Fast skeletal myosin binding protein-C expression exacerbates dysfunction in heart failure.

During heart failure, gene and protein expression profiles undergo extensive compensatory and pathological remodeling. We previously observed that fast skeletal myosin binding protein-C (fMyBP-C) is upregulated in diseased mouse hearts. While fMyBP-C shares significant homology with its cardiac paralog, cardiac myosin binding protein-C (cMyBP-C), there are key differences that may affect cardiac function. However, it is unknown if the expression of fMyBP-C expression in the heart is a pathological or compensatory response. We aim to elucidate the cardiac consequence of either increased or knockout of fMyBP-C expression. To determine the sufficiency of fMyBP-C to cause cardiac dysfunction, we generated cardiac-specific fMyBP-C over-expression mice. These mice were further crossed into a cMyBP-C null model to assess the effect of fMyBP-C in the heart in the complete absence of cMyBP-C. Finally, fMyBP-C null mice underwent transverse aortic constriction (TAC) to define the requirement of fMyBP-C during heart failure development. We confirmed the upregulation of fMyBP-C in several models of cardiac disease, including the use of lineage tracing. Low levels of fMyBP-C caused mild cardiac remodeling and sarcomere dysfunction. Exclusive expression of fMyBP-C in a heart failure model further exacerbated cardiac pathology. Following 8 weeks of TAC, fMyBP-C null mice demonstrated greater protection against heart failure development. Mechanistically, this may be due to the differential regulation of the myosin super-relaxed state. These findings suggest that the elevated expression of fMyBP-C in diseased hearts is a pathological response. Targeted therapies to prevent upregulation of fMyBP-C may prove beneficial in the treatment of heart failure. Significance Statement: Recently, the sarcomere - the machinery that controls heart and muscle contraction - has emerged as a central target for development of cardiac therapeutics. However, there remains much to understand about how the sarcomere is modified in response to disease. We recently discovered that a protein normally expressed in skeletal muscle, is present in the heart in certain settings of heart disease. How this skeletal muscle protein affects the function of the heart remained unknown. Using genetically engineered mouse models to modulate expression of this skeletal muscle protein, we determined that expression of this skeletal muscle protein in the heart negatively affects cardiac performance. Importantly, deletion of this protein from the heart could improve heart function suggesting a possible therapeutic avenue.

Fever and Increased Gastrointestinal Uptake on Positron Emission Tomography after Anti-Tumour Necrosis Factor Therapy: A Case Report of Whipple's Disease.

Introduction: Whipple's disease is a rare condition that can present with atypical and non-specific features requiring a high index of suspicion for diagnosis. Case Presentation: We present a case of a man in his 40s with peripheral arthritis and bilateral sacro-ileitis for 4-5 years that was treated with an anti-tumour necrosis factor therapy, which led to worsening of his symptoms, elevation of the inflammatory markers, and the development of fever, night sweats, anorexia, and a significant weight loss. The patient had no abdominal pain, diarrhoea, or other gastrointestinal symptoms. An FDG-PET scan showed increased uptake in the stomach and caecum. Endoscopic examination showed inflammatory changes in the stomach and normal mucosa of the duodenum, jejunum, terminal ileum, caecum, and colon. Histopathology was inconclusive, but the diagnosis was confirmed with Tropheryma whipplei PCR testing. He had no neurological symptoms, but cerebrospinal fluid Tropheryma whipplei PCR was positive. He was treated with intravenous ceftriaxone 2 g daily for 4 weeks, followed by trimethoprim/sulfamethoxazole 160/800 mg twice daily for 1 year with close monitoring and follow-up. Conclusion: This case presents an atypical and challenging presentation of Whipple's disease and the importance of proactive testing for neurological involvement.

In utero and postnatal ivacaftor/lumacaftor therapy rescues multiorgan disease in CFTR-F508del ferrets.

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, with F508del being the most prevalent mutation. The combination of CFTR modulators (potentiator and correctors) has provided benefit to CF patients carrying the F508del mutation; however, the safety and effectiveness of in utero combination modulator therapy remains unclear. We created a F508del ferret model to test whether ivacaftor/lumacaftor (VX-770/VX-809) therapy can rescue in utero and postnatal pathologies associated with CF. Using primary intestinal organoids and air-liquid interface cultures of airway epithelia, we demonstrate that the F508del mutation in ferret CFTR results in a severe folding and trafficking defect, which can be partially restored by treatment with CFTR modulators. In utero treatment of pregnant jills with ivacaftor/lumacaftor prevented meconium ileus at birth in F508del kits and sustained postnatal treatment of CF offspring improved survival and partially protected from pancreatic insufficiency. Withdrawal of ivacaftor/lumacaftor treatment from juvenile CF ferrets reestablished pancreatic and lung diseases, with altered pulmonary mechanics. These findings suggest that in utero intervention with a combination of CFTR modulators may provide therapeutic benefits to individuals with F508del. This CFTR-F508del ferret model may be useful for testing therapies using clinically translatable endpoints.

Similar rates of reoperation for neuroma after transtibial amputations with and without targeted muscle reinnervation.

Objective: To compare the rates of revision surgery for symptomatic neuromas in patients undergoing primary transtibial amputations with and without targeted muscle reinnervation (TMR). Design: Retrospective cohort study. Setting: Level I trauma hospital and tertiary military medical center. Patients/Participants: Adult patients undergoing transtibial amputations with and without TMR. Intervention: Transtibial amputation with targeted muscle reinnervation. Main Outcome Measurements: Reoperation for symptomatic neuroma. Results: During the study period, there were 112 primary transtibial amputations performed, 29 with TMR and 83 without TMR. Over the same period, there were 51 revision transtibial amputations performed, including 23 (21%) in the patients undergoing primary transtibial amputation at the study institution. The most common indications for revision surgery were wound breakdown/dehiscence (42%, n = 25), followed by symptomatic neuroma 18% (n = 9/51) and infection/osteomyelitis (17%, n = 10) as the most common indications. However, of the patients undergoing primary amputation at the study's institution, there was no difference in reoperation rates for neuroma when comparing the TMR group (3.6%, n = 1/28) and no TMR group (4.0%, n = 3/75) (P = 0.97). Conclusions: Symptomatic neuroma is one of the most common reasons for revision amputation; however, this study was unable to demonstrate a difference in revision surgery rates for neuroma for patients undergoing primary transtibial amputation with or without targeted muscle reinnervation. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

At-Risk Median Motor Branch to the Thenar Musculature Crossing Under the Flexor Carpi Radialis in the Forearm: A Case Report.

CASE: A 77-year-old woman who sustained a distal radius and ulna fracture underwent open reduction internal fixation through a standard flexor carpi radialis (FCR) approach. On dissection, a proximal division of the median nerve was identified, with an aberrant motor branch crossing radial to ulnar deep to FCR and superficial to flexor pollicis longus. CONCLUSION: Although many anatomic variants of the median nerve have been described, the current case demonstrates a particularly important median motor branch variant, imposing a substantial risk of iatrogenic injury during a standard FCR approach.

Inaccurate Citations Are Prevalent Within Orthopaedic Sports Medicine Literature.

Purpose: To evaluate the peer-reviewed orthopaedic sports medicine literature for reference errors within 2 high-impact journals. Methods: In total, 769 references with 1,082 in-line citations were assessed from 20 randomly selected peer-reviewed articles published in 2 high-impact orthopaedic sports medicine journals, Arthroscopy and the American Journal of Sports Medicine. Full-text copies of references were obtained through online literature subscription databases. Two investigators evaluated each citation for agreement between the reference's study design, methods, data, discussion, and conclusion with the citing authors' claims. Error rates, interobserver agreement, and association between error rates and journal demographics were assessed. Results: Cohen's κ coefficient representing interobserver agreement was 0.61. The mean citation error rate across 20 articles from 2 orthopaedic sports medicine journals was 6.6%. The most common error was failure to support the authors' assertions within the citing article, accounting for 32% of errors. There was no significant association between error rate and journal impact factor, number of cited references or total references, ratio of in-line citations to cited references (citation ratio), and number of authors. There was no significant relationship between error rate and journal, study type, and level of evidence. Conclusions: Inaccurate claims and citations are common within the orthopaedic sports medicine literature, occurring in every reviewed article and 6.6% of all in-line citations. Failure to support the assertions of the article in which a reference is cited is a common error. Authors should take care to rigorously assess references with particular attention to accurate citation of primary sources. Clinical Relevance: This study highlights the prevalence of citation errors within a random sampling of high-level orthopaedic sports medicine articles. Given science is cumulative, these errors perpetuate inaccuracies and are at odds with evidence-based practice.

Intravenous Cefazolin Achieves Sustained High Interstitial Concentrations in Open Lower Extremity Fractures.

BACKGROUND: Infection remains a serious clinical concern in patients with open fractures, despite timely antibiotic administration and surgical debridement. Soft tissue and periosteal stripping may alter local tissue homeostasis and antibiotic pharmacokinetics in the injured limb. The tissue (interstitial) concentration of intravenously administered antibiotics at an open fracture site has not been characterized using direct sampling techniques. QUESTION/PURPOSE: We performed this study to evaluate the concentration and pharmacokinetics of intravenously delivered cefazolin at an open fracture site after surgical debridement. METHODS: Twelve patients with an open fracture distal to the knee who presented at a regional Level I trauma center were approached for enrollment in this nonrandomized, observational study. Of the 12 patients, eight adults (one female, seven male) with a median age of 32 years (range 23 to 51 years) were enrolled and underwent successful sample collection for analysis. Three patients had incomplete datasets because of equipment malfunction and one elected not to participate. Seven patients had open tibia fractures, and one patient had an open fibula fracture associated with a closed tibia fracture. There were six Gustilo-Anderson Type II injuries and two Type IIIA injuries. Empiric antibiotics were administered in the prehospital setting or in the emergency department according to institutional protocol. When patients were taken to the operating room, a 2-g intravenous dose of cefazolin was administered. After surgical debridement, fracture stabilization, and wound closure, a microdialysis catheter was placed transdermally into the injury zone (within 5 cm of the fracture site) and a second catheter was placed in the contralateral uninjured (control) limb. Additional doses of cefazolin were administered every 8 hours postoperatively. Baseline and periodic interstitial fluid and whole blood (plasma) samples were collected in the operating room and at prespecified times for 24 hours postoperatively. Free cefazolin in the interstitial fluid and plasma samples were analyzed by ultra-high-performance liquid chromatography using C 18 column separation with quadrupole time-of-flight mass spectrometry detection. Data from the second postoperative dose of cefazolin were used to characterize pharmacokinetic parameters through a noncompartmental analysis using time-concentration curves of free cefazolin and assuming first-order elimination. For pharmacodynamic analyses, the modal cefazolin minimum inhibitory concentration (MIC) of Staphylococcus aureus (1 µg/mL) was used. RESULTS: With the samples available, no difference was observed in the median free cefazolin exposure over 24 hours ( f area under the curve [AUC] 0→24hrs ) between injured limbs (352 µg∙hr/mL [IQR 284 to 594 µg∙hr/mL]) and uninjured limbs (341 µg∙hr/mL [IQR 263 to 438 µg∙hr/mL]; p = 0.64). The median time to achieve the maximum concentration of free cefazolin ( f T max ) for injured limbs was delayed (2.7 hours [IQR 2.2 to 3.1 hours]) compared with control limbs (1.7 hours [IQR 1.2 to 2.0 hours]; p = 0.046). The time to the maximum concentration for plasma was not different from that of control limbs (p = 0.08). The time the cefazolin concentration was above the modal S. aureus MIC (T > MIC) in the injured and control limbs over 24 hours was 100% (IQR 100% to 100%) and 100% (IQR 97% to 100%), respectively. CONCLUSION: These preliminary findings suggest that current prophylactic cefazolin dosing regimens result in successful antibiotic delivery to the traumatized limb in moderately severe open fractures. Although cefazolin delivery to open-fracture wound beds was delayed compared with healthy tissues, the cefazolin concentration was sustained above the European Union Committee Antimicrobial Susceptibility Testing modal MIC for S. aureus , demonstrating a high likelihood of a prophylactic antimicrobial environment at an open fracture site with this empiric antimicrobial regimen. Importantly, patients in this analysis had Gustilo-Anderson Types II and IIIA injuries. Further research with a larger patient cohort is needed to determine whether antibiotic delivery to traumatized soft tissues in patients with higher-grade open fractures (Gustilo-Anderson Types IIIB and IIIC) demonstrates similar pharmacokinetic characteristics. LEVEL OF EVIDENCE: Level II, therapeutic study.

Association of DCIS size and margin status with risk of developing breast cancer post-treatment: multinational, pooled cohort study.

OBJECTIVE: To examine the association between size and margin status of ductal carcinoma in situ (DCIS) and risk of developing ipsilateral invasive breast cancer and ipsilateral DCIS after treatment, and stage and subtype of ipsilateral invasive breast cancer. DESIGN: Multinational, pooled cohort study. SETTING: Four large international cohorts. PARTICIPANTS: Patient level data on 47 695 women with a diagnosis of pure, primary DCIS between 1999 and 2017 in the Netherlands, UK, and US who underwent surgery, either breast conserving or mastectomy, often followed by radiotherapy or endocrine treatment, or both. MAIN OUTCOME MEASURES: The main outcomes were 10 year cumulative incidence of ipsilateral invasive breast cancer and ipsilateral DCIS estimated in relation to DCIS size and margin status, and adjusted hazard ratios and 95% confidence intervals, estimated using multivariable Cox proportional hazards analyses with multiple imputed data RESULTS: The 10 year cumulative incidence of ipsilateral invasive breast cancer was 3.2%. In women who underwent breast conserving surgery with or without radiotherapy, only adjusted risks for ipsilateral DCIS were significantly increased for larger DCIS (20-49 mm) compared with DCIS <20 mm (hazard ratio 1.38, 95% confidence interval 1.11 to 1.72). Risks for both ipsilateral invasive breast cancer and ipsilateral DCIS were significantly higher with involved compared with clear margins (invasive breast cancer 1.40, 1.07 to 1.83; DCIS 1.39, 1.04 to 1.87). Use of adjuvant endocrine treatment was not significantly associated with a lower risk of ipsilateral invasive breast cancer compared to treatment with breast conserving surgery only (0.86, 0.62 to 1.21). In women who received breast conserving treatment with or without radiotherapy, higher DCIS grade was not significantly associated with ipsilateral invasive breast cancer, only with a higher risk of ipsilateral DCIS (grade 1: 1.42, 1.08 to 1.87; grade 3: 2.17, 1.66 to 2.83). Higher age at diagnosis was associated with lower risk (per year) of ipsilateral DCIS (0.98, 0.97 to 0.99) but not ipsilateral invasive breast cancer (1.00, 0.99 to 1.00). Women with large DCIS (≥50 mm) more often developed stage III and IV ipsilateral invasive breast cancer compared to women with DCIS <20 mm. No such association was found between involved margins and higher stage of ipsilateral invasive breast cancer. Associations between larger DCIS and hormone receptor negative and human epidermal growth factor receptor 2 positive ipsilateral invasive breast cancer and involved margins and hormone receptor negative ipsilateral invasive breast cancer were found. CONCLUSIONS: The association of DCIS size and margin status with ipsilateral invasive breast cancer and ipsilateral DCIS was small. When these two factors were added to other known risk factors in multivariable models, clinicopathological risk factors alone were found to be limited in discriminating between low and high risk DCIS.

Orthotopic Ferret Tracheal Transplantation Using a Recellularized Bioengineered Graft Produces Functional Epithelia.

Tracheal grafts may be necessary to bridge long-segment defects after curative resection for airway obstructions. Bioengineered grafts have emerged as an appealing option, given the possibilities of altering the histologic and cellular profile of the conduit. We previously designed a bioreactor capable of luminally decellularizing and recellularizing a ferret trachea with surface airway epithelia (SAE) basal cells (BCs), and we sought to assess the fate of these grafts when transplanted in an orthotopic fashion. As adjuncts to the procedure, we investigated the use of a vascular endothelial growth factor (VEGF)-laden hydrogel and of immunosuppression (IS) in graft revascularization and viability. IS was shown to limit early graft revascularization, but this effect could be counteracted with VEGF supplementation. Submucosal gland (SMG) loss was shown to be inevitable regardless of the revascularization strategy. Lastly, the bioengineered tracheas survived one month after transplant with differentiation of our implanted BCs that then transitioned into a recipient-derived functional epithelium. The work presented in this manuscript has important implications for future cellular and regenerative therapies.

Microcalcification crystallography as a potential marker of DCIS recurrence.

Ductal carcinoma in-situ (DCIS) accounts for 20-25% of all new breast cancer diagnoses. DCIS has an uncertain risk of progression to invasive breast cancer and a lack of predictive biomarkers may result in relatively high levels (~ 75%) of overtreatment. To identify unique prognostic biomarkers of invasive progression, crystallographic and chemical features of DCIS microcalcifications have been explored. Samples from patients with at least 5-years of follow up and no known recurrence (174 calcifications in 67 patients) or ipsilateral invasive breast cancer recurrence (179 microcalcifications in 57 patients) were studied. Significant differences were noted between the two groups including whitlockite relative mass, hydroxyapatite and whitlockite crystal maturity and, elementally, sodium to calcium ion ratio. A preliminary predictive model for DCIS to invasive cancer progression was developed from these parameters with an AUC of 0.797. These results provide insights into the differing DCIS tissue microenvironments, and how these impact microcalcification formation.

Quadriceps Dysfunction Following Joint Preservation Surgery: A Review of the Pathophysiologic Basis and Mitigation Strategies.

PURPOSE OF REVIEW: To characterize quadriceps muscle dysfunction associated with knee joint preservation surgery, with a focus on its pathophysiology and promising approaches to mitigate its impact on clinical outcomes. RECENT FINDINGS: Quadriceps dysfunction (QD) associated with knee joint preservation surgery results from a complex interplay of signaling, related to changes within the joint and from those involving the overlying muscular envelope. Despite intensive rehabilitation regimens, QD may persist for many months postoperatively and negatively impact clinical outcomes associated with various surgical procedures. These facts underscore the need for continued investigation into the potential detrimental effects of regional anesthetic and intraoperative tourniquet use on postoperative quadriceps function, with an outward focus on innovation within the field of postoperative rehabilitation. Neuromuscular stimulation, nutritional supplementation, cryotherapy, blood flow restriction (BFR), and open-chain exercises are all potential additions to postoperative regimens. There is compelling literature to suggest that these modalities are efficacious and may diminish the magnitude and duration of postoperative QD. A clear understanding of QD, with respect to its pathophysiology, should guide perioperative treatment and rehabilitation strategies and influence ongoing rehabilitation-based research and innovation. Moreover, clinicians must appreciate the magnitude of QD's effect on diminished clinical outcomes, risk for re-injury and patients' ability (or inability) to return to pre-injury level of activity following knee joint preservation procedures.

Development and characterization of ferret ex vivo tracheal injury and cell engraftment model.

The field of airway biology research relies primarily on in vitro and in vivo models of disease and injury. The use of ex vivo models to study airway injury and cell-based therapies remains largely unexplored although such models have the potential to overcome certain limitations of working with live animals and may more closely replicate in vivo processes than in vitro models can. Here, we characterized a ferret ex vivo tracheal injury and cell engraftment model. We describe a protocol for whole-mount staining of cleared tracheal explants, and showed that it provides a more comprehensive structural overview of the surface airway epithelium (SAE) and submucosal glands (SMGs) than 2D sections, revealing previously underappreciated structural anatomy of tracheal innervation and vascularization. Using an ex vivo model of tracheal injury, we evaluated the injury responses in the SAE and SMGs that turned out to be consistent with published in vivo work. We used this model to assess factors that influence engraftment of transgenic cells, providing a system for optimizing cell-based therapies. Finally, we developed a novel 3D-printed reusable culture chamber that enables live imaging of tracheal explants and differentiation of engrafted cells at an air-liquid interface. These approaches promise to be useful for modeling pulmonary diseases and testing therapies. Graphical abstract1,2. We describe here a method for differential mechanical injury of ferret tracheal explants that can be used to evaluate airway injury responses ex vivo. 3. Injured explants can be cultured at ALI (using the novel tissue-transwell device on the right) and submerged long-term to evaluate tissue-autonomous regeneration responses. 4. Tracheal explants can also be used for low throughput screens of compounds to improve cell engraftment efficiency or can be seeded with particular cells to model a disease phenotype. 5. Lastly, we demonstrate that ex vivo-cultured tracheal explants can be evaluated by various molecular assays and by immunofluorescent imaging that can be performed live using our custom-designed tissue-transwell.

ExPeCT: a randomised trial examining the impact of exercise on quality of life in men with metastatic prostate cancer.

PURPOSE: All patients living with cancer, including those with metastatic cancer, are encouraged to be physically active. This paper examines the secondary endpoints of an aerobic exercise intervention for men with metastatic prostate cancer. METHODS: ExPeCT (Exercise, Prostate Cancer and Circulating Tumour Cells), was a multi-centre randomised control trial with a 6-month aerobic exercise intervention arm or a standard care control arm. Exercise adherence data was collected via heart rate monitors. Quality of life (FACT-P) and physical activity (self-administered questionnaire) assessments were completed at baseline, at 3 months and at 6 months. RESULTS: A total of 61 patients were included (69.4 ± 7.3 yr, body mass index 29.2 ± 5.8 kg/m2). The median time since diagnosis was 34 months (IQR 7-54). A total of 35 (55%) of participants had > 1 region affected by metastatic disease. No adverse events were reported by participants. There was no effect of exercise on quality of life (Cohen's d = - 0.082). Overall adherence to the supervised sessions was 83% (329 out of 396 possible sessions attended by participants). Overall adherence to the non-supervised home exercise sessions was 72% (months 1-3) and 67% (months 3-6). Modelling results for overall physical activity scores showed no significant main effect for the group (p-value = 0.25) or for time (p-value = 0.24). CONCLUSION: In a group of patients with a high burden of metastatic prostate cancer, a 6-month aerobic exercise intervention did not lead to change in quality of life. Further exercise studies examining the role of exercise for people living with metastatic prostate cancer are needed. TRIAL REGISTRATION: The trial was registered at clinicaltrials.gov (NCT02453139) on May 25th 2015.

Processes of change in a randomized clinical trial of radically open dialectical behavior therapy (RO DBT) for adults with treatment-refractory depression.

OBJECTIVE: Radically open dialectical behavior therapy (RO DBT) is an empirically supported psychotherapy for treatment-refractory depression (TRD) that targets psychological inflexibility and interpersonal functioning within the context of maladaptive overcontrol. However, it is unknown whether change in these mechanistic processes is associated with decreased symptoms. This study tested whether change in psychological inflexibility and interpersonal functioning is associated with change in depressive symptoms in RO DBT. METHOD: Adults with TRD from The Refractory Depression: Mechanisms and Efficacy of RO DBT (RefraMED) randomized controlled trial of RO DBT, n = 250; M (SD) age = 47.2 (11.5); 65% female; 90% White, were assigned to RO DBT or treatment as usual. Psychological inflexibility and interpersonal functioning were assessed at baseline, 3 (midtreatment), 7 (posttreatment), 12, and 18 months. Mediation analyses and latent growth curve modeling (LGCM) assessed whether change in psychological inflexibility and interpersonal functioning was associated with change in depressive symptoms. RESULTS: The effect of RO DBT in decreasing depressive symptoms was mediated by changes in psychological inflexibility and interpersonal functioning at 3 (95% CI [-2.35, -0.15]; [-1.29, -0.04], respectively), 7 (95% CI [-2.80, -0.41]; [-3.39, -0.02]), and only psychological inflexibility at 18 (95% CI [-3.22, -0.62]) months. LGCM indicated only in RO DBT was a decrease in psychological inflexibility through 18 months associated with a decrease in depressive symptoms (B = 0.13, p < .001). CONCLUSIONS: This supports RO DBT theory about targeting processes related to maladaptive overcontrol. Interpersonal functioning, and in particular, psychological flexibility, may be mechanisms that decrease depressive symptoms in RO DBT for TRD. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Surveillance Imaging after Primary Diagnosis of Ductal Carcinoma in Situ.

Background Guidelines recommend annual surveillance imaging after diagnosis of ductal carcinoma in situ (DCIS). Guideline adherence has not been characterized in a contemporary cohort. Purpose To identify uptake and determinants of surveillance imaging in women who underwent treatment for DCIS. Materials and Methods A stratified random sample of women who underwent breast-conserving surgery for primary DCIS between 2008 and 2014 was retrospectively selected from 1330 facilities in the United States. Imaging examinations were recorded from date of diagnosis until first distant recurrence, death, loss to follow-up, or end of study (November 2018). Imaging after treatment was categorized into 10 12-month periods starting 6 months after diagnosis. Primary outcome was per-period receipt of asymptomatic surveillance imaging (mammography, MRI, or US). Secondary outcome was diagnosis of ipsilateral invasive breast cancer. Multivariable logistic regression with repeated measures and generalized estimating equations was used to model receipt of imaging. Rates of diagnosis with ipsilateral invasive breast cancer were compared between women who did and those who did not undergo imaging in the 6-18-month period after diagnosis using inverse probability-weighted Kaplan-Meier estimators. Results A total of 12 559 women (median age, 60 years; IQR, 52-69 years) were evaluated. Uptake of surveillance imaging was 75% in the first period and decreased over time (P < .001). Across the first 5 years after treatment, 52% of women participated in consistent annual surveillance. Surveillance was lower in Black (adjusted odds ratio [OR], 0.80; 95% CI: 0.74, 0.88; P < .001) and Hispanic (OR, 0.82; 95% CI: 0.72, 0.94; P = .004) women than in White women. Women who underwent surveillance in the first period had a higher 6-year rate of diagnosis of invasive cancer (1.6%; 95% CI: 1.3, 1.9) than those who did not (1.1%; 95% CI: 0.7, 1.4; difference: 0.5%; 95% CI: 0.1, 1.0; P = .03). Conclusion Half of women did not consistently adhere to imaging surveillance guidelines across the first 5 years after treatment, with racial disparities in adherence rates. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Rahbar and Dontchos in this issue.

Extensor Tendon Integrity After Percutaneous Placement of Intramedullary Metacarpal Screws: A Cadaveric Study.

BACKGROUND: Intramedullary implants are an increasingly common method for fixation of metacarpal fractures. Numerous techniques for instrumentation have been described with varied consideration for the risk of extensor tendon injury. The current cadaveric study evaluates the prevalence and degree of extensor tendon injury and compares percutaneous approaches with different drilling techniques. METHODS: Ninety-six metacarpals (thumbs excluded) from 24 fresh-frozen cadaveric upper extremities were used to compare 2 percutaneous approaches and 2 drilling techniques. This resulted in 4 subgroups available for comparison: oscillate to bone (OB), forward to bone (FB), oscillating through the skin (OS), and forward through the skin (FS). After instrumentation, the extensor tendons were dissected and disruption was characterized. The main outcome measures were tendon "hit rate" and relative extensor tendon defect width. RESULTS: Tendon hit rate was significantly higher in the long finger (LF), that is, 79.2%, compared with other metacarpals: index finger, 20.8%; ring finger, 12.5%; and small finger 25%. The mean relative tendon disruption was significantly less in the OB group (16.05%) compared with the other groups: FB (31.84%), FS (31.50%), and OS (29.85%). CONCLUSION: Retrograde intramedullary screw fixation of metacarpal fractures can be performed using percutaneous approaches without a significant disruption of the extensor mechanism. Instrumentation through a longitudinal stab incision down to the metacarpal head and the use of drill oscillation minimize injury to the extensor tendons. The LF extensor tendon is most at risk with retrograde intramedullary implant placement.

Krt14 and Krt15 differentially regulate regenerative properties and differentiation potential of airway basal cells.

Keratin expression dynamically changes in airway basal cells (BCs) after acute and chronic injury, yet the functional consequences of these changes on BC behavior remain unknown. In bronchiolitis obliterans (BO) after lung transplantation, BC clonogenicity declines, which is associated with a switch from keratin15 (Krt15) to keratin14 (Krt14). We investigated these keratins' roles using Crispr-KO in vitro and in vivo and found that Krt14-KO and Krt15-KO produce contrasting phenotypes in terms of differentiation and clonogenicity. Primary mouse Krt14-KO BCs did not differentiate into club and ciliated cells but had enhanced clonogenicity. By contrast, Krt15-KO did not alter BC differentiation but impaired clonogenicity in vitro and reduced the number of label-retaining BCs in vivo after injury. Krt14, but not Krt15, bound the tumor suppressor stratifin (Sfn). Disruption of Krt14, but not of Krt15, reduced Sfn protein abundance and increased expression of the oncogene dNp63a during BC differentiation, whereas dNp63a levels were reduced in Krt15-KO BCs. Overall, the phenotype of Krt15-KO BCs contrasts with Krt14-KO phenotype and resembles the phenotype in BO with decreased clonogenicity, increased Krt14, and decreased dNp63a expression. This work demonstrates that Krt14 and Krt15 functionally regulate BC behavior, which is relevant in chronic disease states like BO.

A Matched Survival Analysis of Lung Transplant Recipients With Coronavirus Disease 2019-Related Respiratory Failure.

BACKGROUND: Lung transplantation is an acceptable and potentially life-saving treatment option for coronavirus disease 2019 (COVID-19)-induced acute respiratory distress syndrome and pulmonary fibrosis. This study was conducted to determine whether recipients of lung transplantation (LT) for COVID-19-related lung disease have comparable outcomes to other recipients with a similar level of lung dysfunction. METHODS: The Organ Procurement and Transplant Network database was queried for adult LT candidates between 2006 and 2021. Recipients with COVID-19-related respiratory failure were matched 1:2 using a nearest-neighbor algorithm. Kaplan-Meier methods with log-rank tests were used to compare long-term survival. A proportional hazards model was used to calculate risk of death. RESULTS: A total of 37,333 LT candidates from all causes were compared with 334 candidates from COVID-19-related respiratory failure. COVID-19 recipients were more likely to be younger (50 vs 57 years, P < .001), male (79% vs 60%, P < .001), require extracorporeal membrane oxygenation (56.3% vs 4.0%, P < .001), and have worse lung function (lung allocation score, 82.4 vs 47.8; P < .001) at transplantation. Subsequently, 227 COVID-19 recipients were matched with 454 controls. Patients who received a transplant for COVID-19 had similar rates of mechanical ventilation, extracorporeal membrane oxygenation, postoperative complications, and functional status at discharge compared with controls. There was no difference in overall survival or risk of death from COVID-19 (hazard ratio, 0.82; 95% CI, 0.45-1.53; P = .54). CONCLUSIONS: Six-month survival for recipients of LT for COVID-19-related respiratory failure was comparable to that of other LT recipients.

Alternate Graft Options for Staged Flexor Tendon Reconstruction: A Cadaveric Study of Hamstring Autografts Compared to Conventional Autografts.

PURPOSE: To compare the semitendinosus and gracilis tendon lengths and diameters to the palmaris longus, plantaris, flexor digitorum profundus, and flexor pollicis longus (FPL) tendons in a cadaveric model to evaluate the feasibility of hamstring autograft use for staged flexor tendon reconstruction. METHODS: Fifteen fresh cadavers were evaluated for surgical incisions about the knee, forearm, and hand. All flexor digitorum profundus (FDP), FPL, palmaris longus, plantaris, semitendinosus, and gracilis tendons were harvested from each specimen. Diameter and length were recorded and means with SDs were calculated. The mean diameters of the gracilis and semitendinosus were compared to the mean diameters of the FDP and FPL tendons. The hamstring tendon lengths were then compared in terms of percentage of the palmaris longus and plantaris tendon lengths. RESULTS: The gracilis (18.0 cm) and semitendinosus (19.9 cm) means were notably longer than the palmaris longus (16.0 cm) and shorter than the plantaris (30.0 cm). The average gracilis tendon diameter (3.8 mm) was smaller than the flexor tendon diameters except for the little finger FDP (3.8 mm). The semitendinosus tendon diameter (4.8 mm) was larger than all flexor tendons with the exception of the middle finger FDP (4.6 mm). Average gracilis and semitendinosus tendon diameters were 3.7 mm and 4.5 mm in males, and 3.8 mm and 4.8 mm in females. CONCLUSIONS: This study showed the gracilis tendon to have adequate length and diameter for potential autograft use in staged flexor tendon reconstruction in all digits but the little finger. The semitendinosus is larger in diameter than the native flexor tendons, making it a poor autograft option in cases with an intact pulley system. CLINICAL RELEVANCE: Common tendon autograft options for flexor tendon reconstruction are variably present, and the use of gracilis and semitendinosus autograft present potential graft options.

Medial Elbow Exposure: Modified Taylor-Scham Versus Flexor Carpi Ulnaris-Split.

OBJECTIVE: To compare the exposure of the coronoid process, anteromedial facet, and anterior band of the medial collateral ligament using the flexor carpi ulnaris (FCU)-splitting approach with the Taylor-Scham approach modified with an ulnar nerve transposition. METHODS: Thirty approaches were performed on 15 fresh cadavers using a randomized cross-over design and standardized incision. Access to key anatomic landmarks was assessed, and a calibrated digital image was taken from the surgeon's best perspective of each approach. Images were analyzed using ImageJ (National Institutes of Health) software to calculate the area of osseous exposure. RESULTS: All key anatomic landmarks were visualized using both approaches. The average area of exposure for the Taylor-Scham was 19.5 cm 2 compared with 13.6 cm 2 for the FCU-splitting ( P < 0.0001). The distal extent of the FCU-splitting approach is limited by the ulnar nerve and its branches to the humeral head of the FCU. CONCLUSION: The Taylor-Scham approach provides a more extensile exposure of the anteromedial coronoid and proximal ulna than the FCU-splitting approach while avoiding cross-tensioning of the ulnar nerve.