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Reviewed: Creating Wilderness: A Transnational History of the Swiss National Park By Patrick Kupper. Translated by Giselle Weiss. Oxford, United Kingdom: Berghahn, 2014. xi + 266 pp. US$ 95.00, £ 60.00. ISBN 978-1-78238-373-4.

Abstract Background Focal epilepsy is common in children and adults with mitochondrial disease. Seizures are often refractory to pharmacological treatment and, in this patient group, frequently evolve to refractory focal status epilepticus (also known as epilepsia partialis continua). Where this occurs, the long-term prognosis is poor. Transcranial DC stimulation (tDCS) is a promising, non-invasive, adjunctive treatment alternative to common surgical procedures. Limited recruitment of study participants with this rare disease and the ethical challenges of administering a treatment to one group and not another, while maintaining strict methodological rigour can pose challenges to the design of a clinical study. Method We designed the first delayed start, double-blinded, sham-controlled study to evaluate the efficacy of tDCS as an adjunctive treatment for focal epilepsy. We will include participants with a genetically confirmed diagnosis of mitochondrial disease with drug-resistant focal epilepsy aged ≥ 2 years, aiming to collect 30 episodes of focal status epilepticus, each treated for a maximum period of 14 days. The early start intervention arm will receive tDCS from day 1. The delayed start intervention arm will receive sham stimulation until crossover on day 3. Our primary endpoint is a greater than 50% reduction from baseline (on day 0) in seizure frequency assessed by 3x daily reporting, accelerometery, and video monitoring. Changes in the underlying epileptogenic focus within the brain related to the tDCS intervention will be assessed by magnetic resonance imaging (MRI) and/or electroencephalography (EEG). Discussion Study results in favour of treatment efficacy would support development of tDCS into a mainstream treatment option for focal epileptic seizures related to mitochondrial disease. Trials registration ISRCTN: 18,241,112; registered on 16/11/2021.

Abstract Protein kinases are critical components of a myriad biological processes and strongly associated with various diseases. While kinase research has been a point of focus in biomedical research for several decades, a large portion of the kinome is still considered understudied or “dark,” because prior research is targeted towards a subset of kinases with well-established roles in cellular processes. We present an empirical and in-silico hybrid workflow to extend the functional knowledge of understudied kinases. Utilizing multiplex peptide activity arrays and robust in-silico analyses, we extended the functional knowledge of five dark tyrosine kinases (AATK, EPHA6, INSRR, LTK, TNK1) and explored their roles in schizophrenia, Alzheimer’s dementia (AD), and major depressive disorder (MDD). Using this hybrid approach, we identified 195 novel kinase-substrate interactions with variable degrees of affinity and linked extended functional networks for these kinases to biological processes that are impaired in psychiatric and neurological disorders. Biochemical assays and mass spectrometry were used to confirm a putative substrate of EPHA6, an understudied dark tyrosine kinase. We examined the EPHA6 network and knowledgebase in schizophrenia using reporter peptides identified and validated from the multi-plex array with high affinity for phosphorylation by EPHA6. Identification and confirmation of putative substrates for understudied kinases provides a wealth of actionable information for the development of new drug treatments as well as exploration of the pathophysiology of disease states using signaling network approaches.

Abstract Understanding of past droughts has been mostly shaped by meteorological data, with relatively less known about the human aspects of droughts, their socio‐economic impacts, as well as choices people make in response to droughts in different environmental and socio‐political contexts. The lack of data that systematically record and categorize drought impacts is an important reason for this disparity. In this paper, we present an Irish drought impacts database (IDID) containing 6094 newspaper reports and 11,351 individual impact records for the island of Ireland, covering the period 1733–2019. Relevant articles were identified through systematic searching of the Irish Newspaper Archives, and recorded impacts were categorized using a modified version of the classification scheme employed by the European drought impact inventory (EDII). Drawing on the wealth and diversity of content provided by the newspapers, the IDID database provides information on the documented temporal and geographical extent of drought events, their socio‐economic and political contexts, their consequences, mitigation strategies employed and their change over time. The IDID also facilitates analysis of long‐term patterns in drought incidence, individual impact categories, as well as detailed insight into the impacts of individual drought events over nearly three centuries of Ireland's history. In addition, by allowing an examination of the coherence between meteorological records and identified impacts, it advances our understanding of the influences that contemporary economic, political, environmental and societal events had on the human experience, perception and impact of droughts. This new open‐access database, therefore, provides opportunities for improving understanding of drought vulnerability and is an important step in developing greater capacity to cope with and respond to future droughts on the island of Ireland.

Abstract Background Multiple sclerosis (MS) is a leading cause of neurological disability among young and middle-aged adults worldwide, and disability is measured using a variety of approaches, including patient reported outcome measures (PROMs) such as the Patient Determined Disease Steps (PDDS) scale. There is limited evidence for the validity of inferences from the middle-range of scores on the PDDS (i.e., 3 “gait disability” – 6 “bilateral support”), but that range of scores seemingly represents moderate disability characterized by varying levels of walking dysfunction. Purpose The current study examined whether the middle-range of scores from the PDDS reflect varying levels of walking dysfunction among people with MS. Method Participants (N = 374) completed the Patient Determined Disease Steps (PDDS) scale, Multiple Sclerosis Walking Scale-12 (MSWS-12), timed 25-foot walk (T25FW), six-minute walk (6 MW), Modified Fatigue Impact Scale (MFIS), and Multiple Sclerosis Impact Scale-29 (MSIS-29), and underwent a neurological exam for generating an Expanded Disability Status Scale (EDSS) score as part of screening and baseline data collection for a clinical trial of exercise training in MS. We undertook a series of linear trend analyses that examined differences in the outcomes of EDSS, T25FW, 6 MW, MSWS-12, MFIS subscales, and MSIS-29 subscales across the 4 levels of PDDS scores (i.e., 3–6). Results There were statistically significant and strong linear trends for EDSS (F1,370 = 306.1, p

Background: The management of heart failure (HF) is challenging because of the complexities in recommended therapies. Integrated disease management (IDM) is an effective model, promoting guideline-directed care, but the impact of IDM in the community setting requires further evaluation. Methods: A retrospective evaluation of community-based IDM. Patient characteristics were described, and outcomes using a pre- and post-intervention design were HF-related health-service use, quality of life, and concordance with guideline-directed medical therapy (GDMT). Results: 715 patients were treated in the program (2016 to 2023), 219 in a community specialist–care clinic, and 496 in 25 primary-care clinics. The overall cohort was predominantly male (60%), with a mean age of 73.5 years (± 10.7), and 60% with HF with reduced ejection fraction. In patients with ≥ 6 months of follow-up (n = 267), pre vs post annualized rates of HF-related acute health-service use decreased from 36.3 to 8.5 hospitalizations per 100 patients per year, P < 0.0001, from 31.8 to 13.1 emergency department visits per 100 patients per year, P < 0.0001, and from 152.8 to 110.0 urgent physician visits per 100 patients per year, P = 0.0001. The level of concordance with GDMT improved; the number of patients receiving triple therapy and quadruple therapy increased by 10.1% (95% confidence interval [CI], 2.4%,17.8%) and 19.6% (95% CI, 12.0%, 27.3%), respectively. Within these groups, optimal dosing was achieved in 42.5% (95% CI, 32.0%, 53.6%) and 35.0% (95% CI, 23.1%, 48.4%), respectively. In patients with at least one follow-up visit (n = 286), > 50% experienced a clinically relevant improvement in their quality of life. Conclusions: A community-based IDM program for HF, may reduce HF-related acute health-service use, improve quality of life and level of concordance with GDMT. These encouraging preliminary outcomes from a real-world program evaluation require confirmation in a randomized controlled trial. Résumé: Contexte: La prise en charge de l’insuffisance cardiaque (IC) représente un défi en raison de la complexité des traitements recommandés. La prise en charge intégrée des maladies est un modèle efficace qui favorise les soins reposant sur les lignes directrices, mais la portée de ce modèle en milieu extra-hospitalier mérite une évaluation plus approfondie. Méthodologie: Évaluation rétrospective de la prise en charge intégrée des maladies à l’échelle communautaire. Les caractéristiques des patients ont été établies. Les résultats mesurés avant et après l’intervention ont été l’utilisation des services de santé liés à l’IC, la qualité de vie et le degré de concordance avec le traitement médical recommandé par les lignes directrices. Résultats: Au total, 715 patients ont été traités dans le cadre du programme (de 2016 à 2023) : 219 dans une clinique communautaire de soins spécialisés et 496 dans 25 cliniques de soins primaires. Dans l’ensemble, la majorité des patients étaient de sexe masculin (60 %). L’âge moyen était de 73,5 ans (± 10,7 ans). Soixante pour cent des patients présentaient une IC avec fraction d’éjection réduite. Chez les patients ayant fait l’objet d’un suivi pendant ≥ 6 mois (n = 267), les taux annualisés d’utilisation des services de santé aigus liés à l’IC avant et après l’intervention sont passés de 36,3 à 8,5 hospitalisations pour 100 patients par année (p < 0,0001), de 31,8 à 13,1 visites aux urgences pour 100 patients par année (p < 0,0001) et de 152,8 à 110,0 consultations avec un urgentologue pour 100 patients par année (p = 0,0001). On a observé une augmentation du degré de concordance avec le traitement médical recommandé par les lignes directrices. Le nombre de patients recevant une trithérapie et une quadrithérapie a également augmenté de 10,1 % (intervalle de confiance [IC] à 95 % : 2,4 % à 17,8 %) et de 19,6 % (IC à 95 % : 12,0 % à 27,3 %), respectivement. Dans ces groupes, la dose optimale a été atteinte chez 42,5 % (IC à 95 % : 32,0 % à 53,6 %) et 35,0 % (IC à 95 % : 23,1 % à 48,4 %) des patients, respectivement. Plus de 50 % des patients ayant effectué au moins une visite de suivi (n = 286) ont obtenu une amélioration cliniquement pertinente de leur qualité de vie. Conclusions: Un programme communautaire de prise en charge intégrée de l’IC peut réduire l’utilisation des services de santé liés à l’IC, améliorer la qualité de vie et augmenter le degré de concordance avec le traitement médical recommandé par les lignes directrices. Bien qu’ils soient encourageants, ces résultats préliminaires issus de l’évaluation d’un programme en contexte réel doivent être confirmés par la réalisation d’une étude à répartition aléatoire et contrôlée.

Abstract Background Identifying chemical mentions within the Alzheimer’s and dementia literature can provide a powerful tool to further therapeutic research. Leveraging the Chemical Entities of Biological Interest (ChEBI) ontology, which is rich in hierarchical and other relationship types, for entity normalization can provide an advantage for future downstream applications. We provide a reproducible hybrid approach that combines an ontology-enhanced PubMedBERT model for disambiguation with a dictionary-based method for candidate selection. Results There were 56,553 chemical mentions in the titles of 44,812 unique PubMed article abstracts. Based on our gold standard, our method of disambiguation improved entity normalization by 25.3 percentage points compared to using only the dictionary-based approach with fuzzy-string matching for disambiguation. For the CRAFT corpus, our method outperformed baselines (maximum 78.4%) with a 91.17% accuracy. For our Alzheimer’s and dementia cohort, we were able to add 47.1% more potential mappings between MeSH and ChEBI when compared to BioPortal. Conclusion Use of natural language models like PubMedBERT and resources such as ChEBI and PubChem provide a beneficial way to link entity mentions to ontology terms, while further supporting downstream tasks like filtering ChEBI mentions based on roles and assertions to find beneficial therapies for Alzheimer’s and dementia.

Black rats (Rattus rattus) are one of the most widespread invasive animals and have been implicated in the decline of species representing several wildlife taxa, particularly on islands. However, their impact on more closely related species, i.e. rodents, via competition is less well-understood. Using diet similarity as a metric of competition for food resources, we used stable isotopes to compare diets of two populations of black rats to diets of two endangered populations of rice rats (Oryzomys palustris natator and Oryzomys palustris sanibeli) in southern Florida, USA. Specifically, we analysed hair samples from 32 rice rats and 35 black rats for carbon (δ13C) and nitrogen (δ15N) isotopes. In addition, we analysed samples of 129 potential food items to characterise rodent diets using stable isotope mixing models. Despite considerable overlap in isotope-space, we observed differences between rice rats and black rats in the relative composition of plant and animal foods. Specifically, the diets of both populations of rice rats consisted of mostly animal foods, whereas the diets of black rats consisted mostly of plants. In combination with previous work revealing temporal niche partitioning, our results suggest competition between invasive black rats and endangered native rodents may be limited. As such, expensive and logistically complicated efforts to control black rats may have limited success for conserving endangered rodents.

Abstract Globally, glaciers and icefields contribute significantly to sea level rise. Here we show that ice loss from Juneau Icefield, a plateau icefield in Alaska, accelerated after 2005 AD. Rates of area shrinkage were 5 times faster from 2015–2019 than from 1979–1990. Glacier volume loss remained fairly consistent (0.65–1.01 km3 a−1) from 1770–1979 AD, rising to 3.08–3.72 km3 a−1 from 1979–2010, and then doubling after 2010 AD, reaching 5.91 ± 0.80 km3 a−1 (2010–2020). Thinning has become pervasive across the icefield plateau since 2005, accompanied by glacier recession and fragmentation. Rising equilibrium line altitudes and increasing ablation across the plateau has driven a series of hypsometrically controlled melt-accelerating feedbacks and resulted in the observed acceleration in mass loss. As glacier thinning on the plateau continues, a mass balance-elevation feedback is likely to inhibit future glacier regrowth, potentially pushing glaciers beyond a dynamic tipping point.

The application of adeno-associated virus (AAV) vectors in human gene therapies requires reproducible and homogeneous preparations for clinical efficacy and safety. For the AAV production process, often scalable affinity chromatography columns are utilized, such as the POROS CaptureSelect AAVX affinity resin, during downstream processing to ensure highly purified AAV vectors. The AAVX ligand is based on a camelid single-domain antibody capturing a wide range of recombinant AAV capsids. Described here is the identification of the AAV8 capsid epitope to AAVX at 2.3 Å resolution using cryo-electron microscopy. The ligand binds near the 5-fold axis of the capsid in a similar manner to the previously characterized AVB affinity ligand but does not conform to the capsid's icosahedral symmetry. The cross-reactivity of AAVX to other AAV capsids is achieved by primarily interacting with the peptide backbone of the AAV capsid’s structurally conserved DE and HI loops. These observations will guide AAV capsid engineering efforts to retain the ability of future recombinant capsid designs to be purified using antibody-based affinity ligands.

Purpose: Prurigo nodularis (PN) is a skin disease characterized by intensely itchy skin nodules and is associated with a significant healthcare resource utilization (HCRU). This study aimed to estimate the HCRU of patients in England with PN overall and moderate-to-severe PN (MSPN) in particular.Methods: This retrospective cohort study used data from the Clinical Practice Research Datalink and Hospital Episode Statistics in England. Patients with Mild PN (MiPN) were matched to patients with MSPN by age and gender for the primary analysis. Patients were enrolled in the study between 1st April 2007 and 1st March 2019. All-cause HCRU was calculated, including primary and secondary care contacts and costs (cost-year 2022).Results: Of 23,522 identified patients, 8,933 met the inclusion criteria, with a primary matched cohort of 2,479 PN patients. During follow up, the matched cohort’s primary care visits were 21.27 per patient year (PPY) for MSPN group and 11.35 PPY for MiPN group. Any outpatient visits were 10.72 PPY and 4.87 PPY in MSPN and MiPN groups, respectively. Outpatient dermatology visits were 1.96 PPY and 1.14 PPY in MSPN and MiPN groups, respectively.Conclusion: PN, especially MSPN, has a high HCRU burden in England, highlighting the need for new and improved disease management treatments.

Sperm morphology analysis is crucial in infertility diagnosis and treatment. However, current clinical analytical methods use either chemical stains that render cells unusable for treatment or rely on subjective manual inspection. Here, an ensemble deep‐learning model is presented for classification of live, unstained human sperm using whole‐cell morphology. This model achieves an accuracy and precision of 94% benchmarked against the consensus of three andrology scientists who classified the images independently. The model loses less than a 12% prediction performance even when image resolution is reduced by over sixfold. This ensures compatibility across varied clinical imaging setups. This model also provides a high certainty and robust classification of challenging images, which divided the experts. By providing a consistent, automated approach for classifying live, unstained cells using quantitative data, this model offers promising future opportunities for enhancing clinical sperm selection practices and reducing day‐to‐day variability in clinics.

Abstract Increased circulating histones correlate with sepsis severity and are a potential therapeutic target. Pre‐clinical studies showed benefit with a histone‐neutralizing polyanion molecule (STC3141). We aimed to investigate the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis. We studied 26 patients with sepsis divided into four cohorts of one, five, ten, and ten subjects, respectively. We conducted a dose‐adjusted, open‐label study to determine the safety, tolerability, and pharmacokinetics of STC3141 administered as an IV infusion for up to 72 h, with rate adjusted to estimated creatinine clearance. Four steady‐state concentrations were targeted. Twenty of the 26 subjects (77%) in the study experienced at least one adverse event (AE). The most frequently reported study drug‐related AE was a mildly prolonged aPTT (four events). Only one AE (pulmonary hemorrhage) led to discontinuation of the drug. After excluding patients receiving renal replacement therapy (RRT) patients, clearance ranged from 3.3 to 4.2 L/h across cohorts and was essentially completely renal in nature. Half‐life values ranged from 5 to 7 h. The mean (±SD) terminal half‐life for non‐RRT subjects and for whom it was possible to calculate was approximately 9 (±4.77) h but increased to 19 (±7.94) h for subjects on RRT. Overall, 18 (69.2%) patients completed the study to day eight in the ICU, and 22 (84.6%) survived to 28 days. STC3141 administration appeared to have an acceptable degree of safety and tolerability and expected pharmacokinetics. Cautious, larger randomized efficacy trials in sepsis appear justified.

To determine antimicrobial susceptibility of Neisseria gonorrhoeae, we analyzed phenotypes and genomes of 72 isolates collected in Cambodia in 2023. Of those, 9/72 (12.5%) were extensively drug resistant, a 3-fold increase from 2022. Genomic analysis confirmed expansion of newly emerging resistant clones and ongoing resistance emergence across new phylogenetic backbones.

Abstract Introduction Although viscosupplementation is a commonly used treatment for osteoarthritis and is widely regarded as a safe treatment option, it is associated with the rare complication of pseudoseptic arthritis. Most existing case reports that cite this rare complication employed the use of early broad-spectrum antibiotics. Case presentation In this case report, we present a 61-year-old African American female patient who presented with bilateral knee pseudoseptic arthritis in the setting of viscosupplementation. She presented 3 days after bilateral viscosupplementation injections with bilateral knee swelling, discomfort, and pain with micromotion. Her white blood cell count (WBC) was 12.83 (4.5–11 normal), her C-reactive protein (CRP) level was 159 mg/L (0–10 normal), and her erythrocyte sedimentation rate (ESR) was 79 mm/hour (0–40 normal). Her left knee aspirate yielded 38,580 WBC with a negative gram stain and negative cultures. Her right knee aspirate yielded 29,670 WBC with a negative gram stain and negative cultures. Through the utilization of careful clinical monitoring, ice therapy, and non-steroidal inflammatory medication, we were able to successfully treat this patient while maintaining proper antibiotic stewardship. Conclusion Pseudoseptic arthritis in the setting of viscosupplementation can be adequately treated and monitored without the use of antibiotics.

Abstract Introduction Nail psoriasis is highly prevalent among patients with psoriasis yet remains one of the most challenging areas to treat. To better understand the treatment landscape for psoriatic nail disease, more studies are needed that compare the effectiveness of different biologics for patients with nail psoriasis. This study contributes to this objective by directly comparing the effectiveness of approved biologics in improving nail psoriasis for patients up to month 12 in a real-world setting. Methods Psoriasis Study of Health Outcomes (PSoHO) is an ongoing 3-year, prospective, non-interventional cohort study of adults with chronic moderate-to-severe plaque psoriasis initiating or switching to a new biologic. This study assessed the change in modified Nail Psoriasis Severity Index (mNAPSI) score from baseline to months 3, 6 and 12 for 763 patients and compared the effectiveness of anti-interleukin (IL)-17A biologics versus other approved biologics, as well as ixekizumab versus secukinumab, guselkumab, risankizumab and adalimumab. Comparative adjusted analyses used frequentist model averaging (FMA). Least square mean difference (LSMD) in mNAPSI scores are presented as observed. Results Irrespective of the severity of nail psoriasis at baseline, the anti-IL-17A cohort had greater mean mNAPSI reductions from baseline compared to the other biologics cohort through month 12, reaching significance at months 3 and 6 in the adjusted analysis. For patients with moderate-to-severe nail psoriasis, ixekizumab showed numerically higher mean reductions in mNAPSI scores compared to all other studied biologics, reaching significance versus guselkumab at all timepoints and risankizumab at month 6. Conclusion This real-world study showed that patients with moderate-to-severe psoriasis and any severity of concomitant nail involvement had significantly faster and more substantial improvements in nail psoriasis up to month 6 in the anti-IL-17A cohort compared to the other biologics cohort. Of the individual biologics studied, ixekizumab showed the highest numerical improvements in nail psoriasis at month 12. Trial registration EUPAS24207.

Aims: Young adults undergoing total hip arthroplasty (THA) largely have different indications for surgery, preoperative function, and postoperative goals compared to a standard patient group. The aim of our study was to describe young adult THA preoperative function and quality of life, and to assess postoperative satisfaction and compare this with functional outcome measures. Methods: A retrospective cohort analysis of young adults (aged < 50 years) undergoing THA between May 2018 and May 2023 in a single tertiary centre was undertaken. Median follow-up was 31 months (12 to 61). Oxford Hip Score (OHS) and focus group-designed questionnaires were distributed. Searches identified 244 cases in 225 patients. Those aged aged under 30 years represented 22.7% of the cohort. Developmental dysplasia of the hip (50; 45.5%) and Perthes’ disease (15; 13.6%) were the commonest indications for THA. Results: Preoperatively, of 110 patients, 19 (17.2%) were unable to work before THA, 57 (52%) required opioid analgesia, 51 (46.4%) were reliant upon walking aids, and 70 (63.6%) had sexual activity limited by their pathology. One patient required revision due to instability. Mean OHS was 39 (9 to 48). There was a significant difference between the OHS of cases where THA met expectation, compared with the OHS when it did not (satisfied: 86 (78.2%), OHS: 41.2 (36.1%) vs non-satisfied: 24 (21%), OHS: 31.6; p ≤ 0.001). Only one of the 83 patients (75.5%) who returned to premorbid levels of activity did so after 12 months. Conclusion: Satisfaction rates of THA in young adults is high, albeit lower than commonly quoted figures. Young adults awaiting THA have poor function with high requirements for mobility aids, analgesia, and difficulties in working and undertaking leisure activities. The OHS provided a useful insight into patient function and was predictive of satisfaction rates, although it did not address the specific demands of young adults undertaking THA. Function at one year postoperatively is a good indication of overall outcomes. Cite this article: Bone Jt Open 2024;5(4):304–311.