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Understanding circuit-level manipulations that affect the brain’s capacity for plasticity will inform the design of targeted interventions that enhance recovery after stroke. Following stroke, increased contralesional activity (e.g. use of the unaffected limb) can negatively influence recovery, but it is unknown which specific neural connections exert this influence, and to what extent increased contralesional activity affects systems- and molecular-level biomarkers of recovery. Here, we combine optogenetic photostimulation with optical intrinsic signal imaging to examine how contralesional excitatory activity affects cortical remodeling after stroke in mice. Following photothrombosis of left primary somatosensory forepaw (S1FP) cortex, mice either recovered spontaneously or received chronic optogenetic excitation of right S1FP over the course of 4 weeks. Contralesional excitation suppressed perilesional S1FP remapping and was associated with abnormal patterns of stimulus-evoked activity in the unaffected limb. This maneuver also prevented the restoration of resting-state functional connectivity (RSFC) within the S1FP network, RSFC in several networks functionally distinct from somatomotor regions, and resulted in persistent limb-use asymmetry. In stimulated mice, perilesional tissue exhibited transcriptional changes in several genes relevant for recovery. Our results suggest that contralesional excitation impedes local and global circuit reconnection through suppression of cortical activity and several neuroplasticity-related genes after stroke, and highlight the importance of site selection for targeted therapeutic interventions after focal ischemia.

Live cell imaging is a standard technique in experimental biology that enables the observation of isolated cells and tissue slices in real time and the testing of cellular responses to changes in buffer composition. However, most live cell imaging devices require the use of dedicated microscopes and/or specialised stage adaptors, and come at a reasonably high cost. We employed 3D printing technology to create a low-cost imaging chamber with side ports to exchange fluids, to be used on upright microscopes. The chamber increased the functionality of a standard upright epifluorescent microscope to allow dynamic, real-time calcium imaging of cultured hypothalamic astrocytes from mice, and to test the effects of ATP stimulation upon calcium signalling. It was also used on slices obtained from the mouse brain using a brain matrix slicer. The advantages of this chamber include a very simple design that can be used with upright epifluorescence microscopes, does not require any special stage adaptor, and includes ports to permit fluid exchange during imaging. This chamber is ideal for educational settings with undergraduate laboratories that do not have access to dedicated inverted fluorescent microscopes for tissue culture experiments.

Abstract Shell ring archaeological sites are one of the most visible site types along the lower South Atlantic Coast of the United States. These cultural sites are large, circular to arcuate piles of mollusk shells with some reaching over three meters in elevation and over 100 m in diameter. They are comprised largely of mollusk shells (e.g., Eastern oyster, Crassostrea virginica), but also contain early pottery, nonhuman faunal remains, and other artifacts. Our work establishes that they represent the earliest widespread Native American villages occupied year-round in the Eastern Woodlands of North America. Significantly, our results from sea-level modelling and isotope geochemistry on mollusks establish that the inhabitants of these earliest villages (ca. 5000–3800 yrs. BP) lived within a fluctuating coastal environment, harvested certain resources year-round, and targeted diverse habitats across the estuaries. Both the growth and decline of these earliest villages are associated with a concomitant rise and lowering of sea level that impacted the productivity of the oyster reef fishery along the South Atlantic Coast. Despite these large-scale environmental changes, this research indicates that Native American fishing villages persisted along the coast for over 1000 years.

There are many surgical techniques for reconstruction of the divided or incompetent central slip. Most rely upon postoperative immobilisation to protect the repair. We present our experience using a distally based flexor digitorum superficialis slip to reconstruct the central slip and allow early mobilisation in five patients with intact preoperative intrinsic function. Post-treatment, a mean recovery of 65 degrees of active extension was achieved, albeit at the cost of a mean 22-degree loss of active flexion. We suggest this relatively easy technique provides a useful surgical option in the management of this difficult problem.

Abstract We present new chronologies that inform the timing and tempo of shell ring and shell mound construction on the South Atlantic Bight. Our project combines recently acquired dates with legacy radiocarbon dates from over 25 rings and mounds to provide a higher-resolution chronology regarding the occupation and formation of this larger landscape of the earliest fishing villages along the East Coast of the United States. We resolve the ordering and timing of occupation of these rings and mounds through Bayesian statistical modeling. These new models historicize and contextualize these shell rings in ways previously impossible. Specifically, our new chronologies of these villages indicate that the earliest villages were established prior to the invention of pottery. The early period of village establishment evidences isolated village rings, whereas later periods seem to have more villages, but these appear to have been relocated to other areas and/or islands over time. Shell mounds are fewer in number, are spread throughout the time period, and may represent special purpose sites compared to shell-rings. Once villages spread, they quickly adopted new technologies (i.e., pottery) and created new institutions and practiced village relocation, which allowed this way of life to persist for more than a thousand years.

Abstract The oral tyramine challenge evaluates the safety of novel monoamine oxidase (MAO) inhibitors when taken with tyramine‐containing food or drinks. In its current design, it comprises an extensive series of tyramine escalation steps until a blood pressure threshold is met. Due to the high variation in tyramine bioavailability, and thereby in blood pressure effect, this classical design has various limitations, including safety concerns. Based on data from a previously performed tyramine challenge study, the present study explored a reduced new design that escalates up to 400 mg, and evaluates the dose to a tyramine peak plasma concentration of ≥10 ng/mL, instead of a dose up to 800 mg, and to a blood pressure change of ≥30 mm Hg. Tested by trial simulation, the new design proves more efficient than the classical design in terms of better identifying tyramine sensitivity of test and reference treatments and reducing false‐positive and false‐negative rates in estimating tyramine sensitivity by more than 10‐fold. Since it escalates over a lower tyramine dose range, the new design reduces risk to subjects associated with tyramine‐induced blood pressure excursions, is less demanding for study participants, and is more efficient. By its focus on tyramine bioavailability as the primary concern for novel MAO inhibitors, the new tyramine challenge study provides better answers in a simplified and safer design compared with the classical design in trial simulation, warranting its use in future clinical studies.

Abstract The COVID-19 pandemic has highlighted the importance of understanding what contributes to individual variability in experiences of stress. Increases in stress related to the pandemic have been especially pronounced in parents, indicating a need for research examining what factors contribute to parents’ perceptions of stress. Here, we assessed the relationship between parents’ perceptions of stress, control, loneliness, and experiences of childhood trauma in two populations of caregivers. In Study 1, we examined the relationship between perceptions of stress, control, loneliness, and history of early stress, along with indices of socioeconomic risk and resting parasympathetic nervous systema activity, which has been linked to variability in perceptions of stress, in caregivers of young children. Perceived control, loneliness, childhood stress, and resting parasympathetic nervous system activity predicted caregivers’ stress. In Study 2, we replicated these initial findings in a second sample of caregivers. Additionally, we examined how these processes change over time. Caregivers demonstrated significant changes in perceptions of control, loneliness, and stress, and changes in control and childhood trauma history were associated with changes in perceptions of stress. Together these results indicate the importance of assessing how caregivers perceive their environment when examining what contributes to increased risk for stress. Additionally, they suggest that caregivers’ stress-related processes are malleable and provide insight into potential targets for interventions aimed at reducing parents’ stress.

Abstract Background Breast cancer patients experienced heightened anxiety during the pandemic. Also, modifications to clinical trial activities allowing for virtual platforms, local assessments, and greater flexibility were introduced to facilitate participation. We sought to evaluate the association between pandemic‐related anxiety and willingness to participate in trials and how pandemic‐era modifications to trial activities affect the decision to participate. Methods We conducted an online survey from August to September, 2021 of patients with breast cancer assessing pandemic‐related anxiety; clinical trials knowledge and attitudes; willingness to participate during and before the pandemic; and how each modification affects the decision to participate. Fisher's exact tests evaluated differences in proportions and two‐sample t‐tests evaluated differences in means. The association of pandemic‐related anxiety with a decline in willingness to participate during compared to prior to the pandemic was modeled using logistic regression. Results Among 385 respondents who completed the survey, 81% reported moderate–severe pandemic‐related anxiety. Mean willingness to participate in a trial was lower during the pandemic than prior [2.97 (SD 1.17) vs. 3.10 (SD 1.09), (p 50% of respondents as strategies that would increase their likelihood of deciding to participate. Conclusions While pandemic‐related anxiety was associated with diminished willingness to participate in trials, the leading reasons for reluctance to consider trial participation were unrelated to the pandemic but included worries about not getting the best treatment, side effects, and delaying care. Patients view trial modifications favorably, supporting continuation of these modifications, as endorsed by the National Cancer Institute and others.

IntroductionUnderstanding genetic contributors to sarcopenia (age-related loss of muscle strength and mass) is key to finding effective therapies. Variants of the bradykinin receptor 2 (BDKRB2) have been linked to athletic and muscle performance. The rs1799722-9 and rs5810761 T alleles have been shown to be overrepresented in endurance athletes, possibly due to increased transcriptional rates of the receptor. These variants have been rarely studied in older people or people with sarcopenia.MethodsWe performed a post hoc sub-study of the Leucine and ACE (LACE) inhibitor trial, which enrolled 145 participants aged ≥70 years with low grip strength and low gait speed. Participants' blood samples were genotyped for rs179972 using TaqMan and rs5810761 by amplification through Hotstar Taq. Genotypes were compared with outcomes of physical performance and body composition measures.ResultsData from 136 individuals were included in the analysis. For rs1799722 the genotype frequency (TT: 17, CC: 48, CT: 71) remained in Hardy-Weinberg Equilibrium (HWE p = 0.248). There was no difference between the genotypes for six-Minute Walk Distance (6MWD) or Short Physical Performance Battery (SPPB). Men with the TT genotype had a significantly greater 6MWD than other genotypes (TT 400m vs CT 310m vs CC 314m, p = 0.027), and greater leg muscle mass (TT 17.59kg vs CT 15.04kg vs CC 15.65kg, p = 0.007). For rs5810761, the genotype frequency (-9-9: 31, +9+9: 43, -9+9: 60) remained in HWE (p = 0.269). The +9+9 genotype was associated with a significant change in SPPB score at 12 months (-9-9 0 vs -9+9 0 vs +9+9-1, pConclusionIn men, the rs1799722 TT genotype was associated with longer 6MWD and greater leg muscle mass, while the rs5810761 -9-9 genotype was associated with lower arm fat mass.

[This corrects the article DOI: 10.1371/journal.pone.0258979.].

Category: Ankle Arthritis Introduction/Purpose: Step count and activity monitoring are objective tools to measure improvement in functional ability in patients undergoing Total ankle replacement (TAR); this area is underexplored in literature. Activity monitoring sensors provide additional information on physical activity and energy expenditure in addition to step counts. These carried out in a real-life environment helps us to understand the impact of intervention in improving physical activity. The aim of this study was to study physical activity patterns in the community in patients who underwent TAR surgery. Methods: 10 patients who underwent a TAR between 2017 and 2019 were recruited. Exclusion criteria included previous reconstructive surgery, h/o infection, PVD, neurological disease and other joint replacements. Written consent was obtained. Patients were provided with ActivPAL TM activity monitor to wear over a 7-day period along with a self-reported diary to record activity patterns. This was carried out pre-operatively and 2 years. Data from sensors were downloaded and activity patterns were analysed with SPSS IBM 28 statistical package. Results: 10 patients (7 males, 3 females) were recruited. Mean age of patients were 65.16 years (52.4 to 78.1yrs).there was a trend for improvement in Sitting / Lying (hours) from 121.36 to 132.56 (p=0.367) and Standing (hours) 25.53 to 33.23 (p=0.411), although this did not achieve statistical significance. Step count (in hours) improved from 8.8 hrs to 10.8 hrs (p=0.05); Step count increased from 38544 to 47074 (p=041) from pre-op to 2 years. Energy expenditure (metabolic equivalents) improved from 192.3 to 219.5 (p=0.033). Conclusion: At 2 years post-operatively, TAR patients showed considerable improvement in step count and energy expenditure compared to pre-operative levels. The results of this novel study helps us to understand the functional improvements in terms of physical activity and energy expenditure gained from TAR surgery

Category: Basic Sciences/Biologics; Ankle Introduction/ Purpose: The aim of this study was to investigate plantar pressures changes with gait in patients presenting with ankle arthritis pre and post TAR. Methods: Patients who were listed for a primary TAR with a 3 component mobile bearing prosthesis were included. Exclusion criteria included refusal of consent, previous surgery to foot, h/o infection, peripheral vascular disease, neurological disease and other LL joint replacements. Gait analysis was carried out using TekscanTM plantar preasure (PP) analysis system and PP) were recorded pre- operatively and 1 year post-operatively. Gait asymmetries were recorded in Percentage for ST parameters. 11 patients were recruited to this study. Mean age were 70.5 years. Results: Improvement centre of pressure pattern restoration and Force percentage curve (FP) patterns from pre-op to 1 Year. Improvement in foot progression angle was seen in 6 out of 11 patients (54.5%). Plantar pressure analysis showed deviation from reference ranges for 1) differences in centre of pressure (COP) 2) changes to hindfoot vs. forefoot loading ratio 3) change in loading pattern at heel in KPa (p < 0.05) 4) differences in gait parameters (reduction in cadence, walking velocity, increase in active propulsion time; p< 0.05) 5) changes to foot progression angles. These findings correlate with MOX-FQ scores (p>0.565) for pain, difficulty with walking/standing and difficulty with social activities. Gait asymmetries improved at 1 year for step velocity (76.1 to 93.4%) and mid stance time (76.04 to 93.5% in 8/11patients)(p < 0.05). Conclusion: This study shown that TAR surgery helps in restoring centre of pressure, force percentage curve patterns and reduces asymmetries in step velocity and mid stance times during gait at 1 year post surgery. Plantar pressure analysis is a useful tool to study improvement in function in this patient group.

Abstract Introduction To protect against infection, individuals have evolved context‐dependent pathogen‐avoidant strategies, including selective social behaviors aimed at avoiding foreign individuals who may possess greater risk of infection. Parasympathetic nervous system (PNS) activity is associated with social engagement and regulation of the classical immune system but has not been widely investigated in relation to changes in intergroup perception and the behavioral immune system. Method The current research investigated the relationship between parasympathetic activity and perceived foreignness of in and outgroup speakers during exposure to a pathogen‐relevant odor (butyric acid). High‐frequency heart rate variability was measured at rest and while participants rated foreignness of speakers with and without the odor present. Results Findings show that exposure to the odor was associated with higher foreignness perceptions of outgroup speakers and lower foreignness perceptions of ingroup speakers. This effect was especially evident among individuals with higher resting parasympathetic activity. Conclusion These results suggest that the PNS may play a role in changes in social perceptions during a behavioral immune response.

Background: Cardiac complications of serious SARS-CoV-2 infections, especially Multisystem Inflammatory Syndrome of Children (MIS-C) are well described, however current studies have not considered pediatric patients hospitalized with no cardiac concerns. We established a protocol for cardiac evaluation of all admitted COVID-19 patients three weeks post-discharge, irrespective of cardiac concerns. We assessed cardiovascular outcomes and hypothesized that patients with absent cardiac concerns are at lower risk for cardiac abnormalities. Methods: This was a retrospective study of 160 patients admitted for COVID-19 (excluding MIS-C) between March 2020 and September 2021 with subsequent echocardiogram(s) performed at our center. Patients were divided into 4 subgroups: Group 1 included patients with absent cardiac concerns, admitted to acute care (1a) and intensive care unit (ICU) (1 b). Group 2 included patients with cardiac concerns, admitted to acute care (2a) and ICU (2 b). Groups were compared based on clinical endpoints and echocardiographic measurements, including tissue Doppler imaging (TDI) assessment of diastolic function (z-score of septal Mitral E/TDI E′ and lateral E/TDI E′). Chi-squared, Fisher's exact, and Kruskal-Wallis tests were used. Results: Traditional cardiac abnormalities varied significantly between the groups; with Group 2 b having the most (n = 8, 21%), but still found in Group 1a (n = 2, 3%) and Group 1 b (n = 1, 5%). No patients in Group 1 demonstrated abnormal systolic function, compared to Group 2a (n = 1, 3%) and Group 2 b (n = 3, 9%, p = 0.07). When including TDI assessment of diastolic function, the total incidence of abnormalities found on echocardiogram was increased in all groups. Conclusion: Cardiac abnormalities were found in pediatric patients admitted with COVID-19, even those without apparent cardiovascular concerns. The risk was greatest in ICU-admitted patients with cardiac concerns. The clinical significance of diastolic function assessment in these patients remains unknown. Further studies are needed to assess long-term cardiovascular sequelae of children with COVID-19, irrespective of cardiac concerns.

IntroductionChronic pain is often associated with comorbid anxiety and cognitive dysfunction, negatively affecting therapeutic outcomes. The influence of genetic background on such interactions is poorly understood. The stress-hyperresponsive Wistar–Kyoto (WKY) rat strain, which models aspects of anxiety and depression, displays enhanced sensitivity to noxious stimuli and impaired cognitive function, compared with Sprague–Dawley (SD) counterparts. However, pain- and anxiety-related behaviors and cognitive impairment following induction of a persistent inflammatory state have not been investigated simultaneously in the WKY rats. Here we compared the effects of complete Freund's adjuvant (CFA)-induced persistent inflammation on pain-, negative affect- and cognition-related behaviors in WKY vs. SD rats.MethodsMale WKY and SD rats received intra-plantar injection of CFA or needle insertion (control) and, over the subsequent 4 weeks, underwent behavioral tests to assess mechanical and heat hypersensitivity, the aversive component of pain, and anxiety- and cognition-related behaviors.ResultsThe CFA-injected WKY rats exhibited greater mechanical but similar heat hypersensitivity compared to SD counterparts. Neither strain displayed CFA-induced pain avoidance or anxiety-related behavior. No CFA-induced impairment was observed in social interaction or spatial memory in WKY or SD rats in the three-chamber sociability and T-maze tests, respectively, although strain differences were apparent. Reduced novel object exploration time was observed in CFA-injected SD, but not WKY, rats. However, CFA injection did not affect object recognition memory in either strain.ConclusionsThese data indicate exacerbated baseline and CFA-induced mechanical hypersensitivity, and impairments in novel object exploration, and social and spatial memory in WKY vs. SD rats.

‘Commercial fisheries have decimated keystone species, including oysters in the past 200 years. Here, the authors examine how Indigenous oyster harvest in North America and Australia was managed across 10,000 years, advocating for effective future stewardship of oyster reefs by centering Indigenous peoples.’

Abstract Many patients discontinue endocrine therapy for breast cancer due to intolerance. Identification of patients at risk for discontinuation is challenging. The minimal important difference (MID) is the smallest change in a score on a patient-reported outcome (PRO) that is clinically significant. We evaluated the association between treatment-emergent symptoms detected by worsening PRO scores in units equal to the MID with discontinuation. We enrolled females with stage 0-III breast cancer initiating endocrine therapy in a prospective cohort. Participants completed PROs at baseline, 3, 6, 12, 24, 36, 48, and 60 months. Measures included PROMIS pain interference, fatigue, depression, anxiety, physical function, and sleep disturbance; Endocrine Subscale of the FACT-ES; and MOS-Sexual Problems (MOS-SP). We evaluated associations between continuous PRO scores in units corresponding to MIDs (PROMIS: 4-points; FACT-ES: 5-points; MOS-SP: 8-points) with time to endocrine therapy discontinuation using Cox proportional hazards models. Among 321 participants, 140 (43.6%) initiated tamoxifen and 181 (56.4%) initiated aromatase inhibitor (AI). The cumulative probability of discontinuation was 23% (95% CI 18–27%) at 48 months. For every 5- and 4-point worsening in endocrine symptoms and sleep disturbance respectively, participants were 13 and 14% more likely to discontinue endocrine therapy respectively (endocrine symptoms HR 1.13, 95% CI 1.02–1.25, p = 0.02; sleep disturbance HR 1.14, 95% CI 1.01–1.29, p = 0.03). AI treatment was associated with greater likelihood of discontinuation than tamoxifen. Treatment-emergent endocrine symptoms and sleep disturbance are associated with endocrine therapy discontinuation. Monitoring for worsening scores meeting or exceeding the MID on PROs may identify patients at risk for discontinuation.

BackgroundAgeing is associated with changes in body composition including an overall reduction in muscle mass and a proportionate increase in fat mass. Sarcopenia is characterised by losses in both muscle mass and strength. Body composition and muscle strength are at least in part genetically determined, consequently polymorphisms in pathways important in muscle biology (e.g., the activin/myostatin signalling pathway) are hypothesised to contribute to the development of sarcopenia.MethodsWe compared regional body composition measured by DXA with genotypes for two polymorphisms (rs10783486, minor allele frequency (MAF) = 0.26 and rs2854464, MAF = 0.26) in the activin 1B receptor (ACVR1B) determined by PCR in a cross-sectional analysis of DNA from 110 older individuals with sarcopenia from the LACE trial.ResultsNeither muscle mass nor strength showed any significant associations with either genotype in this cohort. Initial analysis of rs10783486 showed that males with the AA/AG genotype were taller than GG males (174±7cm vs 170±5cm, p = 0.023) and had higher arm fat mass, (median higher by 15%, p = 0.008), and leg fat mass (median higher by 14%, p = 0.042). After correcting for height, arm fat mass remained significantly higher (median higher by 4% padj = 0.024). No associations (adjusted or unadjusted) were seen in females. Similar analysis of the rs2854464 allele showed a similar pattern with the presence of the minor allele (GG/AG) being associated with greater height (GG/AG = 174±7 cm vs AA = 170 ±5cm, p = 0.017) and greater arm fat mass (median higher by 16%, p = 0.023). Again, the difference in arm fat remained after correction for height. No similar associations were seen in females analysed alone.ConclusionThese data suggest that polymorphic variation in the ACVR1B locus could be associated with body composition in older males. The activin/myostatin pathway might offer a novel potential target to prevent fat accumulation in older individuals.

BackgroundAngiotensin II (AII), has been suggested to promote muscle loss. Reducing AII synthesis, by inhibiting angiotensin converting enzyme (ACE) activity has been proposed as a method to inhibit muscle loss. The LACE clinical trial was designed to determine whether ACE inhibition would reduce further muscle loss in individuals with sarcopenia but suffered from low recruitment and returned a negative result. Polymorphic variation in the ACE promoter (I/D alleles) has been associated with differences in ACE activity and muscle physiology in a range of clinical conditions. This aim of this analysis was to determine whether I/D polymorphic variation is associated with muscle mass, strength, in sarcopenia or contributed to the lack of response to treatment in the LACE study.MethodsSarcopenic individuals were recruited into a 2x2 factorial multicentre double-blind study of the effects of perindopril and/or leucine versus placebo on physical performance and muscle mass. DNA extracted from blood samples (n = 130 72 women and 58 men) was genotyped by PCR for the ACE I/D polymorphism. Genotypes were then compared with body composition measured by DXA, hand grip and quadriceps strength before and after 12 months' treatment with leucine and/or perindopril in a cross-sectional analysis of the influence of genotype on these variables.ResultsAllele frequencies for the normal UK population were extracted from 13 previous studies (I = 0.473, D = 0.527). In the LACE cohort the D allele was over-represented (I = 0.412, D = 0.588, p = 0.046). This over-representation was present in men (I = 0.353, D = 0.647, p = 0.010) but not women (I = 0.458, D = 0.532, p = 0.708). In men but not women, individuals with the I allele had greater leg strength (II/ID = 18.00 kg (14.50, 21.60) vs DD = 13.20 kg (10.50, 15.90), p = 0.028). Over the 12 months individuals with the DD genotype increased in quadriceps strength but those with the II or ID genotype did not. Perindopril did not increase muscle strength or mass in any polymorphism group relative to placebo.ConclusionOur results suggest that although ACE genotype was not associated with response to ACE inhibitor therapy in the LACE trial population, sarcopenic men with the ACE DD genotype may be weaker than those with the ACE I/D or II genotype.

Abstract Background Given the high risk of COVID‐19 mortality, patients with cancer may be vulnerable to fear of COVID‐19, adverse psychological outcomes, and health care delays. Methods This longitudinal study surveyed the pandemic's impact on patients with cancer (N= 1529) receiving Patient Advocate Foundation services during early and later pandemic. Generalized estimating equation with repeated measures was conducted to assess the effect of COVID‐19 on psychological distress. Logistic regression with repeated measures was used to assess the effect of COVID‐19 on any delays in accessing health care (e.g., specialty care doctors, laboratory, or diagnostic testing, etc.). Results Among 1199 respondents, 94% considered themselves high risk for COVID‐19. Respondents with more fear of COVID‐19 had a higher mean psychological distress score (10.21; 95% confidence intervals [CI] 9.38–11.03) compared to respondents with less fear (7.55; 95% CI 6.75–8.36). Additionally, 47% reported delaying care. Respondents with more fear of COVID‐19 had higher percentages of delayed care than those with less (56; 95% CI 39%–72% vs. 44%; 95% CI 28%–61%). These relationships persisted throughout the pandemic. For respondents with a COVID‐19 diagnosis in their household (n = 116), distress scores were similar despite higher delays in care (58% vs. 27%) than those without COVID‐19. Conclusions Fear of COVID‐19 is linked to psychological distress and delays in care among patients with cancer. Furthermore, those who are personally impacted see exacerbated cancer care delays. Timely psychosocial support and health care coordination are critical to meet increased care needs of patients with cancer during the COVID‐19 pandemic.

Background: Premenopausal women with early hormone-receptor positive (HR+) breast cancer receive 5–10 years of adjuvant endocrine therapy (ET) during which pregnancy is contraindicated and fertility may wane. The POSITIVE study investigates the impact of temporary ET interruption to allow pregnancy. Methods: POSITIVE enrolled women with stage I-III HR + early breast cancer, ≤42 years, who had received 18–30 months of adjuvant ET and wished to interrupt ET for pregnancy. Treatment interruption for up to 2 years was permitted to allow pregnancy, delivery and breastfeeding, followed by ET resumption to complete the planned duration. Findings: From 12/2014 to 12/2019, 518 women were enrolled at 116 institutions/20 countries/4 continents. At enrolment, the median age was 37 years and 74.9 % were nulliparous. Fertility preservation was used by 51.5 % of women. 93.2 % of patients had stage I/II disease, 66.0 % were node-negative, 54.7 % had breast conserving surgery, 61.9 % had received neo/adjuvant chemotherapy. Tamoxifen alone was the most prescribed ET (41.8 %), followed by tamoxifen + ovarian function suppression (OFS) (35.4 %). A greater proportion of North American women were

Diabetes and its complications, particularly diabetic foot ulcers (DFUs), pose significant challenges to healthcare systems worldwide. DFUs result in severe consequences such as amputation, increased mortality rates, reduced mobility, and substantial healthcare costs. The majority of DFUs are preventable and treatable through early detection. Sensor-based remote patient monitoring (RPM) has been proposed as a possible solution to overcome limitations, and enhance the effectiveness, of existing foot care best practices. However, there are limited frameworks available on how to approach and act on data collected through sensor-based RPM in DFU prevention. This perspective article offers insights from deploying sensor-based RPM through digital DFU prevention regimens. We summarize the data domains and technical architecture that characterize existing commercially available solutions. We then highlight key elements for effective RPM integration based on these new data domains, including appropriate patient selection and the need for detailed clinical assessments to contextualize sensor data. Guidance on establishing escalation pathways for remotely monitored at-risk patients and the importance of predictive system management is provided. DFU prevention RPM should be integrated into a comprehensive disease management strategy to mitigate foot health concerns, reduce activity-associated risks, and thereby seek to be synergistic with other components of diabetes disease management. This integrated approach has the potential to enhance disease management in diabetes, positively impacting foot health and the healthspan of patients living with diabetes.

Abstract Background Sarcopenia is rarely diagnosed and is not recorded electronically in routine clinical care, posing challenges to trial recruitment. We describe the performance of four components of a strategy to efficiently recruit participants with sarcopenia to a trial of perindopril and/or leucine for sarcopenia: primary care vs. hospital recruitment, a comparison of central vs. local telephone pre‐screening, performance of a questionnaire on physical function conducted as part of the pre‐screening telephone call, and performance of bioimpedance measurement to identify low muscle mass. Methods Hospital‐based recruitment took place through inpatient and outpatient geriatric medicine services. Local research nurses reviewed medical notes and approached potentially eligible patients. Primary care recruitment reviewed primary care lists from collaborating practices, sending mailshots to patients aged 70 and over who were not taking angiotensin‐converting enzyme inhibitors. Telephone pre‐screening was conducted either by research nurses at each site or centrally by Tayside Clinical Trials Unit. The 10‐point SARC‐F questionnaire was used for pre‐screening. De‐identified recruitment information was held on a central electronic tracking system and analysed using SPSS. Bioimpedance was measured using the Akern BIA 101 system, with the Sergi equation used to estimate lean mass. Results Fourteen UK sites recruited to the trial. The 1202 sets of notes in hospital‐based care were reviewed at these sites; 7 participants (0.6% of total notes screened) were randomized. From primary care, 13 808 invitations were sent; 138 (1.0% of total invited) were randomized. 633/2987 primary care respondents were pre‐screened centrally; the mean number of calls per respondent was 2.3. For 10 sites where central and local pre‐screening could be compared, the conversion rate from pre‐screening to randomization was 18/588 (3.1%) for centralized calls, compared with 73/1814 (4.0%) for local pre‐screening calls (P = 0.29). A weak relationship was seen between higher (worse) SARC‐F score at screening and lower likelihood of progression to randomization (r = −0.08, P = 0.03). Muscle mass estimates generated using the Sergi equation were systematically biased, and a recalibrated equation for bioimpedance‐estimated muscle mass was derived. Conclusions Primary care recruitment led to higher response rates and overall numbers randomized than hospital‐based recruitment. Centralized pre‐screening saved local research nurses' time but did not improve conversion to randomization. SARC‐F did not help to target screening activity in this sarcopenia trial, and a recalibration of the equation for estimating muscle mass from bioimpedance measures may improve accuracy of the screening process.

ObjectiveOrganizational responses that support healthcare workers (HCWs) and mitigate health risks are necessary to offset the impact of the COVID-19 pandemic. We aimed to understand how HCWs and key personnel working in healthcare settings in Melbourne, Australia perceived their employing organizations' responses to the COVID-19 pandemic.MethodIn this qualitative study, conducted May-July 2021 as part of the longitudinal Coronavirus in Victorian Healthcare and Aged Care Workers (COVIC-HA) study, we purposively sampled and interviewed HCWs and key personnel from healthcare organizations across hospital, ambulance, aged care and primary care (general practice) settings. We also examined HCWs' free-text responses to a question about organizational resources and/or supports from the COVIC-HA Study's baseline survey. We thematically analyzed data using an iterative process.ResultsWe analyzed data from interviews with 28 HCWs and 21 key personnel and free-text responses from 365 HCWs, yielding three major themes: navigating a changing and uncertain environment, maintaining service delivery during a pandemic, and meeting the safety and psychological needs of staff . HCWs valued organizational efforts to engage openly and honesty with staff, and proactive responses such as strategies to enhance workplace safety (e.g., personal protective equipment spotters). Suggestions for improvement identified in the themes included streamlined information processes, greater involvement of HCWs in decision-making, increased investment in staff wellbeing initiatives and sustainable approaches to strengthen the healthcare workforce.ConclusionsThis study provides in-depth insights into the challenges and successes of organizational responses across four healthcare settings in the uncertain environment of a pandemic. Future efforts to mitigate the impact of acute stressors on HCWs should include a strong focus on bidirectional communication, effective and realistic strategies to strengthen and sustain the healthcare workforce, and greater investment in flexible and meaningful psychological support and wellbeing initiatives for HCWs.

Students in first-year university courses often focus on mimicking application of taught procedures and fail to gain adequate conceptual understanding. One potential approach to support meaningful learning is Productive Failure (PF). In PF, the conventional instruction process is reversed so that learners attempt to solve challenging problems ahead of receiving explicit instruction. While students often fail to produce satisfactory solutions (hence "Failure"), these attempts help learners encode key features and learn better from subsequent instruction (hence "Productive"). Effectiveness of PF was shown mainly in the context of statistical and intuitive concepts, and lessons that are designed and taught by learning scientists. We describe a quasi-experiment that evaluates the impact of PF in a large-enrollment introductory university-level biology course when designed and implemented by the course instructors. One course-section (295 students) learned two topics using PF; another section (279 students) learned the same topics using an active learning approach, which is the standard in this course. Performance was assessed on the subsequent midterm exam, after all students had ample opportunities for practice and feedback, and after some time has elapsed. PF students scored nearly five percentage-points higher on the relevant topics in the subsequent midterm exam. The effect was especially strong for low-performing students. Improvement on the final exam was only visible for low-performing students. We describe the intervention and its potential to transform large introductory university courses.

Abstract Background Chronic and/or extreme stress in early life, often referred to as early adversity, childhood trauma, or early life stress, has been associated with a wide range of adverse effects on development. However, while early life stress has been linked to negative effects on a number of neural systems, the specific mechanisms through which early life stress influences development and individual differences in children’s outcomes are still not well understood. Main text The current paper reviews the existing literature on the neurobiological effects of early life stress and their ties to children’s psychological and behavioral development. Conclusions Early life stress has persistent and pervasive effects on prefrontal–hypothalamic–amygdala and dopaminergic circuits that are at least partially mediated by alterations in hypothalamic–pituitary–adrenal axis function. However, to date, this research has primarily utilized methods of assessment that focus solely on children’s event exposures. Incorporating assessment of factors that influence children’s interpretation of stressors, along with stressful events, has the potential to provide further insight into the mechanisms contributing to individual differences in neurodevelopmental effects of early life stress. This can aid in further elucidating specific mechanisms through which these neurobiological changes influence development and contribute to risk for psychopathology and health disorders.

Abstract Background Hereditary Hemorrhagic Telangiectasia (HHT) is a rare inherited disorder characterized by development of mucocutaneous telangiectases and visceral organ arteriovenous malformations, which can lead to recurrent, spontaneous bleeding and development of iron deficiency anemia. The primary objective of this study was to ascertain the relationship between epistaxis severity scores (ESS), laboratory values, genotype, and phenotype in HHT. Our secondary objective was to assess efficacy of systemic antifibrinolytic therapy in reducing ESS in HHT. Methodology We conducted a retrospective review of patients seen at the UNC HHT Center from January 1, 2009 to February 28, 2015. ESS, demographics, and results of genetic testing were abstracted from the medical record. Response to antifibrinolytic therapy was evaluated by comparing pre-post ESS. Results One hundred and forty nine patients were eligible with 116 having genetic testing and 33 without. Age, hemoglobin and ferritin levels were predictive of ESS. Of the 116 patients that underwent genetic testing: 63 had an ACVRL1 mutation, 40 had an ENG mutation, 2 had a SMAD4 mutation, and 11 patients had no pathologic HHT genetic variation detected. Compared to patients without a detectable HHT-associated genetic variation, patients with a HHT-associated genetic variation had higher ESS scores (p 4 were started on antifibrinolytic therapy (tranexamic acid or aminocaproic acid) and had a post-treatment ESS recorded. All patients had a decrease in ESS of > 0.71 (minimal meaningful difference), but patients taking antifibrinolytics displayed larger decreases. No patients on antifibrinolytics experienced a VTE with median follow up of 13 months. Conclusions We demonstrate that the ESS correlates with age, hemoglobin and ferritin. Additionally, we demonstrate that HHT patients with genetic mutations have higher ESS scores. Our data demonstrate that antifibrinolytics are effective in decreasing epistaxis severity and safe with long-term use in HHT patients.

Objective Diet and exercise (D+E) for knee osteoarthritis (OA) is effective and cost‐effective. However, cost‐effectiveness does not imply affordability; the impact of knee OA–specific D+E programs on insurer budgets is unknown. Methods We estimated changes in undiscounted medical expenditures (2016 US dollars) with and without a D+E program. We accounted for both additional program outlays and potential savings from reduced use of other knee OA treatments and from reduced incidence of comorbidities. We adopted the perspective of a representative commercial insurance plan covering 200 000 individuals aged 25 to 64 years and a representative Medicare Advantage plan covering 200 000 Medicare‐eligible individuals aged 65 years and older. We used the Osteoarthritis Policy Model, a validated microsimulation model of knee OA, to model D+E efficacy (measured by pain and weight reduction), adherence, and price based on the Intensive Diet and Exercise for Arthritis (IDEA) trial. In sensitivity analyses, we varied time horizon, D+E efficacy, and D+E price. Results Over 3 years, the D+E program increased spending by $752 200 ($0.10 per member per month [PMPM]) in the commercial plan and by $6.0 million ($0.84 PMPM) in the Medicare plan. Over 3 years, the D+E program reduced opioid use by 6% and 5% and reduced total knee replacements by 5% and 4% in the commercial and Medicare plans, respectively. Expenses were higher in the Medicare plan because it had more patients with knee OA than the commercial plan. Conclusion Although there is no established threshold to define affordability, a D+E program for knee OA would likely produce expenditures comparable with outlays for other health‐promotion interventions.

The public’s need for timely and trusted COVID-19 information remains high. Governments and global health agencies such as the WHO have sought to disseminate accurate and timely information to counteract misinformation and disinformation that has arisen as part of an ‘infodemic’—the overabundance of information on COVID-19—some accurate and some not. In early 2020, WHO began a collaboration with Google to run online public service announcements on COVID-19, in the form of search ads displayed above results of Google Search queries. Web-based text ads can drive online searchers of COVID-19 information to authoritative COVID-19 content but determining what message is most effective is a challenge. WHO wanted to understand which message framing, that is, the way in which ad information is worded for the public, leads searchers to click through to WHO content. WHO tested 71 text ads in English across four COVID-19 topics using a mix of message frames: descriptive, collective, gain, loss, appeals to values and emphasising reasons. Between 11 September 2020 and 23 November 2020, there were 13 million views of the experimental WHO text ads leading to 1.4 million click-throughs to the WHO website. Within the set of 71 ads, there was a large spread between the most effective and least effective messages; for messages on COVID-19, the best performing framings were more than twice as effective as the worst performing framings (18.7% vs 8.5% engagement rate). Health practitioners can apply the messaging tactics WHO found to be successful to rapidly optimise messages for their own public health campaigns and better reach the public with authoritative information. Similar collaboration between big technology companies and governments and global health agencies has the potential to advance public health.

While the majority of breast cancers are diagnosed at a curable stage, approximately 20% of women will experience recurrence at a distant site during their lifetime. These metastatic recurrences are incurable with current therapeutic approaches. Over the past decade, the biologic mechanisms underlying these recurrences have been elucidated, establishing the existence of minimal residual disease in the form of circulating micrometastases and dormant disease, primarily in the bone marrow. Numerous technologies are now available to detect minimal residual disease (MRD) after breast cancer treatment, but it is yet unknown how to best target and eradicate these cells, and whether clearance of detectable disease prior to the formation of overt metastases can prevent ultimate progression and death. Clinical trials to test this hypothesis are challenging due to the rare nature of MRD in the blood and bone marrow, resulting in the need to screen a large number of survivors to identify those for study. Use of prognostic molecular tools may be able to direct screening to those patients most likely to harbor MRD, but the relationship between these predictors and MRD detection is as yet undefined. Further challenges include the lack of a definitive assay for MRD with established clinical utility, difficulty in selecting potential interventions due to limitations in understanding the biology of MRD, and the emotional impact of detecting MRD in patients who have completed definitive treatment and have no evidence of overt metastatic disease. This review provides a roadmap for tackling these challenges in the design and implementation of interventional clinical trials aimed at eliminating MRD and ultimately preventing metastatic disease to improve survival from this disease, with a specific focus on late recurrences in ER+ breast cancer.

The 2020 Year of the Nurse and Midwife has presented many challenges following the World Health Organisation declaring a world pandemic due to COVID-19 on 11th March 2020. One of these challenges relates to the preparation of undergraduate nurses and midwives for a largely clinically based profession within a tertiary setting. Comprehensive educational preparation of midwives for registration and practice is at the core of quality midwifery care leading to optimisation of outcomes for women and their babies. To ensure graduate midwives are clinically competent, extensive professional placement is complimented by immersive simulation sessions focussing on; midwifery practice, skill, and clinical decision-making development in laboratory sessions. Due to social distancing restrictions imposed by the Australian Government all face-to-face sessions within a Queensland university were moved online between late March and July 2020. This presented opportunities to redesign teaching practices and implement innovations to continue to provide a high quality, award winning Bachelor of Midwifery Program. This paper will present a case study of an innovative strategy utilised within a Blackboard environment to facilitate skills development of two core critical midwifery skills, management of shoulder dystocia and estimation of postpartum blood loss.

Circular shell rings along the South Atlantic Coast of North America are the remnants of some of the earliest villages that emerged during the Late Archaic (5000–3000 BP). Many of these villages, however, were abandoned during the Terminal Late Archaic (ca 3800–3000 BP). We combine Bayesian chronological modeling with mollusk shell geochemistry and oyster paleobiology to understand the nature and timing of environmental change associated with the emergence and abandonment of circular shell ring villages on Sapelo Island, Georgia. Our Bayesian models indicate that Native Americans occupied the three Sapelo shell rings at varying times with some generational overlap. By the end of the complex’s occupation, only Ring III was occupied before abandonment ca. 3845 BP. Ring III also consists of statistically smaller oysters harvested from less saline estuaries compared to earlier occupations. Integrating shell biochemical and paleobiological data with recent tree ring analyses shows a clear pattern of environmental fluctuations throughout the period in which the rings were occupied. We argue that as the environment became unstable around 4300 BP, aggregation at villages provided a way to effectively manage fisheries that are highly sensitive to environmental change. However, with the eventual collapse of oyster fisheries and subsequent rebound in environmental conditions ca. post-3800 BP, people dispersed from shell rings, and shifted to non-marine subsistence economies and other types of settlements. This study provides the most comprehensive evidence for correlations between large-scale environmental change and societal transformations on the Georgia coast during the Late Archaic period.

Arctic amplification (AA), defined as the enhanced warming of the Arctic compared to the global average, is a robust feature of historical observations and simulations of future climate. Despite many studies investigating AA mechanisms, their relative importance remains contested. In this study, we examine the different timescales of these mechanisms to improve our understanding of AA’s fundamental causes. We use the Community Earth System Model v1, Large Ensemble configuration (CESM-LE), to generate large ensembles of 2 years simulations subjected to an instantaneous quadrupling of CO _2 . We show that AA emerges almost immediately (within days) following CO _2 increase and before any significant loss of Arctic sea ice has occurred. Through a detailed energy budget analysis of the atmospheric column, we determine the time-varying contributions of AA mechanisms over the simulation period. Additionally, we examine the dependence of these mechanisms on the season of CO _2 quadrupling. We find that the surface heat uptake resulting from the different latent heat flux anomalies between the Arctic and global average, driven by the CO _2 forcing, is the most important AA contributor on short (1 month) timescales. Our results confirm that AA is an inherently fast atmospheric response to radiative forcing and reveal a new AA mechanism.

Individual animals allowed the opportunity to learn generally outperform those prevented from learning, yet, within a species the capacity for learning varies markedly. The evolutionary processes that maintain this variation in learning ability are not yet well understood. Several studies demonstrate links between fitness traits and visual learning, but the selection pressures operating on cognitive traits are likely influenced by multiple sensory modalities. In addition to vision, most animals will use a combination of hearing, olfaction (smell), gustation (taste), and touch to gain information about their environment. Some animals demonstrate individual preference for, or enhanced learning performance using certain senses in relation to particular aspects of their behaviour (e.g., foraging), whereas conspecific individuals may show different preferences. By assessing fitness traits in relation to different sensory modalities we will strengthen our understanding of factors driving observed variation in learning ability. We assessed the relationship between the olfactory learning ability of bumble bees (Bombus terrestris) and their foraging performance in their natural environment. We found that bees which failed to learn this odour-reward association had shorter foraging careers; foraging for fewer days and thus provisioning their colonies with fewer resources. This was not due to a reduced propensity to forage, but may have been due to a reduced ability to return to their colony. When comparing among only individuals that did learn, we found that the rate at which floral resources were collected was similar, regardless of how they performed in the olfactory learning task. Our results demonstrate that an ability to learn olfactory cues can have a positive impact of the foraging performance of B. terrestris in a natural environment, but echo findings of earlier studies on visual learning, which suggest that enhanced learning is not necessarily beneficial for bee foragers provisioning their colony.

Cyanide is thought to be crucial for the origin of life. Here, the authors showed that iron cyanocarbonyl complexes are present in meteorites and propose that these compounds were a source of free cyanide on early Earth and served as precursors to the active sites of ancient hydrogenases.

Abstract The ability to store information is believed to have been crucial for the origin and evolution of life; however, little is known about the genetic polymers relevant to abiogenesis. Nitrogen heterocycles (N-heterocycles) are plausible components of such polymers as they may have been readily available on early Earth and are the means by which the extant genetic macromolecules RNA and DNA store information. Here, we report the reactivity of numerous N-heterocycles in highly complex mixtures, which were generated using a Miller-Urey spark discharge apparatus with either a reducing or neutral atmosphere, to investigate how N-heterocycles are modified under plausible prebiotic conditions. High throughput mass spectrometry was used to identify N-heterocycle adducts. Additionally, tandem mass spectrometry and nuclear magnetic resonance spectroscopy were used to elucidate reaction pathways for select reactions. Remarkably, we found that the majority of N-heterocycles, including the canonical nucleobases, gain short carbonyl side chains in our complex mixtures via a Strecker-like synthesis or Michael addition. These types of N-heterocycle adducts are subunits of the proposed RNA precursor, peptide nucleic acids (PNAs). The ease with which these carbonylated heterocycles form under both reducing and neutral atmospheres is suggestive that PNAs could be prebiotically feasible on early Earth.

Healthy pediatric immune responses depend on adequate vitamin A and D levels. Relationships between solar ultraviolet B (UVB) radiation and vitamin D are well understood, while relationships between sunlight, vitamin A, and its serum escort, retinol binding protein (RBP), are not. A pediatric clinical study enrolled 2–8-year-old children at various times between September 2016 and March 2017, inclusive, in Memphis, Tennessee. A serum sample from each child was then assayed to examine the influence of season on vitamin levels. We found that RBP and RBP/retinol molar ratios decreased in winter months and RBP/retinol ratios correlated positively with the average daily sunlight hours per month. A food frequency questionnaire given to parents/guardians indicated a shift in dietary intake from plant-based foods to animal-based foods by children between winter and spring months. This translated to higher retinol and zinc (integral to RBP–transthyretin–retinol complexes) in the spring, perhaps explaining the seasonal influence on RBP/retinol. RBP and retinol were associated positively with IgG/IgM and IgA/IgM ratios. RBP and retinol, but not 25(OH)D, also correlated positively with influenza virus-specific antibodies. Retinol correlated negatively, while 25(OH)D correlated positively, with certain serum cytokine/chemokine levels. Significant differences in 25(OH)D, immunoglobulin ratios, and cytokines/chemokines were observed between black and white children. In sum, seasonal changes in dietary foods rich in retinol and zinc may have influenced RBP levels, which in turn influenced innate and adaptive immune responses. Results encourage routine monitoring and reporting of season, RBP, and vitamin levels in future clinical studies, as seasons may affect sunlight exposures, diet, vitamin levels, and immune protection against infectious disease.

BackgroundAromatase inhibitors (AI) reduce recurrence and death in patients with early-stage hormone receptor-positive (HR +) breast cancer. Treatment-related toxicities, including AI-induced musculoskeletal symptoms (AIMSS), are common and may lead to early AI discontinuation. The objective of this study was to replicate previously reported associations for candidate germline genetic polymorphisms with AIMSS.MethodsWomen with stage 0-III HR + breast cancer initiating adjuvant AI were enrolled in a prospective clinic-based observational cohort. AIMSS were assessed by patient-reported outcomes (PRO) including the PROMIS pain interference and physical function measures plus the FACT-ES joint pain question at baseline and after 3 and 6 months. For the primary analysis, AIMSS were defined as ≥ 4-point increase in the pain interference T-score from baseline. Secondary AIMSS endpoints were defined as ≥ 4-point decrease in the physical function T-score from baseline and as ≥ 1-point increase on the FACT-ES joint pain question from baseline. The primary hypothesis was that TCL1A rs11849538 would be associated with AIMSS. Twelve other germline variants in CYP19A1, VDR, PIRC66, OPG, ESR1, CYP27B1, CYP17A1, and RANKL were also analyzed assuming a dominant genetic effect and prespecified direction of effect on AIMSS using univariate logistic regression with an unadjusted α = 0.05. Significant univariate associations in the expected direction were adjusted for age, race, body mass index (BMI), prior taxane, and the type of AI using multivariable logistic regression.ResultsA total of 143 participants with PRO and genetic data were included in this analysis, most of whom were treated with anastrozole (78%) or letrozole (20%). On primary analysis, participants carrying TCL1A rs11849538 were not more likely to develop AIMSS (odds ratio = 1.29, 95% confidence interval: 0.55–3.07, p = 0.56). In the statistically uncorrected secondary analysis, OPG rs2073618 was associated with AIMSS defined by worsening on the FACT-ES joint pain question (OR = 3.33, p = 0.004), and this association maintained significance after covariate adjustment (OR = 3.98, p = 0.003).ConclusionCarriers of OPG rs2073618 may be at increased risk of AIMSS. If confirmed in other cohorts, OPG genotyping can be used to identify individuals with HR + early breast cancer in whom alternate endocrine therapy or interventions to enhance symptom detection and implement strategies to reduce musculoskeletal symptoms may be needed.

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The United Nations deemed internet access to be of critical importance for human rights in 2016. In 2020, schools around the world closed during the COVID-19 pandemic. As schools were closed, inequities in internet access gained widespread public attention as many educational opportunities shifted online. Amidst this shift, this paper analyzes an Ontario provincial announcement to provide 21,000 iPads and free data for young people (ages 4-18), during the pandemic. The closure of schools in Ontario, Canada, meant that young people and families who faced technological challenges, such as a lack of devices, stable and affordable internet connections, or sufficient data allowances, could experience barriers to their right to an education. This paper revisits a community informatics (CI) model of internet access, the Access Rainbow, to analyze attempts to operationalize the right to an education through technology in Ontario. In parallel to rights, however, the field of CI faces the ongoing presence of profit-oriented corporations within universal access efforts. This paper argues that socio-technical infrastructural elements of access to the internet became visible through the breakdown of the pandemic. Furthermore, it considers the multi-stakeholder efforts required to implement useful and effective access, where school boards responded in varied ways locally. The paper contributes the concept of refraction to offer continued theorization of a distributive paradigm and a rights-informed approach in community informatics against the backdrop of the pandemic, which could also act as an opening for privatization and disaster capitalism.

Background: Rates of participation in centre (hospital)-cardiac rehabilitation by patients with heart failure are suboptimal. Heart failure has two main phenotypes differing in underlying pathophysiology: heart failure with reduced ejection fraction is characterised by depressed left ventricular systolic function (‘reduced ejection fraction’), whereas heart failure with preserved ejection fraction is diagnosed after excluding other causes of dyspnoea with normal ejection fraction. This programme aimed to develop and evaluate a facilitated home-based cardiac rehabilitation intervention that could increase the uptake of cardiac rehabilitation while delivering the clinical benefits of centre-based cardiac rehabilitation. Objectives: To develop an evidence-informed, home-based, self-care cardiac rehabilitation programme for patients with heart failure and their caregivers [the REACH-HF (Rehabilitation Enablement in Chronic Heart Failure) intervention]. To conduct a pilot randomised controlled trial to assess the feasibility of a full trial of the clinical effectiveness and cost-effectiveness of the REACH-HF intervention in addition to usual care in patients with heart failure with preserved ejection fraction. To assess the short- and long-term clinical effectiveness and cost-effectiveness of the REACH-HF intervention in addition to usual care in patients with heart failure with reduced ejection fraction and their caregivers. Design: Intervention mapping to develop the REACH-HF intervention; uncontrolled feasibility study; pilot randomised controlled trial in those with heart failure with preserved ejection fraction; randomised controlled trial with a trial-based cost-effectiveness analysis in those with heart failure with reduced ejection fraction; qualitative studies including process evaluation; systematic review of cardiac rehabilitation in heart failure; and modelling to assess long-term cost-effectiveness (in those with heart failure with reduced ejection fraction). Setting: Four centres in England and Wales (Birmingham, Cornwall, Gwent and York); one centre in Scotland (Dundee) for a pilot randomised controlled trial. Participants: Adults aged ≥ 18 years with heart failure with reduced ejection fraction (left ventricular ejection fraction 85% retention at follow-up. Limitations: Key limitations included (1) lack of blinding – given the nature of the intervention and the control we could not mask participants to treatments, so our results may reflect participant expectation bias; (2) that we were not able to capture consistent participant-level data on level of intervention adherence; (3) that there may be an impact on the generalisability of findings due to the demographics of the trial patients, as most were male (78%) and we recruited only seven people from ethnic minorities. Conclusions: Evaluation of the comprehensive, facilitated, home-based REACH-HF intervention for participants with heart failure with reduced ejection fraction and caregivers indicated clinical effectiveness in terms of health-related quality of life and patient self-care but no other secondary outcomes. Although the economic analysis conducted alongside the full randomised controlled trial did not produce significant differences on the EuroQol-5 Dimensions or in quality-adjusted life-years, economic modelling suggested greater cost-effectiveness of the intervention than usual care. Our REACH-HF intervention offers a new evidence-based cardiac rehabilitation option that could increase uptake of cardiac rehabilitation in patients with heart failure not attracted to or able to access hospital-based programmes. Future work: Systematic collection of real-world data would track future changes in uptake of and adherence to alternative cardiac rehabilitation interventions in heart failure with reduced ejection fraction and increase understanding of how changes in service delivery might affect clinical and health economic outcomes. The findings of our pilot randomised controlled trial in patients with heart failure with preserved ejection fraction support progression to a full multicentre randomised controlled trial. Trial registration: Current Controlled Trials ISRCTN86234930 and ISRCTN78539530. Funding details: This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 9, No. 1. See the NIHR Journals Library website for further project information.

Objective: Type II diabetes mellitus (T2DM) is prevalent in knee osteoarthritis (OA) patients undergoing total knee arthroplasty (TKA) and increases risk for prosthetic joint infection (PJI). We examined the cost-effectiveness of antibiotic prophylaxis (AP) before dental procedures to reduce PJI in TKA recipients with T2DM. Design: We used the Osteoarthritis Policy Model, a validated computer simulation of knee OA, to compare two strategies among TKA recipients with T2DM (mean age 68 years, mean BMI 35.4 kg/m2): 1) AP before dental procedures and 2) no AP. Outcomes included quality-adjusted life expectancy (QALE) and lifetime medical costs. We used published efficacy of AP. We report incremental cost-effectiveness ratios (ICERs) and considered strategies with ICERs below well-accepted willingness-to-pay (WTP) thresholds cost-effective. We conducted sensitivity analyses to examine the robustness of findings to uncertainty in model input parameters. We used a lifetime horizon and healthcare sector perspective. Results: We found that AP added 1.0 quality-adjusted life-year (QALY) and $66,000 for every 1000 TKA recipients with T2DM, resulting in an ICER of $66,000/QALY. In sensitivity analyses, reduction of the probability of PJI, T2DM-associated risk of infection, or attribution of infections to dental procedures by 50% resulted in ICERs exceeding $100,000/QALY. Probabilistic sensitivity analyses showed that AP was cost-effective in 32% and 58% of scenarios at WTP of $50,000/QALY and $100,000/QALY, respectively. Conclusions: AP prior to dental procedures is cost-effective for TKA recipients with T2DM. However, the cost-effectiveness of AP depends on the risk of PJI and efficacy of AP in this population.

Arctic amplification (AA)—the greater warming of the Arctic near-surface temperature relative to its global mean value—is a prominent feature of the climate response to increasing greenhouse gases. Recent work has revealed the importance of ozone-depleting substances (ODS) in contributing to Arctic warming and sea-ice loss. Here, using ensembles of climate model integrations, we expand on that work and directly contrast Arctic warming from ODS to that from carbon dioxide (CO _2 ), over the 1955–2005 period when ODS loading peaked. We find that the Arctic warming and sea-ice loss from ODS are slightly more than half (52%–59%) those from CO _2 . We further show that the strength of AA for ODS is 1.44 times larger than that for CO _2 , and that this mainly stems from more positive Planck, albedo, lapse-rate, and cloud feedbacks. Our results suggest that AA would be considerably stronger than presently observed had the Montreal Protocol not been signed.

Abstract Background Sarcopenia (the age-related loss of muscle mass and function) is a major contributor to loss of mobility, falls, loss of independence, morbidity and mortality in older people. Although resistance training is effective in preventing and reversing sarcopenia, many older people are sedentary and either cannot or do not want to exercise. This trial examines the efficacy of supplementation with the amino acid leucine and/or angiotensin converting enzyme inhibition to potentially improve muscle mass and function in people with sarcopenia. Promising preliminary data exist from small studies for both interventions, but neither has yet been tested in adequately powered randomised trials in patients with sarcopenia. Methods Leucine and ACE inhibitors in sarcopenia (LACE) is a multicentre, masked, placebo-controlled, 2 × 2 factorial randomised trial evaluating the efficacy of leucine and perindopril (angiotensin converting enzyme inhibitor (ACEi)) in patients with sarcopenia. The trial will recruit 440 patients from primary and secondary care services across the UK. Male and female patients aged 70 years and over with sarcopenia as defined by the European Working Group on Sarcopenia (based on low total skeletal muscle mass on bioimpedance analysis and either low gait speed or low handgrip strength) will be eligible for participation. Participants will be excluded if they have a contraindication to, or are already taking, an ACEi, angiotensin receptor blocker or leucine. The primary clinical outcome for the trial is the between-group difference in the Short Physical Performance Battery score at all points between baseline and 12 months. Secondary outcomes include appendicular muscle mass measured using dual-energy X-ray absorptiometry, muscle strength, activities of daily living, quality of life, activity using pedometer step counts and falls. Participants, clinical teams, outcomes assessors and trial analysts are masked to treatment allocation. A panel of biomarkers including microRNAs, neurohormones, genetic polymorphisms and markers of inflammation relevant to muscle pathophysiology will be measured to explore predictors of response and further elucidate mechanisms underlying sarcopenia. Participants will receive a total of 12 months of either perindopril or placebo and either leucine or placebo. Discussion The results will provide the first robust test of the overall clinical and cost-effectiveness of these novel therapies for older patients with sarcopenia. Trial registration ISRCTN, ISRCTN90094835 . Registered on 18 February 2015.

Abstract Background We designed and implemented the Brigham and Women’s Wellness Initiative (B-Well), a single-arm study to examine the feasibility of a workplace program that used individual and team-based financial incentives to increase physical activity among sedentary hospital employees. Methods We enrolled sedentary, non-clinician employees of a tertiary medical center who self-reported low physical activity. Eligible participants formed or joined teams of three members and wore Fitbit Flex activity monitors for two pre-intervention weeks followed by 24 weeks during which they could earn monetary rewards. Participants were rewarded for increasing their moderate-to-vigorous physical activity (MVPA) by 10% from the previous week or for meeting the Centers for Disease Control and Prevention (CDC) physical activity guidelines (150 min of MVPA per week). Our primary outcome was the proportion of participants meeting weekly MVPA goals and CDC physical activity guidelines. Secondary outcomes included Fitbit-wear adherence and factors associated with meeting CDC guidelines more consistently. Results B-Well included 292 hospital employees. Participants had a mean age of 38 years (SD 11), 83% were female, 38% were obese, and 62% were non-Hispanic White. Sixty-three percent of participants wore the Fitbit ≥4 days per week for ≥20 weeks. Two-thirds were satisfied with the B-Well program, with 79% indicating that they would participate again. Eighty-six percent met either their personal weekly goal or CDC physical activity guidelines for at least 6 out of 24 weeks, and 52% met their goals or CDC physical activity guidelines for at least 12 weeks. African Americans, non-obese subjects, and those with lower impulsivity scores reached CDC guidelines more consistently. Conclusions Our data suggest that a financial incentives-based workplace wellness program can increase MVPA among sedentary employees. These results should be reproduced in a randomized controlled trial. Trial registration Clinicaltrials.gov, NCT02850094 . Registered July 27, 2016 [retrospectively registered].

Abstract Despite widespread interest in the potential adaptive value of individual differences in cognition, few studies have attempted to address the question of how variation in learning and memory impacts their performance in natural environments. Using a novel split-colony experimental design we evaluated visual learning performance of foraging naïve bumble bees (Bombus terrestris) in an ecologically relevant associative learning task under controlled laboratory conditions, before monitoring the lifetime foraging performance of the same individual bees in the field. We found appreciable variation among the 85 workers tested in both their learning and foraging performance, which was not predicted by colony membership. However, rather than finding that foragers benefited from enhanced learning performance, we found that fast and slow learners collected food at comparable rates and completed a similar number of foraging bouts per day in the field. Furthermore, bees with better learning abilities foraged for fewer days; suggesting a cost of enhanced learning performance in the wild. As a result, slower learning individuals collected more resources for their colony over the course of their foraging career. These results demonstrate that enhanced cognitive traits are not necessarily beneficial to the foraging performance of individuals or colonies in all environments.

Alzheimer's disease (AD), including its mild cognitive impairment (MCI) phase that may or may not progress into the AD, is the most ordinary form of dementia. It is extremely important to correctly identify patients during the MCI stage because this is the phase where AD may or may not develop. Thus, it is crucial to predict outcomes during this phase. Thus far, many researchers have worked on only using a single modality of a biomarker for the diagnosis of AD or MCI. Although recent studies show that a combination of one or more different biomarkers may provide complementary information for the diagnosis, it also increases the classification accuracy distinguishing between different groups. In this paper, we propose a novel machine learning-based framework to discriminate subjects with AD or MCI utilizing a combination of four different biomarkers: fluorodeoxyglucose positron emission tomography (FDG-PET), structural magnetic resonance imaging (sMRI), cerebrospinal fluid (CSF) protein levels, and Apolipoprotein-E (APOE) genotype. The Alzheimer's Disease Neuroimaging Initiative (ADNI) baseline dataset was used in this study. In total, there were 158 subjects for whom all four modalities of biomarker were available. Of the 158 subjects, 38 subjects were in the AD group, 82 subjects were in MCI groups (including 46 in MCIc [MCI converted; conversion to AD within 24 months of time period], and 36 in MCIs [MCI stable; no conversion to AD within 24 months of time period]), and the remaining 38 subjects were in the healthy control (HC) group. For each image, we extracted 246 regions of interest (as features) using the Brainnetome template image and NiftyReg toolbox, and later we combined these features with three CSF and two APOE genotype features obtained from the ADNI website for each subject using early fusion technique. Here, a different kernel-based multiclass support vector machine (SVM) classifier with a grid-search method was applied. Before passing the obtained features to the classifier, we have used truncated singular value decomposition (Truncated SVD) dimensionality reduction technique to reduce high dimensional features into a lower-dimensional feature. As a result, our combined method achieved an area under the receiver operating characteristic (AU-ROC) curve of 98.33, 93.59, 96.83, 94.64, 96.43, and 95.24% for AD vs. HC, MCIs vs. MCIc, AD vs. MCIs, AD vs. MCIc, HC vs. MCIc, and HC vs. MCIs subjects which are high relative to single modality results and other state-of-the-art approaches. Moreover, combined multimodal methods have improved the classification performance over the unimodal classification.

Mild cognitive impairment (MCI) is a transitional state between the cognitive changes in normal aging and Alzheimer’s disease (AD), which induces abnormalities in specific brain regions. Previous studies showed that paired helical filaments Tau (PHF-Tau) protein is a potential pathogenic protein which may cause abnormal brain function and structure in MCI and AD patients. However, the understanding of the PHF-Tau protein network in MCI patients is limited. In this study, 225 subjects with PHF-Tau Positron Emission Tomography (PET) images were divided into four groups based on whether they carried Apolipoprotein E ε4 (APOE 4) or abnormal cerebrospinal fluid Total-Tau (CSF T-Tau). They are two important pathogenic factors that might cause cognitive function impairment. The four groups were: individuals harboring CSF T-Tau pathology but no APOE 4 (APOE 4−T+); APOE 4 carriers with normal CSF T-Tau (APOE 4+T−); APOE 4 carriers with abnormal CSF T-Tau (APOE 4+T+); and APOE 4 noncarriers with abnormal CSF T-Tau (APOE 4−T−). We explored the topological organization of PHF-Tau networks in these four groups and calculated five kinds of network properties: clustering coefficient, shortest path length, Q value of modularity, nodal centrality and degree. Our findings showed that compared with APOE 4−T− group, the other three groups showed different alterations in the clustering coefficient, shortest path length, Q value of modularity, nodal centrality and degree. Simultaneously, voxel-level analysis was conducted and the results showed that compared with APOE 4−T− group, the other three groups were found increased PHF-Tau distribution in some brain regions. For APOE 4+T+ group, positive correlation was found between the value of PHF-Tau distribution in altered regions and Functional Assessment Questionnaire (FAQ) score. Our results indicated that the effects of APOE 4 and abnormal CSF T-Tau may induce abnormalities of PHF-Tau protein and APOE 4 has a greater impact on PHF-Tau than abnormal CSF T-Tau. Our results may be particularly helpful in uncovering the pathophysiology underlying the cognitive dysfunction in MCI patients.

BackgroundNon-invasive brain stimulation (NIBS) has been widely used to treat mild cognitive impairment (MCI). However, there exists no consensus on the best stimulation sites.ObjectiveTo explore potential stimulation locations for NIBS treatment in patients with MCI, combining meta- and resting state functional connectivity (rsFC) analyses.MethodsThe meta-analysis was conducted to identify brain regions associated with MCI. Regions of interest (ROIs) were extracted based on this meta-analysis. The rsFC analysis was applied to 45 MCI patients to determine brain surface regions that are functionally connected with the above ROIs.ResultsWe found that the dorsolateral prefrontal cortex (DLPFC) and inferior frontal gyrus (IFG) were the overlapping brain regions between our results and those of previous studies. In addition, we recommend that the temporoparietal junction (including the angular gyrus), which was found in both the meta- and rsFC analysis, should be considered in NIBS treatment of MCI. Furthermore, the bilateral orbital prefrontal gyrus, inferior temporal gyrus, medial superior frontal gyrus, and right inferior occipital gyrus may be potential brain stimulation sites for NIBS treatment of MCI.ConclusionOur results provide several potential sites for NIBS, such as the DLFPC and IFG, and may shed light on the locations of NIBS sites in the treatment of patients with MCI.