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The present investigation aims to examine the role of α-synuclein seed amplification assays for screening Parkinson’s disease. Parkinson’s disease (PD) is a debilitating neurodegenerative disorder caused by the loss of dopaminergic neurons in the midbrain, leading to symptoms such as tremors, bradykinesia, postural instability, dementia, and depression. It is classified as an α-synucleinopathy related to the role of α-synuclein aggregates in neuron degeneration. Diagnosis relies on clinical assessment without premortem diagnostic tests or imaging, often resulting in delayed detection and impaired symptom management. In this regard, our study explores a screening technique using an amplification assay to measure α-synuclein levels in cerebrospinal fluid, which could potentially identify early pathological changes and improve diagnostic accuracy and patient outcomes. While preliminary results are promising, further studies are needed to evaluate this approach’s accuracy and clinical feasibility. A review of numerous trials demonstrates that α-synuclein seeding amplification assays (SAA) are a highly reliable, sensitive, and specific diagnostic tool for PD. This assay offers a promising opportunity to improve early diagnosis and quantify severity, especially for asymptomatic individuals or those with a family history of PD, allowing for earlier intervention and more effective disease management. In summary, the emerging body of evidence supporting α-synuclein as a biomarker should allow patients with PD to be detected and treated sooner, enhancing patients’ quality of life and potentially changing the disease trajectory.

Abstract Background To describe the societal costs during one year of follow-up among older adults seeking chiropractic care due to a new episode of low back pain (LBP), and to determine what factors predict high societal costs in this population. Methods Prospective cohort study, within chiropractic private practices (n = 38) in the Netherlands. 223 people ≥ 55 years of age with a new episode of LBP seeking chiropractic care participated. The primary outcome was total societal costs. High societal costs were defined as patients with costs in the top 20th percentile. The final prediction models were obtained using forward selection. Results were presented for the total population and stratified for retirement status. The model’s prognostic accuracy (Hosmer–Lemeshow X2, Nagelkerke’s R2) and discriminative ability [area under the receiver operating curve (AUC)] were assessed, and the models were internally validated using bootstrapping. Results The mean total annual societal cost per patient was €5297 [95% confidence interval (CI): 4191–6403]. The biggest cost driver was presenteeism (65% of total costs), and costs were higher among non-retired participants (€7759; 95% CI 6047–9470) than retired participants (€1892; 95% CI 1088–2695). In the total population, younger age [odds ratio (OR): 0.87 for each additional year; 95% CI 0.80–0.95], being male instead of female (OR 2.96; 95% CI 1.19–7.44), less alcohol intake (OR 0.49; 95% CI 0.20–1.19), working instead of retirement (OR 9.37; 95% CI 1.83–48.04), and more disability at baseline (OR 1.08; 95% CI 1.00–1.16) were found to be predictive of high societal costs. Working was found to be the strongest predictor for high societal costs. After internal validation, the model’s fit was good, it’s explained variance was moderate (28%) and their AUCs could be interpreted as moderate (0.85). For non-pensioners, the same predictive factors were identified as for the entire population. The costs for the retired participants showed too little variation to be able to predict high costs. Conclusions This study estimated the mean total annual societal cost of older adults seeking chiropractic care due to a new episode of LBP at €5297 (95% CI 4191–6403).These costs were mainly due to high levels of presenteeism, and extensively differed based upon work status.

Abstract We present the theory, concept and design of an efficient, megawatt coherent Cherenkov radiation source based on a two-dimensional periodic surface lattice (2D-PSL) cavity combined with a novel energy recovery system for the generation of highly efficient (> 50%) single-frequency radiation. We demonstrate the scalability of the transverse dimension of the 2D-PSL cavity of the Cherenkov source and thus the potential for efficient, continuous-wave, high-power (> 1 MW) operation; fundamental to the eventual realization of clean, fusion energy. These new sources, with the capacity to operate in the 0.1-10THz range, hold strong promise to address the long-standing “Terahertz gap”. By combining a Cherenkov oscillator driven by a non-gyrating beam with an innovative four-stage depressed collector energy recovery system, the overall device efficiency can be increased to be competitive with gyrotrons in the requirements for heating and current drive in fusion plasma. In these Cherenkov devices, the frequency independence of the magnetic guide field enables advantageous frequency scaling without deployment constraints, making them especially attractive for high-impact applications in fusion science, turbulence diagnostics, non-destructive testing and biochemical spectroscopy. The novel energy recovery techniques presented in this paper have broad applicability to many electron-beam driven devices, bringing revolutionary potential to future THz source technologies.

Native and exotic C4 grasses currently used in grazing systems in the subtropics have specific limitations with management, decline in feed quality as they mature and variable adaptation to soils and climates, providing opportunities to identify alternative species to complement or replace them. One option is Paspalum lepton (syn. P. nicorae), a sward- forming, rhizomatous grass native to subtropical South America with recognized forage value. An early maturing form of this species has become naturalized in Northern New South Wales since its introduction in the 1940s. More recent introductions with forage and amenity potential are being established vegetatively and by seed as it becomes available. This paper reviews published work on P. lepton and reports largely unpublished results and observations on its performance in research and development studies in subtropical Eastern Australia. The potential value of and threats posed by P. lepton in relation to its adaptation, productivity, competitiveness and role in limiting ingress of existing weedy species are discussed. APG 54281 and APG 54325 are palatable, productive and persistent lines of this grass that have proven to be adapted to livestock production systems in most of the humid lowland subtropics, and to a specific niche in the subtropical uplands of Southeast Queensland where there is a lack of adapted C4 grasses and C3 grasses are only marginally adapted.

Abstract We analyzed genomic data from the prostate cancer of African- and European American men to identify differences contributing to racial disparity of outcome. We also performed FISH-based studies of Chromodomain helicase DNA-binding protein 1 (CHD1) loss on prostate cancer tissue microarrays. We created CHD1-deficient prostate cancer cell lines for genomic, drug sensitivity and functional homologous recombination (HR) activity analysis. Subclonal deletion of CHD1 was nearly three times as frequent in prostate tumors of African American than in European American men and it associates with rapid disease progression. CHD1 deletion was not associated with HR deficiency associated mutational signatures or HR deficiency as detected by RAD51 foci formation. This was consistent with the moderate increase of olaparib and talazoparib sensitivity with several CHD1 deficient cell lines showing talazoparib sensitivity in the clinically relevant concentration range. CHD1 loss may contribute to worse disease outcome in African American men.

Abstract Determining causal relationships between environmental change and early animal evolution has been limited by our lack of a robust temporal framework for the Ediacaran Period (635-539 million years ago). Here we present six new radioisotopic age constraints from the Sultanate of Oman, which furnish a quantitative temporal framework for biogeochemical changes associated with animal radiation in the middle and late Ediacaran Period. In addition to constraining the duration of Earth’s largest negative carbon isotope excursion in its type locality, this temporal framework underpins a new understanding of Ediacaran sedimentation rates, a critical control on geochemical records and fossil preservation. Our new dates quantify early Ediacaran (prior to c. 574 million years ago) condensation in key sections across Gondwanan margins. This temporal framework highlights a pressing need to reassess proxy records of oxygenation—often hypothesized as a critical environmental constraint for the emergence of complex multicellular life—considering non-static sedimentation rates.

Abstract Introduction Atopic dermatitis (AD), with its hallmark symptoms of pruritus and skin lesions, often impairs patients’ quality of life. We assessed time spent with clear/almost clear skin and no/minimal itch during upadacitinib treatment versus placebo or dupilumab among patients with moderate-to-severe AD. Methods This analysis consisted of a post hoc analysis of Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422), and Heads Up (NCT03738397). Measure Up 1 and 2 were replicate, randomized, double-blind, placebo-controlled phase 3 studies with patients randomized (1:1:1) to once-daily oral upadacitinib 15 mg, upadacitinib 30 mg, or placebo for 16 weeks. Heads Up was a head-to-head, randomized, double-blind, double-dummy, phase 3b study with patients randomized (1:1) to upadacitinib 30 mg or subcutaneous dupilumab 300 mg for 24 weeks. Skin clearance was assessed with the Eczema Area and Severity Index (EASI) at baseline, weeks 1, 2, and 4, and every 4 weeks thereafter. Itch was assessed using the Worst Pruritus Numerical Rating Scale (WP-NRS) daily over 16 weeks and every 2 weeks thereafter to week 24 in Heads Up. Results This analysis included 1683 patients in Measure Up 1 and 2 and 673 patients in Heads Up. Through 16 weeks in Measure Up 1 and 2, patients receiving upadacitinib spent 9.8–13.4 times as many days with an EASI 90 response and 7.0–10.3 times as many days with a WP-NRS 0/1 response versus placebo. In Heads Up, patients receiving upadacitinib spent 2.0 and 1.7 times as many days through 16 and 24 weeks, respectively, with an EASI 90 response versus dupilumab. Through 16 and 24 weeks, patients receiving upadacitinib spent 3.0 and 2.6 times as many days, respectively, with a WP-NRS 0/1 response versus dupilumab. Conclusions Patients with moderate-to-severe AD spent more time with clear/almost clear skin and no/minimal itch with upadacitinib versus placebo or dupilumab. Trial Registration ClinicalTrials.gov identifier, Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422), Heads Up (NCT03738397).

Our immune system acts to protect us in times of stress and traumatic injury. As part of the immune response, the body produces various cytokines, which mediate or modulate immune functions. Such cytokines include tumor necrosis factor (TNF) and interleukin 6 (IL-6) and IL-17. These cytokines can also act on the nervous system to influence pain perception. TNF-α triggers an inflammatory response and two forms of programmed cell death, apoptosis and necroptosis, depending on the pathological state. For individuals with chronic conditions relating to immune deficiency, the actions of these cytokines can present as chronic pain states, significantly altering quality of life. One attractive potential solution for treating this immune linked pain is by altering signaling pathways of pain-enhancing cytokines. Infliximab and etanercept are TNF inhibitors that are currently on the market for use in the treatment of chronic pain. Secukinumab and tocilizumab serve as IL inhibitors, utilized for a similar purpose. These novel immunotherapies have shown efficacy in numerous clinical studies with acceptable side effect profiles. In this review, we summarize the pharmacological profiles of these drugs and discuss their usage in treating chronic pain.

Abstract Photovoltaic (PV) panel deployment for decarbonization may reduce local terrestrial albedo, triggering a positive radiative forcing that counteracts the desired negative radiative forcing from carbon emission reductions. Yet, this potential adverse impact remains uncertain due to limited observations at PV sites. Herein we employ a robust linear parameterization method to quantify PV-induced albedo changes based on satellite data globally. We find an overall albedo decrease of −1.28 (−1.80, −0.90) × 10−2 (median and interquartile range), specific for land-cover types and climate regimes. However, the extent of albedo reduction is markedly lower than simplistic assumed values in simulating climate feedback for solar farming in Earth system models. Moreover, the albedo-induced positive radiative forcing can be offset by negative radiative forcing from clean solar generation in most PV farms within one year. Our findings underscore PV’s potential in mitigating global warming and stress the need for more accurate model estimations.

Summary: Background: BK polyomavirus (BKV) DNAaemia occurs in 10% of recipients of kidney transplants, contributing to premature allograft failure. Evidence suggests disease is donor derived. Hypothetically, recipient infection with a different BKV serotype increases risk due to poorer immunological control. Thus, understanding the composition and activity of the humoral anti-BKV responses in donor/recipient (D/R) pairs is critical. Methods: Using 224 paired pre-transplant D/R samples, BKV VP1 genotype-specific pseudoviruses were employed to define the breadth of the antibody response against different serotypes (ELISA) and, to characterise specific neutralising activity (nAb) using the 50% inhibitory concentration (LogIC50). Mismatch (MM) ratios were calculated using the ratio of recipient ELISA or nAb reactive BKV serotypes relative to the number of donor reactive serotypes. Findings: BKV DNAaemia was observed in 28/224 recipients of kidney transplants. These recipients had lower nAb titres against all the serotypes, with median logIC50 values of 1.19–2.91, compared to non-viraemic recipients’ median logIC50 values of 2.13–3.30. nAb D/R MM ratios >0.67 associated with significantly higher risk of BKV viraemia, with an adjusted odds ratio of 5.12 (95% CI 2.07 to 13.04; p

AbstractBackground Lebrikizumab, a high-affinity monoclonal antibody targeting IL-13, previously demonstrated clinical efficacy in three randomized, double-blind, placebo-controlled Phase 3 trials that included adults and adolescents with moderate-to-severe atopic dermatitis (AD): ADvocate1, ADvocate2, and ADhere.Aim This subset analysis evaluated 16-week physician- and patient-reported outcomes of lebrikizumab in the adolescent patients enrolled in these three trials.Methods Eligible adolescents (≥12 to

Background and objectives: California is one of a few states with mandatory reporting of mortality after coronary artery bypass graft (CABG) surgery. The Affordable Care Act restructured Medicaid, preferentially penalizing patients experiencing poverty because payments to hospitals for isolated surgical events overshadow payments to primary care clinicians. We propose outcomes are superior when hospital networks organize surgical episodes within the context of primary care inside that same network. Design and methods: We listed factors impacting outcomes after CABG. CABG surgery outcome depends upon the integration of issues beginning years preoperatively and extending for decades. Therefore, we studied one health maintenance organization (HMO) from 2009 to 2020 compared to surrounding individual hospitals. We divided 58 hospitals in Northern California in 2009 according to income and population. To focus on changes introduced because of COVID-19, we compared a public database for the subset in 2009 for any relationship between poverty in a zip code and low volumes of CABG in that area to overall mortality in 2020. First, we defined low-income zip codes as those with a higher rate of poverty than the state average or with a lower per capita average income, per Census Bureau. Second, low volume was defined as a population under 165,000 because a hospital adjacent to a larger community can easily transfer care, sharing surgeons and processes. Third, we defined low volume as fewer than 180 CABG per year. Results: Our qualitative evidence synthesis reveals that informal communication and hospital HMO policies improve CABG outcomes. In our small pilot data, Chi-square analysis showed higher crude mortality rates in 1507 CABG in 17 low-income low-volume hospitals versus 8163 CABG in the other 41 Northern California hospitals (2.72% vs 1.69%, p = 0.0064). Low-income low-volume hospitals had a relative mortality risk of 1.61 (95% CI: 1.14–2.27). These hospitals had a mean mortality rate of 3.79%, readmission 11.12%, and stroke 1.84%. A patient undergoing CABG in a low-income low-volume hospital has a 61% higher chance of dying. The number needed to treat analysis shows that one life can potentially be saved for every 97 patients referred to another institution. Conclusion: We describe features of an HMO that contribute to up to fourfold lower mortality rates.

Substance use disorder (SUD), based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), is defined by symptoms caused by utilizing a substance that a person continues taking despite its negative effects. Impulsive decision making is commonly defined as a reduced ability to choose a delayed large reward instead of a small immediate reward. Dopamine has been implicated as a prominent neurotransmitter implicated in the development and pattern of addiction and impulsivity, especially in regard to substance use disorder. Discovery as a key player in the development of addiction dates to the 1950s, with a study performed by Olds and Milner on rats placed in a Skinner box. Their original discovery is part of the beginning of what would become the search into the main mechanistic source of addiction, and how exactly it works at a cellular, physiological, and psychological level. The dopaminergic pathways of our brains are well-studied. It is well established that most of the dopaminergic neurons of the brain are located in the ventral mid-brain and consists of four main pathways: mesocortical, mesolimbic, nigrostriatal, and tuberoinfundibular pathways. Dopamine acts various receptors, with dopamine (D) receptors 1, 2, and 3 playing a major role in motor function and receptors D1 and D2 playing a major role in reward. There are additional studies warranted, especially finding ways to manipulate the dopaminergic system to treat addiction disorders of all varieties. The focus of the present investigation is to delve into the current literature regarding dopamine and its clinical implications in substance use disorder and impulsive behavior.

Acetaminophen is one of the most commonly used over-the-counter antipyretic and analgesic drugs on the market and has been relevant in the medical world for almost a hundred years. It has maintained an excellent reputation as a safe therapeutic in several types of patient profiles. However, the number of children diagnosed with neurodevelopmental disorders, namely ADHD, have been on the rise. Recent findings have indicated an association between in utero exposure to acetaminophen and an increased risk of developing neurodevelopmental disorders such as ADHD in offspring. The mechanism by which this potential side effect occurs is difficult to pinpoint. However, it is known that the metabolism of acetaminophen is known to cause oxidative stress, which has been shown to influence the developing fetus. This review highlights the epidemiological data indicating the correlation between prenatal acetaminophen exposure and ADHD and discusses several proposed theories by which this phenomenon may occur. While there is not yet enough clinical evidence to prove that acetaminophen may cause ADHD, there is a strong enough correlation to indicate a warning to pregnant patients of the potential risks. The risks and benefits of treatment should be considered so that the patient may continue with the course of action with the most favorable outcome. This review was mainly based on manuscripts pulled from Google Scholar and PubMed. The purpose of this literature review is to assist clinicians to better understand lesser-known risks in acetaminophen usage in pregnant patients.

Worldwide, hypertension is the leading risk factor for cardiovascular disease and death. An estimated 122 million people, per the American Heart Association in 2023, have been diagnosed with this common condition. It is generally agreed that the primary goal in the treatment of hypertension is to reduce overall blood pressure to below 140/90 mmHg, with a more optimal goal of 130/80 mmHg. Common medications for treating hypertension include calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and diuretics. CCBs are one of the most widely studied agents and are generally recommended as first-line therapy alone and in combination therapies. This is largely based on the vast knowledge of CCB mechanisms and their minimal side effect profile. CCBs can be separated into two classes: dihydropyridine and non-dihydropyridine. Non-dihydropyridine CCBs act on voltage-dependent L-type calcium channels of cardiac and smooth muscle to decrease muscle contractility. Dihydropyridine CCBs act by vasodilating the peripheral vasculature. For many patients with only mild increases in systolic and diastolic blood pressure (e.g., stage 1 hypertension), the medical literature indicates that CCB monotherapy can be sufficient to control hypertension. In this regard, CCB monotherapy in those with stage 1 hypertension reduced renal and cardiovascular complications compared to other drug classes. Combination therapy with CCBs and angiotensin receptor blockers or angiotensin-converting enzyme inhibitors has been shown to be an effective dual therapy based on recent meta-analyses. This article is a review of calcium channel blockers and their use in treating hypertension with some updated and recent information on studies that have re-examined their use. As for new information, we tried to include some information from recent studies on hypertensive treatment involving calcium channel blockers.

Abstract Understanding the dynamics of intracellular signaling pathways, such as ERK1/2 (ERK) and Akt1/2 (Akt), in the context of cell fate decisions is important for advancing our knowledge of cellular processes and diseases, particularly cancer. While previous studies have established associations between ERK and Akt activities and proliferative cell fate, the heterogeneity of single-cell responses adds complexity to this understanding. This study employed a data-driven approach to address this challenge, developing machine learning models trained on a dataset of growth factor-induced ERK and Akt activity time courses in single cells, to predict cell division events. The most predictive models were developed by applying discrete wavelet transforms (DWTs) to extract low-frequency features from the time courses, followed by using Ensemble Integration, a data integration and predictive modeling framework. The results demonstrated that these models effectively predicted cell division events in MCF10A cells (F-measure=0.524, AUC=0.726). ERK dynamics were found to be more predictive than Akt, but the combination of both measurements further enhanced predictive performance. The ERK model`s performance also generalized to predicting division events in RPE cells, indicating the potential applicability of these models and our data-driven methodology for predicting cell division across different biological contexts. Interpretation of these models suggested that ERK dynamics throughout the cell cycle, rather than immediately after growth factor stimulation, were associated with the likelihood of cell division. Overall, this work contributes insights into the predictive power of intra-cellular signaling dynamics for cell fate decisions, and highlights the potential of machine learning approaches in unraveling complex cellular behaviors.

A 2022 canine gastroenteritis outbreak in the United Kingdom was associated with circulation of a new canine enteric coronavirus closely related to a 2020 variant with an additional spike gene recombination. The variants are unrelated to canine enteric coronavirus–like viruses associated with human disease but represent a model for coronavirus population adaptation.

Abstract Etizolam is a thienodiazepine derivative which produces an anxiolytic effect similar to benzodiazepines such as alprazolam (Xanax). Like classic benzodiazepines, etizolam has a high affinity towards the GABAA receptor, and allosterically potentiates the effects of GABA resulting in neuronal hyperpolarization related to chloride influx. When taken in therapeutic doses, etizolam produces a similar effect to Xanax. Counterfeit Xanax tablets contain variable amounts of etizolam. Tablets with high amounts of etizolam can cause toxicity if ingested, especially when combined with other substances. When toxic symptoms occur in patients, they may include severe sedation, unconsciousness, and depression of the medullary respiratory center. In this regard, there is the potential for death. Additionally, the rise in fake Xanax tablets containing etizolam and other counterfeit medications has been exacerbated by the difference in regulations regarding these substances in different countries as well as the illegal drug trade. Healthcare providers may also play a role through the over- or underprescribing of certain medications. Thus, in order to combat the rise in counterfeit medications such as fake Xanax, international cooperation, regulation, and enforcement of laws pertaining to the manufacture, prescription, and distribution of these substances are needed.

Abstract Chronic pain, a complex and debilitating condition, involves intricate interactions between central and peripheral inflammatory processes. Cytokines, specifically tumor necrosis factor (TNF) and interleukins (IL), are key mediators in the initiation and maintenance of chronic pain states. Sensory neurons expressing receptors for cytokines like TNF, IL-1, and IL-6 are implicated in peripheral sensitization, contributing to increased signaling of painful sensations. The potential of targeting TNF and IL for therapeutic intervention in chronic pain states is the focus of this review, with preclinical and clinical evidence supporting the use of TNF and IL modulators for pain management. The physiological and pathological roles of TNF in neuropathic pain is complex. Experimental evidence highlights the effectiveness of TNF modulation in mitigating pain symptoms in animal models and displays promising outcomes of clinical trials with TNF inhibitors, such as infliximab and etanercept. ILs, a diverse group of cytokines, including IL-1, IL-6, and IL-17, are discussed for their contributions to chronic pain through inflammation and peripheral sensitization. Specific IL modulators, such as secukinumab and tocilizumab, have shown potential in managing chronic neuropathic pain, as demonstrated in various studies and clinical trials. The pharmacokinetics, safety profiles, and challenges associated with TNF and IL modulators highlight the need for cautious medication monitoring in clinical practice. Comparative evaluations have revealed distinct efficacy and safety profiles among different cytokine modulators, emphasizing the need for personalized approaches based on the specific underlying causes of pain. Further research is necessary to elucidate the intricate mechanisms by which cytokines contribute to chronic pain, as well as to understand why they may affect pain differently in various contexts. Additionally, long-term safety profiles of cytokine modulators require more thorough investigation. This continued exploration holds the promise of enhancing our comprehension of cytokine modulation in chronic pain and shaping more potent therapeutic strategies for the future.

Abstract Sudden infant death syndrome (SIDS) is the leading cause of post-neonatal infant mortality, but the underlying cause(s) are unclear. A subset of SIDS infants has abnormalities in the neurotransmitter, serotonin (5-hydroxytryptamine [5-HT]) and the adaptor molecule, 14–3–3 pathways in regions of the brain involved in gasping, response to hypoxia, and arousal. To evaluate our hypothesis that SIDS is, at least in part, a multi-organ dysregulation of 5-HT, we examined whether blood platelets, which have 5-HT and 14–3–3 signaling pathways similar to brain neurons, are abnormal in SIDS. We also studied platelet surface glycoprotein IX (GPIX), a cell adhesion receptor which is physically linked to 14–3–3. In infants dying of SIDS compared to infants dying of known causes, we found significantly higher intra-platelet 5-HT and 14–3–3 and lower platelet surface GPIX. Serum and plasma 5-HT were also elevated in SIDS compared to controls. The presence in SIDS of both platelet and brainstem 5-HT and 14–3–3 abnormalities suggests a global dysregulation of these pathways and the potential for platelets to be used as a model system to study 5-HT and 14–3–3 interactions in SIDS. Platelet and serum biomarkers may aid in the forensic determination of SIDS and have the potential to be predictive of SIDS risk in living infants.

Leadership is increasingly recognized as important in medicine. Physician leadership impacts healthcare delivery and quality. Little work has been done to determine how physician leadership in practice aligns with established models in leadership theory. We conducted 40 semi-structured, 50-minute interviews of physicians who had achieved the rank of professor in our school of medicine and were serving, or had served, in leadership positions. We used an inductive content analysis approach to identify content categories, with leadership emerging as one such category. Subsequently, for the present study, we performed a secondary analysis of the data. To do this, we reviewed all transcripts, seeking to identify if and how participants discussed leadership in relation to success in academic medicine. Following identification of subcategories related to leadership, we performed qualitative content analysis. We then used a deductive content analysis approach to determine how participants’ discussions of leadership aligned with major leadership theories. Then, the principal investigator conducted a secondary inductive content analysis revealing leadership themes that were synthesized into a new model of physician leadership. Twenty-nine participants spontaneously discussed leadership and leadership-related topics as important to their own academic success and comprised the present study cohort. Participants identified contributors to leadership success that aligned with multiple major leadership theories, including leadership traits, skills, behaviors styles, and situational leadership. None of the leadership theories aligned completely with our physician leaders’ discussions, suggesting an alternate leadership framework was operating. Further analysis revealed a new model of leadership comprised of the “Four Cs of Physician Leadership”: character, competence, caring, and communication. Our participant group of academic physicians identified leadership capabilities as being important in their academic success. While they discussed leadership in ways that fit to varying degrees with the major leadership theories, their discussions revealed a novel, more holistic leadership framework. Further work will be beneficial to determine if this model of leadership is specific to physicians or is more generalizable.

A low-cost novel spectral camera able to be used for near infrared spectroscopy was made by using a Jetson Nano to synchronize a Sony IMX219 NOIR autofocus image sensor, an AMS AS7265x 18-channel spectral sensor and Osram SFH 4737 broadband infrared LED’s. Synchronizing an image sensor and spectral sensor augments a standard RGB image with light spectrum information; capturing the light distribution information normally lost in RGB image capture. Sutherland et al. [1] used this novel spectral camera to examine the dorsal surface of juvenile lobsters as a possible pre-moult detector. Having the image and spectrum in combination allowed the incomplete and unmineralized post-moult dorsal surface to be characterized with 86.7% accuracy for the first time. A proposed application for the spectral camera is to omit the local SFH 4737 light source and use the camera in daylight, effectively making a low-cost substitute hyperspectral snapshot camera. In this configuration the camera may have application for low-cost drone deployment for small scale agriculture.

In part two of this mini-series, we evaluate the range of machine-learning tools now available for application to veterinary clinical text-mining. These tools will be vital to automate extraction of information from large datasets of veterinary clinical narratives curated by projects such as the Small Animal Veterinary Surveillance Network (SAVSNET) and VetCompass, where volumes of millions of records preclude reading records and the complexities of clinical notes limit usefulness of more “traditional” text-mining approaches. We discuss the application of various machine learning techniques ranging from simple models for identifying words and phrases with similar meanings to expand lexicons for keyword searching, to the use of more complex language models. Specifically, we describe the use of language models for record annotation, unsupervised approaches for identifying topics within large datasets, and discuss more recent developments in the area of generative models (such as ChatGPT). As these models become increasingly complex it is pertinent that researchers and clinicians work together to ensure that the outputs of these models are explainable in order to instill confidence in any conclusions drawn from them.

Rationale & Objective: Research in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) has focused on reducing treatment toxicities, notably through reduction of exposure to glucocorticoids. Glucocorticoid-sparing therapies such as avacopan are not widely available in many countries, and patients are exposed to high glucocorticoid doses. There is little data concerning what clinicians should accept as the lowest glucocorticoid dosing that can be used in induction therapy for AAV. Study Design: International, online survey. Setting & Participants: Clinicians in various countries with experience in managing vasculitis. Exposure and Outcomes: Survey questions to gauge interest and preferences in studying an induction of remission regimen for severe AAV using only 2 or 4 weeks of glucocorticoids without avacopan. Data collected included general opinions about standard of care for induction agents, glucocorticoids, and avacopan. Respondents were presented with 3 candidate trial designs, 2 of which proposed a combination of cyclophosphamide and rituximab induction. Analytical Approach: Using a 10-point Likert scale, respondents ranked each candidate trial on its usefulness in demonstrating whether a minimal glucocorticoid regimen would be safe and effective and their willingness to randomize into the trial. Results: There were 210 respondents to the survey. The candidate trials were rated moderate-to-high for usefulness to demonstrate safety and efficacy (scores 6-7/10), and moderate (scores 5-6/10) for willingness to randomize. Four-week glucocorticoid duration was preferred to 2 weeks, and combination cyclophosphamide-rituximab with 4-week glucocorticoids was the most preferred design. Forty-two percent of respondents felt avacopan had to be incorporated into a minimal GC trial design to want to recruit patients. Limitations: Representativeness of survey sample and generalizability of findings. Conclusions: Combination cyclophosphamide-rituximab may be the ideal way of studying minimal glucocorticoid use in severe AAV. Given its increasing uptake, incorporating avacopan into a potential trial design is important. Plain Language Summary: Research in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) has focused on using less glucocorticoids to limit side effects. New drugs that drastically limit glucocorticoid use are not available in many countries. Studies are needed to find other ways of reducing glucocorticoid exposure to treat AAV, but it is unclear how best to achieve this. We administered a survey to doctors with experience in treating AAV and had them grade different combinations of widely available treatments with 2 or 4 weeks of glucocorticoids. We found that a combination of 2 doses cyclophosphamide with 2 doses rituximab and 4 weeks of glucocorticoids was the preferred treatment. The results will guide the development of a trial studying minimal use of glucocorticoids for the treatment of AAV.

Early awareness of inference performance ensures the feasibility of machine learning for embedded deployment. Often, ML model selection often focuses first on training performance and accuracy, with inference considered second. While prioritizing training is necessary, model inference performance is often impacted by these optimizations. Knowing whether a model will run meaningfully faster or be more energy efficient than its un-optimized-counterpart is required for resource-constrained embedded environments. Training-time optimizations may incur real performance losses at inference time. This paper benchmarks the effect of one such training optimization, clustered attention, and examines its effect on the inference performance of the transformer-based transcription model wav2vec2. The execution time and energy consumption of this model is evaluated on NVIDIA Jetson-embedded GPU devices. Clustered attention is specific to the transformer self-attention mechanism, which exhibits poor memory and execution-time scaling with respect to a variable input size. These scaling characteristics make it a potentially critical bottleneck that must be observed under realistic conditions. Our research considers three model variants: reference (original), clustered, and improved-clustered attention models. The reference model was faster for small input sizes, but the clustered model was faster for input sizes longer than 10 seconds. The clustered model had the lowest maximum energy per inference for input sizes greater than about 12 seconds of audio. With optimal configuration, the improved-clustered model takes 26.34% more time to execute than the reference model. With these operational differences, we show that inference performance and energy consumption of deployment should not be overlooked in selecting model optimizations.

The crescent urbanization across the globe has widespread ecological consequences, affecting species distribution, demography and behaviour. In this study we aimed to identify, quantify, map and predict the occurrences of medium- to large-bodied (≥1 kg) mammal carnivorans across urban and peri-urban landscapes throughout Brazil. We use a news-based search to compose a dataset of occurrences across the Brazilian cities. Additionally, we gather various socio-environmental and geophysical variables from these urban areas to identify the drivers of carnivore presence across urban environments. Employing Kernel interpolation, we generate heatmaps to highlight and pinpoint regions in Brazil with the highest concentration of carnivorans species on urban areas. We also employed a Generalized Additive Models (GAM) approach to assess the predictive power of social-environmental and geophysical variables on the occurrence of carnivorans in urban landscapes of Brazil. Our findings pinpoint to an increase of potential human-wildlife conflicts likely given that the urban expansion over natural habitats had a rampant increase in the last decades. Finally, we highlight that our results can serve as a basis to improve urban planning and offer important insights into the intricate interplay of social and geophysical variables that influence the occurrences of carnivorans within urban environments in Brazil.

Abstract Background Ticks are an important driver of veterinary health care, causing irritation and sometimes infection to their hosts. We explored epidemiological and geo-referenced data from > 7 million electronic health records (EHRs) from cats and dogs collected by the Small Animal Veterinary Surveillance Network (SAVSNET) in Great Britain (GB) between 2014 and 2021 to assess the factors affecting tick attachment in an individual and at a spatiotemporal level. Methods EHRs in which ticks were mentioned were identified by text mining; domain experts confirmed those with ticks on the animal. Tick presence/absence records were overlaid with a spatiotemporal series of climate, environment, anthropogenic and host distribution factors to produce a spatiotemporal regression matrix. An ensemble machine learning spatiotemporal model was used to fine-tune hyperparameters for Random Forest, Gradient-boosted Trees and Generalized Linear Model regression algorithms, which were then used to produce a final ensemble meta-learner to predict the probability of tick attachment across GB at a monthly interval and averaged long-term through 2014–2021 at a spatial resolution of 1 km. Individual host factors associated with tick attachment were also assessed by conditional logistic regression on a matched case–control dataset. Results In total, 11,741 consultations were identified in which a tick was recorded. The frequency of tick records was low (0.16% EHRs), suggesting an underestimation of risk. That said, increased odds for tick attachment in cats and dogs were associated with younger adult ages, longer coat length, crossbreeds and unclassified breeds. In cats, males and entire animals had significantly increased odds of recorded tick attachment. The key variables controlling the spatiotemporal risk for tick attachment were climatic (precipitation and temperature) and vegetation type (Enhanced Vegetation Index). Suitable areas for tick attachment were predicted across GB, especially in forests and grassland areas, mainly during summer, particularly in June. Conclusions Our results can inform targeted health messages to owners and veterinary practitioners, identifying those animals, seasons and areas of higher risk for tick attachment and allowing for more tailored prophylaxis to reduce tick burden, inappropriate parasiticide treatment and potentially TBDs in companion animals and humans. Sentinel networks like SAVSNET represent a novel complementary data source to improve our understanding of tick attachment risk for companion animals and as a proxy of risk to humans. Graphical Abstract

This study compared the chemical, structural, and luminescent properties of xerogel-based ceramic powders (CPs) with those of a new series of crystallized aerogels (CAs) synthesized by the epoxy-assisted sol–gel process. Materials with different proportions of Eu3+ (2, 5, 8, and 10 mol%) were synthesized in Lu2O3 host matrices, as well as a Eu2O3 matrix for comparative purposes. The products were analyzed by infrared spectroscopy (IR), X-ray diffraction (XRD), scanning electron microscopy (SEM) with energy-dispersive spectroscopy (EDS), transmission electron microscopy (TEM), photoluminescence analysis, and by the Brunauer–Emmett–Teller (BET) technique. The results show a band associated with the M-O bond, located at around 575 cm−1. XRD enabled us to check two ensembles: matrices (Lu2O3 or Eu2O3) and doping (Lu2O3:Eu3+) with appropriate chemical compositions featuring C-type crystal structures and intense reflections by the (222) plane, with an interplanar distance of around 0.3 nm. Also, the porous morphology presented by the materials consisted of interconnected particles that formed three-dimensional networks. Finally, emission bands due to the energy transitions (5DJ, where J = 0, 1, 2, and 3) were caused by the Eu3+ ions. The samples doped at 10 mol% showed orange-pink photoluminescence and had the longest disintegration times and greatest quantum yields with respect to the crystallized Eu2O3 aerogel.

Abstract Carboxylic ester hydrolases with the capacity to degrade polyesters are currently highly sought after for their potential use in the biological degradation of PET and other chemically synthesized polymers. Here, we describe MarCE, a carboxylesterase family protein identified via genome mining of a Maribacter sp. isolate from the marine sponge Stelligera stuposa. Based on phylogenetic analysis, MarCE and its closest relatives belong to marine‐associated genera from the Cytophaga–Flavobacterium–Bacteroides taxonomic group and appear evolutionarily distinct to any homologous carboxylesterases that have been studied to date in terms of structure or function. Molecular docking revealed putative binding of BHET, a short‐chain PET derivative, onto the predicted MarCE three‐dimensional structure. The synthetic ester‐degrading activity of MarCE was subsequently confirmed by MarCE‐mediated hydrolysis of 2 mM BHET substrate, indicated by the release of its breakdown products MHET and TPA, which were measured, respectively, as 1.28 and 0.12 mM following 2‐h incubation at 30°C. The findings of this study provide further insight into marine carboxylic ester hydrolases, which have the potential to display unique functional plasticity resulting from their adaptation to complex and fluctuating marine environmentsw.

Summary: The canonical mechanism behind tamoxifen’s therapeutic effect on estrogen receptor α/ESR1+ breast cancers is inhibition of ESR1-dependent estrogen signaling. Although ESR1+ tumors expressing wild-type p53 were reported to be more responsive to tamoxifen (Tam) therapy, p53 has not been factored into choice of this therapy and the mechanism underlying the role of p53 in Tam response remains unclear. In a window-of-opportunity trial on patients with newly diagnosed stage I–III ESR1+/HER2/wild-type p53 breast cancer who were randomized to arms with or without Tam prior to surgery, we reveal that the ESR1-p53 interaction in tumors was inhibited by Tam. This resulted in functional reactivation of p53 leading to transcriptional reprogramming that favors tumor-suppressive signaling, as well as downregulation of oncogenic pathways. These findings illustrating the convergence of ESR1 and p53 signaling during Tam therapy enrich mechanistic understanding of the impact of p53 on the response to Tam therapy.

Staphylococcus aureus (SA) colonizes and can damage skin in atopic dermatitis lesions, despite being commonly found with Staphylococcus epidermidis (SE), a commensal that can inhibit SA’s virulence and kill SA. In this study, we developed an in silico model, termed a virtual skin site, describing the dynamic interplay between SA, SE, and the skin barrier in atopic dermatitis lesions to investigate the mechanisms driving skin damage by SA and SE. We generated 106 virtual skin sites by varying model parameters to represent different skin physiologies and bacterial properties. In silico analysis revealed that virtual skin sites with no skin damage in the model were characterized by parameters representing stronger SA and SE growth attenuation than those with skin damage. This inspired an in silico treatment strategy combining SA-killing with an enhanced SA–SE growth attenuation, which was found through simulations to recover many more damaged virtual skin sites to a non-damaged state, compared with SA-killing alone. This study demonstrates that in silico modelling can help elucidate the key factors driving skin damage caused by SA–SE colonization in atopic dermatitis lesions and help propose strategies to control it, which we envision will contribute to the design of promising treatments for clinical studies.

Perceptions of dog owners and veterinary professionals (surgeons/nurses) can influence the preventive healthcare and treatment provided to dogs, especially at the senior life-stage, when chronic diseases become more common. This study compared perceptions of healthcare of dogs as they age between dog owners and veterinary professionals. Data from two online surveys (owners: N = 633, veterinary professionals: N = 305) examined perceived need for veterinary visits and vaccinations. In addition, 48 clinical signs were rated on perceived prevalence (whether owners’ dogs had experienced them) and how urgently they should seek veterinary advice. Groups were compared using descriptive statistics and chi-square. Owners most often believed a ‘healthy’ senior dog (>7 years) should go to the vet once a year (47% owners vs. 25% veterinary professionals, p

Historically, 23 freshwater mussel species have been documented from the Buffalo National River (BNR), a 246 km, free-flowing river in northern Arkansas. The potential threats to BNR include land use/land cover changes, eutrophication, recreation, physical habitat changes, and various climate change-related effects. Twelve quantitative mussel bed sites were established and then sampled using a stratified random sampling protocol to evaluate the long-term changes between 2006 and 2020–2021 in population and assemblage characteristics. We compared (1) overall mussel bed persistence, sampling confidence levels and study-wide relative abundances, and compared species’ size and size-frequency distributions; (2) 10 overall site assemblage variables using paired t-tests; (3) site-level mean density, richness, and diversity indices using pair-wise Mann–Whitney U statistics; and (4) assemblage composition using Non-Metric Multidimensional Scaling. The major findings included the following: (1) sampling efforts based on a targeted 80% confidence level appears relatively robust, (2) BNR mussel assemblage composition and structure were relatively stable (however, small mussel bed persistence is a concern), (3) 7 of 23 sites were outliers based on freshwater mussel composition and habitat characteristics, and (4) assemblage composition changed with three species declining (Actinonaias ligamentina, Lasmigona costata, and Ptychobranchus occidentalis) and four species increasing (Cambarunio hesperus, Cyclonaias tuberculata, Eurynia dilatata, and Venustaconcha pleasii) between monitoring events.

Neuropathic pain is an increasingly common disease affecting millions of individuals worldwide. Refractory pain poses a significant impact on patients’ quality of life, financial and economic stability, and social interaction. Numerous effective modalities for treatment of refractory neuropathic pain are presently available. Currently, many options provide symptomatic treatment but are associated with an unfavorable side effect profile and increased risk of addiction. The present investigation reviews current medical management for refractory neuropathic pain including the use of antidepressants, anticonvulsants, gabapentinoids and opioid therapy, as well as interventional pain procedures such as spinal cord stimulation (SCS) and intrathecal targeted drug delivery. While multidisciplinary management with lifestyle modification and pharmacologic regimens remains at the forefront of treating many of these patients, interventional modalities are growing in popularity and have been demonstrated to be highly efficacious. In this regard, continued understanding of the pathophysiology surrounding refractory neuropathic pain has led to the development of interventional procedures and better outcomes for patients suffering from refractory neuropathic pain. When and if patients fail conservative therapy, interventional techniques are desirable alternatives for pain management. SCS and intrathecal targeted drug delivery are important tools for the treatment of refractory neuropathic pain. In summary, treatment modalities for refractory neuropathic pain are evolving with demonstrated efficacy. This review aims to outline the efficacy of various interventional procedures for refractory neuropathic pain in comparison to traditional drug therapies.

Abstract The flavivirus envelope protein is a class II fusion protein that drives flavivirus-cell membrane fusion. The membrane fusion process is triggered by the conformational change of the E protein from dimer in the virion to trimer, which involves the rearrangement of three domains, EDI, EDII, and EDIII. The movement between EDI and EDII initiates the formation of the E protein trimer. The EDI-EDII hinge region utilizes four motifs to exert the hinge effect at the interdomain region and is crucial for the membrane fusion activity of the E protein. Using West Nile virus (WNV) NY99 strain derived from an infectious clone, we investigated the role of eight flavivirus-conserved hydrophobic residues in the EDI-EDII hinge region in the conformational change of E protein from dimer to trimer and viral entry. Single mutations of the E-A54, E-I130, E-I135, E-I196, and E-Y201 residues affected infectivity. Importantly, the E-A54I and E-Y201P mutations fully attenuated the mouse neuroinvasive phenotype of WNV. The results suggest that multiple flavivirus-conserved hydrophobic residues in the EDI-EDII hinge region play a critical role in the structure–function of the E protein and some contribute to the virulence phenotype of flaviviruses as demonstrated by the attenuation of the mouse neuroinvasive phenotype of WNV. Thus, as a proof of concept, residues in the EDI-EDII hinge region are proposed targets to engineer attenuating mutations for inclusion in the rational design of candidate live-attenuated flavivirus vaccines.

Abstract In this note, we present an innovative approach called “homologous hypothesis tests” that focuses on cross-sectional comparisons of average tumor volumes at different time-points. By leveraging the correlation structure between time-points, our method enables highly efficient per time-point comparisons, providing inferences that are highly efficient as compared to those obtained from a standard two-sample t test. The key advantage of this approach lies in its user-friendliness and accessibility, as it can be easily employed by the broader scientific community through standard statistical software packages.

Abstract PPTC7 is a resident mitochondrial phosphatase essential for maintaining proper mitochondrial content and function. Newborn mice lacking Pptc7 exhibit aberrant mitochondrial protein phosphorylation, suffer from a range of metabolic defects, and fail to survive beyond one day after birth. Using an inducible knockout model, we reveal that loss of Pptc7 in adult mice causes marked reduction in mitochondrial mass and metabolic capacity with elevated hepatic triglyceride accumulation. Pptc7 knockout animals exhibit increased expression of the mitophagy receptors BNIP3 and NIX, and Pptc7 -/- mouse embryonic fibroblasts (MEFs) display a major increase in mitophagy that is reversed upon deletion of these receptors. Our phosphoproteomics analyses reveal a common set of elevated phosphosites between perinatal tissues, adult liver, and MEFs, including multiple sites on BNIP3 and NIX, and our molecular studies demonstrate that PPTC7 can directly interact with and dephosphorylate these proteins. These data suggest that Pptc7 deletion causes mitochondrial dysfunction via dysregulation of several metabolic pathways and that PPTC7 may directly regulate mitophagy receptor function or stability. Overall, our work reveals a significant role for PPTC7 in the mitophagic response and furthers the growing notion that management of mitochondrial protein phosphorylation is essential for ensuring proper organelle content and function.

Abstract Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.

Hypogonadism is a clinical syndrome resulting from failure to produce physiological concentrations of sex steroid hormones with accompanying symptoms, such as slowed growth and delayed pubertal maturation. Hypogonadism may arise from gonadal disease (primary hypogonadism), dysfunction of the hypothalamic–pituitary axis (secondary hypogonadism) or functional hypogonadism. Disrupted puberty (delayed or absent) leading to hypogonadism can have a significant impact on both the physical and psychosocial well-being of adolescents with lasting effects. The diagnosis of hypogonadism in teenagers can be challenging as the most common cause of delayed puberty in both sexes is self-limited, also known as constitutional delay of growth and puberty (CDGP). Although an underlying congenital cause should always be considered in a teenager with hypogonadism, acquired conditions such as obesity, diabetes mellitus, other chronic diseases and medications have all been associated with low sex steroid hormone levels. In this review, we highlight some forms of functional hypogonadism in adolescents and the clinical challenges to differentiate normal variants from pathological states.

Introduction: This study was conducted to question the findings of a prior study published in Journal of Drugs in Dermatology (JDD) in September 2023, which reported that a topical firming and toning body lotion (FTB—SkinMedica®, Allergan Aesthetics, an AbbVie Company, Irvine, CA, USA) upregulated several genes in a UV-irradiated 3D full-thickness human skin model, outperforming other products, including TransFORM Body Treatment with TriHex Technology® (ATF—Alastin Skincare®, a Galderma company, Fort Worth, TX, USA). Given the unique response reported for FTB, we conducted this study to assess the reproducibility of these results and explore gene expression at multiple time points, along with validating protein expression in an ex vivo model. Materials and Methods: Experiments were conducted using an ex vivo model with photodamaged skin from facelift patients, under an Institutional Review Board-approved study. Skin samples were processed, cultured in transwells with Skin Media, and treated daily with either TransFORM or FTB for 7 days. A control group was left untreated. Gene expression was assessed using RT-PCR on days 1 and 3 and using immunofluorescence after 3 and 7 days of treatment. Skin samples were fixed, paraffin-embedded, sectioned, and stained with an anti-tropoelastin antibody. Fluorescence detection and imaging were conducted to assess protein expression changes. Results: Gene expression data from our study and the initial study showed a few similarities but multiple discrepancies. As opposed to results previously reported at only the 24 h time point, our study was completed at multiple time points and showed a complete reversal of many of these results. For example, COL1A1 expression at 24 h was similar for FTB in both studies but differed for TransFORM, which showed higher levels at 24 h in our study. At day 3, COL1A1 expression decreased markedly for FTB and was sustained for TransFORM. Other genes, such as COL3A1, COL5, ELN, VEGFC, ATG7, ATG12, BECN1, POMP, PSMB5, and PSMB6, exhibited varying expression patterns between the two studies and across different time points. From a translational perspective, histological analysis showed that TransFORM enhanced elastin fiber presence in the dermal–epidermal junction (DEJ) more effectively than FTB at both days 3 and 7. FTB-treated samples maintained a gap in the DEJ, while TransFORM-treated samples exhibited increased cellular proliferation and DEJ undulation, indicative of a healthier regenerative response. Conclusion: This study highlights the problems of examining data and drawing conclusions using a single point of examination. In addition, when a study reports positive results for only one product among a range of eight competitive products, further questioning is essential to exclude the possibility of the experimental model favoring that product. The additional 3-day time point and further translational examination of histological changes paint a completely different picture to that reported in the prior publication. TransFORM outperformed FTB in most gene expressions and histological parameters when assessed over multiple time points in a physiologically relevant ex vivo model.

When cyanobacterial phytoplankton form harmful cyanobacterial blooms (HCBs), the toxins they produce threaten freshwater ecosystems. Hydrogen peroxide is often used to control HCBs, but it is broadly toxic and dangerous to handle. Previously, we demonstrated that glucose addition to lake water could suppress the abundance of cyanobacteria. In this study, glucose was compared to hydrogen peroxide for the treatment of cyanobacterial phytoplankton communities. The six-week study was conducted in the large mesocosms facility at Grand Valley State University’s Annis Water Resources Institute in Michigan. To 1000 L of Muskegon Lake water, glucose was added at either 150 mg or 30 mg glucose/L. Hydrogen peroxide was added at 3 mg/L to two 1000 L mesocosms. And two mesocosms were left untreated as controls. Triplicate 100 mL samples were collected weekly from each mesocosm, which were then filtered and frozen at −80 °C for 16S rRNA amplicon sequencing. The 16S rRNA amplicon sequencing results revealed that hydrogen peroxide treatment quickly reduced the relative abundance of the cyanobacteria compared to the control mesocosms, but the cyanobacteria population returned over the course of the 6-week study. On the other hand, both glucose concentrations caused a rapid proliferation of multiple low abundance proteobacterial and bacteroidotal taxa resulting in notable increases in taxonomic richness over the duration of the study and reducing the relative abundance of cyanobacteria. Although hydrogen peroxide quickly suppressed the cyanobacteria, the population later returned to near starting levels. The glucose suppressed the cyanobacterial phytoplankton apparently by promoting competitive heterotrophic bacteria.

Acromegaly is a condition most commonly diagnosed in the fifth decade of life and has numerous treatment options. In this regard, Mycapssa® is the first FDA-approved oral octreotide capsule for treating acromegaly, combining the efficacy of the somatostatin receptor ligand, octreotide, with the ease of a twice-daily oral capsule. Where surgical treatment is not an option, somatostatin analogs, including octreotide, are the first line of medical treatment for acromegaly, requiring regular subcutaneous or intramuscular injections administered by a patient’s healthcare provider. Octreotide capsules (Mycapssa®) provide an alternative to these somatostatin receptor ligand injections by combining octreotide with other excipients to produce a transient permeability enhancer technology that improves paracellular transport of octreotide across the gastrointestinal wall into the small intestine. Across multiple trials, including open-label (CH-ACM-01), double-blind placebo-controlled (CHIASMA OPTIMAL), and open-label extension of the trial period (CHIASMA OPTIMAL OLE), Mycapssa® octreotide capsules maintained a consistent biochemical normalization of IGF-1 and GH levels, safety profiles similar to injected somatostatin receptor ligands, and patient preference to continued treatment with octreotide capsules. While clinical trial data supports the use of octreotide capsules (Mycapssa®) in the pharmacological management of GH and IGF-1 levels, very little data exist regarding the drug’s efficacy, tolerability, and use in female or pediatric-specific populations. A better understanding of the efficacy, application, and role of oral octreotide capsules in the long-term medical management of acromegaly in a diversity of populations is imperative to best determine the risks/benefits for the clinician.

Abstract Microbial synthesis of nutraceutically and pharmaceutically interesting plant polyphenols represents a more environmentally friendly alternative to chemical synthesis or plant extraction. However, most polyphenols are cytotoxic for microorganisms as they are believed to negatively affect cell integrity and transport processes. To increase the production performance of engineered cell factories, strategies have to be developed to mitigate these detrimental effects. Here, we examine the accumulation of the stilbenoid resveratrol in the cell membrane and cell wall during its production using Corynebacterium glutamicum and uncover the membrane rigidifying effect of this stilbenoid experimentally and with molecular dynamics simulations. A screen of free fatty acid supplements identifies palmitelaidic acid and linoleic acid as suitable additives to attenuate resveratrol’s cytotoxic effects resulting in a three-fold higher product titer. This cost-effective approach to counteract membrane-damaging effects of product accumulation is transferable to the microbial production of other polyphenols and may represent an engineering target for other membrane-active bioproducts.

Abstract Background Management of paediatric atopic dermatitis (AD) remains challenging, and presents a considerable healthcare resource utilisation (HCRU) burden. Objectives To describe secondary HCRU for children and adolescents with moderate‐to‐severe AD in Ireland. Methods This was a single‐centre chart review of children (age 6–11 years) and adolescents (age 12–17 years) with clinician‐confirmed moderate‐to‐severe AD. Eligible patients were selected consecutively, starting with the most recently consulting patient, and working backwards until patient identification for the study was complete. From first secondary care appointment post 1 January 2014, at least 12 months' medical record data were abstracted, including patient demographics/clinical characteristics, treatments, HCRU, and patient‐reported outcomes. Results Data were abstracted for 31 patients (22 children). Mean (SD) duration of observation was 4.4 (1.9) years. Most patients (74.2%) had severe AD at first referral, a mean (SD) of 2.7 (1.5) comorbid conditions, 2.2 (1.1) patient‐reported flare episodes/patient/year‐of‐observation, and 18.5 (12.2) tests/scans/procedures/patient/year‐of‐observation. Patients had tried a mean (SD) of 7.9 (5.3) treatments/patient/year‐of‐observation. Topical corticosteroids (TCS; 48.5% of prescriptions) were most frequently prescribed. Mean (SD) use (duration) of TCS, nonsteroidal topicals (tacrolimus, 4.1% of prescriptions), systemic corticosteroids (prednisolone, 2.2%), and systemic immunosuppressants (10.7%, of which methotrexate was 68.2%) was 38.6 (41.1), 54.4 (41.1), 2.0 (3.1), and 27.6 (21.1) months. Mean (SD) consultations/patient/year‐of‐observation was 15.3 (6.3); 28 (5.9%) for flare. Eight (25.8%) patients were hospitalised (including six children). There were 0.03 hospitalisations/patient/year‐of‐observation, and 4.4 nights spent in hospital, mostly for flare. Earliest mean (SD) Children's Dermatology Life Quality Index score was 9.7 (6.2); latest was 6.6 (5.5). Conclusion This is the first study examining paediatric AD HCRU in an Irish healthcare setting. Moderate‐to‐severe paediatric AD results in complex treatment, with high healthcare burden in hospital outpatient care. Despite treatment and a low hospitalisation rate, patients experience flare, lengthy hospital stays, and minor changes in quality of life.

The overall incidence of sex chromosome aneuploidies is approximately 1 per 500 live-born infants, but far more common at conception. I shall review the fertility aspects of the sex chromosome trisomies, XXY, XYY, and XXX, with special reference to the karyotype 45,X/47,XXX. Each has a ‘specific’ (but variable) phenotype but may be modified by mosaicism. Although the alterations in the hypothalamic–pituitary–gonadal axis are important (and discussed), the emphasis here is on potential fertility and if one might predict that at various epochs within an individual’s life span : fetal, ‘mini’-puberty, childhood, puberty, and adulthood. The reproductive axis is oft en affected in females with the 47,XXX karyotype with diminished ovarian reserve and accelerated loss of ovarian function. Fewer than 5% of females with Turner syndrome have the 45,X/47,XXX karyotype. They have taller stature and less severe fertility issues compared to females with the 45,X or other forms of Turner syndrome mosaicism. For the 47,XXY karyotype, non-obstructive azoospermia is almost universal with sperm retrieval by micro-testicular sperm extraction possible in slightly fewer than half of the men. Men with the 47,XYY karyotype have normal to large testes and much less testicular dysfunction than those with the 47,XXY karyotype. They do have a slight increase in infertility compared to the reference population but not nearly as severe as those with the 47,XXY karyotype. Assisted reproductive technology, especially micro-testicular sperm extraction, has an important role, especially for those with 47,XXY; however, more recent data show promising techniques for the in vitro maturation of spermatogonial stem cells and 3D organoids in culture. Assisted reproductive technology is more complex for the female, but vit rification of oocytes has shown promising advances.

Abstract Tianeptine is an antidepressant drug approved for the treatment of major depressive disorder in countries other than the US. It is classified as an atypical tricyclic antidepressant and has shown potential benefits in addressing anxiety and irritable bowel disease. However, it is important to note that tianeptine is not approved for any use by the United States Federal Drug Administration (FDA). Despite its lack of approval by the FDA, tianeptine has been distributed online and at small retail locations. The term “gas station drugs” refers to a wide range of substances typically available for purchase from gas stations, corner stores, bodegas, mini marts, smoke shops, and the Internet. These substances may be produced commercially by drug manufacturers or in clandestine laboratories to mimic the effects of more well-known illicit/controlled substances such as marijuana, cocaine, opioids, etc. Tianeptine has made its way to convenience stores and gas station shelves, branded as “Zaza” and “Tianna Red.” It can also be obtained online from independent vendors without a prescription. Misuse of tianeptine can lead to euphoric, opioid-like highs with the potential for chronic users to develop dependence and tolerance. Overdose and use in suicide attempts have also been documented. This manuscript is a narrative review, highlighting the dangers of tianeptine and other gas station drugs and underscoring the urgent need to regulate these substances.

Abstract Background Since 2001, Canadians have been able to obtain cannabis for medical purposes, initially through the Access to Cannabis for Medical Purposes Regulations (ACMPR). The Cannabis Act (Bill C-45) came into force on October 17, 2018, replacing the ACMPR. The Cannabis Act enables Canadians to possess cannabis purchased from a licensed retailer without authorization for either medical or nonmedical purposes. The Cannabis Act is currently the guiding legislation which governs both medical and nonmedical access. The Cannabis Act contains some improvements for patients but is essentially the same as its previous legislation. Beginning in October 2022, the federal government is conducting a review of the Cannabis Act and is questioning whether a distinct medical cannabis stream is still required, given the ease of access to cannabis and cannabis products. Although there is overlap in the reasons for medical and recreational cannabis use, the distinct legislation of medical versus recreational use of cannabis in Canada may be under threat. Main body A large segment of the medical, academic, research, and lay communities agree that there is a need for distinct medical and recreational cannabis streams. Perhaps most importantly, separation of these streams is necessary to ensure that both medical cannabis patients and healthcare providers receive the required support needed to optimize benefits while minimizing risks associated with medical cannabis use. Preservation of distinct medical and recreational streams can help to ensure that needs of different stakeholders are met. For example, patients require guidance in the form of assessing the appropriateness of cannabis use, selection of appropriate products and dosage forms, dosing titration, screening for drug interactions, and safety monitoring. Healthcare providers require access to undergraduate and continuing health education as well as support from their professional organizations to ensure medical cannabis is appropriately prescribed. Although there are challenges in conducing research, as motives for cannabis use frequently straddle boundaries between medical versus recreational cannabis use, maintenance of a distinct medical stream is also necessary to ensure adequate supply of cannabis products appropriate for medical use, to reduce stigma associated with cannabis in both patients and providers, to help enable reimbursement for patients, to facilitate removal of taxation on cannabis used for medical purposes, and to promote research on all aspects of medical cannabis. Conclusion Cannabis products for medical and recreational purposes have different objectives and needs, requiring different methods of distribution, access, and monitoring. HCPs, patients, and the commercial cannabis industry would serve Canadians well to continue to advocate to policy makers to ensure the continued existence of two distinct streams and must strive to make ongoing improvements to the current programs.

Background A shift toward human diets that include more fruit and vegetables, and less meat is a potential pathway to improve public health and reduce food system-related greenhouse gas emissions. Associated changes in land use could include conversion of grazing land into horticulture, which makes more efficient use of land per unit of dietary energy and frees-up land for other uses. Methods Here we use Great Britain as a case study to estimate potential impacts on biodiversity from converting grazing land to a mixture of horticulture and natural land covers by fitting species distribution models for over 800 species, including pollinating insects and species of conservation priority. Results Across several land use scenarios that consider the current ratio of domestic fruit and vegetable production to imports, our statistical models suggest a potential for gains to biodiversity, including a tendency for more species to gain habitable area than to lose habitable area. Moreover, the models suggest that climate change impacts on biodiversity could be mitigated to a degree by land use changes associated with dietary shifts. Conclusions Our analysis demonstrates that options exist for changing agricultural land uses in a way that can generate win-win-win outcomes for biodiversity, adaptation to climate change and public health.