Search

Manual handling is a major risk factor for work-related musculoskeletal disorders and one of the leading causes of disability-adjusted life years globally, necessitating multifaceted risk reduction measures. One potential intervention for manual handling tasks is work technique training assisted by augmented feedback on biomechanical exposures. However, there is a research gap regarding its effectiveness specifically for manual handling tasks in both real work environments and controlled settings, as well as its ability to induce retained reductions in biomechanical exposure. The gap was investigated using a rapid review comprising a literature search using two databases and 11 reviews/overviews to identify studies from the past 20 years, up to studies published by 1 June 2024. Sixteen studies were identified, with 14 of them being of high or moderate methodological quality and were included. Three studies were conducted in real work environments and eleven in controlled settings. Most studies (n = 9) used auditory feedback, followed by vibration feedback (n = 6). In real work environments, the evidence for the effectiveness of sensor-based augmented feedback in reducing biomechanical exposure during administration was considered to be inconsistent and very limited directly after administration. For longer periods after administration, ranging from one week to more than six months, there is currently no evidence demonstrating the effectiveness of the feedback. In controlled settings, there was strong evidence for its effectiveness during and immediately after administration, and limited evidence for effectiveness up to six months post-administration when considering the tasks included in the training. Future research needs are discussed. [ABSTRACT FROM AUTHOR]

Work-related diseases and disorders remain a significant global health concern, necessitating multifaceted measures for mitigation. One potential measure is work technique training utilizing augmented feedback through wearable motion capture systems. However, there exists a research gap regarding its current effectiveness in both real work environments and controlled settings, as well as its ability to reduce postural exposure and retention effects over short, medium, and long durations. A rapid review was conducted, utilizing two databases and three previous literature reviews to identify relevant studies published within the last twenty years, including recent literature up to the end of 2023. Sixteen studies met the inclusion criteria, of which 14 were of high or moderate quality. These studies were summarized descriptively, and the strength of evidence was assessed. Among the included studies, six were rated as high quality, while eight were considered moderate quality. Notably, the reporting of participation rates, blinding of assessors, and a-priori power calculations were infrequently performed. Four studies were conducted in real work environments, while ten were conducted in controlled settings. Vibration feedback was the most common feedback type utilized (n = 9), followed by auditory (n = 7) and visual feedback (n = 1). All studies employed corrective feedback initiated by the system. In controlled environments, evidence regarding the effectiveness of augmented feedback from wearable motion capture systems to reduce postural exposure ranged from strong evidence to no evidence, depending on the time elapsed after feedback administration. Conversely, for studies conducted in real work environments, the evidence ranged from very limited evidence to no evidence. Future reach needs are identified and discussed. [ABSTRACT FROM AUTHOR]

Introduction: Circulating tumour human papillomavirus DNA (ctHPVDNA) is an emerging tool to assess post‐treatment response in patients with HPV+ oropharyngeal squamous cell carcinoma (OPSCC). Its use is not a standard practice, however, with interval F‐18 FDG PET/CT and fiberoptic examination preferred. Post‐treatment PET/CT at 3 months has a low positive predictive value (PPV), especially in patients with HPV+ OPSCC treated with (chemo)radiation therapy (CRT). We aimed to compare 3–6 month post‐treatment PET/CT and ctHPVDNA test results to determine the most effective option for post‐treatment response assessment. Methods: Patients with HPV+ OPSCC that underwent commercially available ctHPVDNA blood testing after curative intent treatment were identified. Demographic, clinical, treatment, surveillance and oncologic outcome information were collected for each patient. Specificity and false positive rate were calculated for post‐treatment PET/CT and ctHPVDNA. Results: 80% of patients had Stage I disease. 52% of the population was treated with definitive chemoradiation (43%) or accelerated radiation (9%), with the remaining patients treated with transoral robotic surgery (TORS) +/− risk‐adapted adjuvant therapy. In total, 25 patients underwent ctHPVDNA testing and PET/CT at 3–6 months after finishing treatment. At 3–6 months post‐treatment, specificity of ctHPVDNA and PET/CT was 96% and 56%, correlating to false positive rates of 4% and 44%, respectively. Conclusions: ctHPVDNA is more reliable than PET/CT following treatment in patients with HPV+ OPSCC, and its incorporation in post‐treatment response assessment will decrease the rate of anxiety over persistent disease and lead to a decrease in unnecessary medical procedures, including completion of neck dissection. [ABSTRACT FROM AUTHOR]

This paper presents new classes of exact radial solutions to the nonlinear ordinary differential equation that arises as a saddle-point condition for a Euclidean scalar field theory in D-dimensional spacetime. These solutions are found by exploiting the dimensional consistency of the radial differential equation for a single massless scalar field, which allows it to transform into an autonomous equation. For massive theories, the radial equation is not exactly solvable, but the massless solutions provide useful approximations to the results for the massive case. The solutions presented here depend on the power of the interaction and on the spatial dimension, both of which may be noninteger. Scalar equations arising in the study of conformal invariance fit into this framework, and classes of new solutions are found. These solutions exhibit two distinct behaviors as D → 2 from above. [ABSTRACT FROM AUTHOR]

Numerous in vivo studies on the ketogenic diet, a diet that can induce metabolic conditions resembling those following extended starvation, demonstrate strong outcomes on cancer survival, particularly when combined with chemo-, radio- or immunological treatments. However, the therapeutic application of ketogenic diets requires strict dietary adherence from well-informed and motivated patients, and it has recently been proposed that hemodialysis might be utilized to boost ketosis and further destabilize the environment for cancer cells. Yet, plasma ketones may be lost in the dialysate—lowering blood ketone levels. Here we performed a single 180-min experimental hemodialysis (HD) session in six anesthetized Sprague–Dawley rats given ketogenic diet for five days. Median blood ketone levels pre-dialysis were 3.5 mmol/L (IQR 2.2 to 5.6) and 3.8 mmol/L (IQR 2.2 to 5.1) after 180 min HD, p = 0.54 (95% CI − 0.6 to 1.2). Plasma glucose levels were reduced by 36% (− 4.5 mmol/L), p < 0.05 (95% CI − 6.7 to − 2.5). Standard base excess was increased from − 3.5 mmol/L (IQR − 4 to − 2) to 0.5 mmol/L (IQR − 1 to 3), p < 0.01 (95% CI 2.0 to 5.0). A theoretical model was applied confirming that intra-dialytic glucose levels decrease, and ketone levels slightly increase since hepatic ketone production far exceeds dialytic removal. Our experimental data and in-silico modeling indicate that elevated blood ketone levels during ketosis are maintained during hemodialysis despite dialytic removal. [ABSTRACT FROM AUTHOR]

A delirium can be encountered in almost all hospital sectors. The prevalence varies between 20 and 40 % in internal medicine and surgical wards and between 50 and 60 % in palliative care and intensive care units. A delirium is characterized by impaired attention, consciousness, and cognitive impairment with acute onset and fluctuating course. People with delirium have inferior clinical outcomes, including higher mortality and more need for long-term care after discharge. This article first reviews the clinical and pathophysiologic basis of delirium, followed by a detailed description of individual risk profiles based on a prospective, hospital-wide cohort study (Delir-Path) conducted at the University Hospital Zurich. We will then give a brief update on diagnosis and management of delirium and an outlook on how neurophysiology and blood biomarkers can complement delirium care in the future. [ABSTRACT FROM AUTHOR]

Broad-spectrum insecticides are the main control measure of the invasive and economically damaging soybean aphid (Aphis glycines) in North America, although biological control by resident natural enemies can also greatly diminish population levels. One such natural enemy is the accidentally introduced Eurasian parasitoid Aphelinus certus (Hymenoptera: Aphelinidae), though its impact appears to be limited by low rates of parasitism early in the growing season. We tested the hypothesis that A. certus might experience high overwintering mortality. In the laboratory, we used thermocouple thermometry to measure the supercooling points of diapausing parasitoids and assessed parasitoid survival after exposure to ecologically relevant durations of low temperature. We found A. certus to be freeze-intolerant with a median supercooling point of −28°C. When exposed to temperatures of 0°C for up to 7 months, adults emerged only after exposures of at least 60 days and survival decreased with durations beyond 150 days. We also conducted in-field studies at sites from northern Minnesota to southern Iowa to determine if diapausing A. certus could overwinter above and below the snowpack. Survival was negatively correlated with increasing latitude and was greater for parasitoids placed on the ground than 1 meter off the ground, likely due to the warmer and stabler temperatures of the subnivean microclimate. Our results suggest that A. certus is capable of overwintering in the region inhabited by soybean aphid but may experience substantial mortality even under ideal conditions. Climate change is predicted to bring warmer, drier winters to the North American Midwest, with decreased depth and duration of snow cover, which may further reduce overwintering survival. [ABSTRACT FROM AUTHOR]

The article offers information on bending rigidity parameter for stress granule condensates, in live cells. It further discusses that interfacial tension plays an important role in governing the dynamics of droplet coalescence and determining how condensates interact; flicker spectroscopy pipeline to analyze the shape fluctuations of tens of thousands of stress granules; and stress granules are viscoelastic droplets with a structured interface, rather than simple Newtonian liquids.

I used the 30 Day Map Challenge as a framework to structure my Spring 2023 Cartography and Visualization community college course. Students were tasked with a new mapping assignment following the themes of the Map Challenge to complete during each class meeting throughout the semester, as an alternative to a more traditional project-based lab structure. I sequenced lecture topics to accompany and elucidate the Map Challenge prompts, and used Socratic prompts on Google Jamboard slides to spur collaborative class discussions. As a whole, the ten-student class completed 80% of submissions for 27 required mapping prompts, submitting a total of 218 maps that fulfilled the prompts. Short, thematic mapping activities entailed greater repetition of software workflows as well as more opportunities for independent problem solving. [ABSTRACT FROM AUTHOR]

Objectives: To determine the top 10 research priorities in Smell and Taste Disorders (SATD). Design: After steering group was established, an electronic survey was disseminated to determine the list of questions. After removing out‐of‐scope responses, the remainder were consolidated to create summary questions. A literature search was conducted to remove already answered questions. A second survey was used to determine the top questions that formed the subject of final debate at a workshop attended by clinicians and patients to determine the top 10 priorities. Setting: A James Lind Alliance Priority Setting Partnership (JLAPSP) was established by FifthSense to identify the top 10 research questions in SATDs in the United Kingdom. Participant: All stakeholders in SATDs (patients, healthcare professionals, family, carers, researchers). Main outcome measures: Final 10 research priorities. Results: The 665 respondents to the initial survey provided 1698 research questions. Thirteen were out‐of‐scope and removed; remaining 1685 were then consolidated to form 147 summary questions. Following literature search and discussion with the steering group, 37 questions remained for the second survey, which 235 people responded. The top ten priorities agreed upon in the workshop covered themes of improved understanding of pathophysiologlogy, improving health services, and managing long‐term effects of smell/taste disorders. The most important research question agreed was "How can we further our understanding of the mechanism of disease in the nerve pathways that affect smell and taste disorders, including where parosmia and phantosmia exist." Conclusion: We report the top 10 research priorities in smell and taste disorders. These priorities will now empower researchers to secure research funding and provide the basis of the FifthSense research hub. [ABSTRACT FROM AUTHOR]

Degenerative cervical myelopathy (DCM) is the most common form of spinal cord impairment in adults. APPLICATION OF NEUROIMAGING FRAMEWORK IN DCM In DCM, cervical spine imaging, and in particular MRI, is essential for the diagnosis and is not optional, as spinal canal narrowing is a prerequisite for spinal cord compression. ADVANCED NEUROIMAGING: FROM SPINAL STENOSIS TO MEASURES OF SPINAL CORD DISTRESS To enhance the utility of cervical spine MRI, several advanced neuroimaging methods are in various stages of translation.[17] Their entry into clinical practice may adjust the role of MRI in the diagnosis of DCM, for example, to rule in a diagnosis of DCM. [Extracted from the article]

Spinal cord injury is a severely disabling neurological condition leading to impaired mobility, pain, and autonomic dysfunction. Most often, a single traumatic event, such as a traffic or recreational accident, leads to primary spinal cord damage through compression and laceration, followed by secondary damage consisting of inflammation and ischaemia, and culminating in substantial tissue loss. Patients need appropriate timely surgical and critical care, followed by neurorehabilitation to facilitate neuronal reorganisation and functional compensation. Although some neurological function might be regained, most patients with initially complete lesions have severe, irreversible neurological impairment. Cell-based and stem-cell-based therapies are recognised as promising candidates to promote functional recovery. However, no trials of these therapies in patients have yet provided reproducible evidence for clinical efficacy, challenged by small effect sizes, low immune suppression, and low sensitivity study designs. Nevertheless, in the past decade, clinical trials have shown the feasibility and long-term safety of cell transplantation into the injured spinal cord. This crucial milestone has paved the way to consider refinements and combined therapies, such as the use of biomaterials to augment the effects of cell transplantation. In the future, emerging cell types, scaffolding, and cell engineering might improve cell survival, integration, and therapeutic efficiency. [ABSTRACT FROM AUTHOR]

Glaucoma is linked to raised intraocular pressure (IOP). The trabecular meshwork (TM) plays a major role in regulating IOP by enabling outflow of aqueous humor from the eye through its complex 3D structure. A lack of therapies targeting the dysfunctional TM highlights the need to develop biomimetic scaffolds that provide 3D in vitro models for glaucoma research or as implantable devices to regenerate TM tissue. To artificially mimic the TM's structure, we assessed methods for its decellularization and outline an optimized protocol for cell removal and structural retention. Using bovine TM, we trialed 2 lysing agents—Trypsin (0.05% v/v) and Ammonium Hydroxide (NH4OH; 2% v/v). Twenty-four hours in Trypsin caused significant structural changes. Shorter exposure (2 h) reduced this disruption whilst decellularizing the tissue (dsDNA 26 ± 14 ng/mL (control 1970 ± 146 ng/mL)). In contrast, NH4OH lysed all cells (dsDNA 25 ± 21 ng/mL), and the TM structure remained intact. For human TM, 2% v/v NH4OH similarly removed cells (dsDNA 52 ± 4 ng/mL (control 1965 ± 233 ng/mL)), and light microscopy and SEM presented no structural damage. X-ray computed tomography enabled a novel 3D reconstruction of decellularized human TM and observation of the tissue's intricate architecture. This study provides a new, validated method using NH4OH to decellularize delicate human TM without compromising tissue structure. [ABSTRACT FROM AUTHOR]

Degenerative cervical myelopathy (DCM) is hallmarked by spinal canal narrowing and related cord compression and myelopathy. Cerebrospinal fluid (CSF) pressure dynamics are likely disturbed due to spinal canal stenosis. The study aimed to investigate the diagnostic value of continuous intraoperative CSF pressure monitoring during surgical decompression. This prospective single center study (NCT02170155) enrolled DCM patients who underwent surgical decompression between December 2019 and May 2021. Data from n = 17 patients were analyzed and symptom severity graded with the modified Japanese Orthopedic Score (mJOA). CSF pulsations were continuously monitored with a lumbar intrathecal catheter during surgical decompression. Mean patient age was 62 ± 9 years (range 38-73; 8 female), symptoms were mild-moderate in most patients (mean mJOA 14 ± 2, range 10-18). Measurements were well tolerated without safety concerns. In 15/16 patients (94%), CSF pulsations increased at the time of surgical decompression. In one case, responsiveness could not be evaluated for technical reasons. Unexpected CSF pulsation decrease was related to adverse events (i.e., CSF leakage). Median CSF pulsation amplitudes increased from pre-decompression (0.52 mm Hg, interquartile range [IQR] 0.71) to post-decompression (0.72 mm Hg, IQR 0.96; p = 0.001). Mean baseline CSF pressure increased with lower magnitude than pulsations, from 9.5 ± 3.5 to 10.3 ± 3.8 mm Hg (p = 0.003). Systematic relations of CSF pulsations were confined to surgical decompression, independent of arterial blood pressure (p = 0.927) or heart rate (p = 0.102). Intraoperative CSF pulsation monitoring was related to surgical decompression while in addition adverse events could be discerned. Further investigation of the clinical value of intraoperative guidance for decompression in complex DCM surgery is promising. [ABSTRACT FROM AUTHOR]

Around 50% of cutaneous melanomas harbour therapeutically targetable BRAF V600 mutations. Reliable clinical biomarkers predicting duration of response to BRAF -targeted therapies are still lacking. Recent in vitro studies demonstrated that BRAF-MEK inhibitor therapy response is associated with tumour TERT promoter mutation status. We assessed this potential association in a clinical setting. The study cohort comprised 232 patients with metastatic or unresectable BRAF V600-mutated melanoma receiving combined BRAF/MEK inhibitor treatment, including a single-centre retrospective discovery cohort (N = 120) and a prospectively collected multicenter validation cohort (N = 112). Patients were excluded if they received BRAF or MEK inhibitors in an adjuvant setting, as monotherapy, or in combination with immunotherapy. Kaplan–Meier and univariate/multivariate Cox regression analyses were performed as appropriate. median age at first diagnosis was 54 years (range 16–84 years). The majority of patients were men 147/232 (63.4%). Most tumours harboured TERT promoter mutations (72%, N = 167). A survival advantage was observed in both progression-free survival (PFS) and overall survival (OS) for patients with TERT promoter-mutant versus wild-type tumours in both the discovery cohort (mPFS of 9.6 months [ N = 87] vs 5.0 months [ N = 33]; hazard ratio [HR] = 0.56 [95% confidence interval {CI} 0.33–0.96] and mOS of 33.6 months vs 15.0 months; HR = 0.47 [95%CI 0.32–0.70]) as well as the validation cohort (mPFS of 7.3 months [ N = 80] vs 5.8 months [ N = 32]; HR = 0.67 [95%CI 0.41–1.10] and mOS of 51.1 months vs 15.0 months; HR = 0.33 [95%CI 0.18–0.63]). In the pooled cohort of TERT promoter-mutant (N = 167) versus wild-type (N = 65) tumours, respectively, PFS was 8.9 versus 5.5 months, (HR = 0.62; 95%CI 0.45–0.87; P = 0.004), and OS was 33.6 versus 17.0 months, (HR = 0.51; 95%CI 0.35–0.75, P = 0.0001). In patients with melanoma receiving BRAF/MEK-targeted therapies, TERT promoter mutations are associated with longer survival. If validated in larger studies, TERT promoter mutation status should be included as a predictive biomarker in treatment algorithms for advanced melanoma. • TERT promoter mutations are associated with prolonged progression-free and overall survival in patients receiving MAPKi therapy. • TERT promoter mutations may serve as a biomarker for response to MAPKi ther apy. • In BRAF V600 mutant melanoma patients TERT promoter mutation status may be relevant for deciding which therapy to give. [ABSTRACT FROM AUTHOR]

NF1 -mutated tumours represent a small subset (10–15%) of melanomas, not sufficiently analysed in large clinical cohorts. This study investigated the largest multicentre collection of NF1 -mutated melanomas to date. This study analysed a multicentre tumour tissue sample cohort from 266 patients with NF1 -mutated melanoma. Targeted next-generation sequencing of the TERT promoter and 29 relevant melanoma genes was performed. Survival was compared with NF1 wild-type cohorts from the Tissue Registry in Melanoma project (n = 432). Most NF1 -mutated melanoma arose in the head-and-neck region of patients >60 years. NF1 alterations were frequently inactivating, primarily non-sense, less frequently truncating mutations. Non-inactivating NF1 mutations more frequently co-occurred with activating BRAF and RAS mutations. NF1 -mutated tumours had higher numbers of gene mutations and UV signature C>T and CC>TT transitions than BRAF , RAS and triple wild-type melanomas. NF1- mutated acral and mucosal melanomas harboured a different mutation signature and were frequent in women (69% and 83%, respectively), differing from non-acral cutaneous NF1 -mutated melanomas (men 73%, women 27%). Overall survival in stage IV disease was comparable for patients with NF1 -mutated or wild-type melanoma. However, in patients receiving first-line immune checkpoint inhibitor treatment, better median overall survival (mOS) was observed for NF1- mutated than wild-type tumours (mOS = not reached vs mOS = 25.82, p = 0.0154, n = 80 and 432, respectively). Cutaneous, acral and mucosal NF1 -mutated melanomas vary in clinical and genetic characteristics and demonstrate a favourable outcome on immune checkpoint inhibition therapy. • NF1- mutated melanoma respond favourably to programmed death-1-based immunotherapy. • NF1 -mutated metastatic melanoma had a similar overall survival to NF1 wild-type. • Non-acral, acral and mucosal NF1 -mutated melanoma are clinically distinct. • NF1 -mutated melanomas exhibit a large amount of UV signature mutations. [ABSTRACT FROM AUTHOR]

Mobile technologies provide a unique opportunity to improve menstrual health awareness, management, and care. Nurses should consider incorporating a mobile tracking component into patientcare settings to promote menstrual health awareness and advocacy and to help create individualized healthcare plans. [ABSTRACT FROM AUTHOR]

Introduction: To highlight the importance of the need for new treatment modalities, this study aimed to characterise the experience of patients with postinfectious olfactory dysfunction (PIOD) in terms of the treatment they received. Methods: An online survey was hosted by the Norwich Clinical Trials Unit on the secure REDCap server. Members of the charity Fifth Sense (the UK charity that represents and supports people affected by smell and taste disorders) were invited to participate. Results: There were 149 respondents, of whom 127 had identified themselves as having (or had) PIOD. The age range of respondents to the survey was 28–85 years, with a mean of 58 ± 12 years, with the duration of their disorder <5 years in 63% of cases. Respondents reported experiencing variable treatment with oral and/or intranasal steroids given typically (28%), often with no benefit, but with 50% receiving no treatment whatsoever; only 3% reported undertaking olfactory training. Over two-thirds of patients experience parosmia and, up to 5 years from the onset of the problem, were still actively seeking a solution. Conclusion: There appears to be a need to encourage greater use of guidelines for olfactory disorders amongst medical practitioners and also to develop more effective treatments for patients with PIOD, where there is clearly an unmet need. [ABSTRACT FROM AUTHOR]

Frail older people have a high prevalence of drug use and are susceptible to adverse drug reactions. The physiological changes of frailty are likely to affect pharmacokinetics and pharmacodynamics. We reviewed the methods and findings of published studies of pharmacokinetics in frailty. Nine studies describing pharmacokinetics and an additional three of pharmacokinetic pathways in frail older people were identified. Most pharmacokinetic studies investigated a single administration of a medication, dose or formulation, in small populations, often with limited representation of males or females, and applied variable definitions of frailty. Pharmacokinetic sampling designs generally utilised saturated sampling followed by analysis based on the trapezoidal rule for area under the curve, with more recent studies using sparser sampling and more sophisticated modelling to obtain individual and population values of all pharmacokinetic parameters. Overall, the pharmacokinetic studies reported only small changes in some parameters for some drugs with frailty, with the most consistent change reduced hepatic clearance in frail older people. Recommendations for future studies of pharmacokinetics in frailty include (i) standard objective definitions of frailty; (ii) larger studies including people with mild, moderate and severe frailty; (iii) population pharmacokinetic modelling to allow sparser sampling and consideration of multiple influences on pharmacokinetics; (iv) physiologically based modelling as the physiology of frailty emerges and (v) longitudinal pharmacokinetic studies of chronic drug therapy from middle to old age and from robust to pre-frail to frail, including pre-clinical studies. These data, accompanied by pharmacodynamics data in frailty, will inform safe, effective prescribing for frail older people. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is a leading cause of end‐stage renal disease and renal replacement therapy worldwide. A pathophysiological hallmark of DKD is glomerular basal membrane (GBM) thickening, whereas this feature is absent in minimal change disease (MCD). According to fundamental transport physiological principles, a thicker GBM will impede the diffusion of middle‐molecules such as cystatin C, potentially leading to a lower estimated GFR (eGFR) from cystatin C compared to that of creatinine. Here we test the hypothesis that thickening of the glomerular filter leads to an increased diffusion length, and lower clearance, of cystatin C. Twenty‐nine patients with a kidney biopsy diagnosis of either DKD (n = 17) or MCD (n = 12) were retrospectively included in the study. GBM thickness was measured at 20 separate locations in the biopsy specimen and plasma levels of cystatin C and creatinine were retrieved from health records. A modified two‐pore model was used to simulate the effects of a thicker GBM on glomerular water and solute transport. The mean age of the patients was 52 years, and 38% were women. The mean eGFRcystatin C/eGFRcreatinine‐ratio was 74% in DKD compared to 98% in MCD (p < 0.001). Average GBM thickness was strongly inversely correlated to the eGFRcystatin C/eGFRcreatinine‐ratio (Pearson's r = −0.61, p < 0.01). Two‐pore modeling predicted a eGFRcystatin C/eGFRcreatinine‐ratio of 78% in DKD. We provide clinical and theoretical evidence suggesting that thickening of the glomerular filter, increasing the diffusion length of cystatin C, lowers the eGFRcystatin C/eGFRcreatinine‐ratio in DKD. [ABSTRACT FROM AUTHOR]

Summary: The frequent association between coronavirus disease 2019 (COVID‐19) and olfactory dysfunction is creating an unprecedented demand for a treatment of the olfactory loss. Systemic corticosteroids have been considered as a therapeutic option. However, based on current literature, we call for caution using these treatments in early COVID‐19–related olfactory dysfunction because: (1) evidence supporting their usefulness is weak; (2) the rate of spontaneous recovery of COVID‐19–related olfactory dysfunction is high; and (3) corticosteroids have well‐known potential adverse effects. We encourage randomized placebo‐controlled trials investigating the efficacy of systemic steroids in this indication and strongly emphasize to initially consider smell training, which is supported by a robust evidence base and has no known side effects. [ABSTRACT FROM AUTHOR]

Processing conditions, particularly temperature and duration of heating, impact the digestibility of pet foods. Various alternative commercial pet food formats are now available, but few have been well tested. Therefore, the objective of this study was to determine the amino acid (AA) digestibility and nitrogen-corrected true metabolizable energy (TMEn) of frozen raw, freeze-dried raw, fresh, and extruded dog foods using the precision-fed cecectomized and conventional rooster assays. The diets tested were Chicken and Barley Recipe [extruded diet; Hill's Science Diet (EXT)], Chicken and White Rice Recipe [fresh diet; Just Food for Dogs (FRSH], Chicken Formula [raw frozen diet; Primal (FRZN)], Chicken and Sorghum Hybrid Freeze-dried Formula [hybrid freeze-dried raw diet; Primal (HFD)], and Chicken Dinner Patties [raw freeze-dried diet; Stella & Chewy (FD)]. Two precision-fed rooster assays utilizing Single Comb White Leghorn roosters (1.5 to 2.5 yr, 2.5 to 3 kg) were conducted. In the first assay, 20 cecectomized roosters (n = 4/treatment) were used to determine AA digestibility. In the second assay, 20 conventional roosters (n = 4/treatment) were used to determine TMEn. In both assays, roosters were crop intubated with 12 g of test diet and 12 g of corn, and then excreta were collected for 48 h. The reactive lysine:total lysine ratios were 0.94, 0.96, 0.93, 0.93, and 0.95 for the EXT, FRSH, FRZN, HFD, and FD diets, respectively. In general, FD had the greatest AA digestibilities and EXT had the least AA digestibilities. Arginine digestibilities were different (P < 0.05) across all diets and in this pattern: FD > FRZN > FRSH > HFD > EXT. Isoleucine digestibilities were different (P < 0.05) across all diets, but with a slightly different pattern: FD > FRZN > FRSH > EXT > HFD. Lysine digestibility was greater (P < 0.05) in FD and FRZN than EXT, with other diets being intermediate. Methionine digestibility was greater (P < 0.05) in FD than FRSH, with other diets being intermediate. Threonine digestibility was greater (P < 0.05) in FD than EXT, with other diets being intermediate. Valine digestibilities were different (P < 0.05) across all diets and in this pattern: FD > FRZN > EXT > FRSH > HFD. Digestibilities of the other essential AA were not different among diets. TMEn was greater (P < 0.05) in FRZN than FD, FRSH, and EXT, greater (P < 0.05) in HFD than FRSH and EXT, and greater (P < 0.05) in FD than EXT. In conclusion, our results support the notion that diet processing impacts AA digestibility, with freeze-dried raw, frozen raw, and fresh diets consistently having greater digestibility coefficients, as well greater TMEn, than the extruded diet. More research in dogs is necessary to test the effects of these diet formats on palatability, digestibility, stool quality, and other physiologically relevant outcomes. [ABSTRACT FROM AUTHOR]

The kynurenine pathway of tryptophan degradation produces several neuroactive metabolites such as kynurenic acid (KYNA), quinolinic acid (QUIN), and picolinic acid (PIC) thought to be involved in the pathophysiology of psychosis, major depression, and suicidal behavior. Here, we analyzed cerebrospinal fluid (CSF) concentrations of tryptophan, kynurenine, KYNA, QUIN, and PIC utilizing ultra-performance liquid chromatography – tandem mass spectrometry system (UPLC-MS/MS) in persons with bipolar disorder (n = 101) and healthy controls (n = 80) to investigate if the metabolites correlated with depressive symptoms or to the history of suicidal behavior. Furthermore, we analyzed if genetic variants of the enzyme amino-β-carboxymuconate-semialdehyde-decarboxylase (ACMSD) were associated with the CSF concentrations of PIC and QUIN. We found that CSF KYNA and PIC concentrations, as well as the kynurenine/tryptophan ratio were increased in bipolar disorder compared with controls. CSF PIC concentrations were lower in subjects with a history of suicidal behavior than those without, supporting the hypothesis that low CSF PIC is a marker of vulnerability for suicidality. Bipolar subjects taking antidepressants had higher CSF concentrations of kynurenine and KYNA than subjects not given these medications. A negative association was found between a genetic variant of ACMSD and the ratio of PIC/QUIN, indicating that a polymorphism in ACMSD is associated with excess of QUIN formation at the expense of PIC. The present results confirm that the kynurenine pathway is activated in bipolar disorder, and suggest that shifting the activity of the kynurenine pathway away from QUIN production towards a production of KYNA and PIC might be a beneficial therapeutic strategy. [ABSTRACT FROM AUTHOR]

The current epoch in fisheries science has been driven by continual advances in laboratory techniques and increasingly sophisticated approaches to analysing datasets. We now have the scientific knowledge and tools to proactively identify obstacles to the sustainable management of marine resources. However, in addition to technological advances, there are predicted global environmental changes, each with inherent implications for fisheries. The 2023 symposium of the Fisheries Society of the British Isles called for "open and constructive knowledge exchange between scientists, stakeholders, managers and policymakers" (https://fsbi.org.uk/symposium-2023/), a nexus of collaborative groups best placed to identify issues and solutions. Arguably, the Centre of Environment, Aquaculture and Fisheries Science (Cefas) and their Scientific Advice for Fisheries Management (SAFM) Team sit at the centre of such a network. SAFM regularly engages with managers and stakeholders, undertakes scientific research, provides fisheries advice to the UK government, and are leading experts within the International Council for the Exploration of the Sea (ICES). As such, this paper is an opinion piece, linked to individual authors specialisms, that aims to highlight emerging issues affecting fisheries and suggest where research efforts could be focused that contribute to sustainable fisheries. [ABSTRACT FROM AUTHOR]

One-dimensional -symmetric quantum-mechanical Hamiltonians having continuous spectra are studied. The Hamiltonians considered have the form H = p2 + V(x), where −∞ < x < ∞. The potential V(x) is odd in x, pure imaginary, and vanishes as |x| → ∞. Five -symmetric potentials are studied: the Scarf-II potential V1(x) = iA1 sech(x)tanh(x), which decays exponentially for large |x|; the rational potentials V2(x) = iA2x/(1 + x4) and V3(x) = iA3x/(1 + |x|3), which decay algebraically for large |x|; the step-function potential V4(x) = iA4 sgn(x)θ(2.5 − |x|), which has compact support; the regulated Coulomb potential V5(x) = iA5x/(1 + x2), which decays slowly as |x| → ∞ and thus may be viewed as a long-range potential. The real parameters An measure the strengths of these potentials. Numerical techniques for solving the time-independent Schrödinger eigenvalue problems associated with these potentials reveal that, in general, the spectra of these Hamiltonians are partly real and partly complex. The real eigenvalues form the continuous part of the spectrum and the complex eigenvalues form the discrete part of the spectrum. The real eigenvalues range continuously in value from 0 to +∞. The complex eigenvalues occur in discrete complex-conjugate pairs and for Vn(x) (1 ⩽ n ⩽ 4) the number of these pairs is finite and increases as the value of the strength parameter An increases. However, for V5(x) there is an infinite sequence of discrete eigenvalues with a limit point at the origin. While this sequence is complex, it resembles the Balmer series for the hydrogen atom because it has inverse-square convergence. [ABSTRACT FROM AUTHOR]

1. Although preference–performance relationships in insects are typically studied in a bi‐trophic context, it is well known that host plants can affect both the preference and performance of natural enemies of herbivorous insects. 2. This study presents evidence from field and laboratory studies that two species of milkweeds, the putatively less defended Asclepias incarnata and the putatively more defended Asclepias syriaca, differentially affect adult oviposition and larval performance in Aphidoletes aphidimyza, an aphid‐feeding predatory midge, independent of aphid density. 3. Host plant species affected predatory fly larvae abundance by a factor of 50 in the field and a factor of 8 in the laboratory. Larval and adult emergence rates in our laboratory studies provided strong evidence for reduced performance on A. syriaca. Oviposition in choice and no‐choice settings provided some evidence for preference for A. incarnata, and a potentially suppressive effect of A. syriaca. 4. The results provide limited support for the hypothesis that natural selection can lead to positive correlations between adult oviposition preferences and larval performance upon various food sources, even when predatory insects oviposit onto host plants of their herbivorous prey. 5. Preference and performance are not perfectly aligned in this system, however, because ovipositing females do not reject A. syriaca entirely. Potential explanations for mismatches between preference and performance in this system include the neural constraints associated with being a generalist, adaptive time‐limited foraging strategies, and unique evolutionary histories of laboratory colonies compared with wild insects. [ABSTRACT FROM AUTHOR]

Objectives: There are large numbers of patients with olfactory disturbance in the UK and shortfalls in assessment and support amongst mainstream practice in both primary and secondary care leading to significant quality‐of‐life impairment and potential missed diagnoses. The aim of this study was to determine the key themes which can be identified from the accounts of anosmia sufferers and to identify important areas to target for future research or service development. Design: Qualitative analysis of written patient accounts from patients corresponding with a tertiary smell and taste clinic in the UK. This qualitative study utilised unstructured written patient accounts from consenting patients experiencing olfactory disturbances received by the smell and taste clinic. Framework analysis was performed using Nvivo 10 software. Setting: Tertiary smell and taste clinic. Participants: Consenting patients who contacted the smell and taste clinic with accounts of their experiences. Main outcome measures: Themes generated by qualitative analysis with Nvivo software. Results: Accounts submitted by 71 participants were included in the analysis; age range 31‐80 years, 45 females, 26 males. Themes identified include negative emotional impact, feelings of isolation, impaired relationships and daily functioning, impact on physical health and the difficulty and financial burden of seeking help. Conclusions: Olfactory disturbances have a wide‐ranging impact on the lives of sufferers, compounded by a lack of knowledge of the disorder amongst clinicians. There is a role for further support and education both for sufferers and for clinicians, as well as a need to improve our understanding of olfactory disturbance. [ABSTRACT FROM AUTHOR]

In quantum mechanics the eigenstates of the Hamiltonian form a complete basis. However, physicists conventionally express completeness as a formal sum over the eigenstates, and this sum is typically a divergent series if the Hilbert space is infinite dimensional. Furthermore, while the Hamiltonian can be reconstructed formally as a sum over its eigenvalues and eigenstates, this series is typically even more divergent. For the simple cases of the square-well and the harmonic-oscillator potentials, this paper explains how to use the elementary procedure of Euler summation to sum these divergent series and thereby to make sense of the formal statement of the completeness of the formal sum that represents the reconstruction of the Hamiltonian. [ABSTRACT FROM AUTHOR]

Small cell lung cancer (SCLC) is an aggressive malignancy composed of distinct transcriptional subtypes, but implementing subtyping in the clinic has remained challenging, particularly due to limited tissue availability. Given the known epigenetic regulation of critical SCLC transcriptional programs, we hypothesized that subtype-specific patterns of DNA methylation could be detected in tumor or blood from SCLC patients. Using genomic-wide reduced-representation bisulfite sequencing (RRBS) in two cohorts totaling 179 SCLC patients and using machine learning approaches, we report a highly accurate DNA methylation-based classifier (SCLC-DMC) that can distinguish SCLC subtypes. We further adjust the classifier for circulating-free DNA (cfDNA) to subtype SCLC from plasma. Using the cfDNA classifier (cfDMC), we demonstrate that SCLC phenotypes can evolve during disease progression, highlighting the need for longitudinal tracking of SCLC during clinical treatment. These data establish that tumor and cfDNA methylation can be used to identify SCLC subtypes and might guide precision SCLC therapy. [Display omitted] • Small cell lung cancer subtypes can be assessed using RNA-seq and predictive models • Small cell lung cancer subtypes have subtype-specific DNA methylation profiles • DNA methylation allows subtyping from both tissue and liquid biopsies • Liquid biopsies offer a less invasive alternative for patient subtype assignment Heeke et al. report robust assays utilizing gene expression and DNA methylation to distinguish small cell lung cancer subtypes from tissue and liquid biopsies. DNA methylation is distinct across SCLC subtypes and longitudinal assessment from liquid biopsies allows tracking of SCLC subtype evolution. [ABSTRACT FROM AUTHOR]

• We causally probed the role of spontaneous EEG rhythms in visual attention via phase-locking. • Theta phase predicted behaviour offline, but cues presented in real-time with these oscillations had no effect on behaviour. • Spurious theta rhythmic sampling is an artefact of the evoked potential and acausal analysis. • ecHT accurately computes the phase in real-time and mitigates erroneous phase-behaviour correlations. For over a decade, electrophysiological studies have reported correlations between attention / perception and the phase of spontaneous brain oscillations. To date, these findings have been interpreted as evidence that the brain uses neural oscillations to sample and predict upcoming stimuli. Yet, evidence from simulations have shown that analysis artefacts could also lead to spurious pre-stimulus oscillations that appear to predict future brain responses. To address this discrepancy, we conducted an experiment in which visual stimuli were presented in time to specific phases of spontaneous alpha and theta oscillations. This allowed us to causally probe the role of ongoing neural activity in visual processing independent of the stimulus-evoked dynamics. Our findings did not support a causal link between spontaneous alpha / theta rhythms and behaviour. However, spurious correlations between theta phase and behaviour emerged offline using gold-standard time-frequency analyses. These findings are a reminder that care should be taken when inferring causal relationships between neural activity and behaviour using acausal analysis methods. [ABSTRACT FROM AUTHOR]

Presents a study that characterized metabolic response to provision of mixed protein-carbohydrate supplementation during endurance exercise. Method of the study; Results and discussion; Conclusion.

Investigates the effects of intravenous versus oral rehydration, during a brief period on stress hormone concentrations during subsequent exhaustive exercise in the heat. Effects of dehydration on the physiological function and performance of athletes; Methodology of the study; Stress hormone responses.

Presents isothermal-isobaric Monte Carlo calculations of the elastic coefficients and derived engineering moduli and Poisson ratios for crystalline hexahydro-1,3,5-trinitro-1,3,5-triazine. Potential-energy surface; Elastic constants and derived parameters.

Reflecting on the first 6 months of the pandemic, there was confidence, and perhaps too much comfort, that our available vaccines and approved medicines, developed through suitably rigorous and adaptable drug development and regulatory pathways, would be sufficient to navigate the world out of the SARs-COV-2 pandemic. The use of in silico tools was also emphasised by Dodds et al.5 and Davda et al.6 as important platforms to allow for expedited drug repurposing efforts and drug development in future pandemics. [Extracted from the article]

Background: In the absence of evidence supporting its benefit, the American Academy of Orthopaedic Surgeons (AAOS) strongly recommends against closed wound drainage in TKA; however, drain usage remains common in other joints, including the shoulder. While an extensive body of research exists for drain use in lower extremity joint arthroplasty, large-scale data on drain use and its association with benefits and complications in shoulder arthroplasties is lacking. Such data may be particularly valuable given the rapidly increasing demand for shoulder arthroplasties.Question/purpose: Using national claims data, we (1) evaluated the trends in frequency of drain usage in shoulder arthroplasty procedures over time, as well as the association between drain usage and (2) blood transfusion usage, (3) length of stay (LOS), and (4) readmission or early infection within 30 days.Methods: This retrospective study used data from the nationwide Premier Healthcare claims database (2006-2016; n = 105,116, including total, reverse, and partial shoulder arthroplasties, in which drains were used in 20% [20,886] and no drain was used in 80% [84,230]). Included hospitals were mainly concentrated in the South (approximately 40%) with equal distributions among the Northeast, West, and Midwest (approximately 20% each). The Premier database contains detailed inpatient billing data on approximately 20% to 25% of US hospital discharges, which allows the creation of a variable indicating drain use by evaluating inpatient billing for drains. Baseline demographics differed minimally between patients receiving a drain compared with those who did not, with a median age of 70 years in both groups. The potential for selection bias was addressed by adjusting for measured confounders in mixed-effects models that estimated associations between drain use and blood transfusion usage, LOS, and readmission or (early) infection within 30 days. In addition, alternative statistical approaches were applied to address confounding, including propensity score analysis and instrumental variable analysis where a so-called "instrumental variable" is applied that mimics the treatment assignment process similar to a randomized study. We report odds ratios (OR; or % change for continuous variables) and 95% confidence intervals (CIs).Results: The usage of drains decreased over time, from 1106 of 4503 (25%) in 2006 to 2278 of 14,501 (16%) in 2016. After adjusting for relevant covariates, drain use was associated with an increased usage of blood transfusions (OR, 1.49; 95% CI, 1.35-1.65; p < 0.001) while only associated with a small increase in LOS (+6%, 95% CI, +4% to +7%; p < 0.001). Drain use was not associated with increased odds for early postoperative infection or 30-day readmission. Propensity score analysis and instrumental variable analysis corroborated our main results.Conclusions: Use of drains in patients undergoing shoulder arthroplasty is associated with an almost 50% increased odds for blood transfusions. Given that our findings parallel close to what is known in patients undergoing lower extremity joint arthroplasty, we believe that our results from a large national database are sufficient to discourage the routine use of drains in patients undergoing shoulder arthroplasty.Level Of Evidence: Level III, therapeutic study. [ABSTRACT FROM AUTHOR]

Fronts can be computed from gridded datasets such as numerical model output and reanalyses, resulting in automated surface frontal charts and climatologies. Defining automated fronts requires quantities (e.g., potential temperature, equivalent potential temperature, wind shifts) and kinematic functions (e.g., gradient, thermal front parameter, and frontogenesis). Which are the most appropriate to use in different applications remains an open question. This question is investigated using two quantities (potential temperature and equivalent potential temperature) and three functions (magnitude of the horizontal gradient, thermal front parameter, and frontogenesis) from both the context of real-time surface analysis and climatologies from 38 years of reanalyses. The strengths of potential temperature to identify fronts are that it represents the thermal gradients and its direct association with the kinematics and dynamics of fronts. Although climatologies using potential temperature show features associated with extratropical cyclones in the storm tracks, climatologies using equivalent potential temperature include moisture gradients within air masses, most notably at low latitudes that are unrelated to the traditional definition of a front, but may be representative of a broader definition of an airmass boundary. These results help to explain previously published frontal climatologies featuring maxima of fronts in the subtropics and tropics. The best function depends upon the purpose of the analysis, but Petterssen frontogenesis is attractive, both for real-time analysis and long-term climatologies, in part because of its link to the kinematics and dynamics of fronts. Finally, this study challenges the conventional definition of a front as an airmass boundary and suggests that a new, dynamically based definition would be useful for some applications. [ABSTRACT FROM AUTHOR]

Abstract Background Childhood maltreatment is a major risk factor for psychopathology. However, some maltreated individuals appear remarkably resilient to the psychiatric effects while manifesting the same array of brain abnormalities as maltreated individuals with psychopathology. Hence, a critical aim is to identify compensatory brain alterations that enable resilient individuals to maintain mental well-being despite alterations in stress-susceptible regions. Methods Network models were constructed from diffusion tensor imaging and tractography in physically healthy unmedicated 18- to 25-year-old participants (N = 342, n = 192 maltreated) to develop network-based explanatory models. Results First, we determined that susceptible and resilient individuals had the same alterations in global fiber stream network architecture using two different definitions of resilience: 1) no lifetime history of Axis I or II disorders, and 2) no clinically significant symptoms of anxiety, depression, anger-hostility, or somatization. Second, we confirmed an a priori hypothesis that right amygdala nodal efficiency was lower in asymptomatic resilient than in susceptible participants or control subjects. Third, we identified eight other nodes with reduced nodal efficiency in resilient individuals and showed that nodal efficiency moderated the relationship between maltreatment and psychopathology. Fourth, we found that models based on global network architecture and nodal efficiency could delineate group membership (control, susceptible, resilient) with 75%, 82%, and 80% cross-validated accuracy. Conclusions Together these findings suggest that sparse fiber networks with increased small-worldness following maltreatment render individuals vulnerable to psychopathology if abnormalities occur in specific nodes, but that decreased ability of certain nodes to propagate information throughout the network mitigates the effects and leads to resilience. [ABSTRACT FROM AUTHOR]

C. G. Jung describes the power of the unconscious on our conscious actions. The unconscious is a concept that is difficult for the conscious mind to understand. This article describes an experience that demonstrates the direct influence of unconscious material in the form of dreams throughout the process of individuation. Influenced by Emerson's essay, "Self-Reliance," and Jung's theory of the shadow archetype, I trusted my intuition about the nature of spirit. That decision guided me to transcendent information garnered through a series of dreams. Two frequently recurring dreams of frustration and anxiety transformed into positive unconscious attitudes that had a direct effect on conscious actions. Confronting old information in my mind, I have been gifted with confidence to accept my self-reliance and the reality of mystery. [ABSTRACT FROM AUTHOR]

Background: Respiratory syncytial virus (RSV) causes high morbidity, with mortality rates approaching or exceeding that of influenza in adult and infant patient populations, respectively. Lumicitabine (ALS-008176 or JNJ-64041575) is an oral nucleoside analogue prodrug in clinical development to treat RSV infections. This prodrug converts to plasma-circulating ALS-8112, and then to the 5'-active nucleoside triphosphate (NTP) form within host cells. We conducted an RSV-A challenge study in healthy adults to evaluate lumicitabine's activity during an active RSV infection.Objectives: To develop a semi-mechanistic mathematical model describing RSV kinetics, and the pharmacokinetics (PK) and pharmacodynamics (PD) of lumicitabine during treatment.Methods: Nasopharyngeal viral load and concentrations of ALS-8112 and ALS-8144 (uridine metabolite) were measured frequently over the study duration. Population viral kinetic and PK/PD models were developed using NONMEM. The RSV life-cycle was described using a target-cell-limited model that included a physiological delay.Results: The estimated clearances of ALS-8112 and ALS-8144 were 54.2 and 115 L/h/70 kg, respectively. A semi-physiological model was linked to predict ALS-8112 conversion to active intracellular NTP. Extensive and rapid RSV reduction occurred after lumicitabine treatment (EC50 = 1.79 μM), with >99% viral inhibition at 2 h after loading dose. Simulated NTP exposures and time to EC50 attainment suggested that rapid therapeutic effects and reduced dosing frequency are achievable in adult and paediatric patients.Conclusions: The semi-mechanistic model characterizes RSV kinetics and the antiviral effectiveness of lumicitabine in an adult challenge population. This model is applicable to guide dose selection in adult and paediatric patients. [ABSTRACT FROM AUTHOR]

Climatologies of fronts, airmass boundaries, and airstream boundaries can be calculated using automated approaches on gridded data. Such approaches may require choices to define a front, including a quantity (or quantities) to diagnose the front, a mathematical function(s) that operates upon the quantity to produce a diagnostic field, a level(s) at which the field is calculated, and a minimum threshold(s) in the magnitude of the field. To understand how resulting climatologies depend upon these choices using a consistent dataset, ERA-Interim reanalyses from 1979 to 2016 are used to construct global monthly climatologies for various definitions of fronts and airstream boundaries from potential temperature, equivalent potential temperature, water vapor mixing ratio, and wind, including gradients, thermal front parameter, frontogenesis, and asymptotic contraction rate at the surface and 850 hPa. Maps of automated fronts are similar to manual analyses when about 10% of the map is identified as a front. Definitions of fronts that use potential temperature or frontogenesis produce climatologies similar to those of manually analyzed fronts with maxima along the major storm tracks and their seasonal migrations. In contrast, definitions that use equivalent potential temperature or the thermal front parameter produce fewer fronts at higher latitudes and more fronts at lower latitudes, more akin to airmass boundaries than fronts. Although surface fronts defined by thermodynamic quantities are more infrequent over the oceans than at 850 hPa, they are more frequent when using metrics that include the wind field (e.g., frontogenesis, asymptotic contraction rate). [ABSTRACT FROM AUTHOR]

Background Respiratory syncytial virus (RSV) causes high morbidity, with mortality rates approaching or exceeding that of influenza in adult and infant patient populations, respectively. Lumicitabine (ALS-008176 or JNJ-64041575) is an oral nucleoside analogue prodrug in clinical development to treat RSV infections. This prodrug converts to plasma-circulating ALS-8112, and then to the 5′-active nucleoside triphosphate (NTP) form within host cells. We conducted an RSV-A challenge study in healthy adults to evaluate lumicitabine's activity during an active RSV infection. Objectives To develop a semi-mechanistic mathematical model describing RSV kinetics, and the pharmacokinetics (PK) and pharmacodynamics (PD) of lumicitabine during treatment. Methods Nasopharyngeal viral load and concentrations of ALS-8112 and ALS-8144 (uridine metabolite) were measured frequently over the study duration. Population viral kinetic and PK/PD models were developed using NONMEM. The RSV life-cycle was described using a target-cell-limited model that included a physiological delay. Results The estimated clearances of ALS-8112 and ALS-8144 were 54.2 and 115 L/h/70 kg, respectively. A semi-physiological model was linked to predict ALS-8112 conversion to active intracellular NTP. Extensive and rapid RSV reduction occurred after lumicitabine treatment (EC50 = 1.79 μM), with >99% viral inhibition at 2 h after loading dose. Simulated NTP exposures and time to EC50 attainment suggested that rapid therapeutic effects and reduced dosing frequency are achievable in adult and paediatric patients. Conclusions The semi-mechanistic model characterizes RSV kinetics and the antiviral effectiveness of lumicitabine in an adult challenge population. This model is applicable to guide dose selection in adult and paediatric patients. [ABSTRACT FROM AUTHOR]

Common polymorphisms in the genes encoding CYP2D6, CYP2C19, CYP2C9 and VKORC1 enzymes have an important role in predicting the occurrence of adverse effects and the efficacy of substrate medications. Drug-induced changes to the enzyme's phenotype, a process called phenoconversion, comprise another important factor contributing to interindividual variability in drug response. To date, there is lack of data on the frequency of these common polymorphisms and phenoconversion in the pan-ethnic Australian population. The aim of this study was to (1) describe allele, genotype and phenotype frequencies for CYP2D6, CYP2C19, CYP2C9 and VKORC1 enzymes in the pan-ethnic Australian population and (2) evaluate the frequency of actionable pharmacogenomic (PGx) variants and phenoconversion. Frequencies were calculated using the records of 5408 Australian patients (obtained from myDNA's propriety database), who were consecutively tested with the DNAdose PGx test which included the CYP2D6, CYP2C19, CYP2C9 and VKORC1 genes. In 2509 patients with listed medications at the time of testing, phenoconversion frequencies were calculated for CYP2D6, CYP2C19 and CYP2C9 enzymes. Allele, genotype and phenotype frequencies in our Australian patients correlated with a Caucasian population. Approximately 96% of patients had at least one actionable PGx variant. A five-fold increase in the frequency of poor metabolisers (PMs) for CYP2D6 and CYP2C19 was predicted by phenoconversion. Our study results indicate a high frequency of actionable PGx variants in our Australian population. With the addition of drug-induced phenoconversion, our results provide further support for the utilisation of PGx testing in clinical practice as another tool assisting prescribers in the application of personalised medicine. [ABSTRACT FROM AUTHOR]

The objective was to test the hypothesis that digestible energy (DE), metabolizable energy (ME), standardized ileal digestibility (SID) of amino acids (AA), and standardized total tract digestibility (STTD) of P in soybean meal produced from a new variety of soybeans (Photoseed) are not different from conventional soybean meal (SBM-CV). In Exp. 1, thirty pigs (18.3 ± 1.3 kg) were randomly allotted to a corn diet or 2 diets containing corn and Photoseed or corn and SBM-CV. Pigs were housed in metabolism crates and feces and urine were collected for 4 days after 5 days of adaptation. Feces and urine were analyzed for gross energy and DE and ME were calculated for each ingredient. The statistical model included ingredient as fixed effect and replicate as random effect and pig was the experimental unit. Results indicated that DE and ME of Photoseed were not different from DE and ME in SBM-CV (Table 1). In Exp. 2, nine barrows (30.0 ± 1.5 kg) with a T-cannula in the distal ileum were allotted to a triplicated 3 × 3 Latin Square design with 3 diets and 3 periods in each square. An N-free diet and diets containing SBM-CV or Photoseed were used. Pigs were housed individually in fully slatted pens and ileal digesta were collected on d 6 and 7 of each period. Digesta samples were lyophilized, ground, and analyzed for AA, and SID of AA was calculated. The statistical model included diet as fixed effect and square, period, and pig as random effects, and pig was the experimental unit. Results indicated that the SID of Arg, Ile, and Lys were not different between the two ingredients (Table 2), but the SID of other indispensable AA were greater (P < 0.05) in SBM-CV than in Photoseed. In Exp. 3, forty-eight barrows (12.0 ± 1.6 kg) were allotted to 6 diets with 8 pigs per diet. The SBM-CV or Photoseed were included in diets with 3 levels of microbial phytase (0, 500, or 1,000 units/kg). Pigs were housed in metabolism crates and feces were collected quantitatively for 4 days after 5 days of adaptation. Fecal samples were dried and analyzed for P and the STTD of P was calculated. The statistical model included ingredient, phytase, and the interaction between ingredient and phytase as fixed effects and replicate as the random effect. The pig was the experimental unit. Results indicated that inclusion of phytase in the diets increased (P < 0.05) the STTD of P, but STTD of P in Photoseed was not different from the STTD in SBM-CV (Table 3). In conclusion, no differences in DE and ME, STTD of P, and SID of some indispensable AA between Photoseed and SBM-CV were observed. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study is to determine the clinical utility of second-physician review of radiographs obtained after reduction of distal radius and ankle fractures.Methods: Fifty consecutive ankle and distal radius fractures requiring reduction were reviewed. The time from post-reduction radiograph to second-physician interpretation was obtained. The second-physicians' interpretation was evaluated for clinically influential information. Patients requiring a repeat reduction were identified, and the timing of the repeat reduction radiograph was compared with the timing of the second-physician interpretation of the initial post-reduction radiograph.Results: The mean time of second-physician interpretation for post reduction ankle radiographs was 6 h and 47 min (range 4 min to 43 h and 3 min). Eleven of 50 (22%) interpretations of post reduction ankle radiographs commented on acceptability of reduction. The mean time of second-physician interpretation for post reduction distal radius radiographs was 5 h and 34 min (range 8 min to 22 h and 59 min). Seven of 50 (14%) interpretations of post reduction distal radius radiographs commented on acceptability of reduction. Three distal radius (6%) and 8 ankle fractures (16%) required repeat reduction. Repeat reductions were completed in 10/11 cases (91%) before the second-physician review of the initial post reduction radiograph was obtained. In only 1 case of repeat reduction was the second-physician review of the post reduction radiograph available before repeat reduction was attempted.Conclusion: The timing and quality of second-physician review of post-reduction radiographs offers little utility to the clinical management of ankle and distal radius fractures. [ABSTRACT FROM AUTHOR]

Purpose: Patients with testicular seminoma may face fertility issues because of their underlying disease as well as treatments they undergo. The current patterns of practice among U.S. radiation oncologists aimed at assessing and preserving fertility in patients with Stage I seminoma are unknown. Methods: We surveyed practicing U.S. radiation oncologists via an Institutional Review Board-approved online questionnaire. Respondents' characteristics and perceived patient infertility rates were analyzed for association with treatment recommendations. Results: We received 353 responses, of whom one quarter (23%) consider themselves experts. A vast majority (84%) recommend observation as a default strategy. Fifty-two percent routinely advise fertility assessment for patients before observation or chemotherapy, and 74% routinely do so before adjuvant radiation therapy (RT). Forty-one percent and 43% believe that 10% and 30% of patients are infertile following orchiectomy, respectively. Thirty-seven percent and 22% believe infertility rates following para-aortic RT to be 30% and 50%, respectively. Eighty percent routinely use clamshell scrotal shielding. Responders with higher perceived infertility rates are more likely to recommend fertility assessment/sperm banking (Fisher's exact p < 0.0001). Responders who routinely advised fertility assessment were more likely to use clamshell shielding (Cochran–Armitage trend test p = 0.0007). Clamshell use was positively correlated with higher perceived infertility rates following para-aortic RT (Spearman's correlation coefficient = 0.006). Conclusions: Despite a clear knowledge of fertility issues in men diagnosed with seminoma, there is no universal adoption of fertility assessment among U.S. radiation oncologists. [ABSTRACT FROM AUTHOR]

One of the many unresolved questions regarding the permeability of the glomerular filtration barrier is the reason behind the marked difference in permeability between albumin and polysaccharide probe molecules such as Ficoll and dextran of the same molecular size. Although the differences in permeability have been mainly attributed to charge effects, we have previously shown that this would require a highly charged filtration barrier, having a charge density that is -10 times more than that on the albumin molecule. In this article, the classic two-pore model was extended by introducing size distributions on the solute molecules, making them conformationally flexible. Experimental sieving data for Ficoll from the rat glomerulus and from precision-made silicon nanopore membranes were analyzed using the model. For the rat glomerulus a small-pore radius of 36.2 Å and a geometric standard deviation (gSD) for the Ficoll size-distribution of 1.16 were obtained. For the nanopore membranes, a gSD of 1.24 and a small-pore radius of 43 Å were found. Interestingly, a variation of only -16% in the size of the polysaccharide molecule is sufficient to explain the difference in permeability between albumin and Ficoll. Also, in line with previous data, the effects of applying a size distribution on the solute molecule are only evident when the molecular size is close to the pore size. Surely there is at least some variation in the pore radii, and, likely, the gSD obtained in the current study is an overestimation of the "true" variation in the size of the Ficoll molecule. [ABSTRACT FROM AUTHOR]

The hippocampus is a highly stress susceptible structure and hippocampal abnormalities have been reported in a host of psychiatric disorders including major depression and post-traumatic stress disorder (PTSD). The hippocampus appears to be particularly susceptible to early life stress with a graded reduction in volume based on number of types (multiplicity) or severity of maltreatment. We assessed whether the most important predictors of adult hippocampal volume were multiplicity, severity or duration of exposure or timing of maltreatment during developmental sensitive periods. 3T MRIs were collected on 336 unmedicated, right-handed subjects (132M/204F, 18–25 years). Exposure to broad categories of abuse and neglect during each year of childhood were assessed using the Maltreatment and Abuse Chronology of Exposure scale and evaluated using artificial intelligence and predictive analytics. Male hippocampal volume was predicted by neglect, but not abuse, up through 7 years of age. Female hippocampal volume was predicted by abuse, but not neglect, at 10, 11, 15 and 16 years. Exposure at peak age had greater predictive importance than multiplicity, severity or duration. There were also marked gender differences in subfields and portions (head, body or tail) affected by exposure. History and symptoms of major depression, PTSD or anxiety disorders were not predictive of hippocampal volume once maltreatment was accounted for. Neglect appears to foster inadequate hippocampal development in males while abuse appears to produce a stress-related deficit in females. Studies assessing hippocampal volume in psychiatric disorders need to control for the gender-specific effects of abuse and neglect. [ABSTRACT FROM AUTHOR]