Control of innate olfactory valence by segregated cortical amygdala circuits.

Animals perform innate behaviors that are stereotyped responses to specific evolutionarily relevant stimuli in the absence of prior learning or experience. These behaviors can be reduced to an axis of valence, whereby specific odors evoke approach or avoidance. The cortical amygdala (plCoA) mediates innate attraction and aversion to odor. However, little is known about how this brain area gives rise to behaviors of opposing motivational valence. Here, we sought to define the circuit features of plCoA that give rise to innate olfactory behaviors of valence. We characterized the physiology, gene expression, and projections of this structure, identifying a divergent, topographic organization that selectively controls innate attraction and avoidance to odor. First, we examined odor-evoked responses in these areas and found sparse encoding of odor identity, but not valence. We next considered a topographic organization and found that optogenetic stimulation of the anterior and posterior domains of plCoA elicits attraction and avoidance, respectively, suggesting a functional axis for valence. Using single cell and spatial RNA sequencing, we identified the molecular cell types in plCoA, revealing an anteroposterior gradient in cell types, whereby anterior glutamatergic neurons preferentially express Slc17a6 and posterior neurons express Slc17a7. Activation of these respective cell types recapitulates appetitive and aversive valence behaviors, and chemogenetic inhibition reveals partial necessity for valence responses to innate appetitive or aversive odors. Finally, we identified topographically organized circuits defined by projections, whereby anterior neurons preferentially project to medial amygdala, and posterior neurons preferentially project to nucleus accumbens, which are respectively sufficient and necessary for innate negative and positive olfactory valence. Together, these data advance our understanding of how the olfactory system generates stereotypic, hardwired attraction and avoidance, and supports a model whereby distinct, topographically distributed plCoA populations direct innate olfactory valence responses by signaling to divergent valence-specific targets, linking upstream olfactory identity to downstream valence behaviors, through a population code. This represents a novel circuit motif in which valence encoding is represented not by the firing properties of individual neurons, but by population level identity encoding that is routed through divergent targets to mediate distinct valence.

Longitudinal changes in adiposity following anterior cruciate ligament reconstruction and associations with knee symptoms and function.

Objective: To evaluate adiposity after anterior cruciate ligament reconstruction (ACLR): i) cross-sectionally (1-year post-ACLR) compared to uninjured controls; ii) longitudinally up to 5 years post-ACLR; and iii) associations with patient-reported symptoms and physical performance. Methods: In 107 individuals post-ACLR and 19 controls, we assessed global (BMI), peripheral (subcutaneous adipose tissue thickness on the posteromedial side of knee MRI), and central (waist circumference in ACLR group) adiposity. Patient-reported symptoms (Knee injury and Osteoarthritis Outcome Score) and physical performance (hop for distance) were evaluated at 1 and 5 years post-ACLR. Linear regression models evaluated adiposity between groups. Paired t-tests evaluated changes in adiposity from 1- to 5 years post-ACLR. Linear regression models analyzed adiposity's associations with patient-reported symptoms and physical performance at 1-year post-ACLR, changes in symptoms and performance over 4 years post-ACLR, and longitudinal changes in adiposity and symptoms and performance, controlling for age, sex, and activity level. Results: Individuals 1-year post-ACLR were associated with higher average global (3 â€‹kg/m2) and peripheral adiposity (2.3 â€‹mm). From 1- to 5 years post-ACLR, higher average global (0.58 â€‹kg/m2) and central (5 â€‹cm) adiposity, and lower average peripheral adiposity (1.3 â€‹mm) were observed. In general, adiposity at one-year post-ACLR was negatively associated with patient-reported symptoms and physical performance, and changes from 1 to 5 years post-ACLR. Increases in adiposity were negatively associated with changes in patient-reported symptoms and physical performance over four years post-ACLR. Conclusion: Greater global and central adiposity is a feature of young adults following ACLR and influences current and future patient-reported symptoms and physical performance.

Mixed selectivity: Cellular computations for complexity.

The property of mixed selectivity has been discussed at a computational level and offers a strategy to maximize computational power by adding versatility to the functional role of each neuron. Here, we offer a biologically grounded implementational-level mechanistic explanation for mixed selectivity in neural circuits. We define pure, linear, and nonlinear mixed selectivity and discuss how these response properties can be obtained in simple neural circuits. Neurons that respond to multiple, statistically independent variables display mixed selectivity. If their activity can be expressed as a weighted sum, then they exhibit linear mixed selectivity; otherwise, they exhibit nonlinear mixed selectivity. Neural representations based on diverse nonlinear mixed selectivity are high dimensional; hence, they confer enormous flexibility to a simple downstream readout neural circuit. However, a simple neural circuit cannot possibly encode all possible mixtures of variables simultaneously, as this would require a combinatorially large number of mixed selectivity neurons. Gating mechanisms like oscillations and neuromodulation can solve this problem by dynamically selecting which variables are mixed and transmitted to the readout.

An unbiased method to partition diverse neuronal responses into functional ensembles reveals interpretable population dynamics during innate social behavior.

In neuroscience, understanding how single-neuron firing contributes to distributed neural ensembles is crucial. Traditional methods of analysis have been limited to descriptions of whole population activity, or, when analyzing individual neurons, criteria for response categorization varied significantly across experiments. Current methods lack scalability for large datasets, fail to capture temporal changes and rely on parametric assumptions. There's a need for a robust, scalable, and non-parametric functional clustering approach to capture interpretable dynamics. To address this challenge, we developed a model-based, statistical framework for unsupervised clustering of multiple time series datasets that exhibit nonlinear dynamics into an a-priori-unknown number of parameterized ensembles called Functional Encoding Units (FEUs). FEU outperforms existing techniques in accuracy and benchmark scores. Here, we apply this FEU formalism to single-unit recordings collected during social behaviors in rodents and primates and demonstrate its hypothesis-generating and testing capacities. This novel pipeline serves as an analytic bridge, translating neural ensemble codes across model systems.

Adiposity and cartilage lesions following ACL reconstruction.

OBJECTIVE: To determine if global, central, or peripheral adiposity is associated with prevalent and worsening cartilage lesions following anterior cruciate ligament reconstruction (ACLR). METHODS: In 107 individuals one-year post-ACLR, adiposity was assessed globally (body mass index), centrally (waist circumference), and peripherally (knee subcutaneous adipose tissue thickness) from magnetic resonance imaging (MRI). Tibiofemoral and patellofemoral cartilage lesions were assessed from knee MRIs at 1- and 5-years post-ACLR. Poisson regression evaluated the relation of adiposity with prevalent and worsening tibiofemoral and patellofemoral cartilage lesions adjusting for age, sex, and activity level. RESULTS: The prevalence ratios of adiposity with tibiofemoral (presence in 49%) and patellofemoral (44%) cartilage lesions ranged from 0.99 to 1.03. Adiposity was more strongly associated with longitudinal changes in tibiofemoral (worsening in 21%) and patellofemoral (44%) cartilage lesions. One-unit increase in global (kg/m2), central (cm), and peripheral (mm) adiposity was associated with a higher risk of worsening tibiofemoral cartilage lesions by 17% (risk ratios [95% confidence interval (CI)]: 1.17 [1.09 to 1.23]), 5% (1.05 [1.02 to 1.08]), and 9% (1.09 [1.03 to 1.16]), and patellofemoral cartilage lesions by 5% (1.05 [1.00 to 1.12]), 2% (1.02 [1.00 to 1.04]) and 2% (1.02 [1.00 to 1.04]), respectively. CONCLUSION: Greater adiposity was a risk factor for worsening cartilage lesions up to 5 years post-ACLR. Clinical interventions aimed at mitigating excess adiposity may be beneficial in preventive approaches for early post-traumatic osteoarthritis.

Recruitment and baseline characteristics of young adults at risk of early-onset knee osteoarthritis after ACL reconstruction in the SUPER-Knee trial.

Objectives: The study aims to (1) report the process of recruiting young adults into a secondary knee osteoarthritis prevention randomised controlled trial (RCT) after anterior cruciate ligament reconstruction (ACLR); (2) determine the number of individuals needed to be screened to include one participant (NNS) and (3) report baseline characteristics of randomised participants. Methods: The SUpervised exercise-therapy and Patient Education Rehabilitation (SUPER)-Knee RCT compares SUPER and minimal intervention for young adults (aged 18-40 years) with ongoing symptoms (ie, mean score of <80/100 from four Knee injury and Osteoarthritis Outcome Score subscales (KOOS4)) 9-36 months post-ACLR. The NNS was calculated as the number of prospective participants screened to enrol one person. At baseline, participants provided medical history, completed questionnaires (demographic, injury/surgery, rehabilitation characteristics) and underwent physical examination. Results: 1044 individuals were screened to identify 567 eligible people, from which 184 participants (63% male) enrolled. The sample of enrolled participants was multicultural (29% born outside Australia; 2% Indigenous Australians). The NNS was 5.7. For randomised participants, mean±SD age was 30±6 years. The mean body mass index was 27.3±5.2 kg/m2, with overweight (43%) and obesity (21%) common. Participants were, on average, 2.3 years post-ACLR. Over half completed <8 months of postoperative rehabilitation, with 56% having concurrent injury/surgery to meniscus and/or cartilage. The most affected KOOS (0=worst, 100=best) subscale was quality of life (mean 43.7±19.1). Conclusion: Young adults post-ACLR were willing to participate in a secondary osteoarthritis prevention trial. Sample size calculations should be multiplied by at least 5.7 to provide an estimate of the NNS. The SUPER-Knee cohort is ideally positioned to monitor and intervene in the early development and trajectory of osteoarthritis. Trial registration number: ACTRN12620001164987.

Social isolation recruits amygdala-cortical circuitry to escalate alcohol drinking.

How do social factors impact the brain and contribute to increased alcohol drinking? We found that social rank predicts alcohol drinking, where subordinates drink more than dominants. Furthermore, social isolation escalates alcohol drinking, particularly impacting subordinates who display a greater increase in alcohol drinking compared to dominants. Using cellular resolution calcium imaging, we show that the basolateral amygdala-medial prefrontal cortex (BLA-mPFC) circuit predicts alcohol drinking in a rank-dependent manner, unlike non-specific BLA activity. The BLA-mPFC circuit becomes hyperexcitable during social isolation, detecting social isolation states. Mimicking the observed increases in BLA-mPFC activity using optogenetics was sufficient to increase alcohol drinking, suggesting the BLA-mPFC circuit may be a neural substrate for the negative impact of social isolation. To test the hypothesis that the BLA-mPFC circuit conveys a signal induced by social isolation to motivate alcohol consumption, we first determined if this circuit detects social information. Leveraging optogenetics in combination with calcium imaging and computer vision pose tracking, we found that BLA-mPFC circuitry governs social behavior and neural representation of social contact. We further show that BLA-mPFC stimulation mimics social isolation-induced mPFC encoding of sucrose and alcohol, and inhibition of the BLA-mPFC circuit decreases alcohol drinking following social isolation. Collectively, these data suggest the amygdala-cortical circuit mirrors a neural encoding state similar to social isolation and underlies social isolation-associated alcohol drinking.

Defining hip osteoarthritis feature prevalence, severity, and change using the Scoring of Hip Osteoarthritis with MRI (SHOMRI).

OBJECTIVE: To define the reporting of Scoring Hip Osteoarthritis with MRI (SHOMRI) feature prevalence and severity, and to develop criteria to monitor feature change in longitudinal investigations. METHODS: Twenty-five participants (50 hips) of the femoroacetabular impingement and hip osteoarthritis cohort study underwent baseline and 2-year follow-up 3 T hip MRIs. Eight hip OA features were assessed using the SHOMRI. All MRIs were read paired with knowledge of timepoint by two blinded musculoskeletal radiologists. We provide definitions to report SHOMRI feature prevalence, severity, and longitudinal change. RESULTS: We report clear definitions for SHOMRI feature prevalence, severity, and change. When we applied the definitions to the studied cohort, we could detect the prevalence, severity, and change of hip OA features. For example, 88% of hips had labral tears (34% graded as severe tears) and 76% had cartilage defects (42% graded as full thickness). Over 70% of hips had feature change over 2 years, highlighting the sensitivity of SHOMRI definitions to assess longitudinal change of hip OA features. Intra-reader reliability was almost perfect (weighted (w)-kappa 0.86 to 1.00), with inter-reader reliability substantial to almost perfect (w-kappa 0.80 to 1.00). CONCLUSION: This study is the first to provide definitions to report SHOMRI feature prevalence, severity, and change. The proposed definitions will enable comparison between hip MRI studies and improve our understanding of hip OA pathogenesis.

Orchard Sports Injury and Illness Classification System (OSIICS) Version 15.

BACKGROUND: Sports medicine (injury and illnesses) requires distinct coding systems because the International Classification of Diseases is insufficient for sports medicine coding. The Orchard Sports Injury and Illness Classification System (OSIICS) is one of two sports medicine coding systems recommended by the International Olympic Committee. Regular updates of coding systems are required. METHODS: For Version 15, updates for mental health conditions in athletes, sports cardiology, concussion sub-types, infectious diseases, and skin and eye conditions were considered particularly important. RESULTS: Recommended codes were added from a recent International Olympic Committee consensus statement on mental health conditions in athletes. Two landmark sports cardiology papers were used to update a more comprehensive list of sports cardiology codes. Rugby union protocols on head injury assessment were used to create additional concussion codes. CONCLUSION: It is planned that OSIICS Version 15 will be translated into multiple new languages in a timely fashion to facilitate international accessibility. The large number of recently published sport-specific and discipline-specific consensus statements on athlete surveillance warrant regular updating of OSIICS.

Influences on clinical trial participation: Enhancing recruitment through a gender lens - A scoping review.

Background: Suboptimal clinical trial recruitment contributes to research waste. Evidence suggests there may be gender-based differences in willingness to participate in clinical research. Identifying gender-based differences impacting the willingness of trial participation may assist trial recruitment. Objectives: To examine factors that influence the willingness of men and women to participate in clinical trials and to identify modifiable factors that may be targeted to optimise trial participation. Material and methods: Electronic databases were searched with key words relating to 'gender', 'willingness to participate' and 'trial'. Included studies were English language and reported gender-based differences in willingness to participate in clinical trials, or factors that influence a single gender to participate in clinical trials. Studies were excluded if they described the demographic factors of trial participants or if the majority of participants were pregnant. Extracted data were coded, categorized, analysed thematically and interpreted using Arksey and O'Malley's framework. Results: Sixty-three studies were included. Two main themes were identified: trial characteristics and participant characteristics. A number of gender-based differences moderating willingness to participate were observed although only one, 'concern for self' was found to influence actual trial participation rates between genders. Conclusion: The relationship between factors influencing willingness to participate in clinical trials is complex. The influence of gender on willingness to participate, while important, may be moderated by other factors including socioeconomic status, ethnicity and health condition. Exploring factors that influence willingness to participate specific to a study cohort likely offers the most promise to optimise trial recruitment of that cohort.

No sign of weakness: a systematic review and meta-analysis of hip and calf muscle strength after anterior cruciate ligament injury.

OBJECTIVE: We aimed to determine hip and lower-leg muscle strength in people after ACL injury compared with an uninjured control group (between people) and the uninjured contralateral limb (between limbs). DESIGN: Systematic review with meta-analysis. DATA SOURCES: MEDLINE, EMBASE, CINAHL, Scopus, Cochrane CENTRAL and SportDiscus to 28 February 2023. ELIGIBILITY CRITERIA: Primary ACL injury with mean age 18-40 years at time of injury. Studies had to measure hip and/or lower-leg muscle strength quantitatively (eg, dynamometer) and report muscle strength for the ACL-injured limb compared with: (i) an uninjured control group and/or (ii) the uninjured contralateral limb. Risk of bias was assessed according to Cochrane Collaboration domains. RESULTS: Twenty-eight studies were included (n=23 measured strength ≤12 months post-ACL reconstruction). Most examined hip abduction (16 studies), hip extension (12 studies) and hip external rotation (7 studies) strength. We found no meaningful difference in muscle strength between people or between limbs for hip abduction, extension, internal rotation, flexion or ankle plantarflexion, dorsiflexion (estimates ranged from -9% to +9% of comparator). The only non-zero differences identified were in hip adduction (24% stronger on ACL limb (95% CI 8% to 42%)) and hip external rotation strength (12% deficit on ACL limb (95% CI 6% to 18%)) compared with uninjured controls at follow-ups >12 months, however both results stemmed from only two studies. Certainty of evidence was very low for all outcomes and comparisons, and drawn primarily from the first year post-ACL reconstruction. CONCLUSION: Our results do not show widespread or substantial muscle weakness of the hip and lower-leg muscles after ACL injury, contrasting deficits of 10%-20% commonly reported for knee extensors and flexors. As it is unclear if deficits in hip and lower-leg muscle strength resolve with appropriate rehabilitation or no postinjury or postoperative weakness occurs, individualised assessment should guide training of hip and lower-leg strength following ACL injury. PROSPERO REGISTRATION NUMBER: CRD42020216793.

Injury prevention for women and girls playing Australian Football: programme cocreation, dissemination and early adopter coach feedback.

Background: Adherence to injury prevention programmes may improve with greater end-user involvement and application of implementation frameworks during development. We describe the cocreation, initial dissemination and feedback from programme early adopters (coaches), to develop the first evidence-informed injury prevention programme for women playing community Australian Football (Prep-to-Play). Methods: We used a pragmatic seven-step process for developing sports injury prevention programmes to (1) gain organisational support, (2) compile research evidence, (3) consult experts, (4) engage end-users, (5) test programme acceptability, (6) evaluate against theory and (7) gain early adopter feedback. All Australian Football-registered coaches of women's/girls' teams were sent a postseason survey to determine initial awareness, adoption and implementation (steps 5 and 6). Purposively selected coaches were invited to interviews/focus groups (step 7) to identify competency, organisational and leadership implementation drivers with a deductive thematic analysis applied. Results: Prep-to-Play was cocreated using previous efficacious programmes and expert input (steps 1-4), and disseminated via the national sporting organisation in preseason 2019 to all registered coaches (step 5). 343 coaches (90 women) completed the postseason survey and 22 coaches (5 women) participated in an interview (n=9) or focus group (n=13) (steps 6 and 7). 268 coaches (78%) were aware of Prep-to-Play. Of those aware, 218 (81%) had used (at least one element) Prep-to-Play, and 143 (53%) used it at least twice per week. Competency drivers included local expert-delivered face-to-face workshops complimented by online content and ongoing support. Organisational drivers included coach education integrated into existing league/club. Leadership drivers included compulsory injury prevention education integrated into coach reaccreditation processes or incentivisation via recognition (eg, professional development points). Conclusions: Cocreation and organisational support resulted in high programme awareness and adoption. However, high fidelity implementation and maintenance may need to be facilitated by competency, organisational and leadership drivers. Responsibility should be shared among all stakeholders.

A Risk Profile Using Simple Hematologic Parameters to Assess Benefits From Baricitinib in Patients Hospitalized With COVID-19: A Post Hoc Analysis of the Adaptive COVID-19 Treatment Trial-2.

BACKGROUND: The ACTT risk profile, which was developed from ACTT-1 (Adaptive COVID-19 Treatment Trial-1), demonstrated that hospitalized patients with COVID-19 in the high-risk quartile (characterized by low absolute lymphocyte count [ALC], high absolute neutrophil count [ANC], and low platelet count at baseline) benefited most from treatment with the antiviral remdesivir. It is unknown which patient characteristics are associated with benefit from treatment with the immunomodulator baricitinib. OBJECTIVE: To apply the ACTT risk profile to the ACTT-2 cohort to investigate potential baricitinib-related treatment effects by risk quartile. DESIGN: Post hoc analysis of ACTT-2, a randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT04401579). SETTING: Sixty-seven trial sites in 8 countries. PARTICIPANTS: Adults hospitalized with COVID-19 (n = 999; 85% U.S. participants). INTERVENTION: Baricitinib+remdesivir versus placebo+remdesivir. MEASUREMENTS: Mortality, progression to invasive mechanical ventilation (IMV) or death, and recovery, all within 28 days; ALC, ANC, and platelet count trajectories. RESULTS: In the high-risk quartile, baricitinib+remdesivir was associated with reduced risk for death (hazard ratio [HR], 0.38 [95% CI, 0.16 to 0.86]; P = 0.020), decreased progression to IMV or death (HR, 0.57 [CI, 0.35 to 0.93]; P = 0.024), and improved recovery rate (HR, 1.53 [CI, 1.16 to 2.02]; P = 0.002) compared with placebo+remdesivir. After 5 days, participants receiving baricitinib+remdesivir had significantly larger increases in ALC and significantly larger decreases in ANC compared with control participants, with the largest effects observed in the high-risk quartile. LIMITATION: Secondary analysis of data collected before circulation of current SARS-CoV-2 variants. CONCLUSION: The ACTT risk profile identifies a subgroup of hospitalized patients who benefit most from baricitinib treatment and captures a patient phenotype of treatment response to an immunomodulator and an antiviral. Changes in ALC and ANC trajectory suggest a mechanism whereby an immunomodulator limits severe COVID-19. PRIMARY FUNDING SOURCE: National Institute of Allergy and Infectious Diseases.

Reward contingency gates selective cholinergic suppression of amygdala neurons.

Basal forebrain cholinergic neurons modulate how organisms process and respond to environmental stimuli through impacts on arousal, attention, and memory. It is unknown, however, whether basal forebrain cholinergic neurons are directly involved in conditioned behavior, independent of secondary roles in the processing of external stimuli. Using fluorescent imaging, we found that cholinergic neurons are active during behavioral responding for a reward - even prior to reward delivery and in the absence of discrete stimuli. Photostimulation of basal forebrain cholinergic neurons, or their terminals in the basolateral amygdala (BLA), selectively promoted conditioned responding (licking), but not unconditioned behavior nor innate motor outputs. In vivo electrophysiological recordings during cholinergic photostimulation revealed reward-contingency-dependent suppression of BLA neural activity, but not prefrontal cortex. Finally, ex vivo experiments demonstrated that photostimulation of cholinergic terminals suppressed BLA projection neuron activity via monosynaptic muscarinic receptor signaling, while also facilitating firing in BLA GABAergic interneurons. Taken together, we show that the neural and behavioral effects of basal forebrain cholinergic activation are modulated by reward contingency in a target-specific manner.

If we build it together, will they use it? A mixed-methods study evaluating the implementation of Prep-to-Play PRO: an injury prevention programme for women's elite Australian Football.

OBJECTIVES: We evaluated the implementation of Prep-to-Play PRO, an injury prevention programme for women's elite Australian Football League (AFLW). METHODS: The Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) of Prep-to-Play PRO were assessed based on the proportion of AFLW players and/or staff who: were aware of the programme (R), believed it may reduce anterior cruciate ligament injury (E), attempted to implement any/all programme components (A), implemented all intended components as practically as possible (I) and intended future programme implementation (M). Quantitative and qualitative data were triangulated to assess 58 RE-AIM items (evidence of yes/no/unsure/no evidence) and the 5 RE-AIM dimensions (fully achieved=evidence of yes on >50% dimension items, partially achieved=50% of items evidence of yes and 50% unsure or 50% mix of unsure and unanswered, or not met=evidence of yes on <50% dimension items). RESULTS: Multiple sources including AFLW training observations (n=7 total), post-implementation surveys (141 players, 25 staff), semistructured interviews (19 players, 13 staff) and internal programme records (9 staff) contributed to the RE-AIM assessment. After the 2019 season, 8 of 10 (80%) AFLW clubs fully met all five RE-AIM dimensions. All 10 clubs participating in the AFLW fully achieved the reach (R) dimension. One club partially achieved the implementation (I) dimension, and one club partially achieved the effectiveness (E) and adoption (A) dimensions. CONCLUSION: The Prep-to-Play PRO injury prevention programme for the AFLW achieved high implementation, possibly due to the programme's deliberately flexible approach coupled with our pragmatic definition of implementation. Engaging key stakeholders at multiple ecological levels (organisation, coaches, athletes) throughout programme development and implementation likely enhanced programme implementation.

Knee Confidence, Fear of Movement, and Psychological Readiness for Sport in Individuals With Knee Conditions: A Systematic Review and Meta-analysis.

OBJECTIVES: To (1) compare activity-related psychological factors between individuals with and without knee conditions, and (2) assess associations between these factors and objective measures of function in individuals with knee conditions. DESIGN: A priori registered systematic review with meta-analysis. LITERATURE SEARCH: MEDLINE-Ovid, Embase-Ovid, Scopus-Elsevier, CINAHL-EBSCO, SPORTDiscus-EBSCO, and Cochrane Library were searched to May 27, 2022. STUDY SELECTION CRITERIA: We included peer-reviewed primary data studies (observational and experimental) of human participants with and without knee conditions reporting knee confidence, fear of movement/avoidance beliefs, and/or psychological readiness to return to sport (RTS) or reporting correlations between these factors and objective measures of function in knee conditions. DATA SYNTHESIS: Where possible, data were pooled by knee conditions, otherwise performed narrative syntheses. The Downs and Black checklist assessed the methodological quality of the included studies. RESULTS: Forty studies (3546 participants with knee conditions; 616 participants without knee conditions) were included. There was very low-certainty evidence of higher fear of movement in individuals with knee osteoarthritis (standardized mean difference [SMD], 0.46; 95% confidence interval [CI]: 0.41, 0.52), but not in individuals with patellofemoral pain (SMD, 0.66; 95% CI: -7.98, 9.29) when compared with those without knee conditions. There was very low-certainty evidence of no differences in psychological readiness to RTS after anterior cruciate ligament reconstruction (SMD, -1.14; 95% CI: -2.97, 0.70) compared to no knee condition, and negligible to weak positive correlations between psychological readiness to RTS and objective measures of function. CONCLUSION: There was very low-certainty evidence of higher fear of movement in individuals with knee osteoarthritis compared to those without, and very low-certainty evidence of no correlations between these factors and objective measures of function following anterior cruciate ligament reconstruction. J Orthop Sports Phys Ther 2024;54(4):1-14. Epub 29 January 2024. doi:10.2519/jospt.2024.12070.

Safety and Immunogenicity of an Andes Virus DNA Vaccine by Needle-Free Injection: A Randomized, Controlled Phase 1 Study.

BACKGROUND: Andes virus (ANDV), a rodent-borne hantavirus, causes hantavirus pulmonary syndrome (HPS). The safety and immunogenicity of a novel ANDV DNA vaccine was evaluated. METHODS: Phase 1, double-blind, dose-escalation trial randomly assigned 48 healthy adults to placebo or ANDV DNA vaccine delivered via needle-free jet injection. Cohorts 1 and 2 received 2 mg of DNA or placebo in a 3-dose (days 1, 29, 169) or 4-dose (days 1, 29, 57, 169) schedule, respectively. Cohorts 3 and 4 received 4 mg of DNA or placebo in the 3-dose and 4-dose schedule, respectively. Subjects were monitored for safety and neutralizing antibodies by pseudovirion neutralization assay (PsVNA50) and plaque reduction neutralization test (PRNT50). RESULTS: While 98% and 65% of subjects had at least 1 local or systemic solicited adverse event (AE), respectively, most AEs were mild or moderate; no related serious AEs were detected. Cohorts 2, 3, and 4 had higher seroconversion rates than cohort 1 and seropositivity of at least 80% by day 197, sustained through day 337. PsVNA50 geometric mean titers were highest for cohort 4 on and after day 197. CONCLUSIONS: This first-in-human candidate HPS vaccine trial demonstrated that an ANDV DNA vaccine was safe and induced a robust, durable immune response. Clinical Trials Registration. NCT03682107.

Hepatocellular carcinoma risk decreases as time accrues following hepatitis C virus eradication.

BACKGROUND: It is unclear whether the risk of hepatocellular carcinoma (HCC) decreases over time following hepatitis C virus (HCV) eradication. AIM: To determine if patients who have accrued longer time since sustained virologic response (SVR) have a lower risk of HCC than those with less time since SVR METHODS: We conducted a retrospective cohort study of all HCV-infected Veterans Affairs patients who achieved SVR before 1 January 2018 and remained alive without a diagnosis of HCC as of 1 January 2019 (n = 75,965). We ascertained their baseline characteristics as of 1 January 2019 (time zero), including time accrued since SVR and followed them for the subsequent 12 months for incident HCC. We used multivariable Cox proportional hazards regression to determine the association between time since SVR and HCC risk after adjusting for age, race/ethnicity, sex, diabetes, hypertension, body mass index, alcohol use, Charlson Comorbidity Index, Fibrosis-4 score, HCV genotype, hepatitis B virus co-infection and HIV co-infection. RESULTS: 96.0% were male; mean age was 64.6 years. Among those with cirrhosis (n = 19,678, 25.9%), compared to patients who had accrued only ≥1 to 2 years since SVR (HCC incidence 2.71/100 person-years), those who had accrued >2 to 4 years (2.11/100 person-years, aHR 0.80, 95% CI 0.63-1.01) and >4 to 6 years (1.65/100 person-years, aHR 0.61, 95% CI 0.41-0.90) had progressively lower HCC risk. However, HCC risk appeared to plateau for those with >6 years since SVR (1.68/100 person-years, aHR 0.70, 95% CI 0.46-1.07). Among those without cirrhosis, HCC risk was 0.23-0.27/100 person-years without a significant association between time since SVR and HCC risk. CONCLUSIONS: Among patients with cirrhosis and cured HCV infection, HCC risk declined progressively up to 6 years post-SVR-although it remained well above thresholds that warrant screening. This suggests that time since SVR can inform HCC surveillance strategies in patients with cured HCV infection and can be incorporated into HCC risk prediction models.