Ability of new protected areas to counteract losses from downgrading, downsizing, and degazettement.

Protected area downgrading, downsizing, and degazettement (PADDD) is a common occurrence. Although PADDD is expected to weaken biodiversity protection, PADDD offsets and new unrelated protected areas (PAs) could help restore representation of biodiversity features to the reserve network affected by PADDD. Globally, we analyzed 16 territories with terrestrial PADDD and 4 territories with marine PADDD from 2011 to 2020. Our objective was to evaluate whether PADDD offsets and new PAs could restore the PAs, key biodiversity areas (KBAs), ecoregions, and threatened amphibian, mammal, bird, and reptile species ranges where PADDD had occurred. In our studied territories, offsets of PADDD were rare (enacted in 3 [19%] terrestrial territories and one [25%] marine territory). One territory had PADDD losses that were compensated fully by PADDD offsets in terms of area coverage and ecoregions represented. All other territories failed to achieve compensation goals. In territories affected by PADDD, PADDD offsets and new PAs partially restored area representation (63%) and KBA coverage (57%). However, only 38% of ecoregion representation and 20%, 33%, 31%, and 21% of threatened amphibian, mammal, bird, and reptile representation, respectively, were restored. Overall, we found a large shortfall in PADDD offsets, even when unrelated PAs were included in the calculus. There is an urgent need to expand PADDD offsets and PAs to advance biodiversity conservation and achieve the Global Biodiversity Framework's 30×30 target. Future planning of newly enacted conservation areas needs to prioritize biodiversity conservation and consider the purpose of restoring reserve networks affected by PADDD, rather than solely focusing on areal targets.

Capacidad de las áreas protegidas nuevas para contrarrestar las pérdidas por el cambio de categoría, la reducción de tamaño y la desclasificación Resumen La degradación, reducción y desclasificación de áreas protegidas (DRDAP) es un fenómeno común. Aunque se espera que la DRDAP debilite la protección de la biodiversidad, las compensaciones de la DRDAP y las nuevas áreas protegidas (AP) sin relación podrían ayudar a restaurar la representación de las características de la biodiversidad en la red de reservas afectadas por la DRDAP. Analizamos 16 territorios a nivel mundial con DRDAP terrestre y cuatro territorios con DRDAP marina entre 2011 y 2020. Nuestro objetivo era evaluar si las compensaciones de la DRDAP y las nuevas AP podrían restaurar las AP, las áreas clave para la biodiversidad (ACB), las ecorregiones y las áreas de distribución de especies amenazadas de anfibios, mamíferos, aves y reptiles donde se había producido la DRDAP. En nuestros territorios estudiados, las compensaciones de DRDAP fueron escasas (promulgadas en tres [19%] territorios terrestres y un [25%] territorio marino). Un territorio tuvo pérdidas de DRDAP que fueron compensadas totalmente por compensaciones de DRDAP en términos de cobertura de área y ecorregiones representadas. En los demás territorios no se alcanzaron los objetivos de compensación. En los territorios afectados por la DRDAP, las compensaciones de la DRDAP y las nuevas AP restauraron parcialmente la representación de la superficie (63%) y la cobertura de las ACB (57%). Sin embargo, sólo se restauró el 38% de la representación de la ecorregión y el 20%, 33%, 31% y 21% de la representación de anfibios, mamíferos, aves y reptiles amenazados, respectivamente. En general, encontramos un gran déficit en las compensaciones DRDAP, incluso cuando se incluyeron APs no relacionadas en el cálculo. Existe una necesidad urgente de ampliar las compensaciones DRDAP y las AP para avanzar en la conservación de la biodiversidad y alcanzar el objetivo 30x30 del Marco Global de Biodiversidad. La planificación futura de las áreas de conservación de nueva creación debe dar prioridad a la conservación de la biodiversidad y tener en cuenta el propósito de restaurar las redes de reservas afectadas por la DRDAP, en lugar de centrarse únicamente en objetivos de área.

Procedural interventions for erythromelalgia: A narrative review.

Erythromelalgia is a rare disorder characterized by episodic burning pain with redness and warmth of the extremities. Topical and systemic medications are the mainstay of management. We reviewed the published evidence for using procedural interventions to manage erythromelalgia, including their proposed mechanism of action and possible adverse effects, and included information in this review on epidural infusion, sympathetic ganglion block, sympathectomy, pulsed radiofrequency, spinal cord stimulation, dorsal root ganglion stimulation, brain stimulation, transcranial magnetic stimulation, and botulinum toxin injections. Both successful and unsuccessful outcomes have been reported. Although these procedural interventions extend the therapeutic options for erythromelalgia, the evidence for their use is limited. Case reports and small case series comprise most of the evidence. Based on our review, a multidisciplinary approach to management may be needed for patients with erythromelalgia.

Advancing the chemotherapy of tuberculous meningitis: a consensus view.

Tuberculous meningitis causes death or disability in approximately 50% of affected individuals and kills approximately 78 200 adults every year. Antimicrobial treatment is based on regimens used for pulmonary tuberculosis, which overlooks important differences between lung and brain drug distributions. Tuberculous meningitis has a profound inflammatory component, yet only adjunctive corticosteroids have shown clear benefit. There is an active pipeline of new antitubercular drugs, and the advent of biological agents targeted at specific inflammatory pathways promises a new era of improved tuberculous meningitis treatment and outcomes. Yet, to date, tuberculous meningitis trials have been small, underpowered, heterogeneous, poorly generalisable, and have had little effect on policy and practice. Progress is slow, and a new approach is required. In this Personal View, a global consortium of tuberculous meningitis researchers articulate a coordinated, definitive way ahead via globally conducted clinical trials of novel drugs and regimens to advance treatment and improve outcomes for this life-threatening infection.

Mixed effectiveness of global protected areas in resisting habitat loss.

Protected areas are the cornerstones of conservation efforts to mitigate the anthropogenic pressures driving biodiversity loss. Nations aim to protect 30% of Earth's land and water by 2030, yet the effectiveness of protected areas remains unclear. Here we analyze the performance of over 160,000 protected areas in resisting habitat loss at different spatial and temporal scales, using high-resolution data. We find that 1.14 million km2 of habitat, equivalent to three times the size of Japan, across 73% of protected areas, had been altered between 2003 and 2019. These protected areas experienced habitat loss due to the expansion of built-up land, cropland, pastureland, or deforestation. Larger and stricter protected areas generally had lower rates of habitat loss. While most protected areas effectively halted the expansion of built-up areas, they were less successful in preventing deforestation and agricultural conversion. Protected areas were 33% more effective in reducing habitat loss compared to unprotected areas, though their ability to mitigate nearby human pressures was limited and varied spatially. Our findings indicate that, beyond establishing new protected areas, there is an urgent need to enhance the effectiveness of existing ones to better prevent habitat loss and achieve the post-2020 global biodiversity goals.

The Role of Dimensions of Social Support in the Relationship Between Stigma and Mental Health: A Moderation Analysis.

HIV stigma remains a barrier to good health and understanding how social support may reduce the negative impact of stigma on health may help with designing stigma interventions. This study aims to understand how different types of social support may moderate or change the nature of the relationship between stigma and mental health. We recruited 327 participants to complete the People Living with HIV Stigma Index at baseline (t1) between August 2018 and September 2019 and at follow-up (t2) between February 2021 and October 2021. Separate moderation models were created with different types of social support (emotional/informational, tangible, affectionate, positive social interaction) as moderators, baseline stigma (internalized, enacted, anticipated) as the antecedent, and mental health (t2) as the outcome. Emotional/informational support was a significant moderator for the relationship between enacted (b = -2.12, 95% CI: -3.73, -0.51), internalized (b = -1.72, 95% CI: -3.24, -0.20), and anticipated (b = -2.59, 95% CI: -4.59, -0.60) stigma at t1 and mental health at t2. Tangible support was a significant moderator for internalized stigma (b = -1.54, 95% CI: -2.74, -0.35). Lastly, positive social interaction was a significant moderator for internalized (b = -1.38, 95% CI: -2.71, -0.04) and anticipated stigma (b = -2.14, 95% CI: -3.93, -0.36). In general, the relationship between social support and better mental health was stronger for participants with low stigma. Intervention strategies aimed at both stigma reduction and boosting social supports with different functions may be important for improving the mental health of people living with HIV.

Methaemoglobin as a surrogate marker of primaquine antihypnozoite activity in Plasmodium vivax malaria: A systematic review and individual patient data meta-analysis.

BACKGROUND: The 8-aminoquinolines, primaquine and tafenoquine, are the only available drugs for the radical cure of Plasmodium vivax hypnozoites. Previous evidence suggests that there is dose-dependent 8-aminoquinoline induced methaemoglobinaemia and that higher methaemoglobin concentrations are associated with a lower risk of P. vivax recurrence. We undertook a systematic review and individual patient data meta-analysis to examine the utility of methaemoglobin as a population-level surrogate endpoint for 8-aminoquinoline antihypnozoite activity to prevent P. vivax recurrence. METHODS AND FINDINGS: We conducted a systematic search of Medline, Embase, Web of Science, and the Cochrane Library, from 1 January 2000 to 29 September 2022, inclusive, of prospective clinical efficacy studies of acute, uncomplicated P. vivax malaria mono-infections treated with radical curative doses of primaquine. The day 7 methaemoglobin concentration was the primary surrogate outcome of interest. The primary clinical outcome was the time to first P. vivax recurrence between day 7 and day 120 after enrolment. We used multivariable Cox proportional-hazards regression with site random-effects to characterise the time to first recurrence as a function of the day 7 methaemoglobin percentage (log base 2 transformed), adjusted for the partner schizonticidal drug, the primaquine regimen duration as a proxy for the total primaquine dose (mg base/kg), the daily primaquine dose (mg/kg), and other factors. The systematic review protocol was registered with PROSPERO (CRD42023345956). We identified 219 P. vivax efficacy studies, of which 8 provided relevant individual-level data from patients treated with primaquine; all were randomised, parallel arm clinical trials assessed as having low or moderate risk of bias. In the primary analysis data set, there were 1,747 patients with normal glucose-6-phosphate dehydrogenase (G6PD) activity enrolled from 24 study sites across 8 different countries (Indonesia, Brazil, Vietnam, Thailand, Peru, Colombia, Ethiopia, and India). We observed an increasing dose-response relationship between the daily weight-adjusted primaquine dose and day 7 methaemoglobin level. For a given primaquine dose regimen, an observed doubling in day 7 methaemoglobin percentage was associated with an estimated 30% reduction in the risk of P. vivax recurrence (adjusted hazard ratio = 0.70; 95% confidence interval [CI] [0.57, 0.86]; p = 0.0005). These pooled estimates were largely consistent across the study sites. Using day 7 methaemoglobin as a surrogate endpoint for recurrence would reduce required sample sizes by approximately 40%. Study limitations include the inability to distinguish between recrudescence, reinfection, and relapse in P. vivax recurrences. CONCLUSIONS: For a given primaquine regimen, higher methaemoglobin on day 7 was associated with a reduced risk of P. vivax recurrence. Under our proposed causal model, this justifies the use of methaemoglobin as a population-level surrogate endpoint for primaquine antihypnozoite activity in patients with P. vivax malaria who have normal G6PD activity.

Evaluation of hydroxychloroquine or chloroquine for the prevention of COVID-19 (COPCOV): A double-blind, randomised, placebo-controlled trial.

BACKGROUND: Hydroxychloroquine (HCQ) has proved ineffective in treating patients hospitalised with Coronavirus Disease 2019 (COVID-19), but uncertainty remains over its safety and efficacy in chemoprevention. Previous chemoprevention randomised controlled trials (RCTs) did not individually show benefit of HCQ against COVID-19 and, although meta-analysis did suggest clinical benefit, guidelines recommend against its use. METHODS AND FINDINGS: Healthy adult participants from the healthcare setting, and later from the community, were enrolled in 26 centres in 11 countries to a double-blind, placebo-controlled, randomised trial of COVID-19 chemoprevention. HCQ was evaluated in Europe and Africa, and chloroquine (CQ) was evaluated in Asia, (both base equivalent of 155 mg once daily). The primary endpoint was symptomatic COVID-19, confirmed by PCR or seroconversion during the 3-month follow-up period. The secondary and tertiary endpoints were: asymptomatic laboratory-confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection; severity of COVID-19 symptoms; all-cause PCR-confirmed symptomatic acute respiratory illness (including SARS-CoV-2 infection); participant reported number of workdays lost; genetic and baseline biochemical markers associated with symptomatic COVID-19, respiratory illness and disease severity (not reported here); and health economic analyses of HCQ and CQ prophylaxis on costs and quality of life measures (not reported here). The primary and safety analyses were conducted in the intention-to-treat (ITT) population. Recruitment of 40,000 (20,000 HCQ arm, 20,000 CQ arm) participants was planned but was not possible because of protracted delays resulting from controversies over efficacy and adverse events with HCQ use, vaccine rollout in some countries, and other factors. Between 29 April 2020 and 10 March 2022, 4,652 participants (46% females) were enrolled (HCQ/CQ n = 2,320; placebo n = 2,332). The median (IQR) age was 29 (23 to 39) years. SARS-CoV-2 infections (symptomatic and asymptomatic) occurred in 1,071 (23%) participants. For the primary endpoint the incidence of symptomatic COVID-19 was 240/2,320 in the HCQ/CQ versus 284/2,332 in the placebo arms (risk ratio (RR) 0.85 [95% confidence interval, 0.72 to 1.00; p = 0.05]). For the secondary and tertiary outcomes asymptomatic SARS-CoV-2 infections occurred in 11.5% of HCQ/CQ recipients and 12.0% of placebo recipients: RR: 0.96 (95% CI, 0.82 to 1.12; p = 0.6). There were no differences in the severity of symptoms between the groups and no severe illnesses. HCQ/CQ chemoprevention was associated with fewer PCR-confirmed all-cause respiratory infections (predominantly SARS-CoV-2): RR 0.61 (95% CI, 0.42 to 0.88; p = 0.009) and fewer days lost to work because of illness: 104 days per 1,000 participants over 90 days (95% CI, 12 to 199 days; p < 0.001). The prespecified meta-analysis of all published pre-exposure RCTs indicates that HCQ/CQ prophylaxis provided a moderate protective benefit against symptomatic COVID-19: RR 0.80 (95% CI, 0.71 to 0.91). Both drugs were well tolerated with no drug-related serious adverse events (SAEs). Study limitations include the smaller than planned study size, the relatively low number of PCR-confirmed infections, and the lower comparative accuracy of serology endpoints (in particular, the adapted dried blood spot method) compared to the PCR endpoint. The COPCOV trial was registered with ClinicalTrials.gov; number NCT04303507. INTERPRETATION: In this large placebo-controlled, double-blind randomised trial, HCQ and CQ were safe and well tolerated in COVID-19 chemoprevention, and there was evidence of moderate protective benefit in a meta-analysis including this trial and similar RCTs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04303507; ISRCTN Registry ISRCTN10207947.

Efficient learning of ground and thermal states within phases of matter.

We consider two related tasks: (a) estimating a parameterisation of a given Gibbs state and expectation values of Lipschitz observables on this state; (b) learning the expectation values of local observables within a thermal or quantum phase of matter. In both cases, we present sample-efficient ways to learn these properties to high precision. For the first task, we develop techniques to learn parameterisations of classes of systems, including quantum Gibbs states for classes of non-commuting Hamiltonians. We then give methods to sample-efficiently infer expectation values of extensive properties of the state, including quasi-local observables and entropies. For the second task, we exploit the locality of Hamiltonians to show that M local observables can be learned with probability 1 - Î´ and precision ε using N = O log M δ e polylog ( ε - 1 ) samples - exponentially improving previous bounds. Our results apply to both families of ground states of Hamiltonians displaying local topological quantum order, and thermal phases of matter with exponentially decaying correlations.

The impact of determinants of health on the relationship between stigma and health in people living with HIV.

Determinants of health are important drivers of health states, yet there is little work examining their role in the relationship between HIV stigma and health. This study uses moderation analysis to examine how determinants of health affect the relationship between enacted, internalized, and anticipated stigma and mental health. Quantitative data was collected on 337 participants in Ontario, Canada at baseline (t1) between August 2018 and September 2019 and at follow-up (t2) between February 2021 and October 2021. Separate moderation models were created with each determinant of health (age, gender, sexual orientation, ethnicity, geographic region, education, employment, and basic needs) acting as the moderator between types of stigma at t1 and mental health at t2. Age was a significant moderator for the relationship between internalized and enacted stigma at t1 and mental health at t2. Region was a moderator for enacted and anticipated stigma and mental health. Sexual orientation was a moderator for anticipated stigma and mental health. Lastly, having basic needs was a moderator for enacted and anticipated stigma and mental health. Our findings suggest that intervention strategies may be more effective by incorporating supports for these determinants of health in addition to stigma reduction to improve mental health.

Lineage-informative microhaplotypes for recurrence classification and spatio-temporal surveillance of Plasmodium vivax malaria parasites.

Challenges in classifying recurrent Plasmodium vivax infections constrain surveillance of antimalarial efficacy and transmission. Recurrent infections may arise from activation of dormant liver stages (relapse), blood-stage treatment failure (recrudescence) or reinfection. Molecular inference of familial relatedness (identity-by-descent or IBD) can help resolve the probable origin of recurrences. As whole genome sequencing of P. vivax remains challenging, targeted genotyping methods are needed for scalability. We describe a P. vivax marker discovery framework to identify and select panels of microhaplotypes (multi-allelic markers within small, amplifiable segments of the genome) that can accurately capture IBD. We evaluate panels of 50-250 microhaplotypes discovered in a global set of 615 P. vivax genomes. A candidate global 100-microhaplotype panel exhibits high marker diversity in the Asia-Pacific, Latin America and horn of Africa (median HE = 0.70-0.81) and identifies 89% of the polyclonal infections detected with genome-wide datasets. Data simulations reveal lower error in estimating pairwise IBD using microhaplotypes relative to traditional biallelic SNP barcodes. The candidate global panel also exhibits high accuracy in predicting geographic origin and captures local infection outbreak and bottlenecking events. Our framework is open-source enabling customised microhaplotype discovery and selection, with potential for porting to other species or data resources.

Transmission-blocking activities of artesunate, chloroquine, and methylene blue on Plasmodium vivax gametocytes.

Plasmodium vivax is now the main cause of malaria outside Africa. The gametocytocidal effects of antimalarial drugs are important to reduce malaria transmissibility, particularly in low-transmission settings, but they are not well characterized for P. vivax. The transmission-blocking effects of chloroquine, artesunate, and methylene blue on P. vivax gametocytes were assessed. Blood specimens were collected from patients presenting with vivax malaria, incubated with or without the tested drugs, and then fed to mosquitos from a laboratory-adapted colony of Anopheles dirus (a major malaria vector in Southeast Asia). The effects on oocyst and sporozoite development were analyzed under a multi-level Bayesian model accounting for assay variability and the heterogeneity of mosquito Plasmodium infection. Artesunate and methylene blue, but not chloroquine, exhibited potent transmission-blocking effects. Gametocyte exposures to artesunate and methylene blue reduced the mean oocyst count 469-fold (95% CI: 345 to 650) and 1,438-fold (95% CI: 970 to 2,064), respectively. The corresponding estimates for the sporozoite stage were a 148-fold reduction (95% CI: 61 to 470) and a 536-fold reduction (95% CI: 246 to 1,311) in the mean counts, respectively. In contrast, high chloroquine exposures reduced the mean oocyst count only 1.40-fold (95% CI: 1.20 to 1.64) and the mean sporozoite count 1.34-fold (95% CI: 1.12 to 1.66). This suggests that patients with vivax malaria often remain infectious to anopheline mosquitos after treatment with chloroquine. Use of artemisinin combination therapies or immediate initiation of primaquine radical cure should reduce the transmissibility of P. vivax infections.

Clinical guideline highlights for the hospitalist: International consensus criteria for pediatric sepsis and septic shock.

GUIDELINE TITLE: International Consensus Criteria for Pediatric Sepsis and Septic Shock RELEASE DATE: January 21, 2024 PRIOR VERSION(S): International Pediatric Sepsis Consensus Conference: Definitions for Sepsis and Organ Dysfunction in Pediatrics (2005) DEVELOPER: Society of Critical Care Medicine FUNDING SOURCE: Society of Critical Care Medicine (grant R01HD105939 from the National Institute of Child Health and Human Development) TARGET POPULATION: Children with sepsis and septic shock.

A systematic review of digital access to post-diagnostic health and social care services for dementia.

OBJECTIVES: For many people with dementia and unpaid carers, using technology for care and support has become essential. Rapid proliferation of technology highlights the need to understand digital access to health and social care services for dementia. This mixed-methods systematic review aims to explore digital access to health and social care services for dementia, from the perspective of people with dementia and unpaid carers. METHODS: Nine electronic databases were searched in May 2023 for qualitative, quantitative, or mixed-method studies, published in English or German, focused on experiences of using technology-delivered health and social care services for people with dementia and unpaid carers. After removal of duplicates and screening, 44 empirical papers were included. RESULTS: From the 44 studies, findings were grouped into five categories, highlighting experiences for people with dementia and unpaid carers: (1) Adapting to technology, (2) Inequalities and variations in outcomes, (3) Impact on caring, (4) Impact on health, and (5) Impact on relationships. Proliferation of technology in care access emphasised the need for quick adaptation to technology and examination of its impact. The impact of such service delivery has evidenced mixed findings. There were improvements in the health and wellbeing of people with dementia and unpaid carers, and benefits for their dyadic relationship. However, using technology for health and social care access is not always possible and is often reliant on unpaid carers for support. Lower tech-literacy, lack of equipment or money to buy equipment and poor internet connection can impact the potential for positive outcomes. CONCLUSIONS: Technology can bring great benefits: social inclusion, improved service access and care. However, using technology in service delivery in dementia needs careful thought. Professionals and service providers need to be cognizant of the complex nature of dementia, and the benefits and challenges of hybrid service delivery.

Beak and feather disease virus detected in the endangered Red Goshawk (Erythrotriorchis radiatus).

We report the first detection and prevalence of Beak and feather disease virus (BFDV) in Australia's Red Goshawk (Erythrotriorchis radiatus). This is a new host for this pervasive pathogen amongst a growing list of non-psittacine species including birds of prey from the orders Accipitriformes (hawks, eagles, kites), Falconiformes (falcons and caracas), and Strigiformes (owls). The Red Goshawk is the first non-psittacine species listed as Endangered to be diagnosed with BFDV. We report an initial case of infection discovered post-mortem in a dead nestling and subsequent surveillance of birds from across northern Australia. We reveal BFDV prevalence rates in a wild raptor population for the first time, with detections in 25% (n = 7/28) of Red Goshawks sampled. Prevalence appears higher in juveniles compared to adults, although not statistically significant, but is consistent with studies of wild psittacines. BFDV genotypes were associated with the Loriinae (lorikeets, budgerigar, and fig parrots), Cacatuini (Cockatoos), and Polytelini (long-tailed parrots) tribes; species which are preyed upon by Red Goshawks. A positive BFDV status may be associated with lower body mass but small sample sizes precluded robust statistical analysis. We postulate the possible impacts of the virus on Red Goshawks and discuss future research priorities given these preliminary observations.

Scaling up area-based conservation to implement the Global Biodiversity Framework's 30x30 target: The role of Nature's Strongholds.

The Global Biodiversity Framework (GBF), signed in 2022 by Parties to the Convention on Biological Diversity, recognized the importance of area-based conservation, and its goals and targets specify the characteristics of protected and conserved areas (PCAs) that disproportionately contribute to biodiversity conservation. To achieve the GBF's target of conserving a global area of 30% by 2030, this Essay argues for recognizing these characteristics and scaling them up through the conservation of areas that are: extensive (typically larger than 5,000 km2); have interconnected PCAs (either physically or as part of a jurisdictional network, and frequently embedded in larger conservation landscapes); have high ecological integrity; and are effectively managed and equitably governed. These areas are presented as "Nature's Strongholds," illustrated by examples from the Congo and Amazon basins. Conserving Nature's Strongholds offers an approach to scale up initiatives to address global threats to biodiversity.

Corticosteroid Therapy in Acute and Subacute Arachnoiditis - A Case Series.

Arachnoiditis is difficult to treat. Patients are often left frustrated after many failed trials of conservative therapies without symptom resolution. Surgery may provide symptom relief for a short period of time, but their pain often returned. Herein, we present three cases of acute arachnoiditis following three different pain procedures: epidural blood patch, IDDS implant, and epidural steroid injection. The patients were diagnosed and treated with corticosteroids within 10 days of the procedure. Two patients were treated with the same oral steroid regiment, while the third patient was treated with both oral and IV steroid. All three patients had good outcomes at the completion of their steroid therapy. This case series may provide insight into treating acute and subacute arachnoiditis from pain interventions.

Ecosystem effects of intraspecific variation in a colour polymorphic amphibian.

An emerging consensus suggests that evolved intraspecific variation can be ecologically important. However, evidence that evolved trait variation within vertebrates can influence fundamental ecosystem-level processes remains sparse. In this study, we sought to assess the potential for evolved variation in the spotted salamander (Ambystoma maculatum) to affect aquatic ecosystem properties. Spotted salamanders exhibit a conspicuous polymorphism in the colour of jelly encasing their eggs-some females produce clear jelly, while others produce white jelly. Although the functional significance of jelly colour variation remains largely speculative, evidence for differences in fecundity and the morphology of larvae suggests that the colour morphs might differ in the strength or identity of ecological effects. Here, we assessed the potential for frequency variation in spotted salamander colour morphs to influence fundamental physiochemical and ecosystem properties-dissolved organic carbon, conductivity, acidity and primary production-with a mesocosm experiment. By manipulating colour morph frequency across a range of larval densities, we were able to demonstrate that larva density and colour morph variation were ecologically relevant: population density reduced dissolved organic carbon and increased primary production while mesocosms stocked with white morph larvae tended to have higher dissolved organic carbon and conductivity. Thus, while an adaptive significance of jelly coloration remains hypothetical, our results show that colour morphs differentially influence key ecosystem properties-dissolved organic carbon and conductivity.

Temporal changes in SARS-CoV-2 clearance kinetics and the optimal design of antiviral pharmacodynamic studies: an individual patient data meta-analysis of a randomised, controlled, adaptive platform study (PLATCOV).

BACKGROUND: Effective antiviral drugs prevent hospitalisation and death from COVID-19. Antiviral efficacy can be efficiently assessed in vivo by measuring rates of SARS-CoV-2 clearance estimated from serial viral genome densities quantitated in nasopharyngeal or oropharyngeal swab eluates. We conducted an individual patient data meta-analysis of unblinded arms in the PLATCOV platform trial to characterise changes in viral clearance kinetics and infer optimal design and interpretation of antiviral pharmacometric evaluations. METHODS: Serial viral density data were analysed from symptomatic, previously healthy, adult patients (within 4 days of symptom onset) enrolled in a large multicentre, randomised, adaptive, pharmacodynamic, platform trial (PLATCOV) comparing antiviral interventions for SARS-CoV-2. Viral clearance rates over 1 week were estimated under a hierarchical Bayesian linear model with B-splines used to characterise temporal changes in enrolment viral densities and clearance rates. Bootstrap re-sampling was used to assess the optimal duration of follow-up for pharmacometric assessment, where optimal was defined as maximising the expected Z score when comparing effective antivirals with no treatment. PLATCOV is registered at ClinicalTrials.gov, NCT05041907. FINDINGS: Between Sept 29, 2021, and Oct 20, 2023, 1262 patients were randomly assigned in the PLATCOV trial. Unblinded data were available from 800 patients (who provided 16 818 oropharyngeal viral quantitative PCR [qPCR] measurements), of whom 504 (63%) were female. 783 (98%) patients had received at least one vaccine dose and 703 (88%) were fully vaccinated. SARS-CoV-2 viral clearance was biphasic (bi-exponential). The first phase (α) was accelerated by effective interventions. For all the effective interventions studied, maximum discriminative power (maximum expected Z score) was obtained when evaluating serial data from the first 5 days after enrolment. Over the 2-year period studied, median viral clearance half-lives estimated over 7 days shortened from 16·6 h (IQR 15·3 to 18·2) in September, 2021, to 9·2 h (8·0 to 10·6) in October, 2023, in patients receiving no antiviral drugs, equivalent to a relative reduction of 44% (95% credible interval [CrI] 19 to 64). A parallel reduction in viral clearance half-lives over time was observed in patients receiving antiviral drugs. For example, in the 158 patients assigned to ritonavir-boosted nirmatrelvir (3380 qPCR measurements), the median viral clearance half-life reduced from 6·4 h (IQR 5·7 to 7·3) in June, 2022, to 4·8 h (4·2 to 5·5) in October, 2023, a relative reduction of 26% (95% CrI -4 to 42). INTERPRETATION: SARS-CoV-2 viral clearance kinetics in symptomatic, vaccinated individuals accelerated substantially over 2 years of the pandemic, necessitating a change to how new SARS-CoV-2 antivirals are compared (ie, shortening the period of pharmacodynamic assessment). As of writing (October, 2023), antiviral efficacy in COVID-19 can be efficiently assessed in vivo using serial qPCRs from duplicate oropharyngeal swab eluates taken daily for 5 days after drug administration. FUNDING: Wellcome Trust.