It is thus reasonable that substantial effort has been allocated towards the development of the improved and optimized LV systems for effective and accurate gene-to-cell transfer of CRISPR/Cas tools. The main effort on that end has been put towards the improvement and optimization of the vector’s expression, development of integrase-deficient lentiviral vector (IDLV), aiming to minimize the risk of oncogenicity, toxicity, and pathogenicity, and enhancing manufacturing protocols for clinical applications required large-scale production. In this review, we will devote attention to (i) the basic biology of lentiviruses, and (ii) recent advances in the development of safer and more efficient CRISPR/Cas vector systems towards their use in preclinical and clinical applications. In addition, we will discuss in detail the recent progress in the repurposing of CRISPR/Cas systems related to base-editing and prime-editing applications.CRISPR/Cas technology has revolutionized the fields of the genome- and epigenome-editing by supplying unparalleled control over genomic sequences and expression. Lentiviral vector (LV) systems are one of the main delivery vehicles for the CRISPR/Cas systems due to ( The polycistronic gag gene encodes three products, namely matrix (MA), capsid (CA), and nucleoproteins (NC). The polycistronic pol gene supplies three viral enzymes, namely reverse transcriptase (RT), protease (PR), and integrase (IN)  from the nucleus into the cytoplasm ..gag and  release A. The reev genes B and 9]gag and pthe LTRs C. Insteaassettes D. In facytoplasm . The advytoplasm ,10. Moreytoplasm ,12. ImpoLys3, which supplies a specific primer for the RT-mediated amplification. The PPT element comprises a purine-rich stretch of nucleotides that are resistant to RNase H-mediated degradation of positive strand of vRNA; the undegraded PPT sequence can then act as a primer towards the positive strand synthesis. As mentioned above, the completion of the RT reaction results in double stranded, linear DNA (reviewed in [int gene encodes the protein integrase (IN), which mediates the integration process by binding to and cleavage within the att sites located on the LTR ends [Attachment, binding and entry of the lentivirus is mediated via interaction between the envelope protein and its receptor. Following entry and uncoating, the reverse transcriptase enzyme (RT) is set to start the reverse transcription reaction. The product of the RT reaction is double-stranded (ds) linear DNA. The first step in the RT process depends on two cis-acting elements located within the viral RNA: the primer binding site (PBS) and the polypurine tract (PPT). The PBS is recognized by tRNAiewed in ). It is iewed in ). After LTR ends ,14,15. TLTR ends . The RT As mentioned above, the use of heterologous promoters, e.g., CMV or RSV, instead of the endogenous HIV-1 promoter located in the 5′-LTR, enabled an independence from the Tat protein, which greatly improved the vector’s safety ,18,19. SDespite significant improvement in viral safety, simple retroviruses, e.g., γ-retroviruses have a relatively high risk of insertional mutagenesis (reviewed in ). In facThe above applications required stable and long-lasting expression of the therapeutic transgenes supported by integrase-competent retro- and lentiviruses. Nevertheless, permanently expressed CRISPR/Cas systems being seen rather as substantial disadvantage, as stable expression of their components may facilitate undesirable off-target effects, hindering their utility for genome- and epigenome-editing applications . Indeed,int gene [To that end, we and others worked on the development of an integrase-deficient lentiviral vector (IDLV). IDLVs can be generated by creating non-pleiotropic (class II) mutations within the int gene . Point mint gene ,33. Notaint gene ,35. Moreint gene . Importaint gene ,35,36. Mint gene . Importaint gene . We deteint gene ,39. The int gene ,39. As sThis review is devoted to lentiviral vectors; however, it would be remiss not to mention the most frequently used viral platform for gene therapy, adeno-associated vector (AAV) (reviewed in ). AAV isThe clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein (Cas) system has recently evolved to be a revolutionary platform for both genome- and epigenome-editing manipulations in a broad range of tissues and organs. CRISPR/Cas has tremendously advanced our understanding of hereditary diseases by enabling the rapid generation of novel cellular and animal models. Furthermore, CRISPR/Cas has become a valuable and effective option for the treatment of many diseases and disorders which would otherwise be incurable. In this review, we aim to highlight the ongoing development of innovative gene-editing tools used with LV platforms in a broad range of research and clinical applications.In nature, CRISPR/Cas systems act as a prokaryotic adaptive immunity mechanism to recognize, target, and destroy the foreign DNA and RNA of phages and viruses ,44. The As mentioned above, cleavage mediated by Cas9 results in the generation of DSBs . EukaryoSNCA. Dysregulation of SNCA expression is one of the causative factors for Parkinson’s disease (PD) [SNCA triplication resulted in robust and steady downregulation of SNCA mRNA and protein levels, mediated by targeted DNA methylation at a regulatory sequence located in intron 1 of SNCA. We further demonstrated that this reduction in SNCA levels is capable of rescuing disease-related phenotypes. This developed approach suggests broad potential for this target sequence combined with LV-CRISPR-dCas9 technology as a novel epigenetic-based therapeutic strategy for various cases of PD [The ability of Cas9 to bind to specific sequences with strong affinity is of immense value in and of itself, independently of its endonuclease-enzymatic activity. Cas9 is a modular enzyme that possesses well-characterized catalytic domains. The amino acid residues that are necessary for the endonucleic activity of the enzyme are located in the RuvC and HNH domains ,58. It hase (PD) . The syses of PD .Generally, the most common genetic variants associated with hereditary diseases in humans are point mutations and functional single-nucleotide polymorphisms (SNPs) characterized by high-level penetration . TherefoStreptococcus pyogenes (SpCas9). The incompatibility is due to the low DNA-bound residence-time of non-SpCas9, coupled with the decelerated enzymatic pace of deoxyadenosine deaminase [DMB gene in 17% of myofibers, with no measurable InDels or other off-target effects. It has to be pointed out that this rate of gene correction is therapeutic, considering the threshold level of 4% of the gene expression that is needed to correct muscle function [The development of an adenosine base editor (ABE) platform supporting A-to-G transitions vastly broadened the applications of base editing B. The oreaminase . To circeaminase . ABE8e aeaminase . This nofunction . Most refunction . These dThe majority of mutations linked to human genetic diseases are transitions; nevertheless, according with ClinVar database, correcting about 40% of the hereditary diseases would require transforming a purine-base nucleotide into pyrimidine-base nucleotide or vice versa. Thus, the bottleneck of the base-editing technology was recently addressed by David Liu’s group, who found a very elegant way to address this problem. In their recent publication, entitled “Search-and-replace genome editing without double-strand breaks or donor DNA,” Anzalone et al. described a new method of genome editing based on the rewriting genetic information into a specified DNA site using a dCas9 or nCas9 fused to an engineered viral reverse transcriptase (RT), paired with a prime editing guide RNA (pegRNA) that both specifies the target sequence and encodes the edit-of-interest  and Fig. The autEffective gene-editing using the CRISPR-Cas9 system can only be achieved through efficient delivery of all elements into target cells. Given the proven efficacy and the improved safety of lentiviral vectors for the delivery of therapeutic genes, lentiviral delivery platforms were among the first to be developed and adapted for genome-editing applications In fact, as soon as CRISPR-Cas9 system was reported to function in human cells, all-in-one lentiviral vectors expressing both Cas9 and sgRNAs were designed and constructed . In prinCRISPR/Cas technology has revolutionized all aspects of modern life science research, ranging from basic science to clinical research. Importantly, recent progress in lentiviral vectorology has fully supported and enabled robust and efficient delivery of CRISPR/Cas tools into tissues- and organs-of-interest in vivo, opening doors for novel approaches and strategies previously unimaginable. While these innovative technologies and tools continue to progress, several key issues still need to be solved. One of the issues is the relatively high levels of undesirable off-target effects induced as the consequence of permanent expression of CRISPR/Cas9 tools delivered by LVs. In addition to causing undesirable effects outside of the targeted gene or region, integrating lentivirus  is capable of inducing measurable levels of toxicity and pathogenicity, stemming mostly from its oncogenic potential. Unfortunately, other viral delivery platforms are not fully detached from the adverse effects generally associated with viruses and may cause tragic outcomes. ,72,73. A


We also applied principal component analysis to compare the metallomic pattern of VaD in the hippocampus with our previous hippocampal metal datasets for Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and type-2 diabetes, which had been measured using the same methodology. We found substantive novel evidence for elevated hippocampal Na levels and Na/K ratios in both wet- and dry-weight analyses, whereas decreased K levels were present only in wet tissue. Multivariate analysis revealed no distinguishable hippocampal differences in metal-evoked patterns between these dementia-causing diseases in this study. Contrasting levels of Na and K in hippocampal VaD tissue may suggest dysfunction of the Na+/K+-exchanging ATPase (EC 7.2.2.13), possibly stemming from deficient metabolic energy (ATP) generation. These findings therefore highlight the potential diagnostic importance of cerebral sodium measurement in VaD patients.Vascular dementia (VaD) is thought to be the second most common cause of age-related dementia amongst the elderly. However, at present, there are no available disease-modifying therapies for VaD, probably due to insufficient understanding about the molecular basis of the disease. While the notion of metal dyshomeostasis in various age-related dementias has gained considerable attention in recent years, there remains little comparable investigation in VaD. To address this evident gap, we employed inductively coupled-plasma mass spectrometry to measure the concentrations of nine essential metals in both dry- and wet-weight hippocampal  Within the spectrum of age-related dementias, vascular dementia (VaD) is widely recognized as the second leading cause of dementia after Alzheimer’s disease (AD), and accounts for about 20% of all cases . VaD is post-mortem evidence suggests that AD cases also exhibit a high frequency of cerebrovascular pathology  and non-demented age- and sex-matched controls (n = 10). Increased sodium and decreased potassium levels were evident in VaD cases compared to controls; however, no evidence for cerebral copper or iron perturbations in VaD cases was observed here. These data are consistent with possible effects of energy deficiency and decreased sodium-potassium pump (Na+/K+-ATPase) activity, which could contribute to hippocampal atrophy and cognitive impairment in VaD.Given the similarity between AD and VaD, our research hypothesis was that hippocampal-copper levels in VaD cases would be lowered to levels similar to those previously reported in AD . Althougpost-mortem VaD/control tissue received local Research Ethics Committee approval (18/SW/0029) supplied by the South West Dementia Brain Bank (SWDBB), which is an NHS research ethics committee-approved tissue bank. Informed consent for the collection of tissue for the VaD/control study was obtained by the SWDBB. Consent for collection of tissue for the AD, HD, PDD and type 2 diabetes (T2D) tissue was as previously stated , and no histopathological evidence of other neurological diseases likely to cause dementia. Controls had no history of dementia and no other neurological abnormalities. While all VaD cases displayed histopathological evidence of VaD, the use of the Montreal Cognitive Assessment, which is seen as the superior neuropsychometric test for the assessment VaD  to ensure that the tissue sat at the bottom of the tubes. Concentrated nitric acid  and 5% Agilent Internal Standard mixture  was used to make the tissue digestion mixture. Calibration standards were prepared to the appropriate dilutions , a Scott double-post spray chamber and nickel sample and skimmer cones. Samples were introduced into the spray chamber using an Agilent integrated autosampler. Before each analysis, the peristaltic-pump sample tubing was replaced to limit abnormal sample delivery to the nebulizer. ICP-MS system optimization and performance reports were generated on Agilent MassHunter Workstation software  prior to each analysis to ensure consistent system performance.–1 He), except for selenium which was analyzed in high-energy helium mode  following Agilent’s recommendation to reduce interference by polyatomic ion formation. Germanium and indium internal standards were analyzed in both modes. Integration times for relevant trace metals were 3 s for Se; 0.01 s for Fe; 0.03 s for Mn, Cu, and Zn; and 0.1 s for Na, Mg, K, and Ca. A multi-element method using serial dilutions of environmental calibration standards , although the majority of the metals analyzed here were found to be normally distributed using the Shapiro–Wilk test . Statistical analyses were also performed on log-transformed datasets using Welch’s t-test following demonstration that the data were generally consistent with parametric analysis  were calculated and the significance of inter-group differences were determined by Mann–Whitney analysis , 3. Meanp-values < 0.05 were considered significant and p-values < 0.10 have also been tabulated. Sample-size estimates were based on observations from our previous studies, where n = 9 for each group was sufficient for ICP-MS analysis using human post-mortem brain tissue . n tissue . Post hov3.1.9.4 .To identify possible metallomic cluster separation between VaD and our previous T2D  and age-related dementia dry-weight datasets , princippost-mortem hippocampal tissue from 10 cases with VaD and 10 age-/sex-matched controls to gain an understanding of the metallomic differences in VaD. No significant case-control differences were observed for: age, post-mortem delay (PMD), brain weight, or dry-weight/wet-weight tissue ratios between control and VaD hippocampal tissue , which is linked to the development of dementia/cognitive impairment . DespiteU analysis revealed robust evidence for increased Na (p = 0.0015) and robust evidence for decreased K (p = 0.012) in VaD cases (p = 0.035) was observed in VaD cases. In addition, differences in Cu and Zn failed to reach our criteria for statistical significance   .Of the metals that were perturbed in hippocampal tissue, females displayed higher mean-metal levels for Na only in wet-weight tissue.t-tests on both dry- and wet-weight non-log- and log-transformed metal datasets (s). When using this parametric analysis, robust evidence for increased Na (p = 0.0018) and decreased K (p = 0.0089) in wet-weight tissue remained; however, in the dry-weight tissue, weak evidence for Cu (p = 0.0497) and Zn (p = 0.0498) perturbations, as well as increased Na levels (p = 0.024) were also evident . Therefore, we also performed independent Welch’s  evident , 3.No other physiological metals from both sets of analyses in the present study showed any significant case-control differences.To further understand the significance of the Na and K perturbations in VaD, Na/K ratios were calculated for both wet- and dry-weight hippocampal tissue. In both tissue conditions, mean Na/K ratios were higher in VaD cases  compared to controls , but not wet-weight K (79.7%), fulfilled this criterion , 5.post-mortem tissue from four age-related dementias, including: VaD (n = 10), AD (n = 9), HD (n = 9), and PDD (n = 9); as well as T2D  and grouped controls (n = 40) were included in the initial PCA. Prior to PCA, the suitability of the analytical methods was assessed. The Kaiser-Meyer-Olkin measure for sampling accuracy for the hippocampal dataset was 0.801, which provides robust evidence for the adequacy of these datasets for PCA. Bartlett’s test of sphericity was statistically significant , providing strong evidence for significant correlation between variables to support data reduction. Visual examination of the scree plot for the first nine principal components (PCs) justified the use of PC1 and PC2, which together explained 65.5% of the total variance within the dataset  and Zn (−0.398) for PC1 and Ca (0.470) and K (−0.428) for PC2 were the highest , the Kaiser-Meyer-Olkin measure for sampling accuracy revealed that the VaD vs AD comparison had a score of 0.404, thus suggesting its inadequacy for factor analysis. All other comparisons scored > 0.6 using the Kaiser-Meyer-Olkin measure for sampling accuracy.Lastly, to better understand disease specific relationships, pairwise PCA comparisons between VaD and the other dementia-causing diseases were made; however, no visible separation was apparent across all pairwise disease comparisons . While apost-mortem tissue.Although VaD is widely viewed as the second leading cause of dementia amongst the elderly, post-mortem hippocampal tissue from 10 VaD cases and 10 matched controls. No differences in PMD, brain weight, wet-weight/dry-weight ratio, or age were identified between VaD cases and controls in the present study. Therefore, we determined that case-control differences in brain-metal concentrations were unlikely to be affected by tissue variability in this study. In addition, although the duration of PMD is suggested to affect protein and metabolite expression, based on our group’s previous findings, it is unlikely that the PMDs presented in this study significantly altered brain-metal levels  subunits  may be a risk factor for cardiovascular disease and stroke . Howeverpost-mortem brain tissue, if these ratios can be replicated in VaD patient urine samples, for example, then the measurement of Na/K ratios may prove to be informative if used as an additive measure for the identification of at-risk individuals. However, further research is first required to see if such differences are also evident in preclinical VaD.Here, we found evidence for increased Na/K ratios for both wet- and dry-weight measurements in VaD brain tissue, as well as similar ratio increases in AD from our previous AD metallomic dataset . Althoug+/K+-ATPase also regulates cell volume . In contrast, although of borderline significance, mean Cu levels in wet-weight tissue were probably decreased in the VaD group. This difference between wet- and dry-weight measurements from the same tissue may well reflect the need for a larger sample size as there was a greater degree of wet-weight variability in the control group compared to the VaD group, which could have impacted the results. The notion that an increased sample size would be helpful is further supported by the low statistical power (<80%) observed for both dry- and wet-weight Cu measurements  and its use as a cofactor for various antioxidant enzymes . Previouurements , 5. Addip = 0.0497 and p = 0.0498, respectively) in wet-weight VaD hippocampal tissue using parametric analysis; the strength of this evidence concerning Cu or Zn levels in the hippocampus of VaD patients is weak and this matter requires further investigation.As there is little evidence surrounding the minimum recommended sample size for normality tests, which help determine whether the parametric assumptions are met, here, we have interpreted results from both parametric and non-parametric analyses. However, it is important to note that Na and K perturbations were observed using either type of analysis. The only differences observed were increased Cu and Zn  using the same methodology, PCA was conducted to further understand the metallomic differences observed in VaD in relation to these other neurodegenerative diseases. Although PCA is primarily employed in the testing of large datasets to reduce the number of dimensions, such unsupervised methods can also be particularly useful in revealing patterns in small-scale metallomic data. Prior testing using both the Kaiser-Meyer Olkin measure for sampling accuracy and Bartlett’s test for sphericity confirmed the utility of our multi-dementia dataset for PCA. However, no apparent discrimination was visible between all cohorts, including controls. Furthermore, the top loading scores, which represent the contribution of each metal to the PCs, only showed a modest relationship. This finding implies that despite evidence for cohort-specific metal perturbations in each of these diseases, when grouped together, the overall metallomic profile shows no distinguishable pattern. The hippocampus is understood to be a severely affected region in AD, but only a moderately affected region in VaD and T2D, and even less affected in PDD and HD. Therefore, under the assumption that brain-metal perturbations may be greater in more severely affected regions, data from diseases known to undergo less hippocampal atrophy may have had an impact here on PCA cluster separation, although, one would expect greater discrimination between cohorts based on diseases with low vs high hippocampal atrophy. Therefore, it may be necessary to perform a larger multiregional study to further understand the effects of different regions on PCA cluster separation. The absence of inter-group discrimination after PCA may have also been influenced by brain bank variability. In a study that assessed the influence of several covariates on human AD identity . As the post-mortem tissue. Taken together, these results present novel evidence for contrasting Na and K perturbations in VaD hippocampal tissue as a likely consequence of Na+/K+-ATPase dysfunction resulting from defective energy availability. While the idea of Na+/K+-ATPase dysfunction in VaD has been previously suggested (23Na magnetic resonance imaging, to further understand its diagnostic potential in neurodegenerative disease.In summary, to our knowledge, this is the first study to utilize ICP-MS to assess the metallomic status of hippocampal VaD uggested , the conThe original contributions presented in the study are included in the article/SP designed and performed the experiments, analyzed and interpreted the data, and wrote the manuscript. JX performed the experiments and revised the manuscript. SC performed the experiments and analyzed the data. MS performed the experiments, analyzed the data, and revised the manuscript. RU designed the experiments, interpreted the data, and revised the manuscript. GC designed the experiments, interpreted the data, revised the manuscript, and bears overall responsibility for the integrity of this manuscript and of the study. All authors contributed to the article and approved the submitted version.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Air-rifle and small-bore shooting are fascinating Olympic sports due to their unique performance requirements for accuracy and precision.The purpose of our study was to systematically research the literature to determine and summarize performance determinants in both air-rifle and small-bore shooting. Since some athletes participate internationally in both disciplines in competition, the disciplines must have some similarity in the performance structure. Therefore, we further investigated whether performance in air-rifle and small-bore shooting can be explained by the same performance determinants.We systematically searched in four databases using combined keywords relevant to performance in air-rifle and small-bore shooting. The articles included had undergone peer-review and had a) a direct relation to shooting performance, b) an indirect relation by comparing the performance of shooters of different skill levels, and c) a practical relevance (directly controllable through training). After the quality of each article was assessed, the key data were extracted and summarized.The fourteen articles included achieved an average of 60 ± 14% (range 30–80%) in quality assessment. Altogether, articles covered 268 subjects , of which 19% were elite- and 28% were national-level athletes. Sixteen performance determinants were investigated, which were divided into anthropometric, technical-coordinative, physiological and psychological categories. Both in air-rifle and small-bore shooting, rifle stability and body sway were found to differ between elite- and national-level athletes. In both disciplines, body sway seemed to have no influence on shot score in elite- and national-level athletes. Similarly, heart rate did not correlate with shot score at nearly all performance levels in both disciplines. In national-level air-rifle athletes, horizontal rifle stability, aiming accuracy and aiming time were found to affect shot score.To be competitive at a national-level in air-rifle shooting, a highly developed aiming process is needed to achieve a high shot score. Lack of data prevented us from drawing evidence-based conclusions in elite-level air-rifle athletes and in small-bore shooting. Future research should investigate possible performance determinants both in air-rifle and in small-bore shooting, especially with elite-level athletes, to confirm or disprove existing findings. Further research should use more complex analyses to investigate the multifaceted processes associated with different performance determinants. Shooting is an accuracy and precision sport that can be performed by any individual irrespective of age, sex and performance level . The spoIn air-rifle shooting, 60 shots are fired in the free-standing position and must be completed within 75 minutes. The target, which is 10 m away from the shooter, has a “ten” ring with a diameter of 0.5 mm and lower rings which follow each at a distance of 2.5 mm. In small-bore shooting, 120 shots are fired in three different positions: kneeling, prone and standing (40 shots each) and must be completed within 165 minutes. The target is 50 m away from the shooter and has a “ten” ring of 10.4 mm in diameter and lower rings that follow at 8.0 mm. In both disciplines, the rings are divided into decimal places, so that a maximum of 10.9 points can be scored per shot . For thiWhen looking at average shot scores from the 2019 European Games, it becomes evident that the average shot score for entering the finals in small-bore shooting was with 9.76 points for men and 9.68 points for women lower compared to air-rifle shooting, where at least 10.43 points per shot for women and 10.46 points per shot for men had to be scored to reach the final . The all-field-function was used except in the Pubmed database, where the search string was only used for the title and abstract. In addition, the reference lists of all included articles were searched manually, as well as publications of key researchers .The databases Pubmed and SciVerse Scopus, as well as the German high-performance databases BiSP-surf and Sponet were systematically searched on January 14First, all duplicate articles within the database were removed. Two independent reviewers (SS and HS) subsequently checked all titles, abstracts and full texts (in this order) for the inclusion and exclusion criteria. Next, the results of the two independent examinations were compared and, where opinions differed, a third reviewer (TS) was consulted. The selection process was repeated for articles identified by manual research strategies see .Only original research articles published in English from peer-reviewed journals and peer-reviewed conference papers were included. Other types of articles, such as letters to the editor, symposium reports, conference abstracts, technical publications, expert opinions, commentaries, and literature reviews were also excluded. Performance determinants should either be analyzed using direct relation to shot score or indirectly through differentiation between athletes of different skill levels. Studies that examined a different shooting discipline  or a rifle other than an air-rifle or small-bore caliber were excluded. In addition, studies were excluded if no clear assignment to air-rifle or small-bore shooting was made, i.e., if neither a description of the sample  nor the rifle type  or the international competition standards  were named. Studies were also excluded that examined mixed samples , in which no clear separation was made between the disciplines regarding the direct or indirect relation to shot score. Studies with a sample size below five or studies that examined impaired subjects  were also excluded. Studies using intervention programs or that investigated performance determinants that cannot be controlled by training , drugs or nutrition) were excluded.For quality assessment of the included articles, we used a modified version of the Downs and Black Quality Assessment Checklist  S2 Tabl. It is sa priori sample size calculation or a post-hoc power analysis was reported, and the power was sufficient; one point was given when an analysis was reported; and zero points were given if no power analysis was reported. We further changed the word “patient” to subject”.Several modifications had to be made as the checklist was originally developed for health care interventions. Since intervention studies were excluded, ten questions  could not be answered. For questions 5 and 25, age, skill-level, mean shot score and training and competition experience were defined as covariates. Two points were given when all covariates were reported, one point was given when two or three covariates were reported, and zero points were given when only one or no covariate was reported. For question 27, two points were given when either an The quality score was calculated as follows:  x 100%, with a maximum of 18 points. Therefore, higher scores indicate better study quality. Quality assessment for all included articles was made by SS and HS, and again a third reviewer (TS) was consulted in case of discrepancies. All articles were included independently of their quality score.Data concerning the study aims, subjects, experimental protocol, examined parameters and major findings were extracted and analyzed using Microsoft Excel Professional Plus 2019 . For literature search and administration Citavi 6  was used. Data extraction was done by one reviewer (SS).620 articles were extracted from the databases and 588 articles remained after duplicate removal. When titles, abstracts and full texts were screened, 14 articles that met the inclusion criteria remained. Ten articles were found for air-rifle shooting and four for small-bore shooting. The average quality score of the 14 articles was 56 ± 13% (range 30–73%). Most quality points were lost due to lack of subject data , lack of control for possible covariates, lack of precise reporting of significance level, lack of power analyses, and lack of reliability/validity data of the measuring instruments.In total, 268 subjects were included, 77% in air-rifle and 23% in small-bore shooting. The mean sample size was 19 ± 14 subjects (range 6–55) per study. Most subjects (60%) were male, 32% were female and for one study sex was not specified. The mean age of subjects across the studies was 23.8 ± 4.1 years, but five studies did not mention the age of their subjects and five studies reported only the mean age or the age range without specifying the dispersion. Of the 268 athletes, 19% were ranked as international or elite-level athletes, 28% were ranked as national-level athletes, 14% were junior-national or juvenile athletes, 15% were inexperienced or novice and 24% were ranked experienced or highly and moderately skilled.Fifty percent of the studies reported the mean shot score of the investigated athletes. The mean shot score for elite-level air-rifle athletes in simulated competitions was 10.27 ± 0.15 (three studies). National-level air-rifle athletes scored on average 10.25 ± 0.1 points per shot in simulated competitions (four studies) and 9.94 ± 0.23 in competition (two studies). There was one study in junior-level air-rifle athletes (9.26 ± 0.39 points per shot), as well as for novice (7.25 ± 2.22), highly skilled (9.08 ± 0.9) and moderately skilled (5.70 ± 0.28) air-rifle shooters. Studies in small-bore shooting did not report any mean shot scores.In air-rifle shooting, 10 studies tested performance according to international standards, e.g., 10 m away from the target, whereas in small-bore shooting four studies reduced the original 50 m distance to 18 m and 15,24 m, respectively. All shooters shot in the standing position, except for one study in small-bore shooting which chose a sitting position. Seven studies in air-rifle shooting shot 40 and/or 60 shots (women/men) according to international standards, two studies reduced the number to 20 and 25 shots, and five studies had a much higher number of shots (between 100 and 300). Across all studies, one study investigated shooting performance in competition, nine studies investigated shooting performance in training, three studies examined shooting performance both in training and competition and one study did not assess shooting performance. Eight studies used force plates or pressure insoles to assess shooters’ body sway and nine studies used optoelectronic systems to record the aim-point trajectory of the rifle. Moreover, electrocardiography (five studies), electromyography (one study), or questionnaires (two studies) were used.In the included studies a total of 16 performance determinants were investigated, of which 13 were in air-rifle and six were in small-bore shooting. To enhance the comprehensibility and readability of the review we divided these performance determinants into four different categories: a) anthropometric, b) technical-coordinative, c) physiological, and d) psychological performance. For small-bore shooting, we could only analyze standing shooting, even though it’s a three-position discipline, except for one study, who investigated shooting performance in a sitting position. The resulting performance determinants were partly not congruent between the two disciplines  and small-bore (two studies) shooting, investigating seven different performance determinants regarding postural balance and aim point trajectory of the rifle . PosturaAir-rifle shooting. Studies comparing groups found a difference between elite- and national-level air-rifle athletes concerning horizontal and vertical rifle stability, aiming accuracy and cleanness of triggering [iggering , 24, i.eiggering  and for iggering  did not In elite-level air-rifle athletes, inconsistent results were found for the correlation of horizontal and vertical rifle stability, aiming accuracy, cleanness of triggering, and aiming time with mean shot score. Here again, this was because one study found a correlation  whereas Body sway in the ML-direction 7–2 s, 1–0 s, and 0.5–0 s before shot release  was diffIn elite-level air-rifle athletes, no correlation was found between mean shot score and body sway in both directions during several time intervals before shot release , 11, 24;In addition, correlation analyses were reported between two technical-coordinative performance determinants. In elite-level air-rifle athletes, correlations were found between body sway in the ML- and the AP-directions during all analyzed time intervals before shot release and horizontal rifle stability and cleanness of triggering; except for body sway in the AP-direction 7–2 s before shot release and cleanness of triggering . ContrarRegression analyses have also been used to investigate rifle stability, aiming accuracy, cleanness of triggering and timing of triggering as key performance determinants in air-rifle shooting. These parameters explained 81% of the variance of the mean shooting score. It was found that rifle stability was the most important factor, explaining 54% of variance .An important point in investigating performance determinants is the consideration of competition performance. Two studies of national-level and juvenile air-rifle athletes investigated the influence of technical-coordinative parameters measured in training, and compared these with shooting performance in competition , 22. HerSmall-bore shooting. In small-bore shooting, horizontal and vertical rifle stability [tability , as welltability . This metability .Four papers investigated four particular physiological factors in air-rifle and small-bore shooting: heart rate and location of triggering within the cardiac cycle, breathing patterns and upper body muscle activity.Air-rifle shooting. Results showed that novice and junior-level air-rifle shooters preferred triggering at the beginning of the cardiac cycle, that means in the systolic phase [ic phase , 28. Furic phase , where tic phase , 28. In Small-bore shooting. In small-bore shooting, heart rate differed between elite- and national-level athletes [athletes , showingathletes . Furtherathletes . Breathiathletes . In elitathletes , 27–29. athletes . Also, iTwo papers analyzed psychological factors in air-rifle and small-bore shooting: self-control and trait and state anxiety, measured with questionnaires, and stress, measured via heart rate. Trait anxiety describes a person’s tendency to sense anxiety, while state anxiety is perceived as a reaction to a specific situation, e.g., competition. Self-control and trait anxiety were measured a few days before competition while state anxiety was measured immediately before competition.Air-rifle shooting. In air-rifle shooting, highly and moderately skilled athletes did not differ in terms of trait anxiety and self-control, but state anxiety was lower among highly skilled shooters compared to moderately skilled athletes [athletes . Trait aathletes .Small-bore shooting. In small-bore shooting, Landers et al. [s et al.  showed aThe purpose of this study was to systematically search and summarize the literature on performance-determining factors in air-rifle and small-bore shooting. A secondary objective was to compare the two disciplines to determine whether shot performance can be explained by the same performance determinants. Based on our search strategy, we found 14 original research articles that met the inclusion criteria, which indicates that this field has not been extensively researched. Nevertheless, 16 performance factors were investigated and, categorized into anthropometric, technical-coordinative, physiological and psychological factors. Six of them showed a significant correlation with shooting performance, pointing towards a complex and multifactorial character of shooting performance. These correlations were mainly found in national-level air-rifle athletes.One study in air-rifle shooting showed that body weight and height did not seem to affect competition shot score of juvenile shooters . These rIn air-rifle shooting, studies comparing groups found that elite-level athletes had better values for horizontal and vertical rifle stability compared to national-level athletes , 24, 27.In studies within elite-level athletes, no general statement can be made regarding the relationship between aim-point trajectory factors and shot score, since inconsistent results were found. One study found a correlation between shot score and horizontal rifle stability, aiming accuracy, cleanness of triggering, and aiming time  but the In studies within national-level athletes, lower values for horizontal rifle stability (less rifle movement) led to higher shot scores , 23, 24.In national-level air-rifle athletes higher aiming times led to higher shot scores , 24. TheIn air-rifle shooting, studies comparing groups found that elite-level athletes showed lower values for body sway in both the ML- and AP-directions during several time intervals before shot release compared to national-level athletes , 12, 24.However, in studies within elite-level shooters, body sway showed no influence on shot score , 11, 24.In national- and juvenile-level air-rifle shooters, one study found a correlation between body sway and shot score  and fourIn air-rifle shooting, correlation analyses were reported between two technical-coordinative factors. In studies within elite-level athletes, one study found a correlation between body sway and rifle stability  and one An important point in investigating performance determinants is the consideration of competition performance. So far, nearly all studies examined shooting performance and possible performance determinants in simulated competitions during training (partly under laboratory conditions). A study by Ihalainen and colleagues  in natioMultiple approaches, in the form of multiple regression analyses, have been carried out to gain insight into the importance of aim-point-trajectory factors. Ihalainen and colleagues  identifiIn small-bore shooting, studies that compared groups found that elite-level athletes had better horizontal and vertical rifle stability compared to national-level athletes . These rIn a mixed sample of novice, elite- and national-level small-bore shooters, rifle stability differed between high, moderate and low scores . These rOther inter-group comparisons found that elite-level small-bore shooters had lower body sway in both directions during several time intervals before shot release compared to national-level shooters . These rIn studies within elite-level athletes, body sway did not differ between least and most successful shots. In contrast, when comparing novice small-bore shooters with each other, lower body sway values led to higher shot scores . These rRifle stability and body sway have been investigated in many studies. In air-rifle shooting, results allow the conclusion that horizontal and vertical rifle stability, as well as aiming accuracy, aiming time and body sway, may be used as performance determinants to discriminate between elite- and national-level athletes. The results of rifle stability and body sway also apply to elite- vs. national-level small-bore shooters. Within the same performance level, results from national-level air-rifle athletes showed that horizontal rifle stability and aiming accuracy can be used as performance determinants to discriminate between shot scores. Results also allow the conclusion that for elite- and national-level air-rifle athletes, as well for national-level small-bore athletes, body sway cannot be used as a performance determinant to discriminate between shot scores. Instead, it should be used as a performance requirement to compete at an elite or a national level. Since little research has been done in small-bore shooting, future research should focus on investigating aim-point trajectory variables to understand their influence on shooting performance. Further work could investigate if performance in small-bore shooting can be explained by the same performance determinants as in air-rifle shooting. However, future research should not only focus on small-bore shooting, but also on air-rifle shooting to confirm the existing findings concerning aim-point trajectory and body fluctuations. Above all, more studies should examine elite-level athletes to investigate which performance determinants can differentiate between shot scores and which parameters serve as contributing factors. Future research should investigate the role of postural balance, e.g., the effect of body sway as a mediator between rifle stability and shooting performance. Studies with full body motion capture could help analyze segment movements more precisely than COP movements.In air-rifle shooting, results from novice and junior-level shooters showed a preference for triggering at the beginning of the cardiac cycle, during systole , 28. TheIn studies within novice air-rifle athletes, location of triggering within the cardiac cycle was correlated with shot score  but no cHeart rate showed no influence on shooting performance in novice  and juniIn small-bore shooting, one study that compared groups found that elite-level athletes showed less upper body muscle activity than national-level shooters . This coSimilarly, heart rate during the preparation period could differentiate between elite- and national-level small-bore athletes , but notIn addition, two studies showed that heart rate did not affect shot score in a mixed sample of national-level and novice small-bore athletes ; and, inFurther, a correlation was found between upper body muscle activity and rifle stability in a mixed sample of elite- and national-level small-bore shooters . This meNo evidence-based conclusion can be drawn about the role of physiological parameters as performance determinants due to a lack of data. Initial results indicate that heart rate may not affect shooting performance in both air-rifle and small-bore shooting. Future research should re-examine the role of location of triggering within the cardiac cycle, as well as upper body muscle activity, to confirm or disprove whether these two factors can be used to distinguish between performance classes and/or shot scores. Care should be taken to ensure that elite- and national-level athletes are examined in future interventions and that the groups are analyzed separately. Since no studies exist on conditional abilities, it would be important to answer questions such as: how important is a good endurance level for shooters for long competition days? What is the influence of core muscles for the stability of the body, and therefore for rifle stability and shooting performance? Would a better strength in these muscle groups lead to improved shooting performance?In air-rifle shooting, studies that compared groups found that highly skilled athletes showed lower state anxiety before competition compared to moderately skilled shooters, whereas no difference was found for trait anxiety and self-control . These rIn a mixed sample of high- and moderate-level air-rifle athletes, state anxiety correlated negatively with competition performance : shooterIn small-bore shooting, lower stress levels led to higher shot scores in a mixed sample of national-level athletes and novices . NormallNo evidence-based conclusion can be drawn about the role of psychological factors as performance determinants due to lack of data. Initial trends exist regarding state anxiety as a performance determinant to distinguish between elite- and national-level air-rifle shooters and shot score. Further, stress may be used to discriminate between shot scores in national-level and novice small-bore shooters. Nevertheless, further research is needed to confirm the findings on state anxiety and stress both in air-rifle and small-bore shooting with elite- and national-level athletes. Here, it is important to use specific questionnaires in addition to physiological factors, such as heart rate, as a change in heart rate may have many reasons . Further investigations could shed light on how other emotions fluctuate, especially in competition, and thereby affect shooting performance. Since it is not possible to assess these parameters with questionnaires during competition, other methods need to be developed. In addition to emotions, other shooting-related factors such as attention should be assessed in sport-related tests. Preliminary evidence is provided in a study by Doppelmayr et al. , who shoThe secondary objective of this review was to investigate whether the shooting performance of the two Olympic rifle disciplines are covered by the same performance determinants. However, the studies included in this systematic review focused on different performance determinants in air-rifle and small-bore shooting, therefore, this question cannot be answered . FurtherThere’re several limitations of our review that need to be discussed. First, due to language barriers, we only included English and German articles in the study selection process, which may result in excluding performance determinants from articles written in other languages. However, most articles are written in English, so this should not be a major problem. Second, we excluded studies including EEG analyses or studies concerning drugs and nutrition intake. Therefore, it is not possible to make evidence-based conclusions about the influence of drugs and nutrition intake on shooting performance; instead we investigated performance determinants that can be easily trained. Third, the modified version of the Downs and Black quality assessment checklist needs to be validated in future research. However, modified versions have already been used in other studies in elite sports performance.There’re also several limitations of the studies included in our review that need to be discussed. First, the definition of being an elite- or national-level athlete does not compare across countries. It is therefore possible that elite- and national-level athletes from different countries have the same mean shot score. We want to make readers aware of this difference in defining this categorization. Several studies also failed to state how the classification between elite- and national-level athletes was made. Second, different measuring systems and operationalization of the examined performance determinants were used, which may lead to differences in the methodological quality of studies and to difficulties in comparing studies. However, the same results were often seen regardless of the parametrization used. Third, other covariates exist that may have impacted the study results. For example, in some studies shooters did not use their own rifles, and, in some small-bore studies the distance to the target was reduced from 50 m to 18 m. In other studies, different numbers of shots or dry-firing shots were investigated. Fourth, some studies did not control for group affiliation, which limits the conclusiveness of the results to mixed-performance classes. Fifth, the analyses performed in some of the reviewed studies did not take into account the dependence of the measurements. For example, one study reviewed examined individuals’ parameters within a longitudinal design . For this hierarchical data structure, more appropriate statistics should have been used, such as multi-level modeling.To sum up, there is little research on performance-determining factors in air-rifle and small-bore shooting. It has been shown that in both types of shooting, horizontal and vertical rifle stability as well as body sway may be used as performance determinants to discriminate between elite- and national-level athletes. Since body sway did not influence shot score in elite-level air-rifle and small-bore athletes, it may be a performance requirement to compete at a high level. Further, in air-rifle shooting, horizontal rifle stability and aiming accuracy can be used as performance determinants to discriminate between shot scores on a national level. Inconsistent results, lack of data and methodological issues prevent us from drawing evidence-based conclusions on other performance factors.The wide range of examined factors and possible influence on shooting performance also show that shooting performance is composed of multifaceted processes running simultaneously and sequentially, with possible independent contributions of distinct performance determinants. For example, body fluctuations affect rifle stability with a time delay, while holding ability and aiming accuracy run simultaneously in the aiming process and are therefore closely related to the subsequent triggering. For this reason, future research should focus not only on examining individual performance determinants but should also use more complex analyses comprising more than one performance determinant. Multiple regression analyses are already used, integrating several technical-coordinative factors concurrently into one model. Such analyses could help the understanding of how much single performance determinants contribute to shooting performance and how far performance can be predicted by several performance determinants. Evidence about the interaction beyond the edge of technical-coordinative parameters has not yet been made and should be considered for future research. Future studies could use structural equation models to uncover causality, as well as investigate the complex relationships between performance determinants and shooting performance.Future research should focus on performance determinants from all categories to capture the multilayered influences on shot performance with athletes of different skill levels in both disciplines but especially with elite-level shooters. Psychological performance determinants should be given particular importance: although this area is underrepresented, it is an important component of sport shooting due to the high psychological requirements, such as concentration, that must be maintained during the whole competition for every shot. Future research should investigate possible performance determinants in small-bore shooting in the prone and kneeling positions to make a distinction between the three positions. Moreover, we call for studies with elite-level athletes from different countries and studies using high methodological quality to improve study outcomes. Research into performance determinants in the two Olympic rifle disciplines, air-rifle and small-bore shooting, is still in its infancy; but existing findings open avenues for promising future research endeavors.S1 Table(DOC)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.


Background: Over the past year, engagement with older adults has been severely curtailed given the high rates of COVID-19 morbidity and mortality in this population. This study examined the correlates of social isolation among African American and LatinX older adults during the COVID-19 pandemic. Methods: Working with community-based organizations and senior living centers, we administered a survey to older adults 55+, in the Houston metroplex, between 11/2020 and 01/2021 (n=575). The survey assessed COVID-19 prevention behaviors and health-related social needs. Responses to “How often do you feel lonely or isolated from those around you?” were used to create a dichotomous social isolation dependent variable. The main independent variable, family/community support, was based on responses to the validated question "If for any reason you need help with day-to-day activities such as bathing, preparing meals, shopping, managing finances, etc., do you get the help you need?" Multivariate logistic regression adjusting for socioeconomic status, medical conditions, positive COVID test (for self or family), COVID-19 prevention behaviors, and emergency preparedness levels was used. Results: Limited family/community support was strongly associated with social isolation , as was having any chronic condition . Females and seniors who reported daily social distancing were more likely to report being socially isolated . Of all chronic conditions examined, diabetes was the single strongest predictor of social isolation . Conclusion: Being female, having diabetes and limited family/community supports are associated with COVID-19-induced social isolation in African American and Latinx communities.


The burden of non-obstructive coronary artery disease (CAD) in the society is high, and there is currently limited evidence-based recommendation for risk stratification and treatment. Previous studies have demonstrated an association between increasing extent of non-obstructive CAD and cardiovascular events. Whether hypertension, a modifiable cardiovascular risk factor, is associated with extensive non-obstructive CAD in patients with symptomatic chronic coronary syndrome (CCS) remains unclear.We included 1138 patients  with symptomatic CCS and non-obstructive CAD (1–49% lumen diameter reduction) by coronary computed tomography angiography (CCTA) from the Norwegian Registry for Invasive Cardiology (NORIC). The extent of non-obstructive CAD was assessed as coronary artery segment involvement score (SIS), and extensive non-obstructive CAD was adjudicated when SIS >4. Hypertension was defined as known hypertension or use of antihypertensive medication.Hypertension was found in 45% of patients. Hypertensive patients were older, with a higher SIS, calcium score, and prevalence of comorbidities and statin therapy compared to the normotensive . There was no difference in the prevalence of hypertension between sexes. Univariable analysis revealed a significant association between hypertension and non-obstructive CAD. In multivariable analysis, hypertension remained associated with extensive non-obstructive CAD, independent of sex, age, smoking, diabetes, statin treatment, obesity and calcium score .In symptomatic CCS, hypertension was associated with extensive non-obstructive CAD by CCTA. Whether hypertension may be a new treatment target in symptomatic non-obstructive CAD needs to be explored in future studies.NCT 04009421.ClinicalTrials.gov: Identifier  Non-obstructive coronary artery disease (CAD) is commonly detected by coronary computed tomography angiography (CCTA) in patients with chronic coronary syndrome (CCS) . Even thHypertension has been established as a modifiable CV risk factor through several studies demonstrating a significant CV risk reduction by antihypertensive treatment , 13. TheEven though current guidelines recommend initiation of antihypertensive drug treatment in patients with high normal BP or hypertension with established CV disease or subclinical atherosclerosis detected by CV imaging, recommendations for antihypertensive treatment in patients with CCS and non-obstructive CAD remain unclear , 18, 19.We conducted a cross-sectional registry-based study using the Norwegian Registry of Invasive Cardiology (NORIC), a national quality control registry. The study includes a total of 1138 individuals electively referred to CCTA due to suspected CAD and stable chest pain or dyspnoea. The patients were diagnosed with atherosclerotic plaques in the coronary arteries with a lumen diameter reduction between 1–49% by CCTA at the Department of Heart Disease, Haukeland University Hospital, Bergen, Norway, between January 2016 and September 2019. Patients with smooth coronary arteries, obstructive CAD, previous myocardial infarction, heart surgery and percutaneous coronary interventions were excluded. Clinical and CCTA characteristics of the study population were extracted from the registry. The study was approved by the South-East Regional Ethical Committee for Medical and Health Research Ethics in Norway (reference number REK 2017/1573). The participants’ records and information were de-identified; hence the requirement of informed consent from participants was waived. The study was also registered at ClinicalTrials.gov with identification number NCT04009421.2. Smoking was classified as current or former smokers. GFR was estimated using the CKD-EPI equation [Patient information on demographics, CV risk factors and CV disease were reported on a standardized questionnaire and quality controlled against patients’ records by the registry staff. Systemic arterial hypertension was defined as known hypertension or use of antihypertensive medication. Diabetes mellitus was defined as known diabetes or on antidiabetic treatment. Body mass index (BMI) was calculated as body weight divided by height in meters squared, and obesity was defined as BMI≥30kg/mequation . ClusterCCTA was performed on clinical indication by dual source scanners  with electrocardiographic gated acquisition following current guidelines . In patiAll CCTA images were analysed by experienced readers using a dedicated analysis software, SyngoVia . Coronary artery calcium score was reported as area-density (Agatston score) in HU. Non-obstructive disease was visually identified as a stenosis with 1–49% lumen diameter reduction in any segment of the coronary arteries using the modified 20-segment American Heart Association classification . All patt-test for continuous variables, Chi-Square test for categorical variables and Mann-Whitney U test for variables with skewed distribution. Univariable logistic regression analysis was carried out to explore the association between CV risk factors and extensive non-obstructive CAD. Multivariable logistic regression analysis was used to explore whether hypertension remained independently associated with extensive non-obstructive CAD after adjusting for known covariables. Both uni- and multivariable analyses were reported as odds ratio (OR) with 95% confidence intervals (CI). A two-sided p-value < 0.05 was considered significant.Statistical analyses were performed using IBM SPSS statistics version 25 . Categorical variables were presented as percentages and numbers. Continuous variables were presented as mean± SD or as median and interquartile range where appropriate. The patient population was divided into groups of hypertension and no hypertension. The groups were compared using unpaired Student’s Hypertension was present in 45% of the patient population . PatientMean coronary artery SIS was higher in patients with hypertension compared to those without hypertension p<0.05, , and extIn univariable logistic regression analysis presence of hypertension, diabetes, statin treatment, as well as higher age, higher calcium score, and female sex were significantly associated with extensive non-obstructive CAD . There wThis study demonstrates that in patients with symptomatic CCS and non-obstructive CAD, hypertension is associated with more extensive non-obstructive CAD independent of other known CV risk factors, coronary artery calcium score, sex and statin treatment. In particular, non-obstructive CAD was more often located in the left main stem in hypertensive patients. Furthermore, hypertensive patients with non-obstructive CAD were older with higher coronary artery calcium score, clustering of other CV risk factors and higher prevalence of triple-vessel disease and comorbidities compared to patients without hypertension.Hypertension is an important CV risk factor associated with increased prevalence and severity of CAD , 23. TheThe clinical syndrome of ischemia with non-obstructive coronary arteries (INOCA) is a common finding in patients undergoing CCTA due to suspected CCS . MyocardIn general, larger extent of non-obstructive CAD is associated with an increased risk of CV events as well as heart failure with preserved ejection fraction , 28, 34.Recommendations for risk stratification and treatment in CCS and non-obstructive CAD are still limited. Furthermore, patients with non-obstructive CAD are often underdiagnosed and undertreated . This isThis is a large observational study including over 1000 patients with non-obstructive CAD defined by CCTA from a clinical registry. The registry only includes patients referred to CCTA after clinical evaluation by experienced cardiologists, and the study population is therefore representative of patients encountered in clinical practice. There are, however, some study limitations to be considered. First, this is a cross-sectional study and therefore no causal relationships can be established. Second, the NORIC registry holds limited information on some patient demographics, such as BP values and antihypertensive medication class, as well as duration and stage of hypertension and diabetes. Therefore, we were unable to evaluate BP control in patients with treated hypertension at the time of the CCTA examination and possible treatment effect on the extent of non-obstructive CAD. Third, only non-obstructive CAD patients with “stable” chest pain and/or dyspnoea, and a low to moderate CV risk, referred to CCTA due to suspected CAD are included in the study. This may introduce a selection bias, and the results cannot be generalized to all patients with CCS .Hypertension is associated with extensive non-obstructive CAD in patients with symptomatic CCS independent of the significant association of other CV risk factors, sex, calcium score and statin treatment. Our results emphasise the importance of diagnosing hypertension among patients with CCS and non-obstructive CAD. Whether early and aggressive antihypertensive treatment and optimal BP control may delay or reduce disease progression, impact symptoms and improve prognosis in patients with non-obstructive CAD and CCS should be further evaluated in follow-up studies.S1 Checklist(DOCX)Click here for additional data file.


There is a pressing need to equip youth-serving community organizations to respond to the unique needs of trauma-exposed children. Early prevention measures can be an effective means of redirecting children to self-regulatory healing, while facilitating their transition toward strength-based thriving. Sport can offer a powerful opportunity to reach these children; however there remains little information on how to effectively develop, deliver, evaluate, and sustain trauma-sensitive sport programs in a community context. The purpose of this paper is to outline a case study of integrating sport-based trauma-sensitive practices with BGC Canada’s national Bounce Back League program. An interdisciplinary partnership of academic, community, and practice experts used a community-based participatory action research approach, paired with a knowledge translational approach, to guide the process of program development. Mixed methods  were used to generate ongoing insights of staff’s training experiences, successes and challenges of program implementation, and potential impact of program on club members. Several stages of program development are described, including: (a) collaboratively planning the program; (b) piloting the program to three clubs; (c) adapting the program using pilot insights; (d) expanding the adapted program to ten clubs; and (e) creating opportunities to maintain, sustain, and scale-out practices throughout grant duration and beyond. Lessons learned regarding the leadership team’s experiences in terms of developing, adapting, and integrating trauma-sensitive practices in this community context are shared.The online version contains supplementary material available at 10.1007/s10560-021-00776-7. The high prevalence of traumatic exposure in childhood underscores the need for systematic approaches to mitigate potential harm  and strength-based approaches . In trauma-sensitive sport programs, staff are trained on the negative impacts of trauma , how trauma symptoms may be exhibited in sport , how sport can be used to build children’s resilience from traumatic exposure , and how to leverage and re-design sport  to support children’s resilience building . Knowledge creation involves synthesizing primary studies to inform and develop knowledge products that can be actioned by knowledge users. The action cycle concerns the use of these knowledge products and spans seven phases: (a) identifying the problem; determining the know-do gap; and identifying, reviewing, and selecting knowledge relevant to the problems or gaps; (b) adapting selected knowledge to the context in which it will be used; (c) assessing barriers and facilitators to knowledge use in the local context; (d) selecting, tailoring, and implementing interventions to enhance knowledge use by potential knowledge users; (e) monitoring knowledge use; (f) evaluating outcomes of knowledge use; and (g) sustaining knowledge use. The application of KTAC can be iterative, with fluid boundaries between phases and reciprocal loops where practices in one phase can inform practices in other phases  face risk of traumatic exposure . These members may lack access to health promotional supports, especially if they have not been screened with a trauma-related disorder, despite exhibiting trauma-related symptoms. As well, many members may not have the developmental capacities to understand or articulate their experiences of trauma—or lack power to disclose when the sources of trauma are from their close relationships. Thus, the leadership team identified the need to equip BGC Canada staff to support members’ unique needs. Many staff were already equipped with training related to facilitating positive youth development , mental health first-aid, crisis intervention, and referral protocols when identifying children who needed external health supports or clinical care. As well, many staff possessed experience in facilitating several youth developments programs across domains of leadership, education, creative arts, and recreation. However, many staff were not equipped with knowledge (know) or skills (do) to support trauma-exposed members in times of dysregulation, promote self-regulation practices, or design environments that minimize harm and foster resilience-building.In the planning stage, the KTAC phase of know-do gap, the knowledge that was identified, reviewed, and selected was sport-based trauma-sensitive practices and the purpose of this project was to build BGC Canada staff’s application of these practices. These practices were chosen given the popularity of BGC Canada’s sport programs, the numerous benefits these practices offer  provide psychoeducation to stakeholders on sport-based trauma-sensitive practice, (b) conceptualize a program that can be adapted to BGC Canada clubs, (c) generate buy-in from key BGC Canada managers who may champion the approaches, (d) develop a plan and establish timelines for the project, (e) formulate an evaluation process and identify key outcomes, and (f) solidify a process for collaboration and communication as a leadership team.Next, From these meetings, the leadership team developed connections with each other, generated value and excitement for the project, and collaboratively established the project goals, which included: (a) develop a training program that will build staff’s competencies to apply sport-based trauma-sensitive practices at their clubs, (b) have staff implement these practices as the BBL program across 13 clubs , (c) use a train-the-trainer model to build BGC Canada’s capacity to maintain and sustain BBL, and (d) evaluate program components to inform BBL adaptations. In line with each goal were the intended outcomes: (a) staff implement BBL effectively at their clubs; (b) BBL members experience improvements in basic psychological needs support, resilience-related life skills, and well-being; (c) a master trainer team is formed to train future BBL staff beyond grant duration; and (d) program materials are developed with guidelines for effective BBL implementation.The leadership team established to communicate regularly on BBL program development over monthly phone/video calls. Roles of team members were also established. Here, BGC Canada administrators were responsible for coordinating, communicating, and checking-in with clubs on an ongoing basis, which included relaying expectations and arranging for staff involvement in BBL trainings. The consultants were responsible for designing and delivering the sport-based trauma-sensitive practice training to staff and holding ongoing phone/video calls with lead staff at each club to answer design questions and offer feedback. BGC Canada managers were responsible for participating in trainings and managing their own club’s design and delivery of BBL.The researchers were responsible for developing evaluation tools, training staff on how to use the tools, assisting clubs with collecting data during on-site visits, analyzing and communicating these data, and soliciting staff feedback regarding the feasibility of evaluation activities in practice. The program was to be carried out over 4 subsequent years, including 2 years of piloting across three clubs with ongoing adaptation. Evaluation findings from pilot and adaptation stages would inform the expansion to 10 clubs in the final 2 years. Use of a train-the-trainer model would help build and maintain project sustainability beyond grant duration.assess barriers and facilitators to knowledge use, this BBL stage focused on exploring the successes and challenges that arose in the pilot. Given that multiple KTAC phases can be an undergone concurrently, three sub-phases were also carried out: select, tailor, and implement an intervention, monitor knowledge use, and evaluate outcomes. A multi-faceted, sport-based, trauma-sensitive practice training intervention was designed for staff to learn how to develop BBL programs at their home clubs. Twelve staff participants  across three clubs, were gathered to attend an initial 3-day intensive workshop.The pilot stage involved implementing the BBL training with three BGC Canada clubs, who then went on to design and deliver their first seasons of BBL—with the leadership team’s close monitoring, evaluation, and ongoing support, as per their established roles in the planning stage. In alignment with the KTAC phase Slack, where the leadership team and participating clubs shared experiences, resources, strategies, media, and questions with one another throughout the project, in effort to ease access to communications, resources, and learning opportunities.The workshop was primarily facilitated by the consultants, with the support and participation of the researchers and BGC Canada administrators. The topics broadly covered: (a) psychoeducation of the prevalence and impact of trauma on the child, (b) factors that contribute to trauma healing in sport, (c) strategies to intervene with members in times of dysregulation, (d) strategies for coaching and re-designing sport to facilitate resilience-building, (e) strategies to facilitate members’ skill development. The topics were further adapted in subsequent iterations of the training workshop during the BBL’s adaptation stage  per season. The goal was for each club to run three seasons a year, with each season building on the relationships and skill development of the previous season. Members were welcome to participate in multiple seasons. Clubs could choose season length (6–10 weeks), the sport , and session frequency . All clubs were responsible for structuring sessions around a universal BBL workout structure, comprised of seven intentional components . Staff also adopted a 4-step framework to connect with members in times of dysregulation: (a) stabilize—support member in a triggered state to re-regulate and arrive to a place where they can have a conversation, (b) explore—facilitate a judgment-free inquiry about what the member is experiencing, (c) plan—co-construct strategies to resolve what happened and to regulate better in the future, and (d) return—co-construct strategies to transition back to the activities on the member’s own will.Staff were trained on several techniques to proactively facilitate members’ regulation  how did staff perceive their training experiences and what value was generated from these experiences? (b) what were the successes and challenges that staff met in implementing their training into practice? and (c) what was the impact of programs on members? A mixed-methods approach was used to address these questions. To explore staff’s training experiences, knowledge surveys and interviews were conducted pre- and post-training, and field notes, pictures, and audio-recordings were taken during training. To monitor successes and challenges, staff completed structured logbooks after each BBL session, participated in multiple focus groups and interviews, and shared conversations on Slack. To examine program impact, members completed surveys on well-being  tailoring the training intervention, (b) supporting staff’s motivations and accounting for staff turnover, (c) enhancing recruitment strategies, and (d) transition of training responsibilities to master trainers.Concurrently with the pilot stage, the adaptation stage was informed by the combination of ongoing leadership team meetings, consultations and check-ins with each club, and evaluation results. The KTAC phase of The leadership team worked together to develop 12 BGC Canada-adapted modules, covering how to build staff’s awareness and value for sport-based trauma-sensitive practice, and how to structure and design a BBL program  with BBL branding for clubs to use in their marketing. To enhance recruitment, all clubs were encouraged to remove limits to BBL membership and invite all children to participate regardless of pre-identified risk status. This strategy helped maximize reach and inclusiveness to unscreened trauma-exposed children.To promote the self-sustaining capacity of the BBL, a train-the-trainer model was used to train BGC Canada managers and other key staff to become BBL master trainers . Here, the master trainers carried out the training intervention as an intensive, in-person workshop to 20 staff, covering the 12 BGC Canada-adapted training modules. The leadership team supported master trainers in communicating expectations, coordinating travel and logistics for clubs, and modifying evaluation tools. The newly trained staff went on to deliver programs at their home clubs, while continuing to receive support from master trainers , and the leadership team . The same evaluation questions were used to monitor BBL training and program implementation, using a slightly modified mixed-methods approach. For instance, items on knowledge assessments and logbooks were matched to the adapted training modules, and the length and wording of member’s surveys were simplified.The expansion involved rolling out, monitoring, and evaluating the adapted training intervention and BBL programs in ten additional clubs across Canada. Three KTAC phases of Each club ran one season (~ 6–10 weeks); the second season was cut short due to the COVID-19 pandemic. Currently, evaluation is still ongoing, as clubs offer either in-person, physically distanced program delivery, or virtual delivery. However, initial outcomes of the BBL expansion have indicated that: (a) the training intervention was successful in improving knowledge and attitudes of participating staff in sport-based trauma-sensitive practice; (b) the training intervention was perceived as enjoyable and useful for staff; (c) in most clubs, recruitment of members successfully reached 20–25 + members; however, at least two clubs were well under this mark; (d) having trained staff is essential for running high-quality BBL programs; yet, with staff turnover, clubs without trained staff resorted to traditional practices of youth engagement in sport, resulting in loss of trauma-sensitive practice. Thus, there is a need for incorporating alternative sustainability practices within BGC Canada to maintain BBL quality during and beyond grant duration.sustain outcomes phase of KTAC. The first goal in this plan was to maintain and expand the BBL (as a sport-based trauma-sensitive practice program) to more clubs across Canada. A second, broader goal was to build staff’s capacities in trauma-sensitive practices across BGC Canada clubs and programs, beyond sport. This second goal was constructed based on advocacy from BBL staff of the value of trauma-sensitive practices and their applicability in club work outside the BBL, as well as interest from additional clubhouses in building their club’s trauma-sensitive capacity. Several processes will contribute to reaching these two goals: (a) using a train-the-trainer model, (b) developing context-specific resources, (c) expanding to reach Canadian newcomers, (d) transitioning to a virtual platform in COVID-19.The sustainability stage involves initiatives put in place to continue BBL beyond grant- end, in alignment with the Using a train-the-trainer model helped build the organization’s ownership of the program, promoting internal sustainability . Monitoring and evaluation are currently ongoing, to gain insights of successes and challenges of facilitating BBL in a COVID world.problem identified was the need for integrating trauma-sensitive practices across all BGC Canada clubs; the selected knowledge was the BGC Canada-adapted trauma-sensitive practice modules and program materials; this knowledge will be adapted from in-person to virtual via BGC Canada’s virtual e-learning platform; and this training will be implemented to ten BGC Canada clubs, reaching ~ 150 staff.The abrupt shift, the need for trauma-sensitive practices across clubs in Canada, and the success in adapting the BBL based on changing conditions, made it ideal for the leadership team to pursue further options for project scale-out  meaningful change starts with small steps, (b) maintain ongoing two-way communication with stakeholders, and (c) integrate-with rather than add-on to existing activities.high impact behaviors—staff skills used to generate effective results. High impact behaviors are not necessarily known from the outset—their effectiveness will depend on the staff’s characteristics, the demands of the context, and the member’s needs .The leadership team avoided using an all-at-once approach in both the training and implementation to ease integration and prevent overburdening staff  from the outset, and communicate using easy channels of access . This ongoing communication aligned with the project’s CBPR approach and was conducive to relationship building between the leadership team, stakeholders, and their peers  that could be integrated within existing programming  reinforce a shared vision, (b) co-construct insights of barriers, facilitators, and potential impacts, (c) use insights to develop high-quality adaptations, and (d) build towards sustainability, expansion, and scale-out. The success of this project helped train 80 + staff across Canada, reach 600 + members, and build increased awareness of—and need for—integrating trauma-sensitive practices across all BGC Canada clubs nationally beyond the BBL. The story of developing the BBL can offer foundational understandings of best practices in integrating trauma-sensitive practices in this community organization, which may be useful for informing intentionally planned sport in similar youth-serving groups and organizations.Supplementary Information (PDF 597 KB)Below is the link to the electronic supplementary material.


Objective: There is an increase in persons entering substance use treatment who co-use opioids and methamphetamines in recent years. Co-using these substances may negatively impact treatment retention in the residential setting. We explored predictors of adults completing short-term residential treatment among persons with primary opioid use disorder (OUD) who co-use either alcohol, benzodiazepines, cocaine, or methamphetamines.Methods: This study used the 2019 de-identified, publicly available Treatment Episode Dataset-Discharges. The sample included adults discharged from short-term residential treatment with primary OUD who co-used either alcohol, benzodiazepines, cocaine, or methamphetamines. The final sample size included 24,120 treatment episodes. Univariate statistics were used to describe the sample. Two logistic regression models were used to predict completing treatment. The first logistic regression model included the co-use groups as predictors and the second model added other demographic and treatment-relevant covariates.Results: A slight majority (51.4%) of the sample prematurely discharged from treatment. Compared to the other three co-use groups, the opioid and methamphetamine co-use group had the highest proportion of individuals who were women (45.0%), unemployed (62.5%), current injection drug use (76.0%), living in the Midwest (35.9%), living in the south (33.5%), and living in the west (15.5%). The opioid and methamphetamine co-use group also had the highest proportion of individuals not receiving medications for OUD (84.9%), not having a prior treatment episode (28.7%), and not completing treatment (57.4%). In the final logistic regression model, which included covariates, the opioid and alcohol , opioid and benzodiazepine , and opioid and cocaine  co-use groups had higher odds of completing treatment than the opioid and methamphetamine co-use group.Conclusions: Opioid and methamphetamine co-use may complicate short-term residential treatment retention. Future work should identify effective strategies to retain persons who co-use opioids and methamphetamines in treatment. Different combinations of polysubstance use have been identified among individuals who use opioids, which must be considered in the context of opioid use disorder (OUD) treatment. One study among 356 people found over 55% of individuals with OUD co-use other substances such as alcohol, benzodiazepines, and cocaine . SometimCo-use of opioids and methamphetamine is associated with low socioeconomic status and health consequences such as overdose and increased need for medical care –10, and Residential treatment is recommended for individuals who are unstable and have moderate to severe substance use disorders , 17. WhiThis study examined differences in demographic, drug use, and treatment characteristics among adults discharged from short-term residential treatment in four distinct opioid co-use groups: (1) alcohol, (2) benzodiazepines, (3) cocaine, and (4) methamphetamine. These four groups were chosen because another study that examined these groups found a decrease in the prevalence of opioid and alcohol co-use and opioid and cocaine co-use, and an increase in the prevalence of opioid and benzodiazepine co-use and opioid and methamphetamine co-use . FurtherThe publicly available de-identified Treatment Episode Dataset–Discharges (TEDS-D) 2019, which is provided annually by the Substance Abuse and Mental Health Services Administration was used for this study . TEDS-D Co-use groups were created if opioids were the primary substance and alcohol, benzodiazepines, cocaine, and methamphetamine/speed were the secondary substances. The discharge reason was dichotomized as treatment completed and premature discharge. Length of stay was a continuous variable with values from 1 to 30 which describes the length of the treatment episode in days. Age was recoded to include the following age ranges 18–29 years old, 30–39 years old, 40–49 years old, and 50 years and older. Race was recoded with the following categories, Black, White, and Other. Non-Black and non-White groups were combined into the Other category due to low frequencies. Gender was a binary variable with women and men as values. Receiving medication for opioid use disorder (MOUD) in the current treatment plan was dichotomized as Yes or No. The frequency of use variables (primary substance and secondary substance) had No use, Some use, and Daily use as values. Prior substance use treatment refers to ever having a previous substance use treatment episode and was dichotomized as Yes or No.p = 0.134) provided evidence that listwise deletion was adequate. Listwise deletion was used for treatment episodes that were missing values for variables included in the final logistic regression model. The first logistic regression model included only the co-use groups as predictors (reference group: Opioid and Methamphetamine co-use group). The second logistic regression model retained the co-use groups and added the following covariates: age (reference group: 18–29 years old), gender (reference group: Women), race (reference group: White), receiving MOUD (reference group: No), frequency of primary substance (reference group: Daily), frequency of secondary substance (reference group: Daily), and prior substance use treatment (reference group: No). Due to the large sample size, p < 0.001 was established as the threshold for significance in the bivariate and multivariate analyses. Analyses were performed using SPSS Version 27 .Univariate analyses including counts, percentages, and means were used to describe the full sample and the four co-use groups. An analysis of variance (ANOVA) was used to examine the associations between the co-use groups and length of stay in treatment. Two logistic regression models were conducted to predict completing treatment. Little's Missing Completely at Random (MCAR) test was utilized for treatment episodes missing values for variables included in the final logistic regression model. Little's MCAR test  treatment episodes in the opioids and alcohol co-use group, 3,230 (13.4%) in the opioids and benzodiazepines co-use group, 11,575 (48.0%) in the opioids and cocaine co-use group, and 5,397 (22.4%) in the opioids and methamphetamine co-use group.There were 28,483 treatment episodes that met initial eligibility criteria, however 4,363 did not have complete data and were thus excluded, leaving a final sample of F = 95.97, p < 0.001]. Using Tukey's honest significant difference, the opioid and methamphetamine group had a significantly higher average number of days in treatment than the other three co-use groups.Demographic, substance use, and treatment characteristics of the full sample and the four co-use groups are shown in p = < 0.001), opioid and benzodiazepine , and opioid and cocaine  co-use groups all had higher odds of completing treatment than the opioid and methamphetamine co-use group.Results from the first logistic regression model are shown in p < 0.001), opioid and benzodiazepine , and opioid and cocaine  co-use groups also had higher odds of completing treatment than the opioid and methamphetamine co-use group. Individuals aged ≥50 years old  had higher odds of completing treatment than those between the ages of 18–29 years old. Men  had higher odds of completing treatment than women. Those who were Black had lower odds  of completing treatment than those who were White. Conversely, those whose race was categorized as “Other”  had higher odds of completing treatment than those who were White. Treatment episodes that received MOUD  had higher odds of completing treatment than those that did not. Individuals who used their primary opioid substance sometimes  had higher odds of completing treatment than those who used their primary substance daily. Conversely, individuals who used their secondary substance sometimes  had lower odds of completing treatment than those who used their secondary substance daily.Results from the final logistic regression model are shown in The current study identified adults who co-use opioids and methamphetamine as having lower odds of completing treatment than other opioid co-use groups, namely alcohol, benzodiazepines, and cocaine. Considering the alarming increase of opioid and methamphetamine co-use in recent years , 7, thisThis study also found that the opioid and methamphetamine co-use group had a higher proportion of women than the other three co-use groups. A review of the literature found that women start using methamphetamine at an earlier age and are more dependent on methamphetamine than men . Among rThe regional distribution of opioid and methamphetamine co-use is also noteworthy. This co-use group had the highest proportion in the Southern, Midwestern, and Western regions. While data have shown that methamphetamine use and related overdose deaths are more common in the Western region , recent The opioid and methamphetamine co-use group had the highest proportion of injection drug use, as over three-fourths of the treatment episodes in this group indicated current injection drug use. Another study found that opioid and methamphetamine co-use was associated with a 132% higher prevalence of injection drug use when compared to those who only use opioids . InjectiThis study is not without limitations. One limitation is this study focused on treatment episodes from treatment providers that receive public funding. These results may not be generalizable to private substance use treatment providers. Including treatment episodes that do not use their primary or secondary substance in the past month is a limitation, although this subgroup might be fundamentally different than those who enter treatment with active use. A second limitation is only including primary and secondary substances while excluding tertiary substances. Although data were analyzed in this way to focus on the two main substances, if tertiary substances were considered there could be potential overlap between the co-use groups. For example, an individual could use heroin, methamphetamine, and cocaine prior to entering short-term residential treatment. This creates a challenge for group comparisons as there are several potential 3-group combinations of polysubstance use, and it is difficult to interpret the importance of tertiary drug use within the TEDS dataset. A third limitation is the potential duplication or overestimation of polysubstance use given that TEDS-D cases are discharges and not individuals, although we countered this limitation by controlling for prior treatment episodes in the multivariate model. Since this study utilized a secondary dataset, we were constrained by the available variables. Considering this limitation, we were unable to include other predictors such as sexual orientation, type of medication for OUD, family support, and treatment provider characteristics. Finally, we were limited by not having follow-up data beyond discharge from treatment, and although completing treatment is associated with better posttreatment outcomes, this cannot be assessed in the current study. Considering these limitations, this study provides key insight into opioid co-use groups and short-term residential treatment completion.https://www.datafiles.samhsa.gov/dataset/teds-d-2019-ds0001-teds-d-2019-ds0001.Publicly available datasets were analyzed in this study. This data can be found at: All authors have contributed to the design, preparation, and editing of the manuscript.This research was funded by the National Institute on Drug Abuse (NIDA) T32 training grant .AH receives research funding from Ashley Addiction Treatment through his university. The remaining 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. The reviewer PM declared a shared affiliation, with no collaboration, with the author JM at the time of the review.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.