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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.

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.

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.

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.

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.

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.

AimsThe primary aim of our study was to assess the influence of age on hip-specific outcome following total hip arthroplasty (THA). Secondary aims were to assess health-related quality of life (HRQoL) and level of activity according to age.MethodsA prospective cohort study was conducted. All patients were fitted with an Exeter stem with a 32 mm head on highly cross-linked polyethylene (X3RimFit) cemented acetabulum. Patients were recruited into three age groups: < 65 years, 65 to 74 years, and ≥ 75 years, and assessed preoperatively and at three, 12, 24, and 60 months postoperatively. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Harris Hip Score (HHS), and Hip disability and Osteoarthritis Outcome Score (HOOS), were used to assess hip-specific outcome. EuroQol five-dimension five-level questionnaire (EQ-5D-5L) and 36-Item Short Form Survey (SF-36) scores were used to assess HRQoL. The Lower Extremity Activity Scale (LEAS) and Timed Up and Go (TUG) were used to assess level of activity.ResultsThere were no significant (p > 0.05) differences in the WOMAC scores, HSS, HOOS, or EQ-5D-5L at any postoperative timepoint between the age groups. Patients aged ≥ 75 years had significantly lower physical function (p ≤ 0.010) and physical role (p ≤ 0.047) SF-36 scores at 12, 24, and 60 months, but were equal to that expect of an age-matched population. No differences according to age were observed for the other six domains of the SF-36 (p > 0.060). The ≥ 75 years group had a lower LEAS (p < 0.001) and longer TUG test times (p ≤ 0.032) compared to the < 65 years group, but older age groups had significant (p < 0.001) improvement relative to their preoperative baseline measures.ConclusionAge did not influence postoperative hip-specific outcome or HRQoL (according to the EQ-5D) following THA. Despite a significant improvement, older patients had lower postoperative activity levels compared to younger patients, but this may be reflective of the overall physical effect of ageing.Cite this article: Bone Jt Open 2022;3(9):692–700.

Abstract To effectively navigate their environments, infants and children learn how to recognize events predict salient outcomes, such as rewards or punishments. Relatively little is known about how children acquire this ability to attach value to the stimuli they encounter. Studies often examine children’s ability to learn about rewards and threats using either classical conditioning or behavioral choice paradigms. Here, we assess both approaches and find that they yield different outcomes in terms of which individuals had efficiently learned the value of information presented to them. The findings offer new insights into understanding how to assess different facets of value learning in children.

Abstract Background This trial aimed to determine the efficacy of leucine and/or perindopril in improving physical function in older people with sarcopenia. Methods Placebo‐controlled, parallel group, double‐blind, randomized two‐by‐two factorial trial. We recruited adults aged ≥ 70 years with sarcopenia, defined as low gait speed (