Robust and heritable knockdown of gene expression using a self-cleaving ribozyme in Drosophila.

The current toolkit for genetic manipulation in the model animal Drosophila melanogaster is extensive and versatile but not without its limitations. Here, we report a powerful and heritable method to knockdown gene expression in D. melanogaster using the self-cleaving N79 hammerhead ribozyme, a modification of a naturally occurring ribozyme found in the parasite Schistosoma mansoni. A 111 bp ribozyme cassette, consisting of the N79 ribozyme surrounded by insulating spacer sequences, was inserted into four independent long noncoding RNA genes as well as the male-specific splice variant of doublesex using scarless CRISPR/Cas9-mediated genome editing. Ribozyme-induced RNA cleavage resulted in robust destruction of 3' fragments typically exceeding 90%. Single molecule RNA fluorescence in situ hybridization results suggest that cleavage and destruction can even occur for nascent transcribing RNAs. Knockdown was highly specific to the targeted RNA, with no adverse effects observed in neighboring genes or the other splice variants. To control for potential effects produced by the simple insertion of 111 nucleotides into genes, we tested multiple catalytically inactive ribozyme variants and found that a variant with scrambled N79 sequence best recapitulated natural RNA levels. Thus, self-cleaving ribozymes offer a novel approach for powerful gene knockdown in Drosophila, with potential applications for the study of noncoding RNAs, nuclear-localized RNAs, and specific splice variants of protein-coding genes.

Robotic-arm-assisted lateral unicompartmental knee arthroplasty leads to high implant survival and patient satisfaction at mean 10-year follow-up.

BACKGROUND: There is a lack of literature reporting on long-term outcomes following robotic-arm-assisted lateral unicompartmental knee arthroplasty (UKA). This study assessed the long-term survivorship, patient-reported satisfaction and pain scores following robotic-arm-assisted lateral UKA for lateral compartment osteoarthritis (OA). METHODS: A single surgeon's database was reviewed to identify all patients who underwent robotic-arm-assisted lateral UKA with a cemented, fixed-bearing prosthesis prior to May 2015. Patients were contacted to determine implant survivorship, satisfaction and pain. Kaplan-Meier models were applied to analyse survival. RESULTS: A total of 77 knees (70 patients) with a mean follow-up of 10.2 ± 1.5 years (range: 8.1-13.3) were included. Five knees were revised, corresponding to a 10-year survivorship of 96.1% and estimated survival time of 12.7 ± 0.3 years (95% confidence interval: 12.2-13.2) with all-cause revision as the endpoint. Unexplained pain (40.0%) and progression of OA (40.0%) in contralateral compartments were the most reported reasons for revision. Among patients without revision, 94.4% were either satisfied or very satisfied with their lateral UKA and the average pain score was 1.1. CONCLUSION: Robotic-arm-assisted lateral UKA led to high implant survivorship and patient satisfaction, and low pain scores at long-term follow-up. Progression of OA in contralateral compartments and unexplained pain were the most frequent reasons for revision. These findings support the continued use of robotic-arm-assisted lateral UKA for lateral compartment OA; however, its clinical value over conventional techniques remains to be established in prospective comparative studies. LEVEL OF EVIDENCE: Therapeutic Level IV.

Impact of outside referral and dental extractions on package time with post-operative radiation therapy for head and neck cancer.

INTRODUCTION: Patients with squamous cell carcinoma of the head and neck (HNSCC) often receive post-operative radiotherapy (RT). A package time between surgery and completion of RT of ≤100 days is associated with lower recurrence and longer survival. In this study, we investigate the impact of outside referral and dental extractions on package time, with secondary detriment to relapse-free survival (RFS) and overall survival (OS). METHODS: We conducted a retrospective chart review on patients with HNSCC who received primary surgical resection at an academic medical centre. RESULTS: Ninety-four patients met eligibility criteria, 35% experienced recurrence, and 21% died. Median package time was 89.5 days, with 76% of patients achieving a package time ≤100 days. Receiving RT in-house was associated with a shorter package time (P = 0.0004) and higher completion rate within 100 days (P = 0.01). Dental extractions did not affect package time. A Kaplan-Meier analysis was performed to study survival, and a package time ≤100 days was not associated with a change in RFS or OS. A Cox proportional hazard model was used to investigate other factors hypothesized to impact patient survival; none had an effect on RFS, but cancer stage had an effect on OS (P = 0.01). CONCLUSIONS: We identified that outside referrals, but not dental extractions, prolong treatment package times. We also saw no effect of package time on RFS or OS. These results suggest that patients requesting outside facility referrals for RT may benefit from a streamlined program that expedites the referral process.

Genetic mutation of Cep76 results in male infertility due to abnormal sperm tail composition.

The transition zone is a specialised gate at the base of cilia/flagella, which separates the ciliary compartment from the cytoplasm and strictly regulates protein entry. We identified a potential new regulator of the male germ cell transition zone, CEP76. We demonstrated that CEP76 was involved in the selective entry and incorporation of key proteins required for sperm function and fertility into the ciliary compartment and ultimately the sperm tail. In the mutant, sperm tails were shorter and immotile as a consequence of deficits in essential sperm motility proteins including DNAH2 and AKAP4, which accumulated at the sperm neck in the mutant. Severe annulus, fibrous sheath, and outer dense fibre abnormalities were also detected in sperm lacking CEP76. Finally, we identified that CEP76 dictates annulus positioning and structure. This study suggests CEP76 as a male germ cell transition zone protein and adds further evidence to the hypothesis that the spermatid transition zone and annulus are part of the same functional structure.

A Consecutive Series of Vancouver B2 Periprosthetic Femur Fractures Treated With Contemporary Monoblock Versus Modular Revision Stems: Clinical and Radiographic Outcomes.

BACKGROUND: Tapered fluted titanium (TFT) stems are the implant design of choice for managing Vancouver B2 periprosthetic femur fractures (PFFs), producing reliable results over the past few decades. The aim of this study was to compare the radiographic and clinical outcomes of Vancouver B2 PFFs treated with contemporary monoblock versus modular TFTs. METHODS: A consecutive series of 113 patients (72 women, 64%, mean age 70 years [range, 26 to 96]) who had a B2 PFF were treated with either a monoblock (n = 42) or modular (n = 71) TFT stem between 2008 and 2021. The mean body mass index was 30 ± 7. The mean follow-up was 2.9 years. A radiographic review was performed to assess leg length and offset restoration, endosteal cortical contact length, and stem subsidence. Kaplan-Meier analyses were used to determine survivorship without revision, reoperation, or dislocation. RESULTS: There was no difference in the restoration of leg length (0.3 ± 8.0 mm) or offset (2.8 ± 8.2 mm) between the monoblock and modular cohorts (P > .05). Mean endosteal cortical contact length (47.2 ± 26.6 versus 46.7 ± 2 6.4 mm, P = .89) and stem subsidence (2.7 ± 3.5 versus 2.4 ± 3.2 mm, P = .66) did not differ. No difference in patient-reported outcome measures (Hip Disability and Osteoarthritis Outcome Score-Joint Replacement; Veterans RAND 12 Item Health Survey Physical and Mental; visual analog score; and Lower Extremity Activity Scale) between the groups was observed. Survivorship at 2 years free from reoperation, revision, and dislocation was 90.4, 90.3, and 97.6%, respectively, for the monoblock cohort; and 84.0, 86.9, and 90.0%, respectively, for the modular cohort. CONCLUSIONS: No significant differences in radiographic or clinical outcomes were observed between patients treated with monoblock or modular TFTs in this large series of B2 PFFs.

Investigating Steric and Electronic Effects in the Synthesis of Square Planar 6d1 Th(III) Complexes.

The factors affecting the formation and crystal structures of unusual 6d1 Th(III) square planar aryloxide complexes, as exemplified by [Th(OArMe)4]1- (OArMe = OC6H2tBu2-2,6-Me-4), were explored by synthetic and reduction studies of a series of related Th(IV) tetrakis(aryloxide) complexes, Th(OArR)4 (OArR = OC6H2tBu2-2,6-R-4). Specifically, electronic, steric, and countercation effects were explored by varying the aryloxide ligand, the alkali metal reducing agent, and the alkali metal chelating agent. Salt metathesis reactions between ThBr4(DME)2 (DME = 1,2-dimethoxyethane) and 4 equiv of the appropriate potassium aryloxide salt were used to prepare a series of Th(IV) aryloxide complexes in high yields: Th(OArH)4 (OArH = OC6H3tBu2-2,6), Th(OArtBu)4 (OArtBu = OC6H2tBu3-2,4,6), Th(OArOMe)4 (OArOMe = OC6H2tBu2-2,6-OMe-4), and Th(OArPh)4 (OArPh = OC6H2tBu2-2,6-Ph-4). Th(OArH)4 can be reduced by KC8, Na, or Li in the absence or presence of 2.2.2-cryptand (crypt) or 18-crown-6 (crown) to form dark purple solutions that have EPR and UV-visible spectra similar to those of the square planar Th(III) complex, [Th(OArMe)4]1-. Hence, the para position of the aryloxide ligand does not have to be alkylated to obtain the Th(III) complexes. Furthermore, reduction of Th(OArOMe)4, Th(OArtBu)4, and Th(OArPh)4 with KC8 in THF generated purple solutions with EPR and UV-visible spectra that are similar to those of the previously reported Th(III) anion, [Th(OArMe)4]1-. Although many of these reduction reactions did not produce single crystals suitable for study by X-ray diffraction, reduction of Th(OArH)4, Th(OArtBu)4, and Th(OArOMe)4 with Li provided X-ray quality crystals whose structures had square planar coordination geometries. Reduction of Th(OArPh)4 with Li also gave a product with EPR and UV-visible spectra that matched those of [Th(OArMe)4]1-, but X-ray quality crystals of the reduction product were too unstable to provide data. Neither Th(Odipp)4(THF)2 (Odipp = OC6H3iPr2-2,6) nor Th(Odmp)4(THF)2 (Odmp = OC6H3Me2-2,6) could be reduced to Th(III) products under similar conditions. Reduction of U(OArH)3(THF) with KC8 in the presence of 2.2.2-cryptand (crypt) was examined for comparison and formed [K(crypt)][U(OArH)4], which has a tetrahedral arrangement of the aryloxide ligands. Moreover, no further reduction was observed when either [K(crypt)][U(OArH)4] or [K(crown)(THF)2][U(OArH)4] were treated with KC8 or Li.

Resident Performance on the Fundamentals of Arthroscopic Surgery Training (FAST) Workstation Does Not Predictably Improve With Postgraduate Year.

Purpose: To identify differences in performance on the Fundamentals of Arthroscopic Surgery Training (FAST) workstation between residents across different postgraduate years and training sites. Methods: During the 2018-2019 academic year, 102 orthopaedic surgery residents from 4 training sites completed 6 FAST modules. Failure was defined as either completion time exceeding benchmark time or commission of task-specific errors. With the exception of knot tying, each module was completed by participants twice-once with each hand serving as the camera hand. Time to completion (except for knot tying) and errors were recorded for each of the modules. Completion times and failure rates were compared between postgraduate years, seniority groups, and training sites. Results: In all modules for which time was recorded, except for the suture-passage module, there was no significant difference in time to completion based on seniority (P < .01 for suture passage and P > .05 for all others). Significant differences in completion time were observed between sites for all modules except for the suture-passage module (P = .957 for suture passage and P < .05 for all others). Site predicted failure by at least 1 measure (time or technical error) for all modules (P < .05) except for number probing and suture passage. Failure rate across training years varied for each module. Conclusions: Time to completion and rate of failure did not predictably decrease with level of training. Training site proved to be a significant predictor of performance. Factors such as hand dominance and familiarity with the equipment proved to be important considerations for some modules. Clinical Relevance: Objective assessment of arthroscopic skills among orthopaedic trainees is difficult. Using reproducible methodology to assess trainees on specific skills at all postgraduate years and at multiple training sites may provide important information about orthopaedic training.

Factors Associated With Higher Utilization of Outpatient Physical Therapy for Patients Who Have Undergone Primary Total Joint Arthroplasty: A Retrospective Cohort Study.

Background: Research has identified predictive factors for inpatient complications and short-term recovery following total knee arthroplasty (TKA) and total hip arthroplasty (THA). Predictors that may influence length of care in outpatient physical therapy (PT) have yet to be examined. Doing so may improve the quality and efficiency of PT care following TKA and THA. Purpose: The aim of this study was to determine factors associated with a higher utilization of outpatient PT visits for patients who have had primary THA or TKA. Methods: A retrospective cohort study was performed using a population of 5147 patients who underwent THA and TKA between January 2017 and October 2022. Demographic and clinical factors were analyzed to determine which factors influenced PT utilization. Results: Our multivariable linear regression model revealed that female sex, need for inpatient PT visits, and TKA as opposed to THA were significantly associated with an increase in outpatient PT visits. Older age, number of telerehabilitation visits, and history of depression were associated with fewer outpatient PT visits while accounting for all other variables. Conclusions: The results of this retrospective analysis may help to identify some potential factors including TKA vs THA, patient age, and a history of depression that can be evaluated prospectively in future studies to determine whether they predict subsequent outpatient PT utilization.

RAPT and AM-PAC "6-Clicks": Do They Correlate on Predicting Discharge Destination After Total Joint Arthroplasty?

Background: The Risk Assessment and Prediction Tool (RAPT) and the Activity Measure for Post-Acute Care "6-Clicks" Mobility Score (AM-PAC) are validated discharge planning tools for patients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA). Planning for discharge with these tools considers very different factors and it is important to determine if they relate. Purpose: We sought to determine whether the preoperative RAPT score would correlate with postoperative AM-PAC score for predicting discharge destination for THA and TKA populations. Secondarily, we sought to examine whether the AM-PAC and RAPT scores would remain statistically significant predictors of discharge destination despite covariates. Methods: A retrospective cohort study was performed for patients who underwent THA or TKA from January 2020 to December 2022 at a specialty orthopedic hospital. Primary variables included the RAPT score, the AM-PAC score, and discharge disposition. Correlation between AM-PAC and RAPT scores was tested using Pearson's correlation coefficient, and association between both scores and discharge destination was tested using chi-square tests and multivariable logistic regression. Results: Our comparison of AM-PAC scores and RAPT scores found a statistically significant, positive correlation in both THA and TKA patients. Regression analysis found that increased RAPT and AM-PAC scores resulted in higher odds of being discharged home for both populations, after adjusting for all other variables. In both cohorts, patients discharged to a facility were more likely to be female, be over the age of 70 years, have Medicare/Medicaid insurance, and have a higher number of preoperative social work visits or any incidence of an intraoperative or hospital complication. Conclusions: This retrospective study found that RAPT score correlated with AM-PAC score for predicting discharge destination for elective THA and TKA populations, suggesting that these scores may be predictors of home discharge destination even when accounting for covariates. Further study is recommended.

Scaled TelePhysical Therapy Program a Promising Option for Post-acute Care of Lower-Extremity Arthroplasty Patients.

Background: Post-acute care for orthopedic surgery patients continues to evolve with the reduction in hospital length of stay (LOS), shift to ambulatory surgery, increased number of surgeries, and focus on value-based care. Purpose: We sought to examine outcomes of a cohort of lower-extremity arthroplasty patients receiving telephysical therapy (TelePT) according to hospital LOS, as a means of exploring the viability of TelePT as a value-based discharge option. Methods: A retrospective review was conducted of patients who participated in our institution's HSS@Home TelePT program after undergoing primary unilateral hip or knee arthroplasty, unicondylar knee replacement, or hip resurfacing. Demographic data and outcomes such as hospital LOS, number of days between discharge and TelePT evaluation, number of TelePT visits, number of re-admissions, Hip dysfunction and Osteoarthritis Outcome (HOOS Jr.) or Knee injury and Osteoarthritis Outcome (KOOS Jr.) scores, and patient satisfaction scores were collected. Patients were divided into categories based on hospital LOS to help determine the versatility of program. Results: In the 2814 patients included, we observed an average of 4.1 TelePT visits; 1% of patients were readmitted within 90 days, and 97% of patients were satisfied or highly satisfied. There was no difference in HOOS or KOOS Jr. scores at each follow-up time point, except for the 6-month HOOS Jr. scores. Conclusion: This retrospective study suggests that TelePT may be a viable option for care of lower-extremity arthroplasty patients in the post-acute setting, regardless of hospital LOS. As a discharge option, it may meet the needs of select patients to fill a gap in providing value-based care.

Preoperative Education Prior to Hip or Knee Arthroplasty Is Associated With Home Discharge but Not Reduced Length of Stay.

Background: Increasing numbers of patients are undergoing total joint arthroplasty as a treatment for osteoarthritis, which can be an anxiety-provoking experience. Setting expectations through a preoperative physical therapy (pre-op PT) session can alleviate some of these stressors, potentially decrease hospital length of stay (LOS), and promote home discharge. Purpose: We sought to determine whether attending a pre-op PT session is associated with decreased hospital LOS and home discharge in total hip arthroplasty (THA) and total knee arthroplasty (TKA) patients. Methods: A retrospective cohort study was performed of 20,822 patients who underwent THA or TKA between January 2020 and December 2023. Pre-op PT attendance and covariates, including patient demographics and clinical data, were collected and analyzed for association with LOS and discharge disposition. Results: Unadjusted univariate analysis revealed that THA and TKA patients who received pre-op PT had a significantly lower average LOS and were more likely to be discharged home. Our multivariate regression model showed that pre-op PT was not significantly associated with LOS in both groups but was significantly associated with home discharge among THA patients. Conclusions: Our retrospective study of the effect of pre-op PT education on LOS and discharge disposition for elective THA and TKA patients found different results in univariate and multivariate analysis. Further study is needed to confirm the association found on multivariate analysis between pre-op PT and home discharge in THA patients.

Echocardiographic derived pulmonary artery wedge pressure is associated with mortality, heart hospitalizations, and functional capacity in chronic systolic heart failure: insights from the HF-ACTION trial.

BACKGROUND: Heart Failure (HF) is associated with increased morbidity and mortality. Identification of patients at risk for adverse events could lead to improved outcomes. Few studies address the association of echocardiographic-derived PAWP with exercise capacity, readmissions, and mortality in HF. METHODS: HF-ACTION enrolled 2331 outpatients with HF with reduced ejection fraction (HFrEF) who were randomized to aerobic exercise training versus usual care. All patients underwent baseline echocardiography. Echocardiographic-derived PAWP (ePAWP) was assessed using the Nagueh formula. We evaluated the relationship between ePAWP to clinical outcomes. RESULTS: Among the 2331 patients in the HF-ACTION trial, 2125 patients consented and completed follow-up with available data. 807 of these patients had complete echocardiographic data that allowed the calculation of ePAWP. Of this cohort, mean age (SD) was 58 years (12.7), and 255 (31.6%) were female. The median ePAWP was 14.06 mmHg. ePAWP was significantly associated with cardiovascular death or HF hospitalization (Hazard ratio [HR] 1.02, coefficient 0.016, CI 1.002-1.030, p = 0.022) and all-cause death or HF hospitalization (HR 1.01, coefficient 0.010, CI 1.001-1.020, p = 0.04). Increased ePAWP was also associated with decreased exercise capacity leading to lower peak VO2 (p = < 0.001), high Ve/VCO2 slope (p = < 0.001), lower exercise duration (p = < 0.001), oxygen uptake efficiency (p = < 0.001), and shorter 6-MWT distance (p = < 0.001). CONCLUSIONS: Among HFrEF patients, echocardiographic-derived PAWP was associated with increased mortality, reduced functional capacity and heart failure hospitalization. ePAWP may be a viable noninvasive marker to risk stratify HFrEF patients.

AXDND1 is required to balance spermatogonial commitment and for sperm tail formation in mice and humans.

Dynein complexes are large, multi-unit assemblies involved in many biological processes including male fertility via their critical roles in protein transport and axoneme motility. Previously we identified a pathogenic variant in the dynein gene AXDND1 in an infertile man. Subsequently we identified an additional four potentially compound heterozygous variants of unknown significance in AXDND1 in two additional infertile men. We thus tested the role of AXDND1 in mammalian male fertility by generating a knockout mouse model. Axdnd1-/- males were sterile at all ages but could undergo one round of histologically complete spermatogenesis. Subsequently, a progressive imbalance of spermatogonial commitment to spermatogenesis over self-renewal occurred, ultimately leading to catastrophic germ cell loss, loss of blood-testis barrier patency and immune cell infiltration. Sperm produced during the first wave of spermatogenesis were immotile due to abnormal axoneme structure, including the presence of ectopic vesicles and abnormalities in outer dense fibres and microtubule doublet structures. Sperm output was additionally compromised by a severe spermiation defect and abnormal sperm individualisation. Collectively, our data highlight the essential roles of AXDND1 as a regulator of spermatogonial commitment to spermatogenesis and during the processes of spermiogenesis where it is essential for sperm tail development, release and motility.

Factors Influencing Surgical Decision Making in Trapeziometacarpal Osteoarthritis.

Purpose: With trapeziometacarpal osteoarthritis (TMC OA), the relationship between disease severity and pretreatment dysfunction, patient expectations, and preferred patient treatment and management remains unclear. This study aimed to assess the association between functional status, pretreatment expectations, and demographic and clinical characteristics of TMC OA patients who decide to undergo operative management. Methods: Patients diagnosed with TMC OA (n = 96) were administered the Thumb Arthritis Expectations Survey and the Brief Michigan Hand Questionnaire (bMHQ) during their initial office visit. Demographic data (sex, age, race, education level, marital status, comorbidities, and hand dominance) and clinical characteristics (prior injury, and therapeutic interventions including splinting, steroid injections, therapy, and anti-inflammatory medication) were collected. Multiple logistic regression was used to assess the association between surgical treatment and expectation scores. Results: Our logistic regression model found that lower bMHQ scores, high thumb arthritis expectation survey scores, and prior treatments for TMC OA were associated significantly with the surgical treatment of TMC OA. After controlling for all possible covariates, the odds of having surgery was 3.9 times higher among patients with high expectations (above median) compared to patients with low expectations (adjusted odds ratio [AOR], 3.9; 95% confidence interval [CI], 1.3-11.2). Patients with average function, as measured by bMHQ scores, were 74.5% less likely to elect for surgery than those with the lowest bMHQ (AOR, 0.3; 95% CI, 0.1-0.9). Patients treated previously with steroids were 13 times more likely to elect for surgery than those who were never treated for TMC arthritis (AOR,13.1; 95% CI, 2.2-77.0). Conclusions: Patients with TMC OA who elect to proceed with surgical management have lower bMHQ (greater perceived dysfunction) and higher expectations, and have had prior treatment. Age was not a significant predictor of surgical management of TMC OA. Type of study/level of evidence: Prognostic IV.

Chondral Injury Associated With ACL Injury: Assessing Progressive Chondral Degeneration With Morphologic and Quantitative MRI Techniques.

BACKGROUND: Anterior cruciate ligament (ACL) injuries are associated with a risk of post-traumatic osteoarthritis due to chondral damage. Magnetic resonance imaging (MRI) techniques provide excellent visualization and assessment of cartilage and can detect subtle and early chondral damage. This is often preceding clinical and radiographic post-traumatic osteoarthritis. HYPOTHESIS: Morphologic and quantitative MRI techniques can assess early and progressive degenerative chondral changes after acute ACL injury. STUDY DESIGN: Prospective longitudinal cohort. LEVEL OF EVIDENCE: Level 3. METHODS: Sixty-five participants with acute unilateral ACL injuries underwent bilateral knee MRI scans within 1 month of injury. Fifty-seven participants presented at 6 months, while 54 were evaluated at 12 months. MRI morphologic evaluation using a modified Noyes score assessed cartilage signal alteration, chondral damage, and subchondral bone status. Quantitative T1ρ and T2 mapping at standardized anatomic locations in both knees was assessed. Participant-reported outcomes at follow-up time points were recorded. RESULTS: Baseline Noyes scores of MRI detectable cartilage damage were highest in the injured knee lateral tibial plateau (mean 2.5, standard error (SE) 0.20, P < 0.01), followed by lateral femoral condyle (mean 2.1, SE 0.18, P < 0.01), which progressed after 1 year. Longitudinal prolongation at 12 months in the injured knees was significant for T1ρ affecting the medial and lateral femoral condyles (P < 0.01) and trochlea (P < 0.01), whereas T2 values were prolonged for medial and lateral femoral condyles (P < 0.01) and trochlea (P < 0.01). The contralateral noninjured knees also demonstrated T1ρ and T2 prolongation in the medial and lateral compartment chondral subdivisions. Progressive chondral damage occurred despite improved patient-reported outcomes. CONCLUSION: After ACL injury, initial and sustained chondral damage predominantly affects the lateral tibiofemoral compartment, but longitudinal chondral degeneration also occurred in other compartments of the injured and contralateral knee. CLINICAL RELEVANCE: Early identification of chondral degeneration post-ACL injury using morphological and quantitative MRI techniques could enable interventions to be implemented early to prevent or delay PTOA.

The katanin A-subunits KATNA1 and KATNAL1 act co-operatively in mammalian meiosis and spermiogenesis to achieve male fertility.

Katanins, a class of microtubule-severing enzymes, are potent M-phase regulators in oocytes and somatic cells. How the complex and evolutionarily crucial, male mammalian meiotic spindle is sculpted remains unknown. Here, using multiple single and double gene knockout mice, we reveal that the canonical katanin A-subunit KATNA1 and its close paralogue KATNAL1 together execute multiple aspects of meiosis. We show KATNA1 and KATNAL1 collectively regulate the male meiotic spindle, cytokinesis and midbody abscission, in addition to diverse spermatid remodelling events, including Golgi organisation, and acrosome and manchette formation. We also define KATNAL1-specific roles in sperm flagellum development, manchette regulation and sperm-epithelial disengagement. Finally, using proteomic approaches, we define the KATNA1, KATNAL1 and KATNB1 mammalian testis interactome, which includes a network of cytoskeletal and vesicle trafficking proteins. Collectively, we reveal that the presence of multiple katanin A-subunit paralogs in mammalian spermatogenesis allows for 'customised cutting' via neofunctionalisation and protective buffering via gene redundancy.

Association between Haloperidol use and Risk of Rheumatoid Arthritis.

Haloperidol is an anti-psychotic used for the treatment of schizophrenia or Tourette disorder. Here we report, by studying three large administrative health insurance databases, that haloperidol use is associated with a reduced risk of developing rheumatoid arthritis. A meta-analysis revealed a 31% reduced hazard of incident rheumatoid arthritis among individuals with schizophrenia or Tourette disorder treated with haloperidol compared to those treated with other anti-psychotic drugs. These findings suggest a potential benefit of haloperidol in rheumatoid arthritis and provide a rationale for randomized controlled trials to provide causal insights.

Anti-HIV Drugs Reduce Risk of Prediabetes and Progression to Type 2 Diabetes in HIV-Infected Patients.

The aim of this study was to investigate whether the use of nucleoside reverse transcriptase inhibitors (NRTIs) impacts the incidence of prediabetes or type 2 diabetes mellitus (T2DM) or the progression from prediabetes to T2DM in people living with HIV (PLWH). We conducted a retrospective cohort study using the U.S. Veterans Health Administration database among adult patients with an HIV diagnosis from the year 2000 until 2021 to determine the incidence of prediabetes and further progression to T2DM among NRTI exposed and unexposed patients. A multistate model was used to evaluate progression from normoglycemia to prediabetes and then to T2DM, and covariate adjustment with the Cox proportional hazards model was used to estimate the hazard ratios. Among 32,240 veterans diagnosed with HIV, prediabetes and T2DM were observed among 20.2% and 20.7% of patients, respectively. Among those diagnosed with prediabetes, 31.8% progressed to T2DM. Patients exposed to NRTIs at any time (86.6%), had a reduced risk of prediabetes [HR 0.50 (0.47-0.53 95% CI)] and among prediabetics, a lower risk of progression to T2DM [HR 0.73 (0.63-0.85 95% CI)] when compared to patients who never used NRTIs. In summary, NRTIs may reduce the risk of developing prediabetes and the progression from prediabetes to T2DM in PLWH.

Exploring Correlations Between Pain and Deformity in Idiopathic Scoliosis With Validated Self-reported Pain Scores, Radiographic Measurements, and Trunk Surface Topographic Measurements.

BACKGROUND: Up to 75% of patients with idiopathic scoliosis (IS) report back pain, but the exact contributors are unclear. This study seeks to assess how pain correlates with demographics, radiographic and surface topographic (ST) measurements, and patient-reported outcome measures (PROMs) in patients with IS. METHODS: Patient-Reported Outcome Measurement Information System (PROMIS) Pain Interference (PI) and Scoliosis Research Society revised (SRS-22r) pain domain from an IRB approved prospectively collected registry containing patients 11 to 21 years old with IS were correlated (Spearman coefficients) with measurements from whole-body EOS radiography and ST scanning, PROMIS 1.0 PROMs, Trunk Appearance Perception Scale (TAPS), and SRS-22r domains. SRS-22r and PROMIS-PI were also compared between different sex, scoliosis severities, and primary curve locations with Mann-Whitney U or Kruskal-Wallis tests, and if significant differences were found, included with the 5 highest univariate correlated variables into stepwise multivariate linear regression models ( P <0.05 to enter, P >0.1 to remove) predicting SRS-22r pain and PROMIS-PI. RESULTS: One hundred and forty-nine patients (14.5 ± 2.0 y, body mass index 20.6 ± 4.1 kg/m 2 , 96 (64%) female, mean major coronal curve 40 ± 19 deg, range: 10 deg, 83 deg) reported mean PROMIS-PI of 42.2 ± 10.0 and SRS-22r pain of 4.4 ± 0.6. SRS-22r self-image was the most correlated variable with both SRS-22r pain (rho=0.519) and PROMIS-PI (rho=-0.594). Five variables, none of which were ST or radiographic measures, strongly predicted SRS pain domain (R=0.711, R2=0.505, N=138). Two variables (SRS-22r self-image and SRS-22r function) were utilized by a model correlated with PROMIS-PI (R=0.687, R2=0.463, N=124). CONCLUSIONS: SRS-22r function and self-image domains were more strongly correlated with SRS-22r pain and PROMIS-PI than any radiographic or ST measurements. LEVEL OF EVIDENCE: Level II-retrospective study.

Impact of, Factors for the Success of, and Concerns Regarding Transplant Patients' Skin Cancer Campaigns: Observational Study.

BACKGROUND: Due to rising health care costs, patients have sought alternative ways of addressing medical expenses. In particular, transplant patients have complex and expensive medical needs-including skin cancer surveillance-that may not be fully covered by insurance. One such method of financing medical costs is by crowdsourcing through web-based platforms, most notably GoFundMe. OBJECTIVE: Previous work identified factors associated with GoFundMe campaigns' fundraising success for dermatologic diseases. We sought to characterize these factors in transplant recipients' campaigns for funds raised for covering skin cancer-related costs. These factors include demographics, campaign traits, and subjective themes. METHODS: From January to April 2022, we analyzed GoFundMe campaigns using the following search terms chosen on the basis of author consensus: "transplant skin cancer," "transplant basal cell," "transplant squamous," "transplant melanoma," and "dermatologist transplant." Demographic data were coded from campaign text or subjectively coded based on author consensus. Campaigns were read completely by 2 independent coders and associated with up to 3 different themes. Linear regression was performed to examine the qualities associated with success, which was defined as funds raised when controlling for campaign goals. Logistic regression was used to examine qualities associated with extremely successful campaigns, defined as those raising funds over 1.5 times the IQR. RESULTS: Across 82 campaigns, we identified several factors that were associated with fundraiser success. Patients who experienced complications during infectious disease treatment, those who received a pancreas transplant, or those who died from their disease raised significantly more money. Patients older than 61 years raised significantly less money. Extremely successful campaigns (>US $20,177) were associated with campaigners who emphasized a disability from their disease, those who were reluctant to ask for help, or those who died due to their disease. CONCLUSIONS: Demographic and thematic factors are associated with transplant patients' skin cancer-related fundraising success, favoring those who are younger, in more extreme situations, and appear reluctant to ask for help; these findings are consistent with those of previous studies. Additionally, transplant patients have complex and expensive dermatologic needs that may not be fully covered by insurance, as reflected in their GoFundMe campaigns. The most commonly mentioned reasons for fundraising included living expenses or loss of income, inadequate or no insurance, and end-of-life costs. Our findings may inform transplant patients how to maximize the success of their campaigns and highlight gaps in health care coverage for skin cancer-related costs. Limitations include the possibility for misclassification due to the data abstraction process and limiting data collection to fundraisers available on GoFundMe while excluding those on other websites. Further research should investigate the ethical implications of crowdfunding, financial needs of this patient population, and potential ways to improve access to routine skin cancer surveillance among patients receiving transplants.