Previous Knee Surgery, Anteromedial Portal Drilling, Quadriceps Tendon Autograft, and Meniscal Involvement Associated With Delayed Return to Sport After Anterior Cruciate Ligament Reconstruction in Amateur Athletes.

Purpose: To identify prognostic factors associated with a delayed return-to-sport (RTS) time in amateur athletes who return to full participation after a primary isolated anterior cruciate ligament (ACL) reconstruction. Methods: A retrospective review was performed among athletes who underwent ACL reconstruction between October 2014 and October 2021. Inclusion criteria were any amateur athletes with an ACL reconstruction who had a documented RTS and greater than 1-year follow-up. Nonathletes, those with multiligamentous knee injury, and those missing documented RTS timelines were excluded. RTS was defined as participation in athletics at a level equivalent to or greater than the preinjury level participation. Demographic and prognostic factors, including previous knee surgery, meniscal involvement, level of participation, surgical approach, and graft type, were recorded along with RTS time and analyzed via Poisson regression. Results: In total, 91 athletes, average age 18.8 (± 6.7) years, who underwent ACL reconstruction at a single institution from 2014 to 2021 were identified with an average follow-up time of 4.6 (± 2.5) years (range 1.1, 9.0). Meniscal involvement (1.11; 95% confidence interval [CI] 1.08-1.15, P < .001) and previous knee surgery (1.43; 95% CI 1.29-1.58; P < .001) were related to a delayed RTS. Quadriceps tendon and bone-patellar tendon-bone autografts, as well as allograft, showed a significant association with a longer RTS time when compared with hamstring autograft (1.16, 95% CI 1.13-1.20, P < .001; 1.04, 95% CI 1.01-1.07, P = .020; 1.11, 95% CI 1.03-1.19, P = .004, respectively), as did anteromedial portal drilling, when compared with the outside in approach for femoral drilling (1.19, 95% CI 1.16-1.23, P < .001). Conclusions: Previous knee surgery, anteromedial femoral drilling, quadriceps tendon autograft, and meniscus tear were most associated with a delayed timeline for RTS among young athletes who were able to return. Level of Evidence: Level IV, prognostic case series.

Editorial Commentary: The Shoulder Instability-Return to Sports After Injury Scale Is More Than Just a Psychological Readiness Tool-It Is a Potential Predictive Model for Outcomes and Recurrence.

The Shoulder Instability-Return to Sports After Injury (SIRSI) scale is a useful psychological readiness tool to determine whether athletes are prepared to return to sport. Although questions remain on the optimal timing of survey administration based on the type of procedure (i.e., arthroscopic Bankart repair vs Latarjet procedure) and external factors contributing to psychological readiness, its current use begs the question of what other applications may be appropriate. The SIRSI scale has recently been able to effectively predict patient-reported and clinical outcomes, such as postoperative instability recurrence. However, it also may have added value as a serial screening tool for determining a safe return to preinjury activity rather than just serving as a harbinger of further negative outcomes after shoulder stabilization. Increasingly, we must recognize the fundamental limitations in our current rehabilitation pathways and sometimes myopic, 1-dimensional return-to-play criteria (e.g., range of motion or isokinetic testing) in facilitating a safe return to competition. We must transition to a more regimented, criteria-based return-to-play battery that incorporates optimized psychological readiness. As such, the SIRSI scale, like its anterior cruciate ligament counterpart, could become the standard of care in determining confidence in returning to sport and ultimately serve as a benchmark of surgical success.

Rates and predictors of reimplantation of matrix-induced autologous chondrocyte implantation following first stage cartilage harvest: A cohort study.

PURPOSE: To assess the reimplantation rate and predictors of patients requiring second-staged matrix-induced autologous chondrocyte implantation (MACI) reimplantation after initial first stage cartilage biopsy. METHODS: A retrospective review was performed from 2018 to 2022 among patients who underwent only phase I MACI biopsy procedure (biopsy group) or both phase I with transition to phase II implantation of chondrocytes (implantation group) at a single tertiary center. Demographic, qualitative, and quantitative measurements were recorded, and univariate and multivariate regression analysis was performed to assess predictors of ultimately requiring second stage MACI implantation. RESULTS: A total of 71 patients (51% female, age 27.7 ± 10.6 years (range 12-50)) were included in this study. Eventually, 25 of 71 patients (35.2%) experienced persistence of symptoms after initial MACI biopsy and other concomitant procedures, requiring second-stage implantation. Univariate analysis showed the implantation group compared to the biopsy group had a greater lesion size (5.2 cm2 ± 3.3 vs. 3.3 cm2 ± 1.4, p = 0.024), a higher proportion patients ≥ 26 years of age (76% vs. 43%, p = 0.009), a medial femoral condyle lesion more commonly (33% vs 11%, p = 0.005), were more often female (72% vs. 39%, p = 0.008), and had less often soft tissue repair at time of biopsy (32% vs. 61%, p = 0.020). Backward multivariate logistic regression analysis revealed that size of the lesion (OR 1.43, p = 0.031) and age ≥ 26 years old at time of biopsy (OR 3.55, p = 0.042) were independent predictors of not responding to initial surgery and requiring implantation surgery. CONCLUSION: This study found that 35% of patients undergoing MACI phase I biopsy harvest eventually required autologous implantation. Independent risk factors for progressing to implantation after failed initial surgery were larger defect size and older age. LEVEL OF EVIDENCE: III, Cohort Study.

An Expedited Sling Immobilization Protocol After Isolated Biceps Tenodesis Results in Clinical and Patient-Reported Postoperative Outcomes Equivalent to a Standard Rehabilitation Protocol.

Purpose: To characterize clinical and patient-reported outcomes for patients after isolated biceps tenodesis (BT) who underwent either standard or expedited sling immobilization protocols following surgery. Methods: This retrospective cohort study compared patients who were assigned to use a sling for either 4 to 6 weeks (standard) or 0 to 2 weeks (expedited) following an isolated BT. Primary endpoint included rate of re-rupture, surgical revision, loss of fixation, and Popeye deformity. Secondary endpoints included shoulder range of motion (ROM) as well as pre- and postoperative patient-reported outcomes (PROs) of pain and function. Missing data were managed via multiple imputation with chained equations. Complication prevalence 95% confidence intervals were calculated using the Clopper Pearson method and a series of hierarchical mixed effects linear regressions were performed to assess differences between sling interventions in PROs and ROM. Results: The average age of the standard cohort (n = 66) was 49 years (±14 years), and the average age of the expedited cohort (n = 69) was 47 years (±14 years). The expedited and standardized cohorts demonstrated 0.4 and 0.3 complications per 10,000 exposure days, respectively, with no significant difference between groups (1.4 [95% confidence interval 0.2-10.0], P = .727). There was no demonstrated difference in forward flexion, abduction, or external ROM. The expedited group had less improvement in visual analog scale for pain scores that was not clinically significant and there were no differences in PROs of function. Conclusions: No statistically significant difference in the rate of re-rupture, surgical revision, loss of fixation, or Popeye deformity was noted between protocols after isolated BT. Furthermore, there were no clinically significant differences in ROM or PROs identified between protocols after isolated BT. This study suggests that patients who have undergone isolated BT may safely discontinue sling use within 2 weeks after surgery. Level of Evidence: Level III, retrospective comparative study.

Low Recurrence of Instability and Satisfying Patient-Reported Outcomes Following Various Surgical Treatments of Reverse Hill-Sachs Lesions in the Setting of Posterior Instability: A Systematic Review.

PURPOSE: To systematically review the literature and report the outcomes of various surgical treatments for reverse Hill-Sachs lesions (RHSL) in the setting of posterior shoulder instability. METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. All studies assessing outcomes of surgical treatment of RHSL from inception to January 2023 were identified in PubMed, Embase, and Cochrane Library. Inclusion criteria consisted of studies reporting outcomes, minimum mean 1-year follow-up, and minimum Level IV evidence. Outcomes were assessed using Forest plots with random effects models using R software. RESULTS: A total of 29 studies consisting of 291 patients were included with a mean age of 42 years (range 16-88 years), 87% male gender, and mean follow-up of 4.5 years. The mean size of impacted or affected cartilage was 35%, and time from injury to surgery was mean 15 weeks. Nearly all studies were Level IV evidence, and quality of studies was low. Random effect models were performed, and data are presented as range. A low incidence of instability was noted for all surgical techniques with good patient-reported outcome measures. Most studies reported outcomes of the modified McLaughlin procedure (13 studies, 126 patients) with overall Constant-Murley Score of 65 to 92. Trends were seen towards better Constant-Murley Score and external rotation with a shorter delay between injury, and when arthroscopic and joint preserving treatments were performed. CONCLUSIONS: This systematic review showed low rates of instability recurrence, reproducible range of motion, and favorable patient-reported outcome measures were reported following all treatments for RHSLs with posterior instability. There was a significant association between better outcomes and a shorter delay between injury and surgery. The level of evidence is limited, given the small and retrospective studies which can be explained by the rarity of these injuries. LEVEL OF EVIDENCE: Level IV; systematic review of Level III and IV studies.

Management of hypertensive crisis: British and Irish Hypertension Society Position document.

Patients with hypertensive emergencies, malignant hypertension and acute severe hypertension are managed heterogeneously in clinical practice. Initiating anti-hypertensive therapy and setting BP goal in acute settings requires important considerations which differ slightly across various diagnoses and clinical contexts. This position paper by British and Irish Hypertension Society, aims to provide clinicians a framework for diagnosing, evaluating, and managing patients with hypertensive crisis, based on the critical appraisal of available evidence and expert opinion.

HOPON (Hyperbaric Oxygen for the Prevention of Osteoradionecrosis): A Randomized Controlled Trial of Hyperbaric Oxygen to Prevent Osteoradionecrosis of the Irradiated Mandible After Dentoalveolar Surgery.

PURPOSE: Hyperbaric oxygen (HBO) has been advocated in the prevention and treatment of osteoradionecrosis (ORN) of the jaw after head and neck radiation therapy, but supporting evidence is weak. The aim of this randomized trial was to establish the benefit of HBO in the prevention of ORN after high-risk surgical procedures to the irradiated mandible. METHODS AND MATERIALS: HOPON was a randomized, controlled, phase 3 trial. Participants who required dental extractions or implant placement in the mandible with prior radiation therapy >50 Gy were recruited. Eligible patients were randomly assigned 1:1 to receive or not receive HBO. All patients received chlorhexidine mouthwash and antibiotics. For patients in the HBO arm, oxygen was administered in 30 daily dives at 100% oxygen to a pressure of 2.4 atmospheres absolute for 80 to 90 minutes. The primary outcome measure was the diagnosis of ORN 6 months after surgery, as determined by a blinded central review of clinical photographs and radiographs. The secondary endpoints included grade of ORN, ORN at other time points, acute symptoms, pain, and quality of life. RESULTS: A total of 144 patients were randomized, and data from 100 patients were analyzed for the primary endpoint. The incidence of ORN at 6 months was 6.4% and 5.7% for the HBO and control groups, respectively (odds ratio, 1.13; 95% confidence interval, 0.14-8.92; P = 1). Patients in the hyperbaric arm had fewer acute symptoms but no significant differences in late pain or quality of life. Dropout was higher in the HBO arm, but the baseline characteristics of the groups that completed the trial were comparable between the 2 arms. CONCLUSIONS: The low incidence of ORN makes recommending HBO for dental extractions or implant placement in the irradiated mandible unnecessary. These findings are in contrast with a recently published Cochrane review and previous trials reporting rates of ORN (non-HBO) of 14% to 30% and challenge a long-established standard of care.

Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia.

Thiazide diuretics are among the most widely used treatments for hypertension, but thiazide-induced hyponatremia (TIH), a clinically significant adverse effect, is poorly understood. Here, we have studied the phenotypic and genetic characteristics of patients hospitalized with TIH. In a cohort of 109 TIH patients, those with severe TIH displayed an extended phenotype of intravascular volume expansion, increased free water reabsorption, urinary prostaglandin E2 excretion, and reduced excretion of serum chloride, magnesium, zinc, and antidiuretic hormone. GWAS in a separate cohort of 48 TIH patients and 2,922 controls from the 1958 British birth cohort identified an additional 14 regions associated with TIH. We identified a suggestive association with a variant in SLCO2A1, which encodes a prostaglandin transporter in the distal nephron. Resequencing of SLCO2A1 revealed a nonsynonymous variant, rs34550074 (p.A396T), and association with this SNP was replicated in a second cohort of TIH cases. TIH patients with the p.A396T variant demonstrated increased urinary excretion of prostaglandin E2 and metabolites. Moreover, the SLCO2A1 phospho-mimic p.A396E showed loss of transporter function in vitro. These findings indicate that the phenotype of TIH involves a more extensive metabolic derangement than previously recognized. We propose one mechanism underlying TIH development in a subgroup of patients in which SLCO2A1 regulation is altered.

Antitumor Activity of Lankacidin Group Antibiotics Is Due to Microtubule Stabilization via a Paclitaxel-like Mechanism.

Lankacidin group antibiotics show strong antimicrobial activity against various Gram-positive bacteria. In addition, they were shown to have considerable antitumor activity against certain cell line models. For decades, the antitumor activity of lankacidin was associated with the mechanism of its antimicrobial action, which is interference with peptide bond formation during protein synthesis. This, however, was never confirmed experimentally. Due to significant similarity to paclitaxel-like hits in a previous computational virtual screening study, we suggested that the cytotoxic effect of lankacidin is due to a paclitaxel-like action. In this study, we tested this hypothesis computationally and experimentally and confirmed that lankacidin is a microtubule stabilizer that enhances tubulin assembly and displaces taxoids from their binding site. This study serves as a starting point for optimization of lankacidin derivatives for better antitumor activities. It also highlights the power of computational predictions and their aid in guiding experiments and formulating rigorous hypotheses.

Hyperbaric oxygen for patients with chronic bowel dysfunction after pelvic radiotherapy (HOT2): a randomised, double-blind, sham-controlled phase 3 trial.

BACKGROUND: Hyperbaric oxygen has been used as a therapy for patients experiencing chronic intestinal syndromes after pelvic radiotherapy for decades, yet the evidence to support the use of this therapy is based almost exclusively on non-randomised studies. We aimed to provide conclusive results for the clinical benefits of hyperbaric oxygen in patients with chronic bowel dysfunction after radiotherapy for pelvic malignancies. METHODS: HOT2 was a double-blind, sham-controlled, phase 3 randomised study of patients (≥18 years) with chronic gastrointestinal symptoms for 12 months or more after radiotherapy and which persisted despite at least 3 months of optimal medical therapy and no evidence of cancer recurrence. Participants were stratified by participating hyperbaric centre and randomly assigned (2:1) by a computer-generated list (block size nine or 12) to receive treatment with hyperbaric oxygen therapy or sham. Participants in the active treatment group breathed 100% oxygen at 2·4 atmospheres of absolute pressure (ATA) and the control group breathed 21% oxygen at 1·3 ATA; both treatment groups received 90-min air pressure exposures once daily for 5 days per week for a total of 8 weeks (total of 40 exposures). Staff at the participating hyperbaric medicine facilities knew the allocated treatment, but patients, clinicians, nurse practitioners, and other health-care professionals associated with patients' care were masked to treatment allocation. Primary endpoints were changes in the bowel component of the modified Inflammatory Bowel Disease Questionnaire (IBDQ) score and the IBDQ rectal bleeding score 12 months after start of treatment relative to baseline. The primary outcome was analysed in a modified intention-to-treat population, excluding patients who did not provide IBDQ scores within a predetermined time-frame. All patients have completed 12 months of follow-up and the final analysis is complete. The trial is registered with the ISRCTN registry, number ISRCTN86894066. FINDINGS: Between Aug 14, 2009, and Oct 23, 2012, 84 participants were randomly assigned: 55 to hyperbaric oxygen and 29 to sham control. 75 (89%) participants received 40 pressure exposures, all participants returned the IBDQ at baseline, 75 (89%) participants returned the IBDQ at 2 weeks post-treatment, and 79 (94%) participants returned the IBDQ at 12 months post-start of treatment. Patients were excluded from analyses of co-primary endpoints if they had missing IBDQ scores for intestinal function or rectal bleeding at baseline or at 12 months. In an analysis of 46 participants in the active treatment group and 23 participants in the control group, we found no significant differences in the change of IBDQ bowel component score (median change from baseline to 12 months of 4 (IQR -3 to 11) in the treatment group vs 4 (-6 to 9) in the sham group; Mann-Whitney U score 0·67, p=0·50). In an analysis of 29 participants in the active treatment group and 11 participants in the sham group with rectal bleeding at baseline, we also found no significant differences in the change of IBDQ rectal bleeding score (median change from baseline to 12 months of 3 [1 to 3] in the treatment group vs 1 [1 to 2] in the sham group; U score 1·69, p=0·092). Common adverse events in both groups were eye refractive changes (three [11%] of 28 patients in the control group vs 16 [30%] of 53 patients in the treatment group), increased fatigue (three [11%] vs two [4%]), and ear pain (six [21%] vs 15 [28%]). Eight serious adverse events were reported in eight patients: two were reported in two patients in the control group (tonsillitis requiring surgery [grade 3]; recurrent cancer of the vulva [grade 4]) and six serious adverse events were reported in six patients in the treatment group (malignant spinal cord compression requiring surgery [grade 3]; malignant paraortic lymph node involvement requiring surgery [grade 3]; recurrence of vomiting and dehydration [grade 3]; diarrhoea and fever associated with Campylobacter infection [grade 3]; recurrence of abdominal pain, bloating, diarrhoea, and urinary tract infection [grade 3]; aneurysm [grade 4]), none of which were deemed treatment-related. INTERPRETATION: We found no evidence that patients with radiation-induced chronic gastrointestinal symptoms, including those patients with rectal bleeding, benefit from hyperbaric oxygen therapy. These findings contrast with evidence used to justify current practices, and more level 1 evidence is urgently needed. FUNDING: Cancer Research UK and National Health Service (NHS) funding to the National Institute of Health Research Biomedical Research Centre at The Royal Marsden and the Institute of Cancer Research.

MicroRNA miR-92a-1 biogenesis and mRNA targeting is modulated by a tertiary contact within the miR-17~92 microRNA cluster.

While functional mature microRNAs (miRNAs) are small ∼22 base oligonucleotides that target specific mRNAs, miRNAs are initially expressed as long transcripts (pri-miRNAs) that undergo sequential processing to yield the mature miRNAs. We have previously reported that the pri-miR-17∼92 cluster adopts a compact globular folded structure that internalizes a 3' core domain resulting in reduced miRNA maturation and subsequent mRNA targeting. Using a site-specific photo-cross-linker we have identified a tertiary contact within the 3' core domain of the pri-miRNA between a non-miRNA stem-loop and the pre-miR-19b hairpin. This tertiary contact is involved in the formation of the compact globular fold of the cluster while its disruption enhances miR-92a expression and mRNA targeting. We propose that this tertiary contact serves as a molecular scaffold to restrict expression of the proposed antiangiogenic miR-92a, allowing for the overall pro-angiogenic effect of miR-17∼92 expression.

Randomised phase II trial of hyperbaric oxygen therapy in patients with chronic arm lymphoedema after radiotherapy for cancer.

BACKGROUND: A non-randomised phase II study suggested a therapeutic effect of hyperbaric oxygen (HBO) therapy on arm lymphoedema following adjuvant radiotherapy for early breast cancer, justifying further investigation in a randomised trial. METHODS: Fifty-eight patients with ≥ 15% increase in arm volume after supraclavicular ± axillary radiotherapy (axillary surgery in 52/58 patients) were randomised in a 2:1 ratio to HBO (n=38) or to best standard care (n=20). The HBO group breathed 100% oxygen at 2.4 atmospheres absolute for 100 min on 30 occasions over 6 weeks. Primary endpoint was ipsilateral limb volume expressed as a percentage of contralateral limb volume. Secondary endpoints included fractional removal rate of radioisotopic tracer from the arm, extracellular water content, patient self-assessments and UK SF-36 Health Survey Questionnaire. FINDINGS: Of 53/58 (91.4%) patients with baseline assessments, 46 had 12-month assessments (86.8%). Median volume of ipsilateral limb (relative to contralateral) at baseline was 133.5% (IQR 126.0-152.3%) in the control group, and 135.5% (IQR 126.5-146.0%) in the treatment group. Twelve months after baseline the median (IQR) volume of the ipsilateral limb was 131.2% (IQR 122.7-151.5%) in the control group and 133.5% (IQR 122.3-144.9%) in the treatment group. Results for the secondary endpoints were similar between randomised groups. INTERPRETATION: No evidence has been found of a beneficial effect of HBO in the treatment of arm lymphoedema following primary surgery and adjuvant radiotherapy for early breast cancer.

Mitomycin dimers: polyfunctional cross-linkers of DNA.

The three dimers 3, 4, and 5 of mitomycin C (MC), a natural antibiotic and cancer chemotherapeutic agent, were synthesized in which two MC molecules were linked with -(CH(2))(4)-, -(CH(2))(12)-, and -(CH(2))(3)N(CH(3))(CH(2))(3)- tethers, respectively. The dimeric mitomycins were designed to react as polyfunctional DNA alkylators, generating novel types of DNA damage. To test this design, their in vitro DNA alkylating and interstrand cross-linking (ICL) activities were studied in direct comparison with MC, which is itself an ICL agent. Evidence is presented that 3-5 multifunctionally alkylate and cross-link extracellular DNA and form DNA ICLs more efficiently than MC. Reductive activation, required for these activities, is catalyzed by the same reductases and chemical reductants that activate MC. Dimer 5, but not MC, cross-linked DNA under activation by low pH also. Sequence specificities of cross-linking of a 162-bp DNA fragment (tyrT DNA) by MC, 3, and 5 were determined using DPAGE. The dimers and MC cross-linked DNA with the same apparent CpG sequence specificity, but 5 exhibited much greater cross-linking efficacy than MC. Greatly enhanced regioselectivity of cross-linking to G.C rich regions by 5 relative to MC was observed, for which a mechanism unique to dimeric MCs is proposed. Covalent dG adducts of 5 with DNA were isolated and characterized by their UV and mass spectra. Tri- and tetrafunctional DNA adducts of 5 were detected. Although the dimers were generally less cytotoxic than MC, dimer 5 was highly and uniformly cytotoxic to all 60 human tumor cell cultures of the NCI screen. Its cytotoxicity to EMT6 tumor cells was enhanced under hypoxic conditions. These findings together verify the expected features of the MC dimers and warrant further study of the biological effects of dimer 5.