Citations

Abstract The purpose of this study was to assess the long-term clinical and radiographic outcomes after distal ulna resection (Darrach procedure) in young adults. A retrospective chart review identified all adult patients who underwent Darrach resection at 40 years of age or younger and had a minimum of 5-year follow-up. Twenty-one patients (24 wrists) were available for final follow-up. Fifteen patients (16 wrists) returned for in-person evaluation, and seven patients (eight wrists) completed questionnaires by phone. Mean PRWE and QuickDASH scores were 32 and 34, respectively. The median visual analog scale at rest was 0 and 1 with activity. In 88% of cases, patients reported they would have the same surgery again. Of those who were employed preoperatively, 81% (13/16) returned to work, with all but one patient returning to their preoperative job. Radioulnar convergence occurred in all patients, but only three (23%) were symptomatic. The Darrach procedure may be a viable surgical option for DRUJ pathology in younger adults when other options are unavailable. Therapeutic IV.

ABSTRACT Background and hypothesis Podocytopathy associated with likely pathogenic/pathogenic variants of Transient receptor potential cation channel subfamily C member 6 (TRPC6) (TRPC6-AP) has been recognized for about 20 years. As a result of its rarity however, the spectrum of clinical phenotypes and genotype–phenotype correlation of TRPC6-AP remains poorly understood. Here, we characterized clinical, histological and genetic correlates of familial and sporadic patients with TRPC6-AP. Methods In this multicentre observational study, an online questionnaire followed by a systematic literature review was performed to create a cohort with comprehensive data on genetic and clinical outcomes [age of onset, clinical presentation, treatment response, kidney biopsy findings and progression to kidney failure (KF)]. Logistic regression, Cox proportional hazards model and Kaplan–Meier analyses investigated the associations between genetic variants and disease progression. Results Among 87 families (96 familial and 45 sporadic cases), 31 distinct missense TRPC6 variants (including 2 novel) were identified, with c.2683C>T p.(Arg895Cys) and c.523C>T p.(Arg175Trp) the commonest variants. Proteinuric kidney disease/nephrotic syndrome was the most common clinical presentation (83.7%), while focal segmental glomerulosclerosis was the most common histological finding (89.4%). By 33 (interquartile range 17–40) years, 48.9% (69/141) of patients had progressed to KF. Sporadic TRPC6-AP demonstrated an earlier progression to KF than familial cases (P = .001) and were more likely to present with nephrotic syndrome [odds ratio 4.34 (1.85–10.15); P = .001]. Gain-of-function TRPC6 variants were more frequent in familial than sporadic TRPC6-AP (70.8% vs 44.4%; P = .004). Compared with patients with other TRPC6 variants, patients with TRPC6 p.R175W and p.R895C variants progressed to KF earlier [median kidney survival of 21 years, hazard ratio 2.985 (95% confidence interval 1.40–5.79); and 38 years, hazard ratio 1.65 (95% confidence interval 1.01–2.81), respectively, log-rank P = .005]. Conclusion Our study shows unique clinical and genetic correlations of TRPC6-AP, which may enable personalized care and promising novel therapies.

Background: Osteochondral allograft transplant and autograft transplant for femoral head defects have emerged as promising treatments for concomitant cartilage and subchondral bone injuries in young patients. Purpose: To evaluate the clinical and radiological outcomes of patients who underwent osteochondral allograft or autograft transplant for femoral head defects and identify any risk factors that may lead to conversion to total hip arthroplasty (THA). Study Design: Case series; Level of evidence, 4. Methods: All patients who underwent osteochondral allograft or autograft transplant for femoral head defects across 2 institutions were analyzed. Clinical outcomes were assessed at final follow-up with the modified Harris Hip Score (mHHS), Hip Outcome Score–Activities of Daily Living (HOS-ADL), Hip Outcome Score–Sport-Specific Subscale (HOS-SSS), and International Hip Outcome Tool (iHOT-12). Complications and reoperations were recorded. Patients were assessed radiographically preoperatively and at final follow-up for osteoarthritis using Tönnis grading. Results: A total of 27 patients were included in this study (19 osteochondral allograft transplant, 8 osteochondral autograft transplant). The mean follow-up for the allograft and autograft cohorts was 2.8 and 9.5 years, respectively. The mean defect size for patients who underwent allograft and autograft transplant was 2.8 × 2.1 cm and 1.6 × 1.0 cm, respectively. The mean mHHS, HOS-ADL, HOS-SSS, and iHOT-12 for the allograft cohort were 86.7, 92.8, 81.4, and 79.0, respectively, and for the autograft cohort were 87.6, 92.7, 83.1, and 82.0, respectively. No significant difference in outcomes was noted for patients who underwent femoral head allograft versus nonorthotopic femoral condyle allograft transplant. For the allograft cohort, 4 patients (21.1%) underwent conversion to THA at a mean of 1.9 years. Of the remaining 15 allograft patients, only 1 patient (6.7%) had radiographic osteoarthritis progression. None of the patients in the autograft cohort underwent conversion to THA. Conclusion: Osteochondral allograft and autograft transplant for femoral head defects demonstrated overall favorable clinical outcomes and rates of conversion to THA. Additionally, nonorthotopic femoral condyle allografts demonstrated similar outcomes to femoral head allografts. Both osteochondral allograft and autograft transplant should be considered for patients with focal femoral head defects.

ABSTRACT Evidence indicates that the integrity of in utero development influences late life healthy or unhealthy aging; however, specific links between them are unclear. Histone chaperone HIRA is thought to play a role in both life stages, and here, we explore this role using the murine pigmentary system by investigating and comparing the effects of its lineage‐specific knockout, either conditionally during embryogenesis or postnatally. Embryonic knockout of Hira in tyrosinase+ neural crest‐derived lineages, including melanoblasts, led to reduced melanoblast numbers during embryogenesis, with single‐cell RNA sequencing analysis indicating evidence of lineage‐specificity defects. This was supported in an in vitro model using melb‐a melanoblasts in which Hira knockdown affected lineage identity and melanoblast differentiation potential, with ATAC‐seq data indicating a role of HIRA in orchestrating chromatin accessibility. Interestingly, however, newborn Hira knockout mice had wild type numbers of differentiated melanocytes, albeit functionally defective, as demonstrated by very mild hypopigmentation of the first hair coat, increased melanocyte telomere‐associated DNA damage foci, and impaired response to proliferative challenge. Moreover, as they aged, mice with embryonic melanoblast Hira knockout displayed marked defects in melanocyte stem cell maintenance and premature hair graying. Importantly, this phenotype was not observed after postnatal inducible knockout, indicating an essential role for HIRA at embryonic stages that is transmitted to adulthood, rather than a direct postnatal requirement within the pigmentary system. This genetic model shows that HIRA function during early development lays a foundation for maintaining lineage identity and subsequent maintenance of adult tissue‐specific stem cells during aging.

INTRODUCTION: There is an urgent need for effective and safe treatment of gastroparesis. Metopimazine, a selective, peripherally restricted dopamine D 2 receptor antagonist, is used in France for the symptomatic treatment of nausea and vomiting and chemotherapy-induced nausea and vomiting. The aim of this study is to assess the safety and efficacy of oral NG101, the mesylate salt of metopimazine, for the treatment of gastroparesis. METHODS: We conducted a 12-week phase 2 multicenter trial with NG101 5, 10, and 20 mg 4 times a day versus placebo. The primary end point was the change in mean nausea severity from the Diabetic and Idiopathic Gastroparesis Symptoms Daily Diary (DIGS-DD) during weeks 7–12 of the Treatment Period from baseline. The DIGS-DD measured nausea, abdominal pain, early satiety, postprandial fullness, and vomiting at their worst in the past 24 hours using a 0-10 point numeric rating scale. Patient Global Impression of Change questionnaires, including nausea, were assessed weekly using a 7-point balanced ordinal score. RESULTS: Of 161 randomized participants (45.3% diabetic and 54.7% idiopathic), mean DIGS-DD nausea severity scores decreased from baseline during weeks 7–12 in all treatment groups, but these improvements were not statistically significant compared with placebo. However, there were statistically significant improvements in nausea Patient Global Impression of Change during weeks 1–12 for all treatment groups compared with placebo. Trends in safety and efficacy favored patients with idiopathic gastroparesis compared with those with diabetic gastroparesis. DISCUSSION: While NG101 did not meet statistical significance in its primary end point for reducing nausea severity, it demonstrated a favorable safety profile and significant improvement in some secondary end points. Further study is needed to determine whether NG101 is an effective treatment for patients with idiopathic gastroparesis.

Abstract Rationale: While survival of premature infants has improved with NICU interventions, prematurity remains a risk for developing chronic lung diseases. Oxygen supplementation in the NICU is unfortunately necessary, and clinical practice has shifted towards use of moderate hyperoxia (<60% O2) to minimize detrimental effects of very high O2 concentration (80-90%) such as bronchopulmonary dysplasia. However, even moderate hyperoxia increases the risk of bronchial airway diseases and wheezing/asthma with airway hyperreactivity and remodeling. We previously found that moderate hyperoxia induces cellular senescence in human fetal airway smooth muscle cells (fASM) and fibroblasts. However, the mechanisms by which hyperoxia enhances cellular senescence in fASM are not known. We investigated the role of endoplasmic reticulum (ER) stress and mitochondrial dysfunction, using fASM cells exposed to 21% (normoxia) vs. 50% O2 (hyperoxia). Methods: fASM isolated from lungs of 18-20 week aborted fetuses (Mayo IRB exempt; period of rapid bronchial airway growth) were exposed to normoxia, hyperoxia or etoposide (10 µM; positive control for senescence induction). Cells and lysates were harvested at days 2, 3 or 7 to assess markers of senescence markers, ER stress and mitochondrial morphology, and levels of cytosolic and mitochondrial ROS, using real-time fluorescence imaging, Western blotting, immunofluorescence, and a novel immuno-FISH staining of telomere associated foci (TAF). Mitochondria-specific antioxidant MitoQ [100 nM], ER stress inhibitor Salubrinal [12.5 µM] or mitochondrial fission inhibitor Mdivi-1 [10 µM] were used to assess their effects on senescence markers and interactions between ER stress and mitochondria in inducing senescence. Results: Hyperoxia enhanced cellular senescence via upregulation of p21, PAI-1, and Cav-1; downregulation of LMNB1 and Ki-67, with increased γH2A.X- and TAF-positive cells. Hyperoxia increased cytosolic and mitochondrial ROS, and markers of the three ER stress pathways (ATF6, IRE1α, XBP1s, PDI, GADD34). Hyperoxia altered mitochondrial morphology with increased fission protein Drp1 and fusion proteins Mfn1/2. Inhibition of Drp1 with Mdivi-1 blocked mitochondrial fragmentation, but not senescence. However, hyperoxia-induced p21 was reduced by the PERK pathway inhibitor Salubrinal and MitoQ. Conclusions: Hyperoxia induces senescence in fASM via mitochondrial ROS and ER stress: pathways that offer new opportunities to blunt detrimental effects of oxygen in developing lung via mitochondrial targeted antioxidants and/or ER stress inhibition.

OBJECTIVE Pelvic incidence (PI) is a key parameter of sagittal alignment. While conventionally held to be fixed, increasing evidence suggests PI may be variable. This study aimed to identify predictors of change in PI with patient position and to assess the association of preoperative radiographic characteristics and intraoperative maneuvers with postoperative PI. METHODS Patients who underwent thoracolumbosacral fusion were identified, and data were gathered on preoperative spinopelvic parameters, patient demographic characteristics, and operative details. Preoperative spinopelvic parameters were measured on upright, supine, and prone radiographs. Univariable comparisons of PI between the different patient positions were performed. Multivariable analysis was performed to identify variables independently correlated with PI on 6-week postoperative radiographs. Change in PI was defined as ≥ 5° change between positions. RESULTS In total, 138 patients were identified (mean ± SD age 66.0 ± 8.7 years; 38.4% male). Statistically significant differences in PI were noted between preoperative standing and supine (mean −3.2° ± 4.2°, p < 0.001), preoperative supine and prone (3.5° ± 4.7°, p < 0.001), preoperative and 6-week postoperative standing (1.5° ± 6.2°, p = 0.01), and immediate and 6-week upright (1.1° ± 3.9°, p = 0.007) radiographs. Univariable comparisons showed PI decrease from standing to supine was predicted only by weight (87.0 ± 15.0 vs 81.1 ± 19.3 kg, p = 0.04); there were no significant predictors of increase in PI from standing to prone. Increase in PI from preoperative to 6-week standing radiographs was predicted by lower preoperative PI class (p < 0.001), L5/S1 interbody placement (74.4% vs 52.0%, p = 0.02), and change in PI from preoperative standing to supine (12.8% vs 39.8%, p = 0.002) and from standing to prone (51.3% vs 13.3%, p < 0.001). Multivariable analysis showed that 6-week postoperative PI was associated with only preoperative supine PI (B = 0.293, 95% CI 0.10–0.48, p = 0.003) and prone PI (B = 0.647, 95% CI 0.44–0.85, p < 0.001). CONCLUSIONS There are position-dependent changes in PI among patients without prior pelvic fixation. Statistically significant changes in PI are seen even after pelvic fixation with a single S2-alar-iliac screw bilaterally. Postoperative PI was best predicted by preoperative PI on supine and prone radiographs rather than upright radiographs, suggesting that preoperative prone and supine radiographs may provide surgeons with the best information for achieving PI–lumbar lordosis mismatch < 10°.

OBJECTIVE Transforaminal lumbar interbody fusion (TLIF) offers both indirect decompression and segmental correction through restoration of disc height. However, stresses exerted on the vertebral endplates by the interbody device can result in implant subsidence and loss of correction. The present time-to-event analysis aimed to identify predictors of interbody subsidence. METHODS Patients who underwent 1- or 2-level TLIF were identified. Data on demographics, surgical details, preoperative bone quality using CT-based Hounsfield units (HU), and pre- and postoperative lumbopelvic parameters were collected. Univariable analyses were conducted to identify predictors of subsidence (≥ 2-mm intrusion of interbody into cranial or caudal vertebrae) and significant subsidence (≥ 4-mm intrusion). Multivariable Cox regression was performed to identify independent predictors of subsidence, expressed as hazard ratios with 95% confidence intervals. RESULTS A total of 198 patients treated at 241 levels were included (median age 66.6 years, IQR 59.5, 73.7 years; 56.6% were women). In 92 levels (38.2%) there was some subsidence and in 25 (10.4%) there was significant subsidence. Implanted levels demonstrating subsidence (≥ 2 mm) were associated with lower HU in cranial and caudal vertebrae; had interbodies positioned farther from the anterior apophyseal ring; were implanted with taller, more lordotic interbodies; and underwent greater disc height restoration. Those showing significant subsidence (≥ 4 mm) were similarly associated with lower HU in the cranial and caudal vertebrae; had interbodies positioned farther from the anterior apophyseal ring of the caudal vertebrae; and underwent greater disc height restoration. Multivariable Cox regression showed that time to subsidence was predicted by greater implant height (HR 1.20/mm, 95% CI 1.05–1.38; p = 0.009), greater postoperative disc height (HR 1.21/mm, 95% CI 1.09–1.34; p < 0.001), and greater disc height restoration (HR 1.11/mm, 95% CI 1.04–1.19; p = 0.002). The time-to-subsidence analysis for significant (≥ 4 mm) subsidence showed that it was predicted by lower HU in the cranial vertebrae (HR 0.98/unit, 95% CI 0.97–0.99; p = 0.001); increasing number of levels instrumented (HR 1.26, 95% CI 1.04–1.52; p = 0.016); and greater disc height restoration (HR 1.33/mm, 95% CI 1.18–1.51; p < 0.001). CONCLUSIONS This time-to-event analysis suggests that interbody subsidence following TLIF is best predicted by implantation of a taller interbody and aggressive disc height restoration. Significant subsidence is similarly predicted by aggressive disc height restoration along with poor baseline bone quality. The results suggest the need to balance aggressive correction at the time of surgery against the increased risk of subsequent interbody subsidence.

Background: Little is known about the association between intraplaque hemorrhage (IPH) and other features of high-risk carotid atherosclerotic plaques, such as the presence of plaque ulceration, plaque enhancement, and lipid-rich necrotic core (LRNC). This study set out to assess the relationship between IPH and other vulnerable plaque features. Materials and Methods: A retrospective review was done of 102 patients with IPH in one or both of the internal carotid arteries (ICA) on neck MRA between 1/1/2016 and 3/31/2021. IPH was defined as a ≥200% signal intensity of the adjacent sternocleidomastoid muscle on MPRAGE images. All ICA plaques were assessed for the presence or absence of IPH, plaque ulceration, plaque enhancement, and LRNC, as well as IPH volume. IPH volume was measured manually by outlining the region of interest. Results: A total of 102 patients were included, with 88 (86.3%) being male. The average age was 73.5 years (SD = 9.0). Both IPH and LRNC were more commonly seen in the left carotid artery ( p = .018 and p = .047, respectively). For right-sided ICAs, there was a significant association between IPH and LRNC ( p < .0001). Lesions without IPH were more likely to have plaque enhancement than lesions with IPH ( p = .04). For left-sided ICAs, there was also a significant association between the presence of IPH and LRNC ( p < .0001). Conclusions: There is a significant association between the presence of IPH and LRNC. An inverse relationship was found between the presence of IPH and plaque enhancement for right-sided plaques. No associations were found between IPH and plaque ulceration.