Citations

Purpose The aim of part-one of this EU-US consensus was to combine literature research and expertise to provide recommendations for the usage of rehabilitation (including physical therapy) of patients undergoing surgical treatment for degenerative meniscus lesions or acute meniscus tears (including meniscectomy, repair, or reconstruction). Prevention programs, non-operative treatment of acute tears and degenerative lesions, return to sports and patient-reported outcome measures (PROMS) will be presented in a part-II article. Methods This consensus followed ESSKA “formal consensus” methodology. For this combined ESSKA (European Society for Sports Traumatology and Arthroscopy), AOSSM (American Orthopedic Society for Sports Medicine), ASSPT (American Academy of Sports Physical Therapy) initiative, 67 experts (26 in the steering group and 41 in the rating group) from 14 countries (USA and 13 European countries) including orthopedic surgeons, sports medicine doctors and physiotherapists were involved. Steering group members established guiding questions, searched the literature, proposed statements. Rating group members assessed the statements according to a Likert scale and provided grades of recommendations reaching final agreement about rehabilitation of the knee after meniscus surgery. Final documents were then assessed by a peer review group to adress the geographical adaptability. Results The overall level of evidence of the literature was low. Of the 19 questions (leading to 29 statements), one received a grade A of recommendation, two a grade B, nine a grade C and 17 a Grade D. Nevertheless, the mean median rating of all questions was 8.2/9 (9 being the highest rating on a scale of 1-9) and the global mean rating was 8.4+/-0.2, indicating a high agreement. Rehabilitation depends on the type of lesion, the treatment performed and is the same after medial or lateral meniscus surgery. Rehabilitation after meniscectomy should follow a criterion-based rehabilitation protocol, based on milestones rather than a time-based protocol. After meniscus repair and reconstruction, rehabilitation should be progressed according to both time and criterion-based milestones. Conclusion Rehabilitation after meniscus surgery is a debated topic that may influence surgical outcomes if not optimally performed. This international formal consensus established clear, updated, and structured recommendations for both surgeons and physiotherapists treating patients after meniscus surgery. Level of Evidence I, Consensus.

Abstract Purpose The aim of part one of this EU‐US consensus was to combine literature research and expertise to provide recommendations for the usage of rehabilitation (including physical therapy) of patients undergoing surgical treatment for degenerative meniscus lesions or acute meniscus tears (including meniscectomy, repair, or reconstruction). Prevention programmes, non‐operative treatment of acute tears and degenerative lesions, return to sports and patient‐reported outcome measures will be presented in a part II article. Methods This consensus followed the European Society for Sports Traumatology and Arthroscopy (ESSKA)'s ‘formal consensus’ methodology. For this combined ESSKA, American Orthopedic Society for Sports Medicine and American Academy of Sports Physical Therapy initiative, 67 experts (26 in the steering group and 41 in the rating group) from 14 countries (US and 13 European countries), including orthopaedic surgeons, sports medicine doctors and physiotherapists were involved. Steering group members established guiding questions, searched the literature and proposed statements. Rating group members assessed the statements according to a Likert scale and provided grades of recommendations, reaching a final agreement about rehabilitation of the knee after meniscus surgery. Final documents were then assessed by a peer review group to address the geographical adaptability. Results The overall level of evidence in the literature was low. Of the 19 questions (leading to 29 statements), 1 received a Grade A of recommendation, 2 a Grade B, 9 a Grade C and 17 a Grade D. Nevertheless, the mean median rating of all questions was 8.2/9 (9 being the highest rating on a scale of 1–9). The global mean rating was 8.4 ± 0.2, indicating a high agreement. Rehabilitation depends on the type of lesion, the treatment performed and is the same after medial or lateral meniscus surgery. Rehabilitation after meniscectomy should follow a criterion‐based rehabilitation protocol, based on milestones rather than a time‐based protocol. After meniscus repair and reconstruction, rehabilitation should be progressed according to both time and criterion‐based milestones. Conclusion Rehabilitation after meniscus surgery is a debated topic that may influence surgical outcomes if not optimally performed. This international formal consensus established clear, updated and structured recommendations for both surgeons and physiotherapists treating patients after meniscus surgery. Level of Evidence Level I, consensus.

Abstract Introduction Sex-based differences in morbidity and mortality for pulmonary hypertension (PH) are insufficiently addressed in current research. However, recognizing these differences is crucial for optimal clinical management and improving outcomes. This study assesses the effect of sex on survival among PH patients, while accounting for disease severity, comorbidities, treatment, and race. Methods We analyzed data from the PVRI GoDeep meta-registry, including all incident patients with complete hemodynamic profiles. Survival was evaluated using Kaplan-Meier and Cox proportional hazards models, adjusted for various confounders. Analyses included both PAH and non-PAH groups and risk assessment by the ESC/ERS 2022, REVEAL lite 2, and COMPERA 4-strata scores. All analyses were performed using R (The R Foundation). Results A total of 19,663 incident PH patients were included in the analysis, with 5,581 patients (28%) diagnosed with Group 1 PH and a median age of 64 years [IQR: 52-73]. Among these, male patients (8,704, 44%) had a significantly higher mortality risk than female patients across the entire cohort and within all PH subtypes. The adjusted hazard ratio for mortality in male versus female patients was 1.391 [95% CI: 1.260-1.536] in the overall population and 1.404 [95% CI: 1.264-1.561] for those with PAH. This survival difference was consistent across various severity levels, age groups, and in the presence of comorbidities such as obesity and cardiovascular diseases, as well as among those receiving PAH-specific therapies as well as patients who remained without treatment during the observation period. Notably, male disadvantage in survival was observed in low, intermediate, and high-risk categories for ESC/ERS 2022, REVEAL lite 2, and COMPERA scores but not within REVEAL 2.0, which includes male sex as a non-modifiable risk factor. Racial analysis revealed a greater mortality risk for males among White patients, with no significant differences noted in Black or Asian populations. Conclusion Our PVRI GoDeep meta-registry analysis demonstrates that male PH patients face higher mortality risk across both PAH and non-PAH groups, independent of disease etiology, age, severity, comorbidities, and treatment factors, with this risk amplified in White patients. These findings suggest that male sex should be further considered as a risk factor to refine predictive models for survival in PH.

Abstract RATIONALE: Chronic kidney disease (CKD) is common in the general population and is associated with inflammation and compromised immune function. Since these mechanisms are hypothesized to promote severe COVID-19, we tested associations of pre-pandemic CKD with incident COVID-19 hospitalization or death in a large, multi-ethnic, US general population-based meta-cohort of adults. METHODS: Data were harmonized and pooled from 9 NIH-funded longitudinal cohorts participating in the Collaborative Cohort of Cohorts for COVID-19 Research (C4R). CKD was classified by KDIGO 2024 CKD guideline (Low Risk, Moderately Increased Risk, High Risk, Very High Risk) using pre-pandemic urinary albumin-to-creatinine ratio (uACR) and estimated glomerular filtration rate using creatinine (eGFRcr). Incident COVID-19 hospitalization or death was ascertained over 2020−2023 via self-report and active surveillance, with medical record adjudication in a subset. In our primary analysis, we assessed associations between CKD stages and incident COVID-19 hospitalization or death. A secondary analysis examined joint association of CKD stages and the number of comorbidities (obesity, hypertension, diabetes, and cardiovascular disease) with the severe COVID-19. Multivariable hazard ratios (HRs) were estimated by cause-specific Cox regression, adjusting for socio-demographics and smoking. RESULTS: Among 26,039 multi-ethnic adult participants (mean age 66.1±14.8, 60.6 % female, 28.6% Whites, 3.2% Asians, 20.6% Blacks, 41.3% Hispanics, 6.3% American Indians) with a median follow-up of 550 days since the onset of the pandemic (baseline: March 1, 2020), there were 734 incident COVID-19 hospitalizations or deaths. The mean time since CKD markers were measured before the baseline was 6.5 years. The cumulative incidence of severe COVID-19 was 2.3, 3.5, 6.5, and 7.3% across CKD risk stages, and similar patterns were observed within variant types (Figure 1). Compared to participants with Low Risk of CKD, there was a graded increased hazards of severe COVID-19 across CKD stages, with HRs (95% CIs) of 1.27 (1.03−1.55) for Moderately Increased Risk, 2.33 (1.77−3.06) for High Risk, and 2.72 (1.89−3.92) for Very High Risk. In a joint analysis, both increased CKD risk and a higher number of comorbidities were associated with a higher risk of severe COVID-19, showing the highest HR of 12.29 (5.75−26.27) in Very High Risk individuals with four comorbidities compared to Low Risk individuals with none. CONCLUSIONS: Higher CKD stages were associated with a greater risk of COVID-19 hospitalization or death and the risk is substantially heightened with additional comorbidities. These results suggest that adults with CKD and related comorbidities may merit enhanced COVID-19 risk mitigation.

Abstract Background:Chronic obstructive pulmonary disease (COPD) is a major global health burden, with genome-wide association studies explaining only a fraction of its heritability. Recent advancements, including large-scale, multi-ancestry whole-genome sequencing and a focus on severe, early-onset cases, offer promising avenues to identify additional COPD-related variants. Furthermore, recent studies show that adjusting for polygenic risk scores (PRS) enhances statistical power to detect rare variants, advancing efforts to understand COPD's genetic basis. Methods:We performed a whole genome sequencing association study of severe, early-onset COPD (FEV1 < 50%, age ≤ 55), FEV1 and FEV1/FVC in eight population-based studies (ARIC, CARDIA, CFS, CHS, FHS, HCHS/SOL, JHS, MESA) and seven COPD-enriched studies (COPDGene, ECLIPSE, Boston Early-Onset COPD Study, LTRC, TCGS (Poland), ICGN, SPIROMICS). We performed single-variant analyses using regenie software, applying a genome-wide significance threshold of P < 5.0 x 10-8. For rare variant set (MAF <1%) analysis, we annotated variants with loss of function or deleterious missense using WGS Annotator and prediction tools LOFTEE, SIFT, and PolyPhen2, then analyzed these variants with SKATO-ACAT method in regenie, adjusting for covariates including sex, sequencing center, and principal components of ancestry. We additionally evaluated adjusting the analyses for PRSs for lung function traits. Results: We analyzed 53,028 participants including 34,751 European, 12,508 African, 1,088 Latino American, and 674 East Asian ancestry. Across cohorts, we analyzed 5,063 severe (FEV1 < 50%) COPD cases, among whom 1,103 were early-onset (age ≤ 55). Excluding variants within 1 Mbp of known variants, single-variant analysis identified 68 novel associations (MAC ≥ 30), with 8 common associations (MAF ≥ 1%) in 6 genomic regions. Our most significant novel association for severe early-onset COPD was rs74297390 (intergenic to POM121L12, MAF = 9.6%, Beta = 0.41, P = 3.5 x 10-8). For FEV1 and FEV1/FVC ratio, variants near DKK2 and AKR1E2 were significantly associated and were replicated in an independent dataset (Shrine et al., 2019). DKK2 is an antagonist in the Wnt pathway. In a preliminary variant set analysis, CHRM3-AS1 was associated with severe early-onset COPD, GPAT with FEV1, and COL8A1I and HMCN1 with FEV1/FVC. With PRS adjustment, ST6GALNAC5 was associated with FEV1/FVC. Conclusions: In a whole genome sequencing study of lung function and severe early-onset COPD, we identified new loci for COPD-related phenotypes, including two novel loci that replicated in an independent dataset. Ongoing work involves variant set-based analyses with additional covariate adjustments, as well as PRS adjustments for binary traits.

Abstract KIF5A (Kinesin family member 5A) is a motor protein that functions as a key component of the axonal transport machinery. Variants in KIF5A are linked to several neurodegenerative diseases, mainly spastic paraplegia type 10 (SPG10), Charcot-Marie-Tooth disease type 2 (CMT2), and amyotrophic lateral sclerosis (ALS). These diseases share motor neuron involvement but vary significantly in clinical presentation, severity, and progression. KIF5A variants are mainly categorized into N-terminal variants associated with SPG10/CMT2 and C-terminal variants linked to ALS. This study utilized a novel multiplex NULISA targeted platform to analyze plasma proteome from KIF5A -linked SPG10, ALS patients and compared to healthy controls. Our results revealed distinct proteomic signatures, with significant alterations in proteins related to synaptic function, and inflammation. Notably, neurofilament light polypeptide, a biomarker for neurodegenerative diseases, was elevated in KIF5A ALS but not in SPG10 patients. Moreover, these findings can now be taken forward to gain mechanistic understanding of axonopathies linking to N- vs C-terminal KIF5A variants affecting both central and peripheral nervous systems.