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Timothy Kwok,1,2 Anita Wong,3 Grace Chan,4 YY Shiu,3 Ko-Chuen Lam,2 Daniel Young,2 Daniel WH Ho,2 Florence Ho21Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, People's Republic of China; 2Jockey Club Centre for Positive Ageing, Shatin, Hong Kong, People's Republic of China; 3The Hong Kong Chinese Women's Club Madam Wong Chan Sook Ying Memorial Care and Attention Home for the Aged, Hong Kong, People's Republic of China; 4The Hong Kong Council of Social Service, Hong Kong, People's Republic of ChinaAbstract: In Hong Kong, the evidence for cognitive-training programs in fighting against memory complaints is lacking. This study aimed to evaluate the effectiveness of the Active Mind cognitive-training program in improving the cognitive function and quality of life (QoL) for local community-dwelling Chinese older adults. A total of 200 subjects were recruited from 20 different district elderly community centers (DECCs). Centers were randomly assigned into either the intervention group or control group. The intervention group underwent eight 1-hour sessions of cognitive training, while the control group were included in the usual group activities provided by the DECCs. Standardized neuropsychological tests (the Chinese version of Mattis Dementia Rating Scale [CDRS] and the Cantonese version of the Mini-Mental State Examination) and the QoL questionnaire SF12 were used to assess participants' cognitive function and QoL before and after the trial. A total of 176 subjects completed the study. The intervention group showed greater improvement in the cognitive function measured by total CDRS score (treatment: 12.24 ± 11.57 vs control: 4.37 ± 7.99; P < 0.001) and QoL measured by total SF12 score (treatment: 7.82 ± 13.19 vs control: 3.18 ± 11.61; P = 0.014). Subjects with lower education level were associated with better cognitive response to the cognitive-training program. The current findings indicated that the Active Mind cognitive-training program was effective in improving the cognitive function and QoL for community-dwelling Chinese older adults in Hong Kong.Keywords: cognitive training, cognitive stimulation, memory, older adults, effectiveness

Timothy CY Kwok1,2, KC Lam2, PS Wong2, WW Chau2, Kenneth SL Yuen2,3, KT Ting2, Elite WK Chung2, Jessie CY Li2, Florence KY Ho2,41Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 2Jockey Club Centre for Positive Ageing, 3Laboratory of Neuropsychology, Department of Psychology, The University of Hong Kong, 4Jockey Club CADENZA Hub, Hong Kong SARBackground: Studies on the effect of a low intensity coordination exercise on the elderly with limited mobility are sparse. This prospective study attempted to compare the effectiveness of a customized coordination exercise and a strength exercise in improving the cognitive functioning and physical mobility on the elderly.Methods: Participants from two centers for the elderly were allocated to practice either an 8-week coordination training (CT) program or an 8-week towel exercise (TE) program. The Chinese Mini-Mental State Examination and Chinese Dementia Rating Scale (CDRS) were used to measure cognitive functioning of participants, and Timed Up-and-Go test for physical mobility. These assessments were administered before and after the program.Results: Paired t-tests showed that the CDRS scores of the CT group improved significantly from 114.8 at pre-test to 119.3 after training (P = 0.045). The CDRS scores of the TE group also improved from 114.9 at pre-test to 116.9 after training.Conclusion: Findings from this prospective study demonstrated that low-intensity level mind-body exercise could be beneficial to the cognitive functioning of older adults.Keywords: coordination exercise, cognitive function, elderly, Chinese

Background: Single-agent doxorubicin has been widely used to treat unresectable hepatocellular carcinoma (HCC), but the response rate is low (< 20%) and there is no convincing evidence for improved survival. Cisplatin, interferon, doxorubicin, and fluorouracil (PIAF) used in combination, by contrast, has shown promise in a phase II study. We compared doxorubicin to PIAF in patients with unresectable HCC in a phase III trial.Methods: Patients with histologically confirmed unresectable HCC were randomly assigned to receive either doxorubicin or PIAF every 3 weeks, for up to six cycles. The primary endpoint was overall survival, and secondary endpoints were response rate and toxicity. Survival differences were calculated using the Kaplan-Meier method. Treatment groups were compared for differences in the incidence of adverse events using chi-square tests. All statistical tests were two-sided.Results: The median survival of the doxorubicin and PIAF groups was 6.83 months (95% confidence [CI] = 4.80 to 9.56) and 8.67 months (95% CI = 6.36 to 12.00), respectively (P = 0.83). The hazard ratio for death from any cause in the PIAF compared with the doxorubicin groups was 0.97 (95% CI = 0.71 to 1.32). Eighty-six of the 94 patients receiving doxorubicin and 91 of the 94 receiving PIAF were assessable for response. The overall response rates in the doxorubicin and PIAF groups were 10.5% (95% CI = 3.9% to 16.9%) and 20.9% (95% CI = 12.5% to 29.2%), respectively. Neutropenia, thrombocytopenia, and hypokalemia were statistically significantly more common in patients treated with PIAF than in patients treated with doxorubicin.Conclusion: Although patients on PIAF had a higher overall response rate and better survival than patients on doxorubicin, the differences were not statistically significant. PIAF was also associated with increased treatment-related toxicity. The prognosis of patients with unresectable HCC remains poor. [ABSTRACT FROM AUTHOR]

1 To study the effect of cimetidine on gonadal function in man, eleven male subjects with chronic duodenal ulcer were given cimetidine orally at a dosage of 1000 mg per day 3 months and 400 mg nocte for the subsequent 3 months. 2 Testosterone levels were found to be elevated during therapy when compared to pre- and post-treatment periods. Serum LH remained unchanged but FSH was increased during therapy. In five out of eleven subjects serum PRL levels were increased. Mean sperm count was lower during cimetidine therapy when compared with that after drug withdrawal. The motility and morphology of the spermatozoa were not affected. [ABSTRACT FROM AUTHOR]

1 The haemodynamic responses to a bolus intravenous injection of 400 mg cimetidine were studied in eight subjects with normal lung function and sixteen with chronic obstructive airway disease (COAD), under continuous systemic and pulmonary arterial monitoring. In all subjects there were significant immediate but transient (less than 10 min) drops in the systemic and pulmonary arterial pressures (both systolic and diastolic), the systemic vascular resistance and total pulmonary resistance. The percentage drops were significant more marked in the COAD group in the following: systemic arterial pressures (systolic and diastolic), systemic vascular resistance and total pulmonary resistance. The cardiac output showed no significant change in the group with normal lung function but rose significantly in the COAD group. None of the subjects had any symptoms associated with the haemodynamic changes. 2 These results can be explained by a generalized vasodilatory effect of cimetidine, but the relationship to its H2- receptor blocking effect is undetermined. Hypoxia and/or hypercapnia may sensitize an individual to the vasodilatory effect of cimetidine. [ABSTRACT FROM AUTHOR]

We studied the effect of ranitidine on gonadal function in 20 male subjects with chronic duodenal ulcer. Eleven were treated with ranitidine 150 mg twice daily for 3 months and 150 mg at night for 9 months, nine with placebo for 3 months. Similar to placebo, treatment with ranitidine did not influence basal serum concentrations of testosterone (T), luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin (PRL). No significant changes were found in sperm concentration, motility or morphology. Ranitidine does not affect gonadal function in man. [ABSTRACT FROM AUTHOR]

Despite the promising results of immune checkpoint blockade (ICB) therapy, outcomes for patients with brain metastasis (BrM) remain poor. Identifying resistance mechanisms has been hindered by limited access to patient samples and relevant preclinical models. Here, we developed two mouse melanoma BrM models that recapitulate the disparate responses to ICB seen in patients. We demonstrate that these models capture the cellular and molecular complexity of human disease and reveal key factors shaping the tumor microenvironment and influencing ICB response. BR1-responsive tumor cells express inflammatory programs that polarize microglia into reactive states, eliciting robust T cell recruitment. In contrast, BR3-resistant melanoma cells are enriched in neurological programs and exploit tolerance mechanisms to maintain microglia homeostasis and limit T cell infiltration. In humans, BR1 and BR3 expression signatures correlate positively or negatively with T cell infiltration and BrM patient outcomes, respectively. Our study provides clinically relevant models and uncovers mechanistic insights into BrM ICB responses, offering potential biomarkers and therapeutic targets to improve therapy efficacy., Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.

Neuronal connections provide the scaffolding for neuronal function. Revealing the connectivity of functionally identified individual neurons is necessary to understand how activity patterns emerge and support behavior. Yet, the brain-wide presynaptic wiring rules that lay the foundation for the functional selectivity of individual neurons remain largely unexplored. Cortical neurons, even in primary sensory cortex, are heterogeneous in their selectivity, not only to sensory stimuli but also to multiple aspects of behavior. Here, to investigate presynaptic connectivity rules underlying the selectivity of pyramidal neurons to behavioral state 1-12 in primary somatosensory cortex (S1), we used two-photon calcium imaging, neuropharmacology, single-cell based monosynaptic input tracing, and optogenetics. We show that behavioral state-dependent neuronal activity patterns are stable over time. These are minimally affected by neuromodulatory inputs and are instead driven by glutamatergic inputs. Analysis of brain-wide presynaptic networks of individual neurons with distinct behavioral state-dependent activity profiles revealed characteristic patterns of anatomical input. While both behavioral state-related and unrelated neurons had a similar pattern of local inputs within S1, their long-range glutamatergic inputs differed. Individual cortical neurons, irrespective of their functional properties, received converging inputs from the main S1-projecting areas. Yet, neurons that tracked behavioral state received a smaller proportion of motor cortical inputs and a larger proportion of thalamic inputs. Optogenetic suppression of thalamic inputs reduced behavioral state-dependent activity in S1, but this activity was not externally driven. Our results revealed distinct long-range glutamatergic inputs as a substrate for preconfigured network dynamics associated with behavioral state.

Context: Immediate athletic trainer (AT) availability for acute injuries is essential as worse long-term outcomes are associated with delays in receiving medical care. Several factors have been found to influence AT availability between secondary schools, but few studies have evaluated how medical coverage varies between athlete groups., Objective: The purpose of this project was to identify factors that impact the time to AT evaluation following acute sport-related injury in secondary school setting., Design: Cross-Sectional Study., Setting: Retrospective analysis of de-identified patient records via the Athletic Training Practice-Based Research Network., Patients: High school athletes diagnosed with an acute sport related injury during in-season play from 2010-2023., Main Outcome Measure: Time to AT evaluation was measured as the number of days between injury onset, reported by the patient, to AT evaluation., Results: This report consists of 17,354 patient cases representing 20 different sports. Overall, 46.9% (n=8,138) of patients who sustained an injury during in-season play were evaluated by an AT the same day (range=0-14days). Significant group differences were reported for sex (p <. 001), setting (p <. 001), and sport level (p < .01), with females and in-game injuries associated with longer times to AT evaluation. Freshmen were evaluated sooner than JV (p < .01) and varsity (p < .001) athletes. No difference was observed between JV and varsity athletes (p=0.34)., Conclusions: Almost half of patients received medical care within 24 hours following an acute injury during in-season play, highlighting how qualified health care is accessible for many student athletes through ATs in the secondary school setting. Differences in time to AT evaluation may be attributable to sex discrepancies in immediate medical coverage between sports and injury reporting patterns among athletes.

The tumor microenvironment (TME) consists of complex interactions between cellular and extracellular components, among which the immune system is known to play an integral role in disease progression and response to therapy. Cytokines and chemokines are cell signaling proteins used by immune cells to communicate with each other as well as with other cell types in the body. These proteins control systemic and local immune responses and levels of cytokines/chemokines in the TME have been associated with tumor outcomes. However, cytokines and chemokines have varied expression across cell types, tumors, and host conditions. Therefore, approaches to effectively study the production of these proteins at the single-cell level in the TME are needed to fully elucidate the mechanisms governing the anti-cancer immune response. Here, we detail a protocol to assess the production of cytokines/chemokines across leukocyte populations in mouse tumors using RNA flow cytometry. Importantly, this method can be adapted with minimal changes to study various mouse and human tumors, other RNA analytes, and non-tumor tissues. With this approach, we characterize single-cell production of Ifnb1 , Xcl1 and Ccl5 in mouse tumors and identify monocytes and monocyte-derived macrophages as the main producers of type I interferon transcript Ifnb1 consistent across 4 different syngeneic tumor models.

Resting-state fMRI (rs-fMRI) scans-namely those lacking experimentally-controlled stimuli or cognitive demands-are often used to identify aberrant patterns of functional connectivity (FC) in clinical populations. To minimize interpretational uncertainty, researchers control for across-cohort disparities in age, gender, co-morbidities, and head motion. Yet, studies rarely, if ever, consider the possibility that systematic differences in inner experience (i.e., what subjects think and feel during the scan) may directly affect FC measures. Here we demonstrate that is the case using a rs-fMRI dataset comprising 471 scans annotated with experiential data. Wide-spread significant differences in FC are observed between scans that systematically differ in terms of reported in-scanner experience. Additionally, we show that FC can successfully predict specific aspects of in-scanner experience in a manner similar to how it predicts demographics, cognitive abilities, clinical outcomes and labels. Together, these results highlight the key role of in-scanner experience in shaping rs-fMRI estimates of FC.

Context: Exploring sports-related musculoskeletal injuries and treatment characteristics in middle school sports may help inform patient care decisions such as appropriate medical coverage., Objective: To describe injury and treatment characteristics of middle school-aged athletes receiving care from athletic trainers within the Athletic Training Practice-Based Research Network (AT-PBRN)., Design: Descriptive study., Setting: Middle school., Patient or Other Participants: Middle school-aged athletes (n = 1011; male = 503, female = 506, 2 declined to answer) with sports-related musculoskeletal injuries., Main Outcome Measures: Electronic patient records were analyzed from the AT-PBRN from 59 athletic trainers across 14 states between 2010 and 2022. Summary statistics (frequency, percentages, median, and interquartile ranges [IQR]) were used to describe injury (age at injury, sex, sport, body part, and diagnosis) and treatment characteristics (type of treatment, number of visits, and number of procedures per visit)., Results: Football (17.7%, n = 179), basketball (17.6%, n = 178), and soccer (14.9%, n = 151) reported the highest number of injuries. The ankle (17.2%, n = 174), knee (16.5%, n = 167), and head (14.1%, n = 143) were the most common injury locations. Concussion (13.0%, n = 131), ankle strain/sprain (12.4%, n = 125), and thigh/hip/groin sprain/strain (11.1%, n = 112) were the most reported diagnoses. Therapeutic exercise or activities (27.6%, n = 1068), athletic trainer evaluation or re-evaluation (24.7%, n = 957), and hot/cold packs (19.8%, n = 766) were the most common services, with a median of 2 visits (IQR = 1 to 4) and 2 procedures (IQR = 1 to 2) per visit., Conclusions: Football, basketball, and soccer reported the most musculoskeletal injuries for middle school-aged athletes. Concussions were the most frequent diagnosis, followed by ankle sprains/strains. Our findings are similar to prior investigations at the high school and collegiate levels. Treatments at the middle school level were also similar to those that have been previously reported at the high school level with therapeutic exercise/activity, athletic trainer evaluation or re-evaluation, and hot/cold packs being the most common treatments. This information may be useful for informing patient care decisions at the middle-school level., (© by the National Athletic Trainers' Association, Inc.)

A role for vitamin D in immune modulation and in cancer has been suggested. In this work, we report that mice with increased availability of vitamin D display greater immune-dependent resistance to transplantable cancers and augmented responses to checkpoint blockade immunotherapies. Similarly, in humans, vitamin D-induced genes correlate with improved responses to immune checkpoint inhibitor treatment as well as with immunity to cancer and increased overall survival. In mice, resistance is attributable to the activity of vitamin D on intestinal epithelial cells, which alters microbiome composition in favor of Bacteroides fragilis , which positively regulates cancer immunity. Our findings indicate a previously unappreciated connection between vitamin D, microbial commensal communities, and immune responses to cancer. Collectively, they highlight vitamin D levels as a potential determinant of cancer immunity and immunotherapy success.

Introduction: Interstitial lung disease (ILD) is the most frequent cause of drug-related mortality from EGFR tyrosine kinase inhibitors (TKIs). Yet, for patients with symptomatic osimertinib-induced ILD, the risk of recurrent ILD associated with EGFR TKI rechallenge, either with osimertinib or another TKI, such as erlotinib, is unclear., Methods: Retrospective study of 913 patients who received osimertinib treatment for EGFR mutation-positive NSCLC. Clinical characteristics, ILD treatment history, and subsequent anticancer therapy of patients with symptomatic osimertinib-induced ILD were collated. The primary end point was to compare the incidence of recurrent ILD with osimertinib versus erlotinib rechallenge., Results: Of 913 patients, 35 (3.8%) had symptomatic osimertinib-induced ILD, of which 12 (34%), 15 (43%), and eight (23%) had grade 2, 3 to 4, and 5 ILD, respectively. On ILD recovery, 17 patients had EGFR TKI rechallenge with eight received osimertinib and nine received erlotinib. The risk of recurrent ILD was higher with osimertinib rechallenge than erlotinib ( p  = 0.0498). Of eight, five (63%) developed recurrent ILD on osimertinib rechallenge, including three patients with fatal outcomes. In contrast, only one of nine patients (11%) treated with erlotinib had recurrent ILD. Median time to second ILD occurrence was 4.7 (range 0.7-12) weeks. Median time-to-treatment failure of patients with erlotinib rechallenge was 13.2 months (95% confidence interval: 8.6-15.0)., Conclusions: The risk of recurrent ILD was considerably higher with osimertinib rechallenge than erlotinib. Osimertinib rechallenge should be avoided, whereas erlotinib may be considered in patients with symptomatic osimertinib-induced ILD., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors.)

Importance: Preoperative anxiety is common among adult patients undergoing elective surgery and is associated with negative outcomes. Virtual reality (VR)-based interventions have been considered simpler, safer, and more effective for reducing anxiety in patients undergoing surgery than conventional care., Objective: To examine the effectiveness of a VR-based intervention with preoperative education in reducing preoperative anxiety among adult patients undergoing elective surgery., Design, Setting, and Participants: An assessor-blinded prospective randomized clinical trial was conducted to recruit adult patients aged 18 years or older who were scheduled for their first elective surgery procedure under general anesthesia within the next 2 to 4 weeks at a preanesthesia assessment clinic in Hong Kong from July to December 2022., Interventions: Participants were randomly assigned to either an intervention group (an 8-minute immersive 360° VR video tour in the operating theater via a head-mounted display console) or a control group (standard care)., Main Outcomes and Measures: The primary outcome of preoperative anxiety was measured using the Amsterdam Preoperative Anxiety and Information Scale (range, 6-30; higher scores indicate greater anxiety), and the secondary outcomes (ie, stress, preparedness, and pain) were assessed by Visual Analog Scale at 3 time points: baseline at beginning of clinical session (T0), at the end of the clinical session immediately after the intervention (T1), and before the surgery (T2). Pain, satisfaction levels, and postoperative length of stay were evaluated after the surgery (T3). Simulation sickness was assessed after the intervention by use of the Simulation Sickness Questionnaire. A generalized estimating equations model was applied to compare changes in outcomes over time., Results: A total of 74 participants (mean [SD] age, 46.34 [14.52] years; 38 men [51.4%] and 36 women [48.6%]) were recruited and randomized to the control group (37 participants) and intervention group (37 participants). Compared with the control group, the VR-based intervention group showed significantly decreased preoperative anxiety at T1 (β, -5.46; 95% CI, -7.60 to -3.32; P < .001) and T2 (β, -5.57; 95% CI, -7.73 to -3.41; P < .001), lower stress at T1 (β, -10.68; 95% CI, -16.00 to -5.36; P < .001) and T2 (β, -5.16; 95% CI, -9.87 to -0.45; P = .03), and higher preparedness at T1 (β, 6.60; 95% CI, 0.97 to 12.19; P = .02). Satisfaction levels were significantly increased in the intervention group vs the control group (mean [SD] score, 81.35 [9.24] vs 65.28 [8.16]; difference, 16.07; 95% CI, 12.00 to 20.15; P < .001). No significant differences in pain and postoperative length of stay were found., Conclusions and Relevance: The findings of this study suggest that a VR-based intervention is a feasible and effective way to reduce preoperative anxiety in adult patients undergoing elective surgery. Given the promising results of this study, further study in the form of large-scale, multicenter, randomized clinical trials with broader implementation is warranted., Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2100051690.

Whole-brain functional connectivity ( FC ) measured with functional MRI (fMRI) evolves over time in meaningful ways at temporal scales going from years (e.g., development) to seconds [e.g., within-scan time-varying FC ( tvFC )]. Yet, our ability to explore tvFC is severely constrained by its large dimensionality (several thousands). To overcome this difficulty, researchers often seek to generate low dimensional representations (e.g., 2D and 3D scatter plots) hoping those will retain important aspects of the data (e.g., relationships to behavior and disease progression). Limited prior empirical work suggests that manifold learning techniques ( MLTs )-namely those seeking to infer a low dimensional non-linear surface (i.e., the manifold) where most of the data lies-are good candidates for accomplishing this task. Here we explore this possibility in detail. First, we discuss why one should expect tv FC data to lie on a low dimensional manifold. Second, we estimate what is the intrinsic dimension ( ID ; i.e., minimum number of latent dimensions) of tvFC data manifolds. Third, we describe the inner workings of three state-of-the-art MLTs : Laplacian Eigenmaps ( LEs ), T-distributed Stochastic Neighbor Embedding ( T-SNE ), and Uniform Manifold Approximation and Projection ( UMAP ). For each method, we empirically evaluate its ability to generate neuro-biologically meaningful representations of tvFC data, as well as their robustness against hyper-parameter selection. Our results show that tvFC data has an ID that ranges between 4 and 26, and that ID varies significantly between rest and task states. We also show how all three methods can effectively capture subject identity and task being performed: UMAP and T-SNE can capture these two levels of detail concurrently, but LE could only capture one at a time. We observed substantial variability in embedding quality across MLTs , and within- MLT as a function of hyper-parameter selection. To help alleviate this issue, we provide heuristics that can inform future studies. Finally, we also demonstrate the importance of feature normalization when combining data across subjects and the role that temporal autocorrelation plays in the application of MLTs to tvFC data. Overall, we conclude that while MLTs can be useful to generate summary views of labeled tvFC data, their application to unlabeled data such as resting-state remains challenging., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gonzalez-Castillo, Fernandez, Lam, Handwerker, Pereira and Bandettini.)

Context: Limited evidence exists regarding the assessment of single-item patient-reported outcomes when patients are medically cleared to return to sport after a lateral ankle sprain (LAS) injury., Objective: To evaluate self-reports of improvement in health status, pain, function, and disability at return to sport after an LAS., Design: Descriptive study., Setting: Sixty-nine athletic training facilities across 24 states., Patients or Other Participants: A total of 637 patients (males = 53.2%) who were diagnosed with an LAS, restricted from sport after injury, and subsequently medically cleared to return to sport within 60 days were included., Main Outcome Measure(s): Descriptive statistics were used to summarize scores for health status (Global Rating of Change), pain (Numeric Pain Rating Scale), function (Global Rating of Function), and disability (Global Rating of Disability). Mann-Whitney U tests were used to compare score differences between sexes. A Kaplan-Meier analysis was performed to provide a visual depiction of sex differences in the time to return to sport., Results: Most patients sustained an LAS injury while participating in basketball, football, or soccer and were cleared to return to sport 8 days after injury. More than two-thirds of patients reported a meaningful improvement in health status between the time of injury and return to sport. However, many noted deficits related to pain (65.1%), function (86.2%), or disability (35.8%) at return to sport. No differences were seen between males and females for pain (P = .90), function (P = .68), change in health status (P = .45), or disability (P = .21) at return to sport, although males returned to sport slightly sooner than females (P = .025)., Conclusions: Despite self-perceived improvements in health status since the time of injury, patients typically returned to sport with deficits in pain, function, and disability after an LAS. Patients may be returning to unrestricted sport participation before they feel their bodies have fully recovered from the injury., (© by the National Athletic Trainers’ Association, Inc.)

Injury prevention and rehabilitation research often address variables that would be considered clinician-oriented outcomes, such as strength, range of motion, laxity, and return-to-sport. While clinician-oriented variables are helpful in describing the physiological recovery from injury, they neglect the patient perspective and aspects of patient-centered care. Variables that capture patient perspective are essential when considering the impact of injury and recovery on the lives of patients. The inclusion of patient-reported outcome measures (PROMs) as dependent variables in sports medicine research, including injury prevention and rehabilitation research, provides a unique perspective regarding the patient's perception of their health status, the effectiveness of treatments, and other information that the patient deems important to their care. Over the last 20 years, there has been a significant increase in the use of PROMs in sports medicine research. The growing body of work gives opportunity to reflect on what has been done and to provide some ideas of how to strengthen the evidence moving forward. This mini-review will discuss ideas for the inclusion of PROMs in sports medicine research, with a focus on critical factors, gaps, and future directions in this area of research. Important elements of research with PROMs, including instrument selection, administration, and interpretation, will be discussed and areas for improvement, consideration, and standardization will be provided., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Snyder Valier, Huxel Bliven, Lam and Valovich McLeod.)

Recently, there has been an emphasis on collecting large datasets in the field of sports medicine. While there have been great advances in areas of sport performance and sport epidemiology, there have been fewer efforts dedicated to understanding the effectiveness and impact of athletic healthcare, including injury prevention programs and rehabilitation interventions provided at the point-of-care. In 2009, the Athletic Training Practice-Based Research Network (AT-PBRN) was launched to address this need, with the mission of improving the quality of care provided by athletic trainers. Unlike other research efforts in sports and medicine, such as sport epidemiology, there are fewer methodological best practices specifically related to clinical data in athletic healthcare. As a result, the AT-PBRN has encountered several methodological challenges during its tenure and has established guidelines based on various sources within the fields of sports and medicine to address these challenges. Therefore, the purpose of this perspective is to identify the challenges and describe strategies to address these challenges related to characterizing athletic healthcare using a large database. Specifically, challenges related to data entry (data quality and reliability) and data extraction and processing (data variability and missing data) will be discussed. Sharing challenges and perspectives on solutions for collecting and reporting on athletic healthcare data may facilitate a greater consistency in the approach used to collect, analyze, and report on clinical data in athletic healthcare, with the goal of improving patient outcomes and the quality of care provided by athletic trainers., Competing Interests: Author KL is the Director of the Athletic Training Practice-Based Research Network (AT-PBRN), which serves as the basis for this perspective. Also, authors KL, AS, TV, and AM hold a role of “scientist” within the AT-PBRN., (Copyright © 2022 Lam, Snyder Valier, Valovich McLeod and Marshall.)

Context: Ankle sprains are common during sport participation and associated with long-term deficits in self-report of function. However, little is known of short-term changes in self-report of function following injury. The authors aimed to assess statistical and clinically meaningful changes in self-report of function, as measured by the Foot and Ankle Ability Measure (FAAM), during the first 2 weeks after an ankle sprain injury., Design: A retrospective analysis of electronic medical records., Methods: Eighty-eight patients, who were diagnosed with an ankle sprain injury by an athletic trainer, received usual care from an athletic trainer, and completed the FAAM during treatment at weeks 1 and 2 postinjury. The authors calculated the percentage of patients who reported clinically meaningful changes and used Wilcoxon signed-rank tests to compare differences in FAAM scores between time points., Results: Between weeks 1 and 2, significant differences were noted for the FAAM Activities of Daily Living (FAAM-ADL) (P < .001) and FAAM Sport (FAAM-Sport) (P < .001). At the patient level, 86.5% (64/74) and 85.2% (69/81) of patients reported changes that exceeded the minimal clinically important difference value for the FAAM-ADL and FAAM-Sport, respectively, between weeks 1 and 2. At week 2, 31.8% (28/88) and 47.7% (42/88) of patients reported a score below 90% on the FAAM-ADL and below 80% on the FAAM-Sport subscale, respectively. Also, 36.4% (32/88) and 25.0% (22/88) of patients reported a score of 100% on the FAAM-ADL and FAAM-Sport subscales, respectively, at week 2., Conclusions: Patients report statistically significant and meaningful improvements in self-report of function during the first 2 weeks following ankle sprain injury. However, almost half of patients still report deficits in sport function at 2 weeks postinjury. Patient-reported outcome measures such as the FAAM, can help capture the patient's perception of function and inform patient care decisions. Research efforts should explore individual response patterns to treatment.

Background: Odontoid process fractures are among the most common in elderly cervical spines. Their treatment often requires fixation, which may include use of implants anteriorly or posteriorly. Bone density can significantly affect the outcomes of these procedures. Currently, little is known about bone mineral density (BMD) distributions within cervical spine in elderly. This study documented BMD distribution across various anatomical regions of elderly cervical vertebrae., Methods and Findings: Twenty-three human cadaveric C1-C5 spine segments (14 males and 9 female, 74±9.3 y.o.) were imaged via quantitative CT-scan. Using an established experimental protocol, the three-dimensional shapes of the vertebrae were reconstructed from CT images and partitioned in bone regions (4 regions for C1, 14 regions for C2 and 12 regions for C3-5). The BMD was calculated from the Hounsfield units via calibration phantom. For each vertebral level, effects of gender and anatomical bone region on BMD distribution were investigated via pertinent statistical tools. Data trends suggested that BMD was higher in female vertebrae when compared to male ones. In C1, the highest BMD was found in the posterior portion of the bone. In C2, BMD at the dens was the highest, followed by lamina and spinous process, and the posterior aspect of the vertebral body. In C3-5, lateral masses, lamina, and spinous processes were characterized by the largest values of BMD, followed by the posterior vertebral body., Conclusions: The higher BMD values characterizing the posterior aspects of vertebrae suggest that, in the elderly, posterior surgical approaches may offer a better fixation quality., Competing Interests: The authors have declared that no competing interests exist.

Context: The effective use of electronic records (ie, electronic health records or electronic medical records) is essential to professional initiatives and the overall advancement of the athletic training profession. However, evidence suggests that comprehensive patient care documentation and widespread use of electronic records are still limited in athletic training. The lack of formal training and education for clinicians and students is often cited as a primary barrier to electronic record use. Other health care disciplines have used academic electronic health record (AEHR) systems to address these barriers with promising results., Objectives: To identify common challenges associated with the effective use of electronic records in clinical practice, discuss how an AEHR system can address these challenges and encourage more effective use of electronic records, and describe strategies for deploying AEHRs in the athletic training profession., Description: The AEHR is an electronic records system specifically designed for educational use to support simulation learning among all types of learners (eg, practicing clinicians, students). Mimicking the form and function of an electronic health record, the AEHR offers various educational tasks, including patient care documentation projects, critical reviews of standardized patient cases, and assessments of patient care data for quality improvement efforts., Clinical and Research Advantages: Recent evidence suggests that the use of an AEHR can improve knowledge and enhance skills. Specifically, AEHR use has been associated with enhanced attitudes toward electronic health record technology, increased informatics competencies, and improved documentation skills. Also, the use of an AEHR has been associated with improved critical thinking and decision-making skills. This tool appears to be valuable for health professions education, and athletic training stands to benefit from its use to better train and upskill clinicians and students alike for clinical practice. Although the implementation of an AEHR will require much time and large-scale coordinated efforts, it will be a worthy investment to address current challenges and advance the athletic training profession., (© by the National Athletic Trainers' Association, Inc.)

Background: The spread of the coronavirus disease 2019 (COVID-19) has increasingly agonized daily lives worldwide. As an archipelagic country, Indonesia has various physical and social environments, which implies that each region has a different response to the pandemic. This study aims to analyze the spatial differentiation of COVID-19 in Indonesia and its interactions with socioenvironmental factors., Methods: The socioenvironmental factors include seven variables, namely, the internet development index, literacy index, average temperature, urban index, poverty rate, population density (PD) and commuter worker (CW) rate. The multiple linear regression (MLR) and geographically weighted regression (GWR) models are used to analyze the impact of the socioenvironmental factors on COVID-19 cases. COVID-19 data is obtained from the Indonesian Ministry of Health until November 30th 2020., Results: Results show that the COVID-19 cases in Indonesia are concentrated in Java, which is a densely populated area with high urbanization and industrialization. The other provinces with numerous confirmed COVID-19 cases include South Sulawesi, Bali, and North Sumatra. This study shows that the socioenvironmental factors, simultaneously, influence the increasing of confirmed COVID-19 cases in the 34 provinces of Indonesia. Spatial interactions between the variables in the GWR model are relatively better than those between the variables in the MLR model. The highest spatial tendency is observed outside Java, such as in East Nusa Tenggara, West Nusa Tenggara, and Bali., Conclusion: Priority for mitigation and outbreak management should be high in areas with high PD, urbanized spaces, and CW., (© 2022. The Author(s).)

Rice is an important cereal and a staple food in many countries in the world. Climate change is a significant challenge that affects paddy production and threatens food security. However, research and development in this area continue to work to ensure the supply of rice fulfils the demands of the population. The study aims to analyse the transformation of international research power in trends in climate change that threaten food security (rice) worldwide. This study evaluates existing publications, especially research works from the period 1970 to 2020. The Web of Science database and the VOSviewer software were used together to generate a systematic analysis. A total of 1181 publications on climate change and paddy production were identified, written by 2249 authors from 56 countries. The highest number of publications was from China with 240 publications with 4609 citations, followed by India, with 225 publications and 2070 citations. Yield and adaptation are the most frequently used keywords that reflect this field's current significant research direction. Besides that, developing countries have received greater attention from researchers to focus on science, agriculture, climatology, and agriculture engineering as their domains. Therefore, socio-economic aspects should also be highlighted to raise awareness of the dangers of climate change and improve the farmers' economy by increasing paddy production. Attention was given by all countries globally, especially by researchers and stakeholders who need to plan holistic policies and strategies to encourage sustainable rice production and at the same time reduce the impact of climate change worldwide., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Despite a call to incorporate patient-reported outcome measures (PROMs) into all aspects of health care, little is known about which instruments are best suited for a pediatric patient population with sport-related injury. The objective of this article was to perform a systematic review of the currently available evidence to determine which PROMs were used for pediatric patients with sport-related injuries and identify the associated psychometric properties and considerations for clinical utility. We conducted a literature search for articles on PROMs used in the pediatric population through electronic databases and a manual search of reference lists and authors between from inception to 2020. Articles were grouped based on the PROM(s) included, and considerations for clinical utility and psychometric properties were extracted from each article. Thirty-nine articles were included in this review, from which 22 PROMs were identified: 12 PROMs were developed specifically for the pediatric population, 4 were modified versions of an adult scale, and 6 were adult measures used in a pediatric population. Of the PROMs included in this review, the Oxford Ankle Foot Questionnaire for Children and the Pediatric Quality of Life Inventory were the most comprehensive in their development and assessment. Several outcome measures used for pediatric patients had missing or inadequate measurement properties and considerations for clinical utility, particularly in regard to readability, responsiveness, and interpretability. Clinicians and researchers should consider a measure's feasibility, acceptability, appropriateness, and psychometric properties when selecting a PROM for use with the pediatric population., (© by the National Athletic Trainers' Association, Inc.)

Background: Afatinib has been shown as a suitable option for the treatment of epidermal growth factor receptor mutation-positive (EGFRm+) non-small-cell lung cancer (NSCLC) in randomized controlled trials. However, patients treated in real-world clinical practice, including elderly patients, and those with brain metastases or poor Eastern Cooperative Oncology Group (ECOG) performance statuses, are often excluded from these studies., Objective: To report the final results, with a particular focus on patients enrolled in China, from a prospective phase IIIb, "near real-world" study of afatinib in tyrosine kinase inhibitor (TKI)-naïve Asian patients with EGFRm+ NSCLC., Patients and Methods: NCT01953913 was conducted at 34 centers across Asia. Entry criteria were broad to reflect real-world settings. Patients received afatinib 40 mg/day until tumor progression, lack of clinical benefit, or poor tolerability. Assessments included safety, time to symptomatic progression (TTSP), and progression-free survival (PFS)., Results: 541 patients were treated, of whom 412 were enrolled in China. Dose reductions were implemented in 28.7% of patients overall, and 17.7% of patients from China. Safety findings were consistent with phase III studies of afatinib. Median TTSP in all patients was 14.0 months (95% CI 12.9-15.9), and median PFS was 12.1 months (95% CI 11.0-13.6). Median TTSP (13.8 months, 95% CI 12.7-16.1) and PFS (11.4 months, 95% CI 10.9-13.7) were similar in patients from China to the overall population. Among patients from China who had dose reductions, TTSP was numerically longer than in those who did not (16.4 vs. 13.8 months; P = 0.0703), while PFS was significantly longer (13.9 vs. 11.1 months; P = 0.0275). Among patients from China with brain metastases, TTSP was numerically shorter than in those without (11.0 vs. 14.4 months; P = 0.0869), whereas PFS was significantly shorter (9.2 vs. 12.9 months; P = 0.0075)., Conclusions: Safety data for afatinib when used in a "near real-world" setting in patients with EGFRm+ NSCLC was consistent with the known safety profile of afatinib. Supporting efficacy data of afatinib were provided in all patients, and in those enrolled in China. Tolerability-guided afatinib dose reduction allowed patients to remain on treatment and continue to experience clinical benefit., Trial Registration Number and Date of Registration: NCT01953913 (1 October 2013)., (© 2021. The Author(s).)

As the athletic training profession continues to embrace evidence-based practice, athletic trainers should not only critically appraise the best available evidence but also effectively translate it into clinical practice to optimize patient outcomes. Whereas previous authors investigated the effectiveness of educational interventions on increasing knowledge of critical appraisal of evidence, little attention has been given to strategies for both researchers and clinicians to effectively translate evidence into clinical practice. The use of knowledge translation strategies has the potential to bridge the knowledge-to-practice gap, which could lead to reduced health costs, improved patient outcomes, and enhanced quality of care. The purpose of this article is to (1) highlight the current challenges preventing the successful translation of evidence into practice, (2) discuss knowledge translation and describe the conceptual frameworks behind the effective translation of evidence into practice, and (3) identify considerations for athletic trainers as they continue to provide high-quality patient care in an evidence-based manner., (© by the National Athletic Trainers' Association, Inc.)

The tumor microenvironment (TME) influences cancer progression and therapy response. Therefore, understanding what regulates the TME immune compartment is vital. Here we show that microbiota signals program mononuclear phagocytes in the TME toward immunostimulatory monocytes and dendritic cells (DCs). Single-cell RNA sequencing revealed that absence of microbiota skews the TME toward pro-tumorigenic macrophages. Mechanistically, we show that microbiota-derived stimulator of interferon genes (STING) agonists induce type I interferon (IFN-I) production by intratumoral monocytes to regulate macrophage polarization and natural killer (NK) cell-DC crosstalk. Microbiota modulation with a high-fiber diet triggered the intratumoral IFN-I-NK cell-DC axis and improved the efficacy of immune checkpoint blockade (ICB). We validated our findings in individuals with melanoma treated with ICB and showed that the predicted intratumoral IFN-I and immune compositional differences between responder and non-responder individuals can be transferred by fecal microbiota transplantation. Our study uncovers a mechanistic link between the microbiota and the innate TME that can be harnessed to improve cancer therapies., Competing Interests: Declaration of interests J.A.W. is an inventor on a US patent application (PCT/US17/53.717) relevant to the current work; reports compensation for speaker’s bureau and honoraria from Imedex, Dava Oncology, Omniprex, Illumina, Gilead, PeerView, MedImmune, and Bristol-Myers Squibb (BMS); and serves as a consultant/advisory board member for Roche/Genentech, Novartis, AstraZeneca, GlaxoSmithKline, BMS, Merck, Biothera Pharmaceuticals, and Micronoma. All other authors have no competing interests., (Published by Elsevier Inc.)

A recent report in Nature Medicine pinpoints a role for gut microbiota in response and toxicity to combined immune checkpoint blockade targeting CTLA-4 and PD-1. This emergent study provides insights that can be used to leverage microbiota in the design of anticancer therapies to mitigate toxicity while enhancing efficacy., (Published by Elsevier Inc.)

Background: Updated rates and patterns associated with patients with dance-related injuries reporting to US emergency departments (EDs) is needed., Hypothesis: Between the years 2014 and 2018, there will be an observed rise of patients with dance-related injuries seen within US EDs., Study Design: Retrospective analysis., Level of Evidence: Level 4., Methods: Utilizing the National Electronic Injury Surveillance System (NEISS) database, data were abstracted for all structured dance-related injuries for all people who presented to a NEISS participating hospital from January 1, 2014, to December 31, 2018. Data were abstracted on age, sex, race, disposition, location on the body where the injury happened, and free text box regarding the mechanism and nature of the injury. Each patient case was associated with a weight to provide national incidence rate (per 100,000) estimates. Descriptive statistics were used to summarize counts, percentages, and rates across patient cases., Results: Between years 2014 and 2018, 4152 patients reported to the NEISS EDs with a dance-related injury. Most injuries occurred in female patients (83.3%; n = 3459) and among those who were 10 to 18 years old (76.2%; n = 3164). The most common injuries were ankle sprain/strain (12.7%; n = 527) and knee sprain/strain (10.4%; n = 431). Almost all patients were treated and released (97.1%; n = 4033). These data yielded population-weighted estimates of 125,618 injuries for the study period, with an increasing trend over time (19.2% increase over 5 years). Incidence rates were over 4 times higher for female (12.4) than for male patients (3.0) and highest in the 10- to 18-year-old age group (incidence rate = 46.4)., Conclusion: Patients with dance-related injuries reporting to EDs increased over a 5-year period from 2014 to 2018. The majority of dancers in the study were female patients, between the ages of 10 and 18 years, nearly half of the patients reported to the ED with a sprain/strain, and almost all patients were treated and released., Clinical Relevance: An increase in access to proper injury prevention medical services and education should be provided to female dancers between the ages of 10 and 18 years., Strength of Recommendation Taxonomy: B.

Context: Knee injuries are common during sport participation. However, little is known about the overall management and estimated direct costs of care associated with these injuries when under the care of athletic trainers., Objective: To describe the treatment characteristics and direct costs of care for athletic training services provided for patients with knee injuries., Design: Descriptive study., Setting: Ninety-five athletic training facilities across 24 states., Patients or Other Participants: A total of 117 athletic trainers (females = 56.4%, age = 29.4 ± 8.7 years, years certified = 4.7 ± 6.0, years employed at site = 1.6 ± 4.1)., Main Outcome Measure(s): Complete patient cases were identified using International Classification of Disease-10 diagnostic codes between 2009 and 2020. Summary statistics were calculated for patient demographics, treatment characteristics, and direct costs of care. Treatment characteristics included the type of athletic training service, duration, amount (eg, number of visits), and direct costs of care., Results: A total of 441 patient cases were included. The most common injuries reported were cruciate ligament sprain (18.1%, n = 80), medial collateral ligament sprain (15.4%, n = 68), and knee pain (14.1%, n = 62). Injuries occurred most frequently during football (35.4%, n = 156), basketball (14.7%, n = 65), and soccer (12.7%, n = 56). A total of 8484 athletic training services were recorded over 4254 visits, with therapeutic exercise (29.8%, n = 2530), hot or cold pack (25.8%, n = 2189), and therapeutic activities (11.2%, n = 954) being the most frequently reported services. The median duration of care was 23 days and number of visits was 8. The median total cost of care was $564 per injury and $73 per visit., Conclusions: Patients with knee injuries demonstrated greater time loss than those with other lower extremity injuries. Thus, it is unsurprising that knee injuries were associated with a longer duration and higher cost of care than other lower extremity injuries such as ankle sprains. Future researchers should examine the effectiveness of common treatment strategies and aim to identify treatments that can reduce costs and improve patient outcomes., (© by the National Athletic Trainers' Association, Inc.)

Aims: Multiple studies have shown conflicting results on the correlation between the EGFR T790M quantitative level and survival outcomes in osimertinib-treated patients. We sought to validate such correlations using data from an osimertinib early access programme (EAP) providing access for metastatic non-small cell lung cancer patients with limited treatment options., Patients and Methods: This observational, multicentre, retrospective analysis included EAP participants who received osimertinib until disease progression, intolerable toxicities or death. Digital droplet polymerase chain reaction-based quantitative plasma genotyping was carried out upon disease progression and data were analysed to explore the relationships between T790M mutant allele fraction (MAF), T790M copy number, MAF ratio and post-osimertinib overall survival. Real-world treatment outcomes and safety were also evaluated., Results: Data from 156 EAP participants were analysed (median follow-up 37.7 months). The median age was 62 years, 62.2% were women, 79.5% were never-smokers, 60.9% had Eastern Cooperative Oncology Group performance status 0/1. In patients with available plasma data (n = 114), T790M MAF (%) showed no significant relationships with overall survival (hazard ratio 1.02; 95% confidence interval 0.99-1.04) or time to treatment discontinuation (TTD) (hazard ratio 1.01; 95% confidence interval 0.98-1.04). Absolute T790M copy number and T790M to activating EGFR mutation MAF ratio also showed no prognostic value. The investigator-assessed response rate was 42.3% and the disease control rate was 85.5%. The median TTD was 15.8 (95% confidence interval 12.5-18.5) months and the median overall survival was 22.3 (95% confidence interval 18.6-26.1) months., Conclusion: T790M MAF did not correlate with TTD or overall survival in this EAP cohort but limitations should not be overlooked. Observed survival outcomes and the toxicity profile were consistent with data from other real-world series., (Copyright © 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Prime editing (PE) is a versatile genome editing technology, but design of the required guide RNAs is more complex than for standard CRISPR-based nucleases or base editors. Here we describe PrimeDesign, a user-friendly, end-to-end web application and command-line tool for the design of PE experiments. PrimeDesign can be used for single and combination editing applications, as well as genome-wide and saturation mutagenesis screens. Using PrimeDesign, we construct PrimeVar, a comprehensive and searchable database that includes candidate prime editing guide RNA (pegRNA) and nicking sgRNA (ngRNA) combinations for installing or correcting >68,500 pathogenic human genetic variants from the ClinVar database. Finally, we use PrimeDesign to design pegRNAs/ngRNAs to install a variety of human pathogenic variants in human cells.

Context: Cross-country is a popular sport activity, particularly in adolescent populations. Although epidemiologic investigations have provided insight into patient and injury characteristics associated with running injuries, little is known about how these injuries are managed at the point of care., Objective: To describe injury and treatment characteristics of injuries sustained during cross-country., Design: Cross-sectional study., Setting: High school athletic training clinics within the Athletic Training Practice-Based Research Network., Patients or Other Participants: Patient cases were included if the patient was diagnosed with an injury that occurred during interscholastic cross-country participation. All patients received usual care by an athletic trainer., Main Outcome Measure(s): We used summary statistics to describe injury (sex, age, participation level, time of injury, mechanism of injury, body part, injury type, diagnosis) and treatment (type, amount, duration, number of services) characteristics., Results: Most cross-country injuries occurred to the lower extremity and were musculotendinous or ligamentous in nature. The most common injury types were sprain/strain (43.8%), tendinopathy (18.5%), and general pain (9.5%). Injured body parts and diagnoses were typically similar between sexes. The most frequently used treatment was therapeutic exercises or activities (28.7%), and patients received an average of 7.4 ± 17.4 total athletic training services during 5.5 ± 15.1 episodes of care over 27.8 ± 87.5 days., Conclusions: Adolescent cross-country student-athletes frequently sustained non-time-loss injuries that required up to 1 month of treatment and management. These findings will generate awareness surrounding the role of athletic trainers in providing care for cross-country athletes., (© by the National Athletic Trainers' Association, Inc.)