Racial and Ethnic Disparity in Shoulder Surgery: A Systematic Review.

BACKGROUND: Healthcare disparity exists in utilization and delivery of musculoskeletal care and continues to be an obstacle for orthopedic healthcare providers to mitigate. Racial and ethnic disparities exist within various surgical fields including orthopedic surgery and are expected to continue to rise in upcoming years. The aim of this systematic review is to analyze the racial and ethnic disparities on utilization and outcomes after common shoulder surgical procedures. QUESTIONS/PURPOSE: Are there racial or ethnic disparities in outcomes and utilization of shoulder surgeries? Is there evidence to explain the etiology underlying the differences in outcomes among racial and ethnic groups after shoulder surgery? PATIENTS/METHODS: A primary literature search was performed using PubMed, Embase, Cochrane Central Register of Controlled Trials, and Clinicaltrials.gov databases using comprehensive Medical Subject Headings and subject-heading search terms. Studies were included if they reported utilization and or outcomes across two or more racial/ethnic groups in patients (age >16) who underwent shoulder arthroplasty (TSA), rotator cuff repair (RCR), arthroscopic Bankart repair (ABR), Latarjet (LP) and internal fixation (ORIF) of PHF. Baseline demographics, data on procedure utilization, perioperative measures including mortality, operative time, length of stay (LOS), readmission and complications were extracted from included studies, and descriptive statistical analysis performed. RESULTS: Eighteen studies were identified for full text review of which 13 found race and ethnicity as factors affecting utilization and outcomes in TSA, RCR, ABR, LP and ORIF of PHF. Compared to White patients, Black patients were found to have decreased utilization, longer LOS, and greater operative time and mortality after TSA; Black patients also had longer operative times and time to discharge, and lower levels of reported satisfaction after RCR. Hispanic/Latino ethnicity was reported as an independent risk factor for post operative falls following TSA. Hispanic/Latino and Black patients have a higher risk of delayed surgery and greater risk of readmission after surgical treatment of PHF compared to patients of White race. CONCLUSION: This systematic review highlights the limited literature reporting the existence of racial and ethnic disparities in utilization and outcomes after common shoulder surgical procedures. Additionally, there is paucity of studies exploring the underlying etiology of racial and ethnic disparity in outcomes after shoulder surgery. More research is necessary to pave the way for evidence-based action plans to mitigate healthcare disparities after shoulder surgeries, but this review serves as a baseline for where efforts in direct improvement can begin.

Lentiviral vector gene therapy and CFTR modulators show comparable effectiveness in cystic fibrosis rat airway models.

Mutation-agnostic treatments such as airway gene therapy have the potential to treat any individual with cystic fibrosis (CF), irrespective of their CF transmembrane conductance regulator (CFTR) gene variants. The aim of this study was to employ two CF rat models, Phe508del and CFTR knockout (KO), to assess the comparative effectiveness of CFTR modulators and lentiviral (LV) vector-mediated gene therapy. Cells were isolated from the tracheas of rats and used to establish air-liquid interface (ALI) cultures. Phe508del rat ALIs were treated with the modulator combination, elexacaftor-tezacaftor-ivacaftor (ETI), and separate groups of Phe508del and KO tracheal epithelial cells were treated with LV-CFTR followed by differentiation at ALI. Ussing chamber measurements were performed to assess CFTR function. ETI-treated Phe508del ALI cultures demonstrated CFTR function that was 59% of wild-type level, while gene-addition therapy restored Phe508del to 68% and KO to 47% of wild-type level, respectively. Our findings show that rat Phe508del-CFTR protein can be successfully rescued with ETI treatment, and that CFTR gene-addition therapy provides significant CFTR correction in Phe508del and KO ALI cultures to levels that were comparable to ETI. These findings highlight the potential of an LV vector-based gene therapy for the treatment of CF lung disease.

Outcomes Following the Use of Extracellular Matrix Cartilage Allograft for the Management of Osteochondral Lesions of the Talus: A Systematic Review.

Extracellular matrix cartilage allograft (EMCA) is a novel biological strategy utilized to augment the repair of osteochondral lesions of the talus (OLTs). However, there is no consensus on the precise role and outcomes following its use in the treatment of OLTs. The purpose of this systematic review was to evaluate the clinical and radiological outcomes following the use of EMCA for the treatment of OLT. During July 2023, the PubMed, Embase, and Cochrane Library databases were systematically reviewed to identify clinical studies examining outcomes following EMCA for the management of OLTs. In total, 162 patients (162 ankles) across five studies received EMCA as part of their surgical procedure at a weighted mean follow-up time of 23.8±4.2 months. Across all five studies, there were improvements in subjective clinical outcomes following the use of EMCA, regardless of the clinical scoring tool utilized. Two studies demonstrated superior postoperative magnetic resonance observation of cartilage repair tissue (MOCART) scores in the EMCA cohort compared to the bone marrow stimulation (BMS) cohort alone. In the EMCA-BMS cohort, there were seven complications (9%) and three failures (4.1%). In the autologous osteochondral transplantation (AOT) cohort, there were 10 complications (38.5%), zero failures, and six secondary surgical procedures (23.1%). In the EMCA alone cohort, there were zero complications and three failures (4.3%), all of which underwent an unspecified revision procedure. This current systematic review demonstrated improvements in both clinical and radiological outcomes following the use of EMCA for the treatment of OLTs. Further prospective comparative studies with longer follow-up times are warranted to determine the precise role of EMCA in the management of OLT.

Patients with higher numbers of allergies have lower levels of anti-inflammatory cytokines and increased pain at the time of ACL reconstruction.

BACKGROUND: Synovial fluid biomarkers are well studied indicators of inflammation and healing in the setting of orthopedic injuries. However, it has not been studied if patients with one or more allergies have a difference in the concentrations of synovial fluid inflammatory cytokines compared to patients without allergies. The purpose of the current study is to analyze the concentration of 10 pro- and anti-inflammatory cytokines in the synovial fluid of isolated ACL injury patients with and without at least one allergy. STUDY DESIGN: Retrospective Case-Control. METHODS: A database of patients who underwent surgery for isolated ACL injury between September 2011 and July 2023 was analyzed. All patients had SF aspirated from the operative knee prior to the surgical incision and the concentrations of pre- and anti-inflammatory biomarkers were quantified. From this cohort, 24 patients were identified to have allergies by chart review. These patients were matched 1:1 to 24 patients without allergies based on age and sex. RESULTS: There were no significant differences between the allergy and no allergy cohorts with respect to age (28.5 ± 10.3 vs. 29.5 ± 8.9, p = 0.76) and sex (70.8 % female vs. 70.8 % female, p = 1.00). The allergy cohort had a decreased concentration of TIMP-1 (492.41 ± 616.20 ng/mL vs. 1041.48 ± 942.04 ng/mL, p = 0.03) and IL-1Ra (101.70 ± 93.37 pg/mL vs. 359.94 ± 399.77 pg/mL, p = 0.01) compared to patients without allergies. A linear regression analysis found a significant association between increasing number of patients reported allergies and decreasing concentration of TIMP-1 (ß = -231.59, p = 0.03) and IL-1Ra (ß = -71.69p = 0.03) concentrations when controlling for age and sex. Finally, the allergy cohort was found to have a significantly higher value for the VAS pain scale at the time of surgery (26.84 ± 24.73 vs. 7.37 ± 10.98, p < 0.01) compared to those without an allergy. CONCLUSION: Patients undergoing ACL reconstruction with at least one allergy were found to have decreased concentrations of the anti-inflammatory cytokines TIMP-1 and IL-1Ra in their synovial fluid compared to those without allergies on the day of surgery. Furthermore, an increase in total number of allergies was found to be an associated with a decrease in TIMP-1 and IL-1Ra levels. Finally, the allergy cohort also had a higher value for the VAS pain scale at the time of surgery, implicating the role of a patient's innate immune system to their biologic and symptomatic response to injury.

Psychological Readiness to Return to Sport (RTS) and RTS Rates Are Similar in Patients After Either Bilateral or Unilateral Anterior Cruciate Ligament Reconstruction.

Purpose: To compare psychological readiness to return to sport (RTS), RTS rate, level of return, and time to return between patients who underwent bilateral anterior cruciate ligament reconstruction (ACLR) and those who underwent unilateral ACLR. Methods: The electronic medical record at a single academic medical center was queried for patients who underwent ACLR from January 2012 to May 2020. The inclusion criteria were skeletally mature patients who underwent either single or sequential bilateral ACLR and who had undergone either the primary ACLR or second contralateral ACLR at least 2 years earlier. Bilateral ACLRs were matched 1:3 to unilateral reconstructions based on age, sex, and body mass index. Psychological readiness to RTS was assessed using the validated ACL Return to Sport After Injury (ACL-RSI) scale. This, along with time to return and level of RTS, was compared between the 2 cohorts. Results: In total, 170 patients were included, of whom 44 underwent bilateral ACLR and 132 underwent unilateral ACLR. At the time of the first surgical procedure, patients in the unilateral cohort were aged 28.8 ± 9.4 years and those in the bilateral cohort were aged 25.7 ± 9.8 years (P = .06). The average time difference between the first and second surgical procedures was 28.4 ± 22.3 months. There was no difference in psychological readiness to RTS (50.5 in bilateral cohort vs 48.1 in unilateral cohort, P = .66), RTS rate (78.0% in unilateral cohort vs 65.9% in bilateral cohort, P = .16), percentage of return to preinjury sport level (61.2% in unilateral cohort vs 69.0% in bilateral cohort, P = .21), or time to return (41.2 ± 29.3 weeks in unilateral cohort vs 35.2 ± 23.7 weeks in bilateral cohort, P = .31) between the 2 cohorts. Conclusions: Compared with patients who undergo unilateral ACLR, patients who undergo bilateral ACLR are equally as psychologically ready to RTS, showing equal rates of RTS, time to return, and level of return. Level of Evidence: Level III, retrospective cohort study.

Patients who undergo tibial tubercle anteromedialization with medial patellofemoral ligament reconstruction demonstrate similar rates of return to sport compared to isolated MPFL reconstruction.

PURPOSE: To investigate the rate of return to sports and sport psychological readiness between patients who underwent isolated MPFLR (iMPFLR) compared to a matched cohort of patients who underwent MPFLR with anteromedializing tibial tubercle osteotomy (MPFLR/TTO). METHODS: Patients who underwent primary MPFLR with or without TTO for recurrent patellar instability were retrospectively reviewed from 2012 to 2020 at a single institution. Preinjury sport and work information, Kujala, Tegner, Visual Analogue Score for pain, satisfaction and MPFL-Return to Sport after Injury (MPFL-RSI) score were collected. Two readers independently measured the tibial tuberosity-trochlear groove distance, Caton-Deschamps index and Dejour classification for trochlear dysplasia. Patients in iMPFLR and MPFLR/TTO groups were matched 1:1 on age, sex, body mass index and follow-up length. Multivariate regression analysis was performed to determine whether the MPFL-RSI was associated with a return to sport. RESULTS: This study included 74 patients at mean follow-up of 52.5 months (range: 24-117). These groups returned to sport at similar rates (iMPFLR: 67.6%, MPFLR/TTO: 73.0%, not significant [ns]), though iMPFLR patients returned more quickly (8.4 vs. 12.8 months, p = 0.019). Rates of return to preinjury sport level were also similar (45.9% vs. 40.5%, ns). Patients with Dejour B/C took more time to return to sport compared to patients with mild/no trochlear pathology (13.8 vs. 7.9 months, p = 0.003). Increasing MPFL-RSI score was significantly predictive of the overall return to sport (odds ratio [OR]: 1.08, 95% confidence interval [CI] [1.03, 1.13], p < 0.001) and return to preinjury level (OR: 1.07, 95% CI [1.04, 1.13], p < 0.001). Most patients in iMPFLR and MPFLR/TTO groups resumed work (95.7% vs. 88.5%, ns), though iMPFLR patients who returned to preinjury work levels did so more quickly (1.7 vs. 4.6 months, p = 0.005). CONCLUSION: Patients who underwent MPFLR with anteromedializing TTO demonstrated similar rates of return to sport and psychological readiness compared to an isolated MPFLR matched comparison group, though iMPFLRs returned more quickly. Patients with more severe trochlear pathology required more time to return to sports. LEVEL OF EVIDENCE: Level III.

Increased kinesiophobia leads to lower return to sport rate and clinical outcomes following osteochondral allograft transplantation of the knee.

PURPOSE: The purpose of this study is to describe the postoperative psychological state of patients following osteochondral allograft (OCA) transplantation in the knee and to determine whether patient-perceived kinesiophobia is associated with the rate of return to sport (RTS). METHODS: A retrospective review of the electronic medical record at a single institution was conducted for all patients that underwent OCA transplantation from January 2010 to 2020. Patient-reported outcomes including the visual analog scale (VAS), knee injury and osteoarthritis outcome score (KOOS) and the Tampa scale of kinesiophobia-11 (TSK-11) were collected. Patients were surveyed regarding their postoperative RTS status. RESULTS: A total of 38 patients (52.6% female) were included in our analysis. Overall, 24 patients (63.2%) returned to sport with 12 (50%) of these patients returning at a lower level of play. When comparing patients that return to sport to those that did not, patients that return had significantly superior KOOS pain (p = 0.019) and KOOS QOL (p = 0.011). Measures of kinesiophobia (TSK-11) were significantly higher among patients that did not return to sport (p = 0.014), while satisfaction (n.s.) and pain intensity (n.s.) were comparable between groups. Logistic regression models controlling for demographic factors, VAS pain scores and lesion size showed that for every one-point increase in TSK-11 kinesiophobia score, patients were 1.33 times more likely to return to sport at a lower level (p = 0.009). For every one-point increase in TSK-11 scores KOOS QOL decreased by 2.4 points (p < 0.001). CONCLUSION: Fear of reinjury decreases the likelihood that patients will return to their preoperative level of sport after OCA transplantation. Patients that do not return to sport report significantly greater fear of reinjury and inferior clinical outcomes, despite similar levels of satisfaction and pain compared to those that return. LEVEL OF EVIDENCE: Level III.

A Superolateral Cam Lesion Location Increases Odds of Total Hip Arthroplasty 5 Years After Hip Arthroscopy.

PURPOSE: To determine if radiographic cam location is associated with hip survivorship and postoperative patient-reported outcomes (PROs) at 5-year follow-up. METHODS: We conducted a review of prospectively collected data of patients with cam lesions who underwent hip arthroscopy for femoroacetabular impingement syndrome. Cam lesions were categorized into 3 locations: superolateral, anterolateral, or anterior. Conversion to total hip arthroplasty (THA), revision rates, and reoperation rates were assessed. Patient-reported outcome measures, including modified Harris Hip Scores (mHHS) and Non-Arthritic Hip Scores (NAHS), were collected preoperatively and at 5-year follow-up. RESULTS: Of the 156-patients, 125 met the final criteria (80.1%). Mean age was 41.1 ± 12.7 years. Seventy-one patients (56.8%) had superolateral cam lesions, 41 (32.8%) had anterolateral lesions, and 13 (10.4%) had anterior lesions. Revision rates within 5 years were 7.7% for anterior, 24.4% for anterolateral, and 14.1% for superolateral lesions; conversions to THAs were 15.4% for anterior), 7.3% for anterolateral, and 8.5% for superolateral. Reoperations were 23.1% for anterior, 29.3% for anterolateral, and 21.1% for superolateral. The superolateral cohort was younger than the anterior and anterolateral cohorts (anterior, 46.6 ± 12.2 years; anterolateral, 44.7 ± 12.2 years; superolateral, 38.1 ± 12.3 years; P = .006). Multivariable analysis showed the anterolateral group was significantly predictive of lower odds of undergoing THA compared to the superolateral group (odds ratio, 0.01; 95% CI, <0.01-0.72; P = .03). There were no differences in the 5-year improvement in mHHS (anterior, 32.4; anterolateral, 36.8; superolateral, 33.0; P = .29) or NAHS (anterior, 34.8; anterolateral, 39.0; superolateral, 37.3; P = .65). CONCLUSIONS: A superolateral cam lesion increases the odds of conversion to THA within 5 years of hip arthroscopy compared to those with anterolateral lesions on multivariable analysis. Those with superolateral lesions were significantly younger compared to those with anterior or anterolateral lesions. Cam lesion location did not affect improvement in PROs at 5-year follow-up. LEVEL OF EVIDENCE: Level III, retrospective comparative prognostic trial.

Interferon ß-1a ring prophylaxis to reduce household transmission of SARS-CoV-2: a cluster randomised clinical trial.

Background: Accumulating evidence indicates that an early, robust type 1 interferon (IFN) response to SARS-CoV-2 is important in determining COVID-19 outcomes, with an inadequate IFN response associated with disease severity. Our objective was to examine the prophylactic potential of IFN administration to limit viral transmission. Methods: A cluster randomised open label clinical trial was undertaken to determine the effects of pegylated IFNß-1a administration on SARS-CoV-2 household transmission between December 3rd, 2020 and June 29th, 2021. Index cases were identified from databases of confirmed SARS-CoV-2 individuals in Santiago, Chile. Households were cluster randomised (stratified by household size and age of index cases) to receive 3 doses of 125 µg subcutaneous pegylated IFNß-1a (172 households, 607 participants), or standard care (169 households, 565 participants). The statistical team was blinded to treatment assignment until the analysis plan was finalised. Analyses were undertaken to determine effects of treatment on viral shedding and viral transmission. Safety analyses included incidence and severity of adverse events in all treatment eligible participants in the standard care arm, or in the treatment arm with at least one dose administered. Clinicaltrials.gov identifier: NCT04552379. Findings: 5154 index cases were assessed for eligibility, 1372 index cases invited to participate, and 341 index cases and their household contacts (n = 831) enrolled. 1172 participants in 341 households underwent randomisation, with 607 assigned to receive IFNß-1a and 565 to standard care. Based on intention to treat (ITT) and per protocol (PP) analyses for the primary endpoints, IFNß-1a treatment did not affect duration of viral shedding in index cases (absolute risk reduction = -0.2%, 95% CI = -8.46% to 8.06%) and transmission of SARS-CoV-2 to household contacts (absolute risk reduction = 3.87%, 95% CI = -3.6% to 11.3%). Treatment with IFNß-1a resulted in significantly more treatment-related adverse events, but no increase in overall adverse events or serious adverse events. Interpretation: Based upon the primary analyses, IFNß-1a treatment did not affect duration of viral shedding or the probability of SARS-CoV-2 transmission to uninfected contacts within a household. Funding: Biogen PTY Ltd. Supply of interferon as 'Plegridy (peginterferon beta-1a).' The study was substantially funded by BHP Holdings Pty Ltd.

Patients who undergo bilateral medial patellofemoral ligament reconstruction return to sport at a similar rate as those that undergo unilateral reconstruction.

PURPOSE: Lateral patellar instability is a debilitating condition not only to athletes, but also to a wide range of highly active individuals. Many of these patients experience symptoms bilaterally, though it is unknown how these patients fair with return to sports following a second medial patellofemoral ligament reconstruction (MPFLR). The purpose of this study is to evaluate the rate of return to sport following bilateral MPFLR compared to a unilateral comparison group. METHODS: Patients who underwent primary MPFLR with minimum 2-year follow-up were identified from 2014 to 2020 at an academic center. Those who underwent primary MPFLR of bilateral knees were identified. Pre-injury sport participation and Tegner score, Kujala score, Visual Analog Score (VAS) for pain, satisfaction, and MPFL-Return to Sport after Injury (MPFL-RSI) scale were collected. Bilateral and unilateral MPFLRs were matched in a 1:2 ratio based on age, sex, body mass index, and concomitant tibial tubercle osteotomy (TTO). A sub-analysis was performed regarding concomitant TTO. RESULTS: The final cohort consisted of 63 patients, including 21 patients who underwent bilateral MPFLR, matched to 42 unilateral patients at mean follow-up of 47 ± 27 months. Patients who underwent bilateral MPFLR returned to sport at a rate of 62% at a mean of 6.0 ± 2.3 months, compared to a unilateral rate of 72% at 8.1 ± 4.2 months (n.s.). The rate of return to pre-injury level was 43% among bilateral patients and 38% in the unilateral cohort. There were no significant differences in VAS pain, Kujala, current Tegner, satisfaction, and MPFL-RSI scores between cohorts. Approximately half of those (47%) who failed to return to sport cited psychological factors and had significantly lower MPFL-RSI scores (36.6 vs 74.2, p = 0.001). CONCLUSION: Patients who underwent bilateral MPFLR returned to sports at a similar rate and level compared to a unilateral comparison group. MPFL-RSI was found to be significantly associated with return to sport. LEVEL OF EVIDENCE: III.

Patients With Low-Grade Lumbosacral Transitional Vertebrae Demonstrate No Difference in Achievement of Clinical Thresholds After Hip Arthroscopy for Femoroacetabular Impingement Syndrome.

PURPOSE: To compare clinical outcomes at 2 years following primary hip arthroscopy (HA) for femoroacetabular impingement syndrome (FAIS) between patients with and without low-grade lumbosacral transitional vertebra (LSTV). METHODS: We performed a retrospective matched-cohort analysis of patients who underwent primary HA for FAIS from 2011 to 2018 with minimum 2-year follow-up. LSTV was graded on preoperative radiographs using the Castellvi classification. Patients with grades I and II LSTV were matched 1:1 with controls on age, sex, and body mass index. Radiographic markers of FAIS morphology were measured. Pre- to postoperative improvement in the modified Harris Hip Score (mHHS) and Non-Arthritic Hip Score (NAHS) as well as 2-year achievement rates for the minimum clinically-important difference, substantial clinical benefit, and patient acceptable symptom state were compared between patients with versus without LSTV. The Wilcoxon signed-rank test was used for intergroup mean comparisons and the Cochran-Mantel-Haenszel test for categorical variables. RESULTS: In total, 58 patients with LSTV were matched to 58 controls. Among LSTV patients, 48 were Castellvi type 1 (82.8%) and 32 (55.2%) had bilateral findings. No significant differences were found between groups with respect to radiographic markers of FAIS, including alpha angle (P = .88), lateral center edge angle (P = .42), or crossover sign (P = .71). Although patients with LSTV had greater improvement in NAHS at 2-year follow-up compared with control patients (P = .04), there were no significant differences in modified Harris Hip Score improvement (P = .31) or achievement of the minimum clinically-important difference (P = .73), substantial clinical benefit (P = .61), or patient acceptable symptom state (P = .16). CONCLUSIONS: Patients with low-grade LSTV had greater 2-year improvement in NAHS than controls, whereas no significant differences were observed in achievement of clinical thresholds at 2-year follow-up. There were no differences between groups with respect to any measured radiographic markers of FAIS morphology. Importantly, the findings of this study are underpowered and should be viewed with caution in the greater context of the LSTV literature. LEVEL OF EVIDENCE: Level III; retrospective comparative study.

A National Perspective of Patellar Instability in Children and Adolescents in the United States: MPFL Reconstruction Is Three Times Higher Than the Incidence of Isolated Lateral Release.

PURPOSE: The objective was to (1) evaluate any recent changes in the United States in the incidences of medial patellofemoral ligament (MPFL) reconstruction and isolated lateral release for patellar instability in children and adolescents, (2) identify concomitant procedures with MPFL, and (3) report national complication rates after MPFL reconstruction with and without concomitant procedures in children and adolescents. METHODS: A national database was queried for patients aged 5 to 18 years who underwent operative treatment for patellar instability from 2010 to 2018. Inclusion criteria were either an MPFL reconstruction or lateral release for a diagnosis of patellar instability. Concomitant procedures with MPFL reconstruction assessed were tibial tubercle osteotomy, associated arthroscopic procedures, and lateral release. Changes in incidence in MPFL reconstruction, lateral release and concomitant procedures were assessed. The following postoperative complications were assessed: knee stiffness, infection, patella fracture, and growth arrest or angular deformity. RESULTS: 2,161 patients who underwent MPFL reconstruction and 1,159 patients who underwent isolated lateral release for patellar instability were identified. The incidence of MPFL reconstruction in adolescents from 2010 to 2018 did not change significantly (2010: 7.11, 2018: 5.91, P = .137), while isolated lateral release decreased (2010: 6.06, 2018: 1.83, P < .0001). Concomitant procedures with MPFL reconstruction were common, with arthroscopy being the most frequent (58-67%). The most common complication within 90 days of surgery was patella fracture (0.4% to 2.0%). Infection (0.4% to 1.0%) and growth arrest (0.09% to 0.61%) were the least common. MPFL and arthroscopy had a decreased risk of growth arrest following surgery compared to MPFL alone (P = .038). CONCLUSIONS: The incidence of MPFL reconstruction remained high from 2010 to 2018, while isolated lateral release decreased during the same time period. Complications after MPFL reconstruction, isolated lateral release, and concomitant procedures were infrequent, with postoperative patella fracture the most common. LEVEL OF EVIDENCE: IV, case series.

Dysregulated Notch Signaling in the Airway Epithelium of Children with Wheeze.

The airway epithelium of children with wheeze is characterized by defective repair that contributes to disease pathobiology. Dysregulation of developmental processes controlled by Notch has been identified in chronic asthma. However, its role in airway epithelial cells of young children with wheeze, particularly during repair, is yet to be determined. We hypothesized that Notch is dysregulated in primary airway epithelial cells (pAEC) of children with wheeze contributing to defective repair. This study investigated transcriptional and protein expression and function of Notch in pAEC isolated from children with and without wheeze. Primary AEC of children with and without wheeze were found to express all known Notch receptors and ligands, although pAEC from children with wheeze expressed significantly lower NOTCH2 (10-fold, p = 0.004) and higher JAG1 (3.5-fold, p = 0.002) mRNA levels. These dysregulations were maintained in vitro and cultures from children with wheeze displayed altered kinetics of both NOTCH2 and JAG1 expression during repair. Following Notch signaling inhibition, pAEC from children without wheeze failed to repair (wound closure rate of 76.9 ± 3.2%). Overexpression of NOTCH2 in pAEC from children with wheeze failed to rescue epithelial repair following wounding. This study illustrates the involvement of the Notch pathway in airway epithelial wound repair in health and disease, where its dysregulation may contribute to asthma development.

Can CP Be Less Than CV ?

Can CP be less than CV ? This is a fundamental question in physics, chemistry, chemical engineering, and mechanical engineering. This question hangs in the minds of many students, instructors, and researchers. The first instinct is to answer "Yes, for water between 0 and 4 °C" if one knows that water expands as temperature decreases in this temperature range. The same question is asked in several Physical Chemistry and Physics textbooks. Students are supposed to answer that water contracts when heated at below 4 °C in an isobaric process. Because work is done to the contracting water, less heat is required to increase the water temperature in an isobaric process than in an isochoric process. Therefore, CP is less than CV . However, this answer is fundamentally flawed because it assumes, implicitly and incorrectly, that the internal energy change of water depends solely on its temperature change. Neglecting the variation of the internal energy with volume (internal pressure) will invalidate the Clausius inequality and violate the second law of thermodynamics. Once the internal pressure is properly taken into account, it becomes clear that CP cannot be less than CV for any substance at any temperature regardless of the sign of the thermal expansion coefficient of the substance.

Diagnostic, Surgical, and Technical Considerations for Lumbar Interbody Fusion in Patients with Osteopenia and Osteoporosis: A Systematic Review.

OBJECTIVE: Osteoporosis is increasing in incidence as the ageing population continues to grow. Decreased bone mineral density poses a challenge for the spine surgeon. In patients requiring lumbar interbody fusion, differences in diagnostics and surgical approaches may be warranted. In this systematic review, the authors examine studies performing lumbar interbody fusion in patients with osteopenia or osteoporosis and suggest avenues for future study. METHODS: A systematic literature review of the PubMed and MEDLINE databases was performed for studies published between 1986 and 2020. Studies evaluating diagnostics, surgical approaches, and other technical considerations were included. RESULTS: A total of 13 articles were ultimately selected for qualitative analysis. This includes studies demonstrating the utility of Hounsfield units in diagnosis, a survey of surgical approaches, as well as exploring the use of vertebral augmentation and cortical bone screw trajectory. CONCLUSIONS: This systematic review provides a summary of preliminary findings with respect to the use of Hounsfield units as a diagnostic tool, the benefit or lack thereof with respect to minimally invasive approaches, and the question of whether or not cement augmentation or cortical bone trajectory confers benefit in osteoporotic patients undergoing lumbar interbody fusion. While the findings of these studies are promising, the current state of the literature is limited in scope and, for this reason, definitive conclusions cannot be drawn from these data. The authors highlight gaps in the literature and the need for further exploration and study of lumbar interbody fusion in the osteoporotic spine.

Ivacaftor or lumacaftor/ivacaftor treatment does not alter the core CF airway epithelial gene response to rhinovirus.

BACKGROUND: Aberrant responses by the cystic fibrosis airway epithelium during viral infection may underly the clinical observations. Whether CFTR modulators affect antiviral responses by CF epithelia is presently unknown. We tested the hypothesis that treatment of CF epithelial cells with ivacaftor (Iva) or ivacaftor/lumacaftor (Iva/Lum) would improve control of rhinovirus infection. METHODS: Nineteen CF epithelial cultures (10 homozygous for p.Phe508del as CFTR Class 2, 9 p.Phe508del/p.Gly551Asp as Class 3) were infected with rhinovirus 1B at multiplicity of infection 12 for 24 h. Culture RNA and supernatants were harvested to assess gene and protein expression respectively. RESULTS: RNA-seq analysis comparing rhinovirus infected cultures to control identified 796 and 629 differentially expressed genes for Class 2 and Class 3, respectively. This gene response was highly conserved when cells were treated with CFTR modulators and were predicted to be driven by the same interferon-pathway transcriptional regulators (IFNA, IFNL1, IFNG, IRF7, STAT1). Direct comparisons between treated and untreated infected cultures did not yield any differentially expressed genes for Class 3 and only 68 genes for Class 2. Changes were predominantly related to regulators of lipid metabolism and inflammation, aspects of epithelial biology known to be dysregulated in CF. In addition, CFTR modulators did not affect viral copy number, or levels of pro-inflammatory cytokines produced post-infection. CONCLUSIONS: Though long-term clinical data is not yet available, results presented here suggest that first generation CFTR modulators do not interfere with core airway epithelial responses to rhinovirus infection. Future work should investigate the latest triple modulation therapies.

Race, Gender, and Residency: a Survey of Trainee Experience.

BACKGROUND: Racial minority and female trainees undergo residency attrition at significantly higher rates than their counterparts. We hypothesize that racial minority, and female trainees will report significantly different training experiences from non-minority and male trainees, respectively. Further, we hypothesize that thoughts of withdrawal and summative description of residency experience will be significantly impacted by access to mentorship and feelings of isolation. METHODS: A link to a Qualtrics survey was sent to program officials from all residency programs registered with the ACGME to be distributed to their trainees. It was live from June through August of 2019 and collected data about respondent's demographics and posed questions addressing some of the key elements of the residency experience. RESULTS: Minority trainees reported lower scores for ease of execution of orders placed compared to non-minority trainees 2.12 vs. 2.28 (p = 0.030). Females reported more frequently being mistaken for staff at lower training levels and more frequently feeling overwhelmed than male trainees, 3.29 vs. 1.64 (p < 0.001) and 3.57 vs. 3.16 (p < 0.001). Racial minority and female trainees had numerical but nonsignificant differences in scores for access to mentorship and feelings of isolation compared to non-minority, and male trainees, respectively. Trainees who had thoughts of withdrawal reported less access to mentorship (3.12 vs. 3.88 p < 0.001) and more feelings of isolation (2.22 vs. 1.68 p < 0.001). Trainees reporting more positive experiences had greater access to mentorship and lower feelings of isolation than those who reported a neutral or negative experience, 3.89 vs. 3.14 vs. 2.79 (p < 0.001) and 1.60 vs. 2.21 vs. 2.82 (p < 0.001), respectively. Greater access to mentorship and more frequent family contact both significantly decreased feelings of isolation p < 0.001 and p = 0.035. CONCLUSION: Minority status and female gender impact some of the key elements of the residency experience, manifesting as decreased respect afforded to these trainees. Thoughts of withdrawal and overall residency experience are significantly impacted by access to mentorship and feelings of isolation during residency. Attention should be paid to ensuring that high risk trainees have adequate access to mentorship, making deliberate efforts to cultivate a sense of community and camaraderie among residents, and emphasizing the value of diversity and inclusion.

An adapted novel flow cytometry methodology to delineate types of cell death in airway epithelial cells.

Current methodologies to measure apoptotic and necrotic cell death using flow cytometry do not adequately differentiate between the two. Here, we describe a flow cytometry methodology adapted to airway epithelial cells (AEC) to sufficiently differentiate apoptotic and necrotic AEC. Specifically, cell lines and primary AEC (n = 12) were permeabilized or infected with rhinovirus 1b (RV1b) over 48 h. Cell death was then measured via annexin V/propidium iodide (A5/PI) or annexin V/TO-PRO-3 (A5/TP3) staining using a novel flow cytometry and gating methodology adapted to AEC. We show that A5/PI staining could not sufficiently differentiate between types of cell death following RV1b infection of primary AEC. However, A5/TP3 staining was able to distinguish six cell death populations (viable, necrotic, debris, A5+ apoptotic, A5- apoptotic, apoptotic bodies) after permeabilization or infection with RV1b, with phenotypic differences were observed in apoptotic populations. Collectively, using a staining and gating strategy never adapted to AEC, A5/TP3 could accurately differentiate and quantify viable, necrotic, and apoptotic AEC following RV1b infection.