-2 responses.

Synthesis, Characterization, and the Effect of Lewis Bases on the Nuclearity of Iron Alkoxide Complexes.

Inspired by the potential of alkoxides as weak-field ligands and their ability to bridge, we report herein a series of high-spin iron complexes supported by a bis-alkoxide framework PhDbf. A diiron complex [Fe2(PhDbf)2] (1a) is obtained upon metalation of the ligand, whereas addition of substituted pyridines affords five-coordinate mononuclear iron complexes [(R-Py)2Fe(PhDbf)] (2a-4a, R = H, p-tBu, p-CF3). The potential for nuclearity control of the metal complexes via auxiliary ligands is highlighted by the formation of asymmetric diiron species [(p-CF3-Py)Fe2(PhDbf)2] (5a) and [(m-CF3-Py)Fe2(PhDbf)2] (6a) with trifluoromethyl substituted pyridines, while electron-rich pyridines only produced monomeric species. Electronic properties analysis via UV-vis, electron paramagnetic resonance, 57Fe Mössbauer spectroscopy, and time-dependent density functional theory, along with redox capabilities of these complexes are reported to illustrate the effect of nuclearity on reactivity and the potential of these complexes to access higher oxidation states relevant in oxidative chemistry. Species 1a-5a, [(THF)2Fe(PhDbf)][PF6] (7), [PyFe(PhDbf)Cl] (2b), and [Py2Fe(PhDbf)][PF6] (2c) were characterized via SCXRD. Indirect evidence for the formation of dimeric Fe(III) species (1b, 5b, and 6b) is discussed.

The incremental yield of prenatal exome sequencing over chromosome microarray for congenital heart abnormalities: A systematic review and meta-analysis.

OBJECTIVES: To determine the incremental yield of prenatal exome sequencing (PES) over standard testing in fetuses with an isolated congenital heart abnormality (CHA), CHA associated with extra-cardiac malformations (ECMs) and CHA dependent upon anatomical subclassification. METHODS: A systematic review of the literature was performed using MEDLINE, EMBASE, Web of Science and grey literature January 2010-February 2023. Studies were selected if they included greater than 20 cases of prenatally diagnosed CHA when standard testing (QF-PCR/chromosome microarray/karyotype) was negative. Pooled incremental yield was determined. PROSPERO CRD 42022364747. RESULTS: Overall, 21 studies, incorporating 1957 cases were included. The incremental yield of PES (causative pathogenic and likely pathogenic variants) over standard testing was 17.4% (95% CI, 13.5%-21.6%), 9.3% (95% CI, 6.6%-12.3%) and 35.9% (95% CI, 21.0%-52.3%) for all CHAs, isolated CHAs and CHAs associated with ECMs. The subgroup with the greatest yield was complex lesions/heterotaxy; 35.2% (95% CI 9.7%-65.3%). The most common syndrome was Kabuki syndrome (31/256, 12.1%) and most pathogenic variants occurred de novo and in autosomal dominant (monoallelic) disease causing genes (114/224, 50.9%). CONCLUSION: The likelihood of a monogenic aetiology in fetuses with multi-system CHAs is high. Clinicians must consider the clinical utility of offering PES in selected isolated cardiac lesions.

Biomechanical and ergonomic risks associated with cervical musculoskeletal dysfunction amongst surgeons: A systematic review.

INTRODUCTION: Surgeons are at high risk of developing musculoskeletal symptoms due to a range of factors including, maladaptive positioning and surgical ergonomics. Cervical muscle strain and biomechanical load is most prevalent due to repetitive motions and prolonged static neck positioning. This issue is apparent through reports of prevalence between 10 and 74.4% among surgeons. The aim of this systematic review is to provide an objective assessment of the clinical evidence available and a descriptive analysis of the effects of kinematics and surgical ergonomics on the prevalence of surgeons' cervical musculoskeletal pain. METHODS: This is PRISMA-compliant systematic review of clinical studies assessing the prevalence of cervical musculoskeletal dysfunction in surgeons by searching PUBMED and Ovid EMBASE databases from inception to 19th October 2023. Study quality was graded according to the National Institutes of Health study quality assessment tools. RESULTS: A total of 9 studies were included in the final qualitative analysis. The use of loupes, open surgery and excessive neck flexion (>30°) were associated with cervical dysfunction. Comparison of study outcomes was challenging due to heterogeneity within study methods and the paucity of methodological quality. CONCLUSION: The current literature assessing ergonomic and biomechanical factors predisposing surgeons to cervical musculoskeletal dysfunction is insufficient to provide reliable guidance for clinicians. Although the literature identifies factors contributing to work-related cervical dysfunction, few attempt to evaluate interventions for improved surgical ergonomics. An objective assessment of interventions that prompt postural correction with the aim to improve neck pain in surgeon cohorts is warranted.

Non-specific cargo-filament interactions slow down motor-driven transport.

Active, motor-based cargo transport is important for many cellular functions and cellular development. However, the cell interior is complex and crowded and could have many weak, non-specific interactions with the cargo being transported. To understand how cargo-environment interactions will affect single motor cargo transport and multi-motor cargo transport, we use an artificial quantum dot cargo bound with few (~ 1) to many (~ 5-10) motors allowed to move in a dense microtubule network. We find that kinesin-driven quantum dot cargo is slower than single kinesin-1 motors. Excitingly, there is some recovery of the speed when multiple motors are attached to the cargo. To determine the possible mechanisms of both the slow down and recovery of speed, we have developed a computational model that explicitly incorporates multi-motor cargos interacting non-specifically with nearby microtubules, including, and predominantly with the microtubule on which the cargo is being transported. Our model has recovered the experimentally measured average cargo speed distribution for cargo-motor configurations with few and many motors, implying that numerous, weak, non-specific interactions can slow down cargo transport and multiple motors can reduce these interactions thereby increasing velocity.

Impact of a dissemination strategy on family day care educators' intentions to adopt outdoor free play guidelines introduced in response to COVID-19: a randomized controlled trial.

In 2021, guidelines for early childhood education and care were released recommending children are provided access to outdoor areas during all free play sessions to reduce the risk of coronavirus disease of 2019 transmission, aligning with the existing recommendations to increase children's physical activity. There is a need to understand how to disseminate guidelines in this setting as dissemination is a prerequisite of adoption and implementation. This randomized controlled trial explored the impact of a video-based strategy to disseminate guidelines on family day care educators' intentions to adopt outdoor free play guidelines. Educators (N = 255) were randomized to receive a video (intervention) or text-based (usual care) resource via email describing recommendations. Educators were invited to participate in a post-intervention survey at 5-week follow-up assessing intentions to adopt guidelines. The secondary outcomes included knowledge, beliefs about capabilities, beliefs about consequences, social/professional role and identity, goals, implementation of guidelines, acceptability of resource and intervention reach. There was no statistically significant difference between groups in intentions to adopt guidelines [ß = 0.01 (95% confidence interval -0.50 to 0.52), P = 0.97], nor for any secondary outcomes. Further investigation is needed to identify effective dissemination strategies in the family day care setting to increase the adoption of public health guidelines.

A qualitative study on the influence of COVID-19 on smoking behaviors through changing social and physical contexts.

Globally, COVID-19 has been a major societal stressor and disrupted social and physical environments for many. Elucidating mechanisms through which societal disruptions influence smoking behavior has implications for future tobacco control efforts. Qualitative interviews were conducted among 38 adults who smoked combustible cigarettes in 2020 and 2021. The majority were women (75.7%), identified as Black (56.8%), were employed (61.3%), had a smoke-free home (66.7%) and lived in a small metro or rural (79.0%) county, primarily in rural southwest Georgia. Participants reported more time at home, increased isolation and less socializing, changed work and financial situations and altered household and family contexts. The vast majority of participants smoked more at some point during the pandemic with about half of these continuing to smoke more at the time of the interview. More time at home, multiple sources of stress and boredom were the main reasons for increased smoking. Decreases in smoking were attributed to financial strain, smoke-free home rules and nonsmoking family members, concerns about COVID-19 and less socializing with friends who smoke. Future tobacco control efforts during societal stressors such as pandemics should take into account specific psychosocial and environmental influences in attempts to minimize negative changes to smoking patterns.

Perspectives of Interstitial Lung Disease Patients and Carers During COVID-19.

Aim To gain an understanding of the impact of COVID-19 on the daily life, healthcare needs, mental wellbeing and outlook of patients with Interstitial Lung Disease (ILD) and their caregivers. Methods ILD patients and caregivers were invited to participate in a quantitative survey. Respondents could self-select to then participate in in-depth structured telephone interviews. Survey data was compared to Department of Health COVID-19 public opinion tracker findings for the comparable time period. Results There were 170 survey respones (111 patients and 59 caregivers) and 14 in-depth interview participants. 32% (n=36) of patients and 42% (n=25) of caregivers expressed extreme worry regarding COVID-19 on a 1-10 scale. 83% (n=92) of patients expressed concern about safe hospital access, 33% (n=37) had received a telephone consultation with their clinician, 43% (n=48) reported test delays, 47% (n=52) were exercising less, 23% (n=26) reported worse sleep and 15% (n=17) reported being financially worse off. Carers reported that sleep was worse for 58% (n=34), 42% (n=25) reported being worse off financially, and 40% (n=24) reported a worse diet. Worry (66%, n=39), stress (51%, n=30), anxiety (49%, n=29) were commonly reported by carers. Discussion ILD patients and caregivers reported higher levels of worry regarding COVID-19 compared to the general public. Alternative pathways for quality ILD patient care and interventions to reduce the burden of care on ILD caregivers are required.

Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma.

Glioblastoma (GBM) is an aggressive cancer with a very poor prognosis. Generally viewed as weakly immunogenic, GBM responds poorly to current immunotherapies. To understand this problem more clearly we used a combination of natural killer (NK) cell functional assays together with gene and protein expression profiling to define the NK cell response to GBM and explore immunosuppression in the GBM microenvironment. In addition, we used transcriptome data from patient cohorts to classify GBM according to immunological profiles. We show that glioma stem-like cells, a source of post-treatment tumour recurrence, express multiple immunomodulatory cell surface molecules and are targeted in preference to normal neural progenitor cells by natural killer (NK) cells ex vivo. In contrast, GBM-infiltrating NK cells express reduced levels of activation receptors within the tumour microenvironment, with hallmarks of transforming growth factor (TGF)-ß-mediated inhibition. This NK cell inhibition is accompanied by expression of multiple immune checkpoint molecules on T cells. Single-cell transcriptomics demonstrated that both tumour and haematopoietic-derived cells in GBM express multiple, diverse mediators of immune evasion. Despite this, immunome analysis across a patient cohort identifies a spectrum of immunological activity in GBM, with active immunity marked by co-expression of immune effector molecules and feedback inhibitory mechanisms. Our data show that GBM is recognized by the immune system but that anti-tumour immunity is restrained by multiple immunosuppressive pathways, some of which operate in the healthy brain. The presence of immune activity in a subset of patients suggests that these patients will more probably benefit from combination immunotherapies directed against multiple immunosuppressive pathways.

Surveillance optimisation to detect poliovirus in the pre-eradication era: a modelling study of England and Wales.

Surveillance for acute flaccid paralysis (AFP) cases are essential for polio eradication. However, as most poliovirus infections are asymptomatic and some regions of the world are inaccessible, additional surveillance tools require development. Within England and Wales, we demonstrate how inclusion of environmental sampling (ENV) improves the sensitivity of detecting both wild and vaccine-derived polioviruses (VDPVs) when compared to current surveillance. Statistical modelling was used to estimate the spatial risk of wild and VDPV importation and circulation in England and Wales. We estimate the sensitivity of each surveillance mode to detect poliovirus and the probability of being free from poliovirus, defined as being below a pre-specified prevalence of infection. Poliovirus risk was higher within local authorities in Manchester, Birmingham, Bradford and London. The sensitivity of detecting wild poliovirus within a given month using AFP and enterovirus surveillance was estimated to be 0.096 (95% CI 0.055-0.134). Inclusion of ENV in the three highest risk local authorities and a site in London increased surveillance sensitivity to 0.192 (95% CI 0.191-0.193). The sensitivity of ENV strategies can be compared using the framework by varying sites and the frequency of sampling. The probability of being free from poliovirus slowly increased from the date of the last case in 1993. ENV within areas thought to have the highest risk improves detection of poliovirus, and has the potential to improve confidence in the polio-free status of England and Wales and detect VDPVs.

Comparison of sporadic and familial behavioral variant frontotemporal dementia (FTD) in a North American cohort.

INTRODUCTION: Behavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments. METHODS: A total of 135 sporadic (s-bvFTD; mean age 63.3 years; 34% female) and 99 familial (f-bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f-bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule-associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation. RESULTS: Participants with f-bvFTD were younger and had earlier age at onset. s-bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI-Q) scores due to more frequent endorsement of depression and irritability. DISCUSSION: f-bvFTD and s-bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other.

Active lifestyles moderate clinical outcomes in autosomal dominant frontotemporal degeneration.

INTRODUCTION: Leisure activities impact brain aging and may be prevention targets. We characterized how physical and cognitive activities relate to brain health for the first time in autosomal dominant frontotemporal lobar degeneration (FTLD). METHODS: A total of 105 mutation carriers (C9orf72/MAPT/GRN) and 69 non-carriers reported current physical and cognitive activities at baseline, and completed longitudinal neurobehavioral assessments and brain magnetic resonance imaging (MRI) scans. RESULTS: Greater physical and cognitive activities were each associated with an estimated >55% slower clinical decline per year among dominant gene carriers. There was also an interaction between leisure activities and frontotemporal atrophy on cognition in mutation carriers. High-activity carriers with frontotemporal atrophy (-1 standard deviation/year) demonstrated >two-fold better cognitive performances per year compared to their less active peers with comparable atrophy rates. DISCUSSION: Active lifestyles were associated with less functional decline and moderated brain-to-behavior relationships longitudinally. More active carriers "outperformed" brain volume, commensurate with a cognitive reserve hypothesis. Lifestyle may confer clinical resilience, even in autosomal dominant FTLD.

Adapting implementation strategies: a case study of how to support implementation of healthy canteen policies.

OBJECTIVES: Although evidence-based interventions (EBIs) and effective strategies to implement them exist, they cannot be used by policy makers and practitioners if they do not align with end users' needs. As such, adaptations to EBIs and implementation approaches are likely to occur to increase 'fit' with end users' capacity. This article describes an approach undertaken by a population health service delivery unit in one Australian state to develop an adapted implementation strategy to support the implementation of the mandatory healthy canteen policy (EBI) to all schools located in the service delivery region. STUDY DESIGN: This is a case study of adapting an intervention to improve implementation of the healthy canteen policy. METHODS AND RESULTS: This is a six-step pragmatic, empirically driven approach. The steps include (i) adapt, where appropriate, the EBI to facilitate implementation; (ii) identify end users' capacity for implementation; (iii) identify opportunities to adapt the implementation interventions while preserving meaningful intervention impact; (iv) undertake program adaptation; (v) develop training and resources to support delivery of implementation strategies and; (vi) evaluate the adapted intervention. This article describes the application of these steps by the authors to develop an adapted support strategy consistent with end users' needs. CONCLUSIONS: This study provides some guidance on how to adapt implementation support approaches particularly when EBIs cannot be adapted. Future empirical research providing guidance on making practical adaptation decisions are needed.

Bacteraemia in the ED: Are We Meeting Targets?

AIM: An audit was performed in an Irish Emergency department (ED) to evaluate adherence to established antimicrobial guidelines and to determine the most common presentations of sepsis. METHODS: Data on ED patients with clinically significant bacteraemia on blood cultures were recorded for three months . The antimicrobial given to the patient was compared to that which the hospital guidelines would recommend for the ED diagnosis. RESULTS: Eleven patients out of 53 had no antimicrobial guidelines for diagnosis. Of the 42/53 patients, non-adherence to antimicrobial guidelines by physicians was observed in 81% (n=34/42) patients and adherence was observed in 19% (n=8/42) patients. Escherichia coli 35.70% (n=18), was the most frequent organism isolated. CONCLUSIONS: Non-adherence to antimicrobial guidelines resulted in 68% (n=23/34) of organisms covered by the antibiotic. Adherence to antimicrobial guidelines resulted in 87% (n=7/8) of organisms covered by the antibiotic.

The influence of androgens on hibernation phenology of free-living male arctic ground squirrels.

Free-living ground squirrel species are sexually dimorphic in hibernation phenology. The underlying causes of these differences are not yet known. Androgens, testosterone (T) in particular, inhibit hibernation. To determine the influence of endogenous androgens on annual timing of hibernation we first measured circulating levels of T and dehydroepiandrosterone (DHEA), an adrenal androgen implicated in non-mating season aggression in other species, in free-living male arctic ground squirrels (Urocitellus parryii, AGS). We also manipulated endogenous androgen levels by surgical castration, and consequently compared body temperature records from intact (n=24) and castrated (n=9) males to elucidate the influence of endogenous androgens on annual body temperature cycles. The highest T levels (0.53±0.10ng/mL) were in reproductively mature male AGS in spring; whereas, both immature males in spring and all males in late summer had T levels an order of magnitude lower (0.07±0.01 and 0.06±0.00ng/mL, respectively). DHEA levels were higher in males during the late summer compared to reproductively mature males in spring (120.6±18.9 and 35.9±2.3pg/mL, respectively). Eliminating gonadal androgens via castration resulted in males delaying euthermy by extending heterothermy significantly in spring (Apr 22 ±2.9) than reproductive males (Mar 28 ±3.9) but did not change the timing of hibernation onset (castrate: Oct 12 ±1.0 vs. intact: Oct 3 ±3.1). We conclude that while androgens play a significant role in spring hibernation phenology of males, their role in fall hibernation onset is unclear.

Anticholinergic burden in schizophrenia and ability to benefit from psychosocial treatment programmes: a 3-year prospective cohort study.

BACKGROUND: Many medications administered to patients with schizophrenia possess anticholinergic properties. When aggregated, pharmacological treatments may result in a considerable anticholinergic burden. The extent to which anticholinergic burden has a deleterious effect on cognition and impairs ability to participate in and benefit from psychosocial treatments is unknown. METHOD: Seventy patients were followed for approximately 3 years. The MATRICS consensus cognitive battery (MCCB) was administered at baseline. Anticholinergic burden was measured with the Anticholinergic Cognitive Burden (ACB) scale. Ability to benefit from psychosocial programmes was measured using the DUNDRUM-3 Programme Completion Scale (D-3) at baseline and follow-up. Psychiatric symptoms were measured using the PANSS. Total antipsychotic dose was measured using chlorpromazine equivalents. Functioning was measured using the Social and Occupational Functioning Assessment Scale (SOFAS). RESULTS: Mediation analysis found that the influence of anticholinergic burden on ability to participate and benefit from psychosocial programmes was completely mediated by the MCCB. For every 1-unit increase on the ACB scale, change scores for DUNDRUM-3 decreased by -0.27 points. This relationship appears specific to anticholinergic burden and not total antipsychotic dose. Moreover, mediation appears to be specific to cognition and not psychopathology. Baseline functioning also acted as mediator but only when MCCB was not controlled for. CONCLUSIONS: Anticholinergic burden has a significant impact on patients' ability to participate in and benefit from psychosocial treatment programmes. Physicians need to be mindful of the cumulative effect that medications can have on patient cognition, functional capacity and ability to benefit from psychosocial treatments.

The burden of illness in patients with hyponatraemia in Sweden: a population-based registry study.

BACKGROUND: Hyponatraemia (HN; serum sodium level < 135 mmol/l) is the most common electrolyte disturbance seen in clinical practice, and is associated with varying spectrum of symptoms. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common aetiology in hospitalised patients, and can be caused by several different underlying conditions. AIMS: The objectives of this study were to retrospectively examine the baseline characteristics, clinical outcomes and hospital resource utilisation of patients with HN and/or SIADH in Sweden over a 10-year period from 2001 to 2011. Additional analysis was performed on subpopulations of patients with hip fracture, pneumonia and small cell lung cancer (SCLC) to see if trends in outcomes were consistent across a broad range of aetiologies commonly associated with the condition. METHODS: Patient information was taken from the Swedish National Patient Registry, the Swedish Cancer Registry, the Swedish Cause of Death Register and the Swedish Prescribed Drug Register. A total of 34,537 patients (4.38%) were identified with HN and/or SIADH, with the incidence and prevalence rising over the 10-year study period. RESULTS: Of the 34,537 patients identified, 841 had hip fracture, 2635 had pneumonia and 106 had SCLC. Compared with matched control patients, those with HN and/or SIADH had a longer length of hospital stay, a higher re-admission rate and a shorter time to re-admission. CONCLUSIONS: This study showed that HN and/or SIADH negatively impact patient outcomes and healthcare resources related to hospital stay irrespective of the underlying cause. The impact of HN is not confined to the initial hospitalisation, as re-admission rates are also affected.

A New Method for Estimating the Coverage of Mass Vaccination Campaigns Against Poliomyelitis From Surveillance Data.

Mass vaccination campaigns with the oral poliovirus vaccine targeting children aged <5 years are a critical component of the global poliomyelitis eradication effort. Monitoring the coverage of these campaigns is essential to allow corrective action, but current approaches are limited by their cross-sectional nature, nonrandom sampling, reporting biases, and accessibility issues. We describe a new Bayesian framework using data augmentation and Markov chain Monte Carlo methods to estimate variation in vaccination coverage from children's vaccination histories investigated during surveillance for acute flaccid paralysis. We tested the method using simulated data with at least 200 cases and were able to detect undervaccinated groups if they exceeded 10% of all children and temporal changes in coverage of ±10% with greater than 90% sensitivity. Application of the method to data from Pakistan for 2010-2011 identified undervaccinated groups within the Balochistan/Federally Administered Tribal Areas and Khyber Pakhtunkhwa regions, as well as temporal changes in coverage. The sizes of these groups are consistent with the multiple challenges faced by the program in these regions as a result of conflict and insecurity. Application of this new method to routinely collected data can be a useful tool for identifying poorly performing areas and assisting in eradication efforts.

Evolution of the oxygen sensitivity of cytochrome c oxidase subunit 4.

Vertebrates possess two paralogs of cytochrome c oxidase (COX) subunit 4: a ubiquitous COX4-1 and a hypoxia-linked COX4-2. Mammalian COX4-2 is thought to have a role in relation to fine-tuning metabolism in low oxygen levels, conferred through both structural differences in the subunit protein structure and regulatory differences in the gene. We sought to elucidate the pervasiveness of this feature across vertebrates. The ratio of COX4-2/4-1 mRNA is generally low in mammals, but this ratio was higher in fish and reptiles, particularly turtles. The COX4-2 gene appeared unresponsive to low oxygen in nonmammalian models (zebrafish, goldfish, tilapia, anoles, and turtles) and fish cell lines. Reporter genes constructed from the amphibian and reptile homologues of the mammalian oxygen-responsive elements and hypoxia-responsive elements did not respond to low oxygen. Unlike the rodent ortholog, the promoter of goldfish COX4-2 did not respond to hypoxia or anoxia. The protein sequences of the COX4-2 peptide showed that the disulfide bridge seen in human and rodent orthologs would be precluded in other mammalian lineages and lower vertebrates, all of which lack the requisite pair of cysteines. The coordinating ligands of the ATP-binding site are largely conserved across mammals and reptiles, but in Xenopus and fish, sequence variations may disrupt the ability of the protein to bind ATP at this site. Collectively, these results suggest that many of the genetic and structural features of COX4-2 that impart responsiveness and benefits in hypoxia may be restricted to the Euarchontoglires lineage that includes primates, lagomorphs, and rodents.

Transport networks and inequities in vaccination: remoteness shapes measles vaccine coverage and prospects for elimination across Africa.

Measles vaccination is estimated to have averted 13·8 million deaths between 2000 and 2012. Persisting heterogeneity in coverage is a major contributor to continued measles mortality, and a barrier to measles elimination and introduction of rubella-containing vaccine. Our objective is to identify determinants of inequities in coverage, and how vaccine delivery must change to achieve elimination goals, which is a focus of the WHO Decade of Vaccines. We combined estimates of travel time to the nearest urban centre (⩾50 000 people) with vaccination data from Demographic Health Surveys to assess how remoteness affects coverage in 26 African countries. Building on a statistical mapping of coverage against age and geographical isolation, we quantified how modifying the rate and age range of vaccine delivery affects national coverage. Our scenario analysis considers increasing the rate of delivery of routine vaccination, increasing the target age range of routine vaccination, and enhanced delivery to remote areas. Geographical isolation plays a key role in defining vaccine inequity, with greater inequity in countries with lower measles vaccine coverage. Eliminating geographical inequities alone will not achieve thresholds for herd immunity, indicating that changes in delivery rate or age range of routine vaccination will be required. Measles vaccine coverage remains far below targets for herd immunity in many countries on the African continent and is likely to be inadequate for achieving rubella elimination. The impact of strategies such as increasing the upper age range eligible for routine vaccination should be considered.