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The aim of this study was to evaluate the type and frequency of falls presenting to an inner city casualty department, and to identify modifiable risk factors in these patients. A prospective descriptive study evaluated those over 65 years presenting to an inner city casualty department with falls. Over a 4-week recruitment period, all consenting subjects completed a semi-structured questionnaire regarding their falls and cognitive status. Those with unexplained (UF) or recurrent falls (RF) underwent a more detailed assessment: history and examination, gait and balance assessment, visual acuity measurement and neurocardiovascular investigations (including orthostatic blood pressure, carotid sinus massage and head-up tilt testing). Of 200 patients with falls, 188 were interviewed; 29% could recall a reason for falling (accidental) and 30% had UF or RF. A cohort of 26 cognitively normal patients with UF and RF was fully investigated. In 23/26 patients risk factors for falls were found (median: three risk factors). These included: culprit medication (10), gait abnormalities (9) and carotid sinus hypersensitivity (19). Falls are a common presenting complaint yet a fall is readily explained in less than one-third of cases. Investigation of RF and UF has a high yield for possibly modifiable cardiac and non-cardiac risk factors. Targeted multi-disciplinary rapid assessment of patients attending the Accident and Emergency Department because of a fall might reduce the number of hospital admissions. [ABSTRACT FROM AUTHOR]

1. Chloroquine diphosphate (15 mg base kg-1) was given by constant rate intravenous infusion to two groups of Thai subjects. Eleven were patients with malaria (10 with Plasmodium vivax and one case with Plasmodium malariae) and 10 were healthy normal volunteers. 2. Plasma and packed red-cell concentrations of chloroquine, electrocardiographic intervals, arterial blood pressure and pulse were measured at frequent intervals. 3. Peak plasma concentrations at the end of the infusion ranged from 979 to 2,900 ng ml-1 in the malaria patients. In the group of healthy subjects the range was 550-2,200 ng ml-1. Values for terminal elimination rate constant, (lambda z) plasma clearance (CL), initial volume of distribution (V1) and volume of distribution at steady state (Vss) were calculated. For the healthy subjects, mean estimates of these parameters were lambda z = 0.062 +/- 0.030 day-1, CL = 597 +/- 238 ml min-1, V1 = 0.66 +/- 0.71 l kg-1 and Vss = 132 +/- 50 l.kg-1 For the group of malaria patients, the corresponding values were lambda z = 0.055 +/- 0.032 day-1, CL = 535 +/- 246 ml min-1, V1 = 0.74 +/- 0.75 l kg-1 and Vss = 136 +/- 64 l kg-1 There was no statistically significant difference in the estimates for any parameter between groups (P less than or equal to 0.05). 4. Chloroquine concentrations in packed red blood cells consistently exceeded those in plasma and showed no consistent change with time throughout the period of study in either group. The median value for the red cell to plasma ratio was between 3 and 4 in each group.(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

The impact of the biophysical environment on the platelet storage lesion (PSL) has mainly focused on reduced temperature storage, overlooking the significance of storage-induced shear stress. Shear stress in platelet storage refers to the frictional force acting parallel to the bag surface and exists solely through the implementation of agitation. This study investigates whether minimizing exposure to agitation-induced shear stress can alleviate the unexplained loss of function in stored platelet concentrates for neonatal transfusion (neonatal PCs). Using particle tracking analysis, fluid motion was measured in neonatal and adult platelet storage bags under agitation frequencies ranging from 20-60 rpm. Platelets stored at 20-60 rpm agitation over 8 days were examined by biochemical analysis, aggregation, and expression of activation markers. Results indicate that neonatal PCs experience significantly higher storage-induced shear stress compared to adult doses, leading to reduced functionality and increased activation from day 2 of storage. Adjusting the neonatal PC agitation frequency to 20 rpm improved functionality in early storage, while 40 rpm maintains this improvement throughout storage with reduced activation, compared to 60 rpm storage. This study confirms that small volume PC storage for neonatal use contributes to the PSL through the induction of shear stress, suggesting further evaluation of the recommended agitation frequency for neonatal PCs or postponement of the production of neonatal PCs until requested for neonatal transfusion.

The advent of immunotherapy in lymphomas, beginning with Rituximab, have led to paradigm shifting treatments that are increasingly bringing a greater number of affected patients within the ambit of durable disease control and cure. Bispecific antibodies harness the properties of the immunoglobulin antibody structure to design molecules which, apart from engaging with the target tumour associated antigen, engage the host's T-cells to cause tumour cell death. Mosunetuzumab, an anti-CD20 directed bispecific antibody was the first to be approved in follicular lymphoma, this has now been followed by quick approvals of Glofitamab and Epcoritamab in diffuse large B-cell lymphomas. This article reviews contemporary data and ongoing studies evaluating the role of bispecific antibodies in indolent b-cell non Hodgkin lymphomas. This is an area of active research and presents many opportunities in advancing the treatment of indolent lymphomas and potentially forge a chemo-free treatment paradigm in this condition., Competing Interests: AD reports a relationship with the following: F Hoffmann-La Roche Ltd that includes consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement; AbbVie Ltd. that includes consulting or advisory; Genmab BV that includes consulting or advisory; AstraZeneca that includes consulting or advisory and funding grants; Sobi Inc that includes consulting or advisory; Incyte Corporation that includes consulting or advisory; CellCentric Limited that includes funding grants; Bristol Myers Squibb Co that includes consulting or advisory and funding grants; Gilead Sciences Kite HQ that includes consulting or advisory. VR reports a relationship with the following: AbbVie Inc that includes travel reimbursement; Cancer Research UK that includes travel reimbursement; AstraZeneca India Private Limited that includes non-financial support; Pfizer India that includes consulting or advisory; Roche Products India Pvt. Ltd that includes consulting or advisory; European Society for Medical Oncology that includes non-financial support; Intas Pharmaceuticals Ltd that includes non-financial support and travel reimbursement., (Copyright © 2024 Radhakrishnan and Davies.)

Dietary practices of masters athletes (MAs) may promote healthy ageing; however, they are poorly understood. The aims of this systematic review were to synthesise the literature on the dietary intakes of MAs and undertake comparisons between younger (35-50 years) and older (>50 years) MAs and the general population. A search was conducted across seven databases to identify relevant publications for screening and data extraction. Averages for energy intake (EI), macronutrients, and micronutrients were compared with data from the 2011-2012 Australian Health Survey (general population). Twenty-six studies ( n = 2819) were included. Energy intake was higher for older (8908 kJ/d versus 7792 kJ/d) but not younger MAs (9073 kJ/d versus 8872 kJ/d) versus the general population. Younger versus older male MAs had higher energy and macronutrient intakes. Energy intake for older was comparable to younger female MAs (7819 kJ/d versus 7485 kJ/d), but older had higher protein, lower carbohydrate, and higher micronutrient intakes. Micronutrient intake was higher in MAs than the general population. Similar EIs for older MAs and younger general population may indicate potential for a higher-quality diet. Younger female MAs may restrict or misreport EI, requiring further investigation. There is a need for more comprehensive assessments of dietary intake in MAs to ascertain diet quality in relation to health.

Predictive models can improve the efficiency of wildlife management by guiding actions at the local, landscape and regional scales. In recent decades, a vast range of modelling techniques have been developed to predict species distributions and patterns of population spread. However, data limitations often constrain the precision and biological realism of models, which make them less useful for supporting decision-making. Complex models can also be challenging to evaluate, and the results are often difficult to interpret for wildlife management practitioners. There is therefore a need to develop techniques that are appropriately robust, but also accessible to a range of end users. We developed a hybrid species distribution model that utilises commonly available presence-only distribution data and minimal demographic information to predict the spread of roe deer ( Capreolus caprelous ) in Great Britain. We take a novel approach to representing the environment in the model by constraining the size of habitat patches to the home-range area of an individual. Population dynamics are then simplified to a set of generic rules describing patch occupancy. The model is constructed and evaluated using data from a populated region (England and Scotland) and applied to predict regional-scale patterns of spread in a novel region (Wales). It is used to forecast the relative timing of colonisation events and identify important areas for targeted surveillance and management. The study demonstrates the utility of presence-only data for predicting the spread of animal species and describes a method of reducing model complexity while retaining important environmental detail and biological realism. Our modelling approach provides a much-needed opportunity for users without specialist expertise in computer coding to leverage limited data and make robust, easily interpretable predictions of spread to inform proactive population management., Competing Interests: The authors declare that no competing interests exist., (© 2023 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Coral reefs are iconic ecosystems that support diverse, productive communities in both shallow and deep waters. However, our incomplete knowledge of cold-water coral (CWC) niche space limits our understanding of their distribution and precludes a complete accounting of the ecosystem services they provide. Here, we present the results of recent surveys of the CWC mound province on the Blake Plateau off the U.S. east coast, an area of intense human activity including fisheries and naval operations, and potentially energy and mineral extraction. At one site, CWC mounds are arranged in lines that total over 150 km in length, making this one of the largest reef complexes discovered in the deep ocean. This site experiences rapid and extreme shifts in temperature between 4.3 and 10.7 °C, and currents approaching 1 m s -1 . Carbon is transported to depth by mesopelagic micronekton and nutrient cycling on the reef results in some of the highest nitrate concentrations recorded in the region. Predictive models reveal expanded areas of highly suitable habitat that currently remain unexplored. Multidisciplinary exploration of this new site has expanded understanding of the cold-water coral niche, improved our accounting of the ecosystem services of the reef habitat, and emphasizes the importance of properly managing these systems., (© 2023. The Author(s).)

Rationale & Objective: PRESERVE seeks to provide new knowledge to inform shared decision-making regarding blood pressure (BP) management for pediatric chronic kidney disease (CKD). PRESERVE will compare the effectiveness of alternative strategies for monitoring and treating hypertension on preserving kidney function; expand the National Patient-Centered Clinical Research Network (PCORnet) common data model by adding pediatric- and kidney-specific variables and linking electronic health record data to other kidney disease databases; and assess the lived experiences of patients related to BP management., Study Design: Multicenter retrospective cohort study (clinical outcomes) and cross-sectional study (patient-reported outcomes [PROs])., Setting & Participants: PRESERVE will include approximately 20,000 children between January 2009-December 2022 with mild-moderate CKD from 15 health care institutions that participate in 6 PCORnet Clinical Research Networks (PEDSnet, STAR, GPC, PaTH, CAPRiCORN, and OneFlorida+). The inclusion criteria were ≥1 nephrologist visit and ≥2 estimated glomerular filtration rate (eGFR) values in the range of 30 to <90 mL/min/1.73 m 2 separated by ≥90 days without an intervening value ≥90 mL/min/1.73 m 2 and no prior dialysis or kidney transplant., Exposures: BP measurements (clinic-based and 24-hour ambulatory BP); urine protein; and antihypertensive treatment by therapeutic class., Outcomes: The primary outcome is a composite event of a 50% reduction in eGFR, eGFR of <15 mL/min/1.73 m 2 , long-term dialysis or kidney transplant. Secondary outcomes include change in eGFR, adverse events, and PROs., Analytical Approach: Longitudinal models for dichotomous (proportional hazards or accelerated failure time) and continuous (generalized linear mixed models) clinical outcomes; multivariable linear regression for PROs. We will evaluate heterogeneity of treatment effect by CKD etiology and degree of proteinuria and will examine variation in hypertension management and outcomes based on socio-demographics., Limitations: Causal inference limited by observational analyses., Conclusions: PRESERVE will leverage the PCORnet infrastructure to conduct large-scale observational studies that address BP management knowledge gaps for pediatric CKD, focusing on outcomes that are meaningful to patients., Plain-Language Summary: Hypertension is a major modifiable contributor to loss of kidney function in chronic kidney disease (CKD). The purpose of PRESERVE is to provide evidence to inform shared decision-making regarding blood pressure management for children with CKD. PRESERVE is a consortium of 16 health care institutions in PCORnet, the National Patient-Centered Clinical Research Network, and includes electronic health record data for >19,000 children with CKD. PRESERVE will (1) expand the PCORnet infrastructure for research in pediatric CKD by adding kidney-specific variables and linking electronic health record data to other kidney disease databases; (2) compare the effectiveness of alternative strategies for monitoring and treating hypertension on preserving kidney function; and (3) assess the lived experiences of patients and caregivers related to blood pressure management., (© 2023 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.)

The dinosaur-bird transition involved several anatomical, biomechanical, and physiological modifications of the theropod bauplan. Non-avian maniraptoran theropods, such as Troodon , are key to better understand changes in thermophysiology and reproduction occurring during this transition. Here, we applied dual clumped isotope (Δ 47 and Δ 48 ) thermometry, a technique that resolves mineralization temperature and other nonthermal information recorded in carbonates, to eggshells from Troodon , modern reptiles, and modern birds. Troodon eggshells show variable temperatures, namely 42 and 29 ± 2 °C, supporting the hypothesis of an endothermic thermophysiology with a heterothermic strategy for this extinct taxon. Dual clumped isotope data also reveal physiological differences in the reproductive systems between Troodon , reptiles, and birds. Troodon and modern reptiles mineralize their eggshells indistinguishable from dual clumped isotope equilibrium, while birds precipitate eggshells characterized by a positive disequilibrium offset in Δ 48 . Analyses of inorganic calcites suggest that the observed disequilibrium pattern in birds is linked to an amorphous calcium carbonate (ACC) precursor, a carbonate phase known to accelerate eggshell formation in birds. Lack of disequilibrium patterns in reptile and Troodon eggshells implies these vertebrates had not acquired the fast, ACC-based eggshell calcification process characteristic of birds. Observation that Troodon retained a slow reptile-like calcification suggests that it possessed two functional ovaries and was limited in the number of eggs it could produce; thus its large clutches would have been laid by several females. Dual clumped isotope analysis of eggshells of extinct vertebrates sheds light on physiological information otherwise inaccessible in the fossil record.

Membranous glomerulonephritis (MGN) is a common cause of nephrotic syndrome in adults, mediated by glomerular antibody deposition to an increasing number of newly recognised antigens. Previous case reports have suggested an association between patients with anti-contactin-1 (CNTN1)-mediated neuropathies and MGN. In an observational study we investigated the pathobiology and extent of this potential cause of MGN by examining the association of antibodies against CNTN1 with the clinical features of a cohort of 468 patients with suspected immune-mediated neuropathies, 295 with idiopathic MGN, and 256 controls. Neuronal and glomerular binding of patient IgG, serum CNTN1 antibody and protein levels, as well as immune-complex deposition were determined. We identified 15 patients with immune-mediated neuropathy and concurrent nephrotic syndrome (biopsy proven MGN in 12/12), and 4 patients with isolated MGN from an idiopathic MGN cohort, all seropositive for IgG4 CNTN1 antibodies. CNTN1-containing immune complexes were found in the renal glomeruli of patients with CNTN1 antibodies, but not in control kidneys. CNTN1 peptides were identified in glomeruli by mass spectroscopy. CNTN1 seropositive patients were largely resistant to first-line neuropathy treatments but achieved a good outcome with escalation therapies. Neurological and renal function improved in parallel with suppressed antibody titres. The reason for isolated MGN without clinical neuropathy is unclear. We show that CNTN1, found in peripheral nerves and kidney glomeruli, is a common target for autoantibody-mediated pathology and may account for between 1 and 2% of idiopathic MGN cases. Greater awareness of this cross-system syndrome should facilitate earlier diagnosis and more timely use of effective treatment., Competing Interests: SR runs a not-for-profit diagnostic testing service for nodal/paranodal antibodies. All other authors have declared that no competing interests exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Fehmi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Children with glomerular disease have unique risk factors for compromised bone health. Studies addressing skeletal complications in this population are lacking., Methods: This retrospective cohort study utilized data from PEDSnet, a national network of pediatric health systems with standardized electronic health record data for more than 6.5 million patients from 2009 to 2021. Incidence rates (per 10,000 person-years) of fracture, slipped capital femoral epiphysis (SCFE), and avascular necrosis/osteonecrosis (AVN) in 4598 children and young adults with glomerular disease were compared with those among 553,624 general pediatric patients using Poisson regression analysis. The glomerular disease cohort was identified using a published computable phenotype. Inclusion criteria for the general pediatric cohort were two or more primary care visits 1 year or more apart between 1 and 21 years of age, one visit or more every 18 months if followed >3 years, and no chronic progressive conditions defined by the Pediatric Medical Complexity Algorithm. Fracture, SCFE, and AVN were identified using SNOMED-CT diagnosis codes; fracture required an associated x-ray or splinting/casting procedure within 48 hours., Results: We found a higher risk of fracture for the glomerular disease cohort compared with the general pediatric cohort in girls only (incidence rate ratio [IRR], 1.6; 95% CI, 1.3 to 1.9). Hip/femur and vertebral fracture risk were increased in the glomerular disease cohort: adjusted IRR was 2.2 (95% CI, 1.3 to 3.7) and 5 (95% CI, 3.2 to 7.6), respectively. For SCFE, the adjusted IRR was 3.4 (95% CI, 1.9 to 5.9). For AVN, the adjusted IRR was 56.2 (95% CI, 40.7 to 77.5)., Conclusions: Children and young adults with glomerular disease have significantly higher burden of skeletal complications than the general pediatric population., (Copyright © 2022 by the American Society of Nephrology.)

Background and Objectives: Recent outbreaks of Zika virus (ZIKV) in South and Central America have highlighted significant neurologic side effects. Concurrence with the inflammatory neuropathy Guillain-Barré syndrome (GBS) is observed in 1:4,000 ZIKV cases. Whether the neurologic symptoms of ZIKV infection are immune mediated is unclear. We used rodent and human live cellular models to screen for anti-peripheral nerve reactive IgG and IgM autoantibodies in the sera of patients with ZIKV with and without GBS., Methods: In this study, 52 patients with ZIKV-GBS were compared with 134 ZIKV-infected patients without GBS and 91 non-ZIKV controls. Positive sera were taken forward for target identification by immunoprecipitation and mass spectrometry, and candidate antigens were validated by ELISA and cell-based assays. Autoantibody reactions against glycolipid antigens were also screened on an array., Results: Overall, IgG antibody reactivities to rat Schwann cells (SCs) (6.5%) and myelinated cocultures (9.6%) were significantly higher, albeit infrequent, in the ZIKV-GBS group compared with all controls. IgM antibody immunoreactivity to dorsal root ganglia neurones (32.3%) and SCs (19.4%) was more frequently observed in the ZIKV-GBS group compared with other controls, whereas IgM reactivity to cocultures was as common in ZIKV and non-ZIKV sera. Strong axonal-binding ZIKV-GBS serum IgG antibodies from 1 patient were confirmed to react with neurofascin 155 and 186. Serum from a ZIKV-infected patient without GBS displayed strong myelin-binding and putative antilipid antigen reaction characteristics. There was, however, no significant association of ZIKV-GBS with any known antiglycolipid antibodies., Discussion: Autoantibody responses in ZIKV-GBS target heterogeneous peripheral nerve antigens suggesting heterogeneity of the humoral immune response despite a common prodromal infection., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Introduction Exacerbations of chronic obstructive pulmonary disease (COPD) are a frequent reason for hospital admission and a major cause of morbidity and mortality. A useful biomarker or indicator of disease severity at the time of presentation could help guide treatment and identify those with poor prognosis who need early aggressive intervention. We hypothesized that patients who present to the hospital with COPD exacerbations who are found to have elevated procalcitonin (PCT) levels will have worse outcomes such as longer admissions, increased intensive care unit (ICU) utilization, and more frequent readmissions than those with normal levels, regardless of presence or absence of infiltrate on initial chest X-ray (CXR). Methods We conducted a retrospective chart review of patients admitted to our facility with a respiratory complaint and a diagnosis of COPD to examine the relation between PCT and disease severity. A total of 156 unique encounters were reviewed, with 87 included in the final data set. Data was collected on baseline medical conditions as well as clinical status at the time of presentation. Primary endpoints included the need for overnight ICU admission, hospital length of stay greater than seven days, and repeat visit within 30 days of discharge. Secondary endpoints included the need for intubation at the time of admission, in-hospital mortality or discharge to hospice, and ICU length of stay. Results Patients with elevated PCT levels (>0.25ng/mL) had a significantly increased likelihood of a need for ICU admission (odds ratio 3.18) and hospital length of stay greater than seven days (odds ratio 3.38). There was no statistically significant difference in the Emergency Department readmission rate or any of the secondary outcomes. Conclusions Our data suggests that PCT may be a useful early biomarker for patients with COPD presenting with an acute respiratory illness., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Davies et al.)

Objective: This study compared the importance of age at adiposity rebound versus childhood BMI to subsequent BMI levels in a longitudinal analysis., Methods: From the electronic health records of 4.35 million children, a total of 12,228 children were selected who were examined at least once each year between ages 2 and 7 years and reexamined after age 14 years. The minimum number of examinations per child was six. Each child's rebound age was estimated using locally weighted regression (lowess), a smoothing technique., Results: Children who had a rebound age < 3 years were, on average, 7 kg/m 2 heavier after age 14 years than were children with a rebound age ≥ 7 years. However, BMI after age 14 years was more strongly associated with BMI at the rebound than with rebound age (r = 0.57 vs. -0.44). Furthermore, a child's BMI at age 3 years provided more information on BMI after age 14 years than did rebound age. In addition, rebound age provided no information on subsequent BMI if a child's BMI at age 6 years was known., Conclusions: Although rebound age is related to BMI after age 14 years, a child's BMI at age 3 years provides more information and is easier to obtain., (© 2021 The Obesity Society (TOS). This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

A complex interplay of biotic and abiotic factors underpins the distribution of species and operates across different levels of biological organization and life history stages. Understanding ecosystem engineer reproductive traits is critical for comprehending and managing the biodiversity-rich habitats they create. Little is known about how the reproduction of the reef-forming worm, Sabellaria alveolata, varies across environmental gradients. By integrating broad-scale environmental data with in-situ physiological data in the form of biochemical traits, we identified and ranked the drivers of intraspecific reproductive trait variability (ITV). ITV was highest in locations with variable environmental conditions, subjected to fluctuating temperature and hydrodynamic conditions. Our trait selection pointed to poleward sites being the most physiologically stressful, with low numbers of irregularly shaped eggs suggesting potentially reduced reproductive success. Centre-range individuals allocated the most energy to reproduction, with the highest number of intermediate-sized eggs, whilst equatorward sites were the least physiologically stressful, thus confirming the warm-adapted nature of our model organism. Variation in total egg diameter and relative fecundity were influenced by a combination of environmental conditions, which changed depending on the trait and sampling period. An integrated approach involving biochemical and reproductive traits is essential for understanding macro-scale patterns in the face of anthropogenic-induced climate change across environmental and latitudinal gradients., (© 2021. The Author(s).)

Relapsed or refractory primary central nervous system lymphoma (rrPCNSL) confers a poor prognosis with no accepted standard of care. Very few prospective studies have been conducted in this patient group. This study was a multicenter phase 1/2 study that investigated thiotepa in combination with ifosfamide, etoposide, and rituximab (TIER) for the treatment of PCNSL relapsed or refractory to high-dose methotrexate-based chemotherapy. A 3 + 3 design investigated the recommended phase 2 dose of thiotepa for a single-stage phase 2 cohort by assessing the activity of 2 cycles of TIER against rrPCNSL. The primary outcome was overall response rate. The dose-finding study demonstrated that 50 mg/m2 of thiotepa could be safely delivered within the TIER regimen. No dose-limiting toxicities were encountered in phase 1, and TIER was well-tolerated by the 27 patients treated in phase 2. The most common grade 3 to 4 toxicities were neutropenia (56% of patients) and thrombocytopenia (39%). An overall response was confirmed in 14 patients (52%), which met the prespecified threshold for clinically relevant activity. The median progression-free survival was 3 months (95% confidence interval [CI], 2 to 6 months) and overall survival 5 months (95% CI, 3 to 9 months). Exploratory analyses suggest a greater benefit for thiotepa-naïve patients. Six patients successfully completed autologous stem cell transplantation (ASCT) consolidation, with 4 experiencing durable remissions after a median follow-up of 50 months. The TIER regimen can be delivered safely and is active against rrPCNSL. When it is followed by ASCT, it can provide durable remission and long-term survival. However, for the majority of patients, prognosis remains poor, and novel treatment strategies are urgently needed. This trial was registered at https://www.clinicaltrialsregister.eu/ctr-search/search as EudraCT 2014-000227-24 and ISRCTN 12857473., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

From microbes to humans, habitat structural complexity plays a direct role in the provision of physical living space, and increased complexity supports higher biodiversity and ecosystem functioning across biomes. Coastal development and the construction of artificial shorelines are altering natural landscapes as humans seek socio-economic benefits and protection from coastal storms, flooding and erosion. In this study, we evaluate how much structural complexity is missing on artificial coastal structures compared to natural rocky shorelines, across a range of spatial scales from 1 mm to 10 s of m, using three remote sensing platforms (handheld camera, terrestrial laser scanner and uncrewed aerial vehicles). Natural shorelines were typically more structurally complex than artificial ones and offered greater variation between locations. However, our results varied depending on the type of artificial structure and the scale at which complexity was measured. Seawalls were deficient at all scales (approx. 20-40% less complex than natural shores), whereas rock armour was deficient at the smallest and largest scales (approx. 20-50%). Our findings reinforce concerns that hardening shorelines with artificial structures simplifies coastlines at organism-relevant scales. Furthermore, we offer much-needed insight into how structures might be modified to more closely capture the complexity of natural rocky shores that support biodiversity.

A central question in the underdoped cuprates pertains to the nature of the pseudogap ground state. A conventional metallic ground state of the pseudogap region has been argued to host quantum oscillations upon destruction of the superconducting order parameter by modest magnetic fields. Here, we use low applied measurement currents and millikelvin temperatures on ultrapure single crystals of underdoped [Formula: see text] to unearth an unconventional quantum vortex matter ground state characterized by vanishing electrical resistivity, magnetic hysteresis, and nonohmic electrical transport characteristics beyond the highest laboratory-accessible static fields. A model of the pseudogap ground state is now required to explain quantum oscillations that are hosted by the bulk quantum vortex matter state without experiencing sizable additional damping in the presence of a large maximum superconducting gap; possibilities include a pair density wave., Competing Interests: The authors declare no competing interest.

Novel 3-D passive particle tracking experiments were performed in the northwest Atlantic to elucidate connectivity among areas closed to protect vulnerable marine ecosystems. We examined (1) the degree of vertical movement of particles released at different depths and locations; (2) the location of potential source populations for the deep-sea taxa protected by the closures; and (3) the degree of functional connectivity. A long-term oceanographic dataset (EN4) was queried to characterize the temperature and salinity regimes in each of the closed areas as a basis for interpreting recently published climate change projections. Using the Parcels Lagrangian particle tracking framework and the BNAM hydrodynamic model, we found enhanced connectivity over previously developed 2-D models and unexpected, current-driven, strong (to a maximum of about 1340 m) downward displacement at depth (450, 1000 and 2250 m), with weaker upward displacement except for the release depth of 2250 m which showed upward movement of 955 m with a drift duration of 3 months. The current velocities create down-stream interdependence among closed areas and allow redundancy to develop in some of the areas of the network, with some of the larger areas also showing retention. Source populations for sponges in the upstream closure are likely in adjacent waters of the Canadian continental shelf. Collectively this information can be used to inform management decisions related to the size and placement of these closed areas, and vertical velocity surfaces have potential for use in species distribution modeling of benthic species and habitats.

Background : Sugar is routinely used to comfort neonates undergoing painful procedures, and animal studies have shown that sucrose increases the time to withdrawal from painful stimuli. However, there are no published studies examining the effects of sweet substances on heat pain thresholds and percept in adult humans. Methods : Healthy adult volunteers (n=27, aged 18-48 years) were recruited to a controlled, double-blind, randomised, cross-over study to characterise the effect of tasting solutions of equivalent sweetness (10% sucrose and 0.016% sucralose) on warm detection and heat pain thresholds and the percept ratings of painfully hot stimuli. The effect of anticipation of a sweet taste on heat pain threshold was also assessed. Results : Tasting either sucrose or sucralose had no significant effect on the percept of an individually titrated hot stimulus (54.5±4.2 and 54.9±3.2 vs 53.2±3.5 for water, 0-100 visual analogue scale), on the warm detection or heat pain threshold (43.3±0.8, 43.2±0.8 vs 43.0±0.8°C). Anticipation of a sweet substance similarly did not affect heat pain thresholds. Conclusions : Sucrose and sucralose solutions had no analgesic effect when assessed using heat detection thresholds and percept ratings of painfully hot stimuli despite being perceived as sweeter and more pleasant than water. These findings are in contrast to results reported from previous animal studies in which thermal analgesia from sweet solutions is robust. Given the ubiquitous availability of sugar rich drinks in the modern environment, the lack of observable effect may be due to an insufficient hedonic value of the test solutions when compared to the experience of a laboratory rodent. Alternatively, sweet tastes may have a specific effect on pain tolerance rather than the threshold and acute percept measures assayed in this study., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Mooney ER et al.)

The inflammatory neuropathies are disabling conditions with diverse immunological mechanisms. In some, a pathogenic role for immunoglobulin G (IgG)-class autoantibodies is increasingly appreciated, and immunoadsorption (IA) may therefore be a useful therapeutic option. We reviewed the use of and response to IA or plasma exchange (PLEx) in a cohort of 41 patients with nodal/paranodal antibodies identified from a total of 573 individuals with suspected inflammatory neuropathies during the course of routine diagnostic testing (PNAb cohort). 20 patients had been treated with PLEx and 4 with IA. Following a global but subjective evaluation by their treating clinicians, none of these patients were judged to have had a good response to either of these treatment modalities. Sequential serology of one PNAb+ case suggests prolonged suppression of antibody levels with frequent apheresis cycles or adjuvant therapies, may be required for effective treatment. We further retrospectively evaluated the serological status of 40 patients with either Guillain-Barré syndrome (GBS) or chronic inflammatory demyelinating polyneuropathy (CIDP), and a control group of 20 patients with clinically-isolated syndrome/multiple sclerosis (CIS/MS), who had all been treated with IgG-depleting IA (IA cohort). 32 of these patients (8/20 with CIDP, 13/20 with GBS, 11/20 with MS) were judged responsive to apheresis despite none of the serum samples from this cohort testing positive for IgG antibodies against glycolipids or nodal/paranodal cell-adhesion molecules. Although negative on antigen specific assays, three patients' pre-treatment sera and eluates were reactive against different components of myelinating co-cultures. In summary, preliminary evidence suggests that GBS/CIDP patients without detectable IgG antibodies on routine diagnostic tests may nevertheless benefit from IA, and that an unbiased screening approach using myelinating co-cultures may assist in the detection of further autoantibodies which remain to be identified in such patients.

Cytotoxicity and consequent cell death pathways are a critical component of the immune response to infection, disease or injury. While numerous examples of inflammation causing neuronal sensitization and pain have been described, there is a growing appreciation of the role of cytotoxic immunity in response to painful nerve injury. In this review we highlight the functions of cytotoxic immune effector cells, focusing in particular on natural killer (NK) cells, and describe the consequent action of these cells in the injured nerve as well as other chronic pain conditions and peripheral neuropathies. We describe how targeted delivery of cytotoxic factors via the immune synapse operates alongside Wallerian degeneration to allow local axon degeneration in the absence of cell death and is well-placed to support the restoration of homeostasis within the nerve. We also summarize the evidence for the expression of endogenous ligands and receptors on injured nerve targets and infiltrating immune cells that facilitate direct neuro-immune interactions, as well as modulation of the surrounding immune milieu. A number of chronic pain and peripheral neuropathies appear comorbid with a loss of function of cellular cytotoxicity suggesting such mechanisms may actually help to resolve neuropathic pain. Thus while the immune response to peripheral nerve injury is a major driver of maladaptive pain, it is simultaneously capable of directing resolution of injury in part through the pathways of cellular cytotoxicity. Our growing knowledge in tuning immune function away from inflammation toward recovery from nerve injury therefore holds promise for interventions aimed at preventing the transition from acute to chronic pain., (Copyright © 2020 Davies, Rinaldi, Costigan and Oh.)

Ecological processes occur over multiple spatial, temporal and thematic scales in three-dimensional (3D) ecosystems. Characterizing and monitoring change in 3D structure at multiple scales is challenging within the practical constraints of conventional ecological tools. Remote sensing from satellites and crewed aircraft has revolutionized broad-scale spatial ecology, but fine-scale patterns and processes operating at sub-metre resolution have remained understudied over continuous extents. We introduce two high-resolution remote sensing tools for rapid and accurate 3D mapping in ecology-terrestrial laser scanning and structure-from-motion photogrammetry. These technologies are likely to become standard sampling tools for mapping and monitoring 3D ecosystem structure across currently under-sampled scales. We present practical guidance in the use of the tools and address barriers to widespread adoption, including testing the accuracy of structure-from-motion models for ecologists. We aim to highlight a new era in spatial ecology that uses high-resolution remote sensing to interrogate 3D digital ecosystems.

Neuropathic pain (NeuP) arises due to injury of the somatosensory nervous system and is both common and disabling, rendering an urgent need for non-addictive, effective new therapies. Given the high evolutionary conservation of pain, investigative approaches from Drosophila mutagenesis to human Mendelian genetics have aided our understanding of the maladaptive plasticity underlying NeuP. Successes include the identification of ion channel variants causing hyper-excitability and the importance of neuro-immune signaling. Recent developments encompass improved sensory phenotyping in animal models and patients, brain imaging, and electrophysiology-based pain biomarkers, the collection of large well-phenotyped population cohorts, neurons derived from patient stem cells, and high-precision CRISPR generated genetic editing. We will discuss how to harness these resources to understand the pathophysiological drivers of NeuP, define its relationship with comorbidities such as anxiety, depression, and sleep disorders, and explore how to apply these findings to the prediction, diagnosis, and treatment of NeuP in the clinic., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Marine encrusting communities play vital roles in benthic ecosystems and have major economic implications with regards to biofouling. However, their ability to persist under projected warming scenarios remains poorly understood and is difficult to study under realistic conditions. Here, using heated settlement panel technologies, we show that after 18 months Antarctic encrusting communities do not acclimate to either +1 °C or +2 °C above ambient temperatures. There is significant up-regulation of the cellular stress response in warmed animals, their upper lethal temperatures decline with increasing ambient temperature and population genetic analyses show little evidence of differential survival of genotypes with treatment. By contrast, biofilm bacterial communities show no significant differences in community structure with temperature. Thus, metazoan and bacterial responses differ dramatically, suggesting that ecosystem responses to future climate change are likely to be far more complex than previously anticipated.

Sensory axons degenerate following separation from their cell body, but partial injury to peripheral nerves may leave the integrity of damaged axons preserved. We show that an endogenous ligand for the natural killer (NK) cell receptor NKG2D, Retinoic Acid Early 1 (RAE1), is re-expressed in adult dorsal root ganglion neurons following peripheral nerve injury, triggering selective degeneration of injured axons. Infiltration of cytotoxic NK cells into the sciatic nerve by extravasation occurs within 3 days following crush injury. Using a combination of genetic cell ablation and cytokine-antibody complex stimulation, we show that NK cell function correlates with loss of sensation due to degeneration of injured afferents and reduced incidence of post-injury hypersensitivity. This neuro-immune mechanism of selective NK cell-mediated degeneration of damaged but intact sensory axons complements Wallerian degeneration and suggests the therapeutic potential of modulating NK cell function to resolve painful neuropathy through the clearance of partially damaged nerves., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The pre-conditioning of adult marine invertebrates to altered conditions, such as low pH, can significantly impact offspring outcomes, a process which is often referred to as transgenerational plasticity (TGP). This study describes for the first time, the gene expression profiles associated with TGP in the green sea urchin Psammechinus miliaris and evaluates the transcriptional contribution to larval resilience. RNA-Seq was used to determine how the expression profiles of larvae spawned into low pH from pre-acclimated adults differed to those of larvae produced from adults cultured under ambient pH. The main findings demonstrated that adult conditioning to low pH critically pre-loads the embryonic transcriptional pool with antioxidants to prepare the larvae for the "new" conditions. In addition, the classic cellular stress response, measured via the production of heat shock proteins (the heat shock response (HSR)), was separately evaluated. None of the early stage larvae either spawned in low pH (produced from both ambient and pre-acclimated adults) or subjected to a separate heat shock experiment were able to activate the full HSR as measured in adults, but the capacity to mount an HSR increased as development proceeded. This compromised ability clearly contributes to the vulnerability of early stage larvae to acute environmental challenge.

Background: Over 12,000 new cases of B-cell malignancies are diagnosed in the UK each year, with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) being the most common subtypes. Standard frontline therapy consists of immunochemotherapy with a CD20 monoclonal antibody (mAb), such as rituximab, delivered in combination with multi-agent chemotherapy. Despite being considered a treatable and potentially curable cancer, approximately 30% of DLBCL cases will relapse after frontline therapy. Advanced stage FL is incurable and typically has a relapsing and remitting course with a frequent need for re-treatment. Based on supportive preclinical data, we hypothesised that the addition of varlilumab (an anti-CD27 mAb) to rituximab (an anti-CD20 mAb) can improve the rate, depth and duration of the response of rituximab monotherapy in patients with relapsed or refractory B-cell malignancies., Methods/design: Combination treatment of varlilumab plus rituximab, in two different dosing regimens, is being tested in the RIVA trial. RIVA is a two-stage open-label randomised phase IIa design in up to 40 patients with low- or high-grade relapsed or refractory CD20 + B-cell lymphoma. The study is open to recruitment in the UK. Enrolled patients are randomised 1:1 to two different experimental varlilumab to rituximab combinations. The primary objective is to determine the safety and tolerability of the combination and the anti-tumour activity (response) in relapsed or refractory B-cell malignancies. Secondary objectives will include an evaluation of the duration of the response and overall survival. Tertiary translational objectives include assessment of B-cell depletion, changes in immune effector cell populations, expression of CD27 as a biomarker of response and pharmacokinetic properties. Analyses will not be powered for formal statistical comparisons between treatment arms., Discussion: RIVA will determine whether the combination of rituximab and varlilumab in relapsed or refractory B-cell malignancies is active and safe prior to future phase II/III trials., Trial Registration: EudraCT, 2017-000302-37. Registered on 16 January 2017. ISRCTN, ISRCTN15025004 . Registered on 16 August 2017.