Situs Ambiguus Is Associated With Adverse Clinical Outcomes in Children With Primary Ciliary Dyskinesia.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare disorder of motile cilia associated with situs abnormalities. At least 12% of patients with PCD have situs ambiguus (SA), including organ laterality defects falling outside normal arrangement (situs solitus [SS]) or mirror image inversion (situs inversus totalis [SIT]). RESEARCH QUESTION: Do patients with PCD and SA achieve worse clinical outcomes compared with those with SS or SIT? STUDY DESIGN AND METHODS: This cross-sectional, multicenter study evaluated participants aged 21 years or younger with PCD. Participants were classified as having SA, including heterotaxy, or not having SA (SS or SIT). Markers of disease severity were compared between situs groups, adjusting for age at enrollment and severe CCDC39 or CCDC40 genotype, using generalized linear models and logistic and Poisson regression. RESULTS: In 397 participants with PCD (mean age, 8.4 years; range, 0.1-21), 42 patients were classified as having SA, including 16 patients (38%) with complex cardiovascular malformations or atrial isomerism, 13 patients (31%) with simple CVM, and 13 patients (31%) without cardiovascular malformations. Of these, 15 patients (36%) underwent cardiac surgery, 24 patients (57%) showed an anatomic spleen abnormality, and seven patients (17%) showed both. The remaining 355 participants did not have SA, including 152 with SIT and 203 with SS. Overall, 70 participants (17%) harbored the severe CCDC39 or CCDC40 genotype. Compared with participants without SA, those with SA showed lower median BMI z scores (P = .03), lower FVC z scores (P = .01), and more hospitalizations and IV antibiotic courses for acute respiratory infections during the 5 years before enrollment (P < .01). Participants with cardiovascular malformations requiring surgery or with anatomic spleen abnormalities showed lower median BMI z scores and more hospitalizations and IV therapies for respiratory illnesses compared with participants without SA. INTERPRETATION: Children with PCD and SA achieve worse nutritional and pulmonary outcomes with more hospitalizations for acute respiratory illnesses than those with SS or SIT combined. Poor nutrition and increased hospitalizations for respiratory infections in participants with SA and PCD are associated with cardiovascular malformations requiring cardiac surgery, splenic anomalies, or both. TRIAL REGISTRY: ClinicalTrials.gov; Nos.: NCT02389049 and NCT00323167; URL: www. CLINICALTRIALS: gov.

Histologic characterization of primary ciliary dyskinesia chronic rhinosinusitis.

KEY POINTS: We present the largest cohort of structured histopathology reports on primary ciliary dyskinesia-related chronic rhinosinusitis (PCD-CRS). Despite endoscopic differences, PCD-CRS and cystic fibrosis-related chronic rhinosinusitis (CF-CRS) had similar structured histopathology reports. Compared to healthy patients and those with idiopathic chronic rhinosinusitis without nasal polyps, patients with PCD-CRS had an increased neutrophil count.

Radiographic and Patient-Reported Outcomes of a Low-Cost Modified Lapidus Bunion Correction Technique.

Background: The modified Lapidus (ML) is a powerful procedure for correction of hallux valgus (HV) with emerging techniques. Studies considering patient-reported outcomes, radiographic measures, complications, and implant costs are currently limited. Methods: Retrospective cohort with prospectively collected Patient Reported Outcome Information System Physical Function (PROMIS-PF) Computerized Adaptive Test (CAT) scores, radiographic parameters (intermetatarsal angle, IMA; hallux valgus angle, HVA; and tibial sesamoid position, TSP), complications, and total operative time and implant costs were reviewed from 2014 to 2019. Results: Seventy-three feet (68 patients) underwent bunion correction by ML with lag-screw fixation. Median age was 55.8 years (IQR 45.6, 53.9), 4 of 73 (5.5%) were male, 11 of 73 (15.1%) were smokers, and 15 of 73 (20.6%) were diabetic (median HbA1c 6.4% [IQR 6.0, 7.4], none insulin dependent, 5 of 15 with neuropathy). Complications included 6 of 73 (8.2%) wound issues resolved with topical or oral treatment, 9 of 73 (12.3%) painful or broken hardware requiring hardware removal. Two of 73 (2.7%) had persistent pain despite union. One of 73 (1.4%) was overcorrected and required first MTP arthrodesis. Of 3 nonunions (2.7%), 1 resolved with corrected hypothyroidism, 1 was asymptomatic and required no treatment, 1 had a hallux valgus recurrence and sought revision surgery elsewhere. Preoperative radiographic angles were HVA 35 degrees, IMA 14 degrees which improved at final postoperative follow up to HVA 10 degrees, IMA 6 degrees. Tibial sesamoid position improved from 6.05 ± 1.00 to 2.22 ± 1.38. Thirty-two patients had preoperative and 42 had 1-year postoperative outcomes. PROMIS-PF (51% collection rate) was 43 (IQR 37,52) preoperatively, 37 (31, 39) at 6 weeks, 46 (42, 51) at 3 months, and 49 (41, 53) at >360 days postoperatively. The drop in PROMIS-PF between preoperative and 6 weeks and the rise from 6 weeks to 3 months were statistically significant. Pre- and postoperative PROMIS-PF scores were not significantly different. Implant cost averaged US$146. Discussion/Conclusion: We report low complication rates and costs with high patient postoperative functional and radiographic outcomes. PROMIS-PF decreased acutely postoperatively but recovered and maintained high levels by 3 months postoperatively. Level of Evidence: Level IV, case series.

Comparing Patient-Reported Outcomes Among Anti-TNF Experienced Patients With Ulcerative Colitis Initiating Vedolizumab Versus Tofacitinib.

Background: Primary and secondary nonresponse to anti-tumor necrosis factor (TNF) therapy is common in patients with ulcerative colitis (UC), yet limited research has compared the effectiveness of subsequent biological therapy. Objective: We sought to compare the effectiveness of vedolizumab and tofacitinib in anti-TNF experienced patients with UC, focusing on patient-prioritized patient-reported outcomes (PROs). Methods: We conducted a prospective cohort study nested within the Crohn's & Colitis Foundation's IBD Partners and SPARC IBD initiatives. We identified anti-TNF experienced patients with UC initiating vedolizumab or tofacitinib and analyzed PROs reported approximately 6 months later (minimum 4 months, maximum 10 months). Co-primary outcomes were Patient Reported Outcome Measurement Information System (PROMIS) domains of Fatigue and Pain Interference. Secondary outcomes included PRO2, treatment persistence, and need for colectomy. Results: We compared 72 vedolizumab initiators and 33 tofacitinib initiators. At follow-up, Pain Interference (P = .04), but not Fatigue (P = .53) was lower among tofacitinib initiators. A trend toward higher Social Role Satisfaction was not significant. The remainder of secondary outcomes (PRO2, treatment persistence, colectomy) did not differ between treatment groups. Conclusions: Among anti-TNF experienced patients with UC, Pain Interference 4-10 months after treatment initiation was lower among tofacitinib users as compared with vedolizumab users. Many, but not all, secondary endpoints and subanalyses also favored tofacitinib. Future studies with larger sample sizes are needed to further evaluate these findings.

Discrimination between Precancerous Gastric Lesions and Gastritis Using a Gastric Cancer Risk Stratification Model.

BACKGROUND: Seropositivity to certain Helicobacter pylori proteins may affect development of gastric lesions that could become cancerous. Previously, we developed a model of gastric cancer risk including gender, age, HP0305 sero-positivity, HP1564 sero-positivity, UreA antibody titer and serologically defined chronic atrophic gastritis (termed: "Lasso model"). METHODS: We evaluated the Lasso model's ability to discriminate individuals with precancerous gastric lesions (n=320) from individuals with superficial or mild atrophic gastritis (n=226) in Linqu County, China, a population at high risk for gastric cancer. We also compared its performance to the ABC Method, a gastric cancer risk stratification tool currently used in East Asia. RESULTS: For distinguishing precancerous lesions from those with gastritis, the receiver operating characteristic curve had an area under the curve (AUC) of 73.41% (95% CI: 69.10%, 77.71%) and, at Youden's Index, a sensitivity of 78.44% (59.38%, 82.50%) and specificity of 64.72% (95% CI: 58.85%, 81.42%). Positive predictive value (PPV) was 75.38% (72.78%, 82.51%). Specificity, AUC and PPV were significantly greater (p < 0.05) than those of the ABC Method. When specificity was held constant, the Lasso model had greater sensitivity, PPV and negative predictive value (NPV) than the ABC Method. However, adjusting the ABC Method for age and gender negated the Lasso model's significant improvement in AUC. CONCLUSIONS: The Lasso model for gastric cancer risk prediction can classify precancerous lesions with significantly greater AUC than the ABC Method and, at constant specificity, with greater sensitivity, PPV and NPV. However, adding age and gender to the ABC Method, as included in the Lasso model, substantially improved its performance and negated the Lasso model's advantage.

The effect of a brief, unplanned treatment delay on neovascular age-related macular degeneration patients: a retrospective cohort study.

Non-compliance to intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy can result in increased disease activity in neovascular age-related macular degeneration (nAMD). Our study aims to determine effects of unplanned delay in anti-VEGF injection treatment for nAMD. This retrospective observational study included patients with delays in receiving intravitreal injections for nAMD treatment from March to May 2020 by at least 21 days. Baseline demographic and clinical characteristics, visual acuity (VA), central macular thickness (CMT) measured on optical coherence tomography (OCT), and duration of delayed treatment were analyzed for 3 time points, the pre-delay visit (v1) and post-delay visits (v2 and v3). Data were compared to age-matched controls treated for nAMD in 2019 without delay. Demographic characteristics were compared using two-sample t-tests for continuous variables and Pearson's chi-square tests for categorical variables. For the two primary outcomes of interest, VA and CMT, means and standard deviations were reported for each combination of group and time. Each outcome was modeled using a linear mixed model with the group, time and group-time interaction as fixed effects. A total of 69 patients (99 eyes) in the treatment delay group and 44 patients (69 eyes) in the control group were identified. Statistically significant differences between control and delayed groups were detected for VA (difference in mean logMAR = 0.16; 95% CI 0.06, 0.27; p = 0.002) and CMT (difference in mean CMT = 29; 95% CI 12, 47; p = 0.001) at v2. No differences were detected for v1 and v3 time points for both outcomes. An unplanned delay in intravitreal injection treatment for nAMD resulted in an increase in CMT and worsening of VA compared to controls observed at v2. At v3, CMT and VA recovered to near v1 levels. This study demonstrates that a one-time, brief interruption in treatment for nAMD results in reversible, temporary worsening.

Question prompt lists and caregiver question asking in pediatric specialty appointments: A randomized controlled trial.

OBJECTIVE: Question prompt lists (QPLs) have been effective at increasing patient involvement and question asking in medical appointments, which is critical for shared decision making. We investigated whether pre-visit preparation (PVP), including a QPL, would increase question asking among caregivers of pediatric patients with undiagnosed, suspected genetic conditions. METHODS: Caregivers were randomized to receive the PVP before their appointment (n = 59) or not (control, n = 53). Appointments were audio-recorded. Transcripts were analyzed to determine questions asked. RESULTS: Caregivers in the PVP group asked more questions (MeanPVP = 4.36, SDPVP = 4.66 vs. Meancontrol = 2.83, SDcontrol = 3.03, p = 0.045), including QPL questions (MeanPVP = 1.05, SDPVP = 1.39 vs. Meancontrol = 0.36, SDcontrol = 0.81, p = 0.002). Caregivers whose child had insurance other than Medicaid in the PVP group asked more total and QPL questions than their counterparts in the control group (ps = 0.005 and 0.002); there was no intervention effect among caregivers of children with Medicaid or no insurance (ps = 0.775 and 0.166). CONCLUSION: The PVP increased question asking but worked less effectively among traditionally underserved groups. Additional interventions, including provider-focused efforts, may be needed to promote engagement of underserved patients. PRACTICE IMPLICATIONS: Patient/family-focused interventions may not be beneficial for all populations. Providers should be aware of potential implicit and explicit biases and encourage question asking to promote patient/family engagement.

Airway Findings in Patients with Hunter Syndrome Treated with Intravenous Idursulfase.

People with Hunter syndrome are known to be affected by a variety of airway pathologies. Treatment of Hunter syndrome with the enzyme replacement therapy (ERT) idursulfase is now the standard of care. However, it is not known how ERT changes the progression of airway involvement. To evaluate this, we performed a retrospective analysis of bronchoscopies performed on children with Hunter syndrome who were part of intrathecal ERT trials. Findings for airway pathology were extracted from bronchoscopy reports and analyses were performed for cross-sectional and longitudinal changes in airway disease. One-hundred and thirty bronchoscopies from 23 subjects were analyzed. Upper airway disease (adenoid hypertrophy and/or pharyngomalacia) was reported in 93% and 87% of bronchoscopies, respectively. Laryngeal abnormalities were recognized in 46% of cases. There were lower airway (tracheal and or bronchial) findings in 64% of all bronchoscopies and prevalence increased with age. Evaluations over time adjusted for repeat evaluations showed that increasing airway involvement was associated with older age (p = 0.0007) despite ongoing ERT. No association was discovered between age of intravenous ERT initiation and progression of airway disease. Individuals with Hunter syndrome who are receiving intravenous enzyme replacement therapy showed the progression of airways disease supporting the need for regular airway monitoring and intervention.

Novel genetic regulators of fibrinogen synthesis identified by an in vitro experimental platform.

BACKGROUND: Fibrinogen has an established, essential role in both coagulation and inflammatory pathways, and these processes are deeply intertwined in the development of thrombotic and atherosclerotic diseases. Previous studies aimed to better understand the (patho) physiological actions of fibrinogen by characterizing the genomic contribution to circulating fibrinogen levels. OBJECTIVES: Establish an in vitro approach to define functional roles between genes within these loci and fibrinogen synthesis. METHODS: Candidate genes were selected on the basis of their proximity to genetic variants associated with fibrinogen levels and expression in hepatocytes and HepG2 cells. HepG2 cells were transfected with small interfering RNAs targeting candidate genes and cultured in the absence or presence of the proinflammatory cytokine interleukin-6. Effects on fibrinogen protein production, gene expression, and cell growth were assessed by immunoblotting, real-time polymerase chain reaction, and cell counts, respectively. RESULTS: HepG2 cells secreted fibrinogen, and stimulation with interleukin-6 increased fibrinogen production by 3.4 ± 1.2 fold. In the absence of interleukin-6, small interfering RNA knockdown of FGA, IL6R, or EEPD1 decreased fibrinogen production, and knockdown of LEPR, PDIA5, PLEC, SHANK3, or CPS1 increased production. In the presence of interleukin-6, knockdown of FGA, IL6R, or ATXN2L decreased fibrinogen production. Knockdown of FGA, IL6R, EEPD1, LEPR, PDIA5, PLEC, or CPS1 altered transcription of one or more fibrinogen genes. Knocking down ATXN2L suppressed inducible but not basal fibrinogen production via a post-transcriptional mechanism. CONCLUSIONS: We established an in vitro platform to define the impact of select gene products on fibrinogen production. Genes identified in our screen may reveal cellular mechanisms that drive fibrinogen production as well as fibrin(ogen)-mediated (patho)physiological mechanisms.

Laterality Defects in Primary Ciliary Dyskinesia: Relationship to Ultrastructural Defect or Genotype.

Rationale: The association between organ laterality abnormalities and ciliary ultrastructural defect or genotype in primary ciliary dyskinesia is poorly understood. Objectives: To determine if there is an association between presence and/or type of laterality abnormality and ciliary ultrastructural defect or genotype. Methods: Participants with primary ciliary dyskinesia in a multicenter, prospective study were grouped based on ciliary ultrastructural defect or genotype. In a retrospective analysis of these data, the association of ciliary ultrastructural defect or genotype and likelihood of a laterality abnormality was evaluated by logistic regression adjusted for presence of two loss-of-function versus one or more not-loss-of-function variants. Results: Of 559 participants, 286 (51.2%), 215 (38.5%), and 58 (10.4%) were identified as having situs solitus, situs inversustotalis, and situs ambiguus, respectively; heterotaxy, defined as situs ambiguus with complex cardiovascular defects, was present in 14 (2.5%). Compared with the group with inner dynein arm defects with microtubular disorganization, laterality defects were more likely in the outer dynein arm defects group (odds ratio [OR], 2.07; 95% confidence interval [CI], 1.21-3.54; P < 0.01) and less likely in the normal/near normal ultrastructure group (OR, 0.04; 95% CI, 0.013-0.151; P < 0.01). Heterotaxy was present in 11 of 242 (4.5%) in the outer dynein arm defects group but 0 of 96 in the inner dynein arm defects with microtubular disorganization group (P = 0.038). Conclusion: In primary ciliary dyskinesia, risk of a laterality abnormality differs by ciliary ultrastructural defect. Pathophysiologic mechanisms underlying these differences require further exploration.

Fixation of humerus shaft fractures in polytrauma patients does not improve short-term outcomes.

BACKGROUND: Surgical fixation of humeral shaft fractures is widely considered a relative indication for polytraumatized patients to improve mobility and expedite care. This study aimed to determine whether operative treatment of humeral shaft fractures improves short term outcomes in polytrauma (PT] patients. METHODS: Using the National Trauma Data Bank, PT patients with humeral shaft fractures were identified from 2010-2015. Three PT groups were analyzed: Group 1 - PT with nonoperative humeral shaft fracture, Group 2 - PT with humeral fixation on Day 1, and Group 3 - PT with humeral fixation on Day 2+. Cox proportional hazards regression models were used to compare discharge timing and days on ventilator and in ICU between the three groups. RESULTS: There were 395 patients in Group 1, 1,346 in Group 2, and 1,318 in Group 3. There were no differences between the three groups when comparing Glasgow Coma Scale (p=0.3]; however, Injury Severity Score and Abbreviated Injury Scale were statistically different (p<0.001]. No differences were found in ICU or ventilator days between the three groups (p=0.2, p=0.5]. For Length of Stay, no difference was observed in Group 1 vs. Group 2 and Group 2 vs. Group 3. However, non-surgical patients were discharged 20% faster than those with Day 1 surgery (p=0.005]. Open fractures were treated one day earlier than closed fractures but discharged one day later (p<0.001]. CONCLUSIONS: This NTDB study demonstrates no differences in length of stay, days in the ICU or on the ventilator in patients with humeral shaft fractures treated non-operatively versus operative fixation. Overall, 44%-58% in all 3 groups had an ISS ≥ 14. Based on these results, we assert that fixation of the humeral shaft provides no short-term benefits in the multiply injured patient.

Impact of occurrence of cardiac arrest in the donor on long-term outcomes of pediatric heart transplantation.

OBJECTIVE: The impact of cardiac arrest in the donor on long-term outcomes of pediatric heart transplantation has not been studied. METHODS: The UNOS database was queried for primary pediatric heart transplantation (1999-2020). The cohort was divided into recipients who received a cardiac allograft from a donor who had a cardiac arrest (CA) versus a donor who did not (NCA). Univariable and multivariable analysis was done to compare recipient outcomes, followed by survival analysis using the Kaplan-Meier method. RESULTS: A total of 7300 patients underwent heart transplantation, of which 579 (7.9%) patients belonged to the CA group. The CA group was younger (median 3 vs. 5 years, p < .001), male (51% vs. 47%, p = .03), and smaller in weight (13 vs. 17 kg, p < .001) and height (101 vs. 109 cm, p < .001) than the NCA group. The groups were similar in recipient heart failure diagnosis and blood type. The CA donors were younger (3 vs. 6 years, p < .001) versus nonwhite (48% vs. 45%, p = .003) and died from drowning and asphyxiation compared to blunt injury and intracranial hemorrhage in the NCA group. The left-ventricular ejection fraction was similar between the groups. There was no difference in VAD and ECMO use before the transplant. The listing status, waitlist days, and allograft ischemic times were similar. Posttransplant morbidity such as stroke, dialysis, pacemaker implantation, and treated rejection were similar. Donor cardiac arrest (hazard ratio = 0.93, p = .5) was not an independent predictor of mortality on multivariable analysis. There was no survival difference even beyond 20 years of follow-up between the groups (p = .88). CONCLUSION: The occurrence of donor cardiac arrest has no impact on long-term survival in pediatric heart transplant recipients.

Serology and Comorbidities in Patients With Fracture Nonunion: A Multicenter Evaluation of 640 Patients.

INTRODUCTION: This multicenter cohort study investigated the association of serology and comorbid conditions with septic and aseptic nonunion. METHODS: From January 1, 2011, to December 31, 2017, consecutive individuals surgically treated for nonunion were identified from seven centers. Nonunion-type, comorbid conditions and serology were assessed. RESULTS: A total of 640 individuals were included. 57% were male with a mean age of 49 years. Nonunion sites included tibia (35.2%), femur (25.6%), humerus (20.3%), and other less frequent bones (18.9%). The type of nonunion included septic (17.7%) and aseptic (82.3%). Within aseptic, nonvascular (86.5%) and vascular (13.5%) nonunion were seen. Rates of smoking, alcohol abuse, and diabetes mellitus were higher in our nonunion cohort compared with population norms. Coronary artery disease and tobacco use were associated with septic nonunion (P < 0.05). Diphosphonates were associated with vascular nonunion (P < 0.05). Serologically, increased erythrocyte sedimentation rate, C-reactive protein, parathyroid hormone, red cell distribution width, mean platelet volume (MPV), and platelets and decreased absolute lymphocyte count, hemoglobin, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and albumin were associated with septic nonunion while lower calcium was associated with nonvascular nonunion (P < 0.05). The presence of four or more of increased erythrocyte sedimentation rate, C-reactive protein, or red cell distribution width; decreased albumin; and age younger than 65 years carried an 89% positive predictive value for infection. Hypovitaminosis D was seen less frequently than reported in the general population, whereas anemia was more common. However, aside from hematologic and inflammatory indices, no other serology was abnormal more than 25% of the time. DISCUSSION: Abnormal serology and comorbid conditions, including smoking, alcohol abuse, and diabetes mellitus, are seen in nonunion; however, serologic abnormalities may be less common than previously thought. Septic nonunion is associated with inflammation, younger age, and malnourishment. Based on the observed frequency of abnormality, routine laboratory work is not recommended for nonunion assessment; however, specific focused serology may help determine the presence of septic nonunion.

The Association of Selective Serotonin Reuptake Inhibitors With Delirium in Critically Ill Adults: A Secondary Analysis of the Bringing to Light the Risk Factors and Incidence of Neuropsychologic Dysfunction in ICU Survivors ICU Study.

OBJECTIVES: To assess the association between selective serotonin reuptake inhibitors (SSRI) and delirium in the subsequent 24 hours after drug administration in critically ill adults. DESIGN: Retrospective cohort study utilizing the Bringing to Light the Risk Factors and Incidence of Neuropsychologic Dysfunction in ICU Survivors dataset. SETTING: Two large U.S. ICUs. PATIENTS: Critically ill adults admitted to a medical or surgery ICU between March 2007 and May 2010 with respiratory failure or shock. INTERVENTIONS: Our primary outcome was the occurrence rate of delirium or coma during each day in the ICU. Our exposure variable was SSRI administration on the prior day in the ICU. As a secondary question, we assessed the association of SSRI administration and delirium the same day of SSRI administration in the ICU. MEASUREMENTS AND MAIN RESULTS: We analyzed 821 patients. The median age was 61.2 years old (interquartile range, 50.9-70.7), and 401 (48.8%) were female. A total of 233 patients (28.4%) received prescribed SSRIs at least once during their ICU admission. Delirium was present in 606 (74%) of the patients at some point during hospitalization in the ICU. Coma was present in 532 (64.8%) of the patients at some point during hospitalization in the ICU. After adjusting for multiple potential confounding factors, we found that SSRI administration in the ICU was associated with lower odds of delirium/coma (odds ratio [OR], 0.75; 95% CI, 0.57-1.00) the next day. An SSRI administered on the same day reduced the odds of delirium/coma as well (OR, 0.66; 95% CI, 0.50-0.87). CONCLUSIONS: SSRI administration is associated with decreased risk of delirium/coma in 24 hours and on the same day of administration in critically ill patients in a medical or surgical ICU.

Analysis of survival data with cure fraction and variable selection: A pseudo-observations approach.

In biomedical studies, survival data with a cure fraction (the proportion of subjects cured of disease) are commonly encountered. The mixture cure and bounded cumulative hazard models are two main types of cure fraction models when analyzing survival data with long-term survivors. In this article, in the framework of the Cox proportional hazards mixture cure model and bounded cumulative hazard model, we propose several estimators utilizing pseudo-observations to assess the effects of covariates on the cure rate and the risk of having the event of interest for survival data with a cure fraction. A variable selection procedure is also presented based on the pseudo-observations using penalized generalized estimating equations for proportional hazards mixture cure and bounded cumulative hazard models. Extensive simulation studies are conducted to examine the proposed methods. The proposed technique is demonstrated through applications to a melanoma study and a dental data set with high-dimensional covariates.

Glenohumeral Hydrodistension for Postoperative Stiffness After Arthroscopic Primary Rotator Cuff Repair.

Background: Postoperative stiffness is a known complication after rotator cuff repair (RCR). Glenohumeral hydrodistension (GH) has been a treatment modality for shoulder pathology but has not been used to treat postoperative stiffness after RCR. Purpose/Hypothesis: The purpose of this study was to identify the risk factors for postoperative stiffness after RCR and review outcomes after treatment with GH. Our hypotheses were that stiffness would be associated with diabetes and hyperlipidemia and correlated with the tendons involved and that patients with stiffness who underwent GH would have significant improvement in range of motion (ROM). Study Design: Case series; Level of evidence, 4. Methods: Included were 388 shoulders of patients who underwent primary RCR by a single surgeon between 2015 and 2019. Shoulders with revision RCRs were excluded. Patient characteristics, medical comorbidities, and perioperative details were collected. A total of 40 shoulders with postoperative stiffness (10.3%) received GH injectate of a 21-mL mixture (15 mL of sterile water, 5 mL of 0.5% ropivacaine, and 1 mL of triamcinolone [10 mg/mL]). The primary outcome measure was ROM in forward flexion, internal rotation, external rotation, and abduction. Statistical tests were performed using analysis of variance. Results: Patients with diabetes had significantly decreased internal rotation at final follow-up after RCR as compared with patients without diabetes. GH to treat stiffness was performed most commonly between 1 and 4 months after RCR (60%), and patients who received GH saw statistically significant improvements in forward flexion, external rotation, and abduction after the procedure. Patients with hyperlipidemia had the most benefit after GH. Among those undergoing concomitant procedures, significantly more patients who had open subpectoral biceps tenodesis underwent GH. Patients who underwent subscapularis repair or concomitant subacromial decompression had significant improvement in ROM after GH. Only 1 patient who received GH underwent secondary surgery for resistant postoperative stiffness. Conclusion: Patients with diabetes had increased stiffness. Patients with a history of hyperlipidemia or concomitant open subpectoral biceps tenodesis were more likely to undergo GH for postoperative stiffness. Patients who underwent subscapularis repair demonstrated the most improvement in ROM after GH. After primary RCR, GH can increase ROM and is a useful adjunct for patients with stiffness to limit secondary surgery.

A Predictive Model of Noncardia Gastric Adenocarcinoma Risk Using Antibody Response to Helicobacter pylori Proteins and Pepsinogen.

BACKGROUND: Blood-based biomarkers for gastric cancer risk stratification could facilitate targeting screening to people who will benefit from it most. The ABC Method, which stratifies individuals by their Helicobacter pylori infection and serum-diagnosed chronic atrophic gastritis status, is currently used in Japan for this purpose. Most gastric cancers are caused by chronic H. pylori infection, but few studies have explored the capability of antibody response to H. pylori proteins to predict gastric cancer risk in addition to established predictors. METHODS: We used the least absolute shrinkage and selection operator (Lasso) to build a predictive model of noncardia gastric adenocarcinoma risk from serum data on pepsinogen and antibody response to 13 H. pylori antigens as well as demographic and lifestyle factors from a large international study in East Asia. RESULTS: Our best model had a significantly (P < 0.001) higher AUC of 73.79% [95% confidence interval (CI), 70.86%-76.73%] than the ABC Method (68.75%; 95% CI, 65.91%-71.58%). At 75% specificity, the new model had greater sensitivity than the ABC Method (58.67% vs. 52.68%) as well as NPV (68.24% vs. 66.29%). CONCLUSIONS: Along with serologically defined chronic atrophic gastritis, antibody response to the H. pylori proteins HP 0305, HP 1564, and UreA can improve the prediction of gastric cancer risk. IMPACT: The new risk stratification model could help target more invasive gastric screening resources to individuals at high risk.

Complications With Surgical Treatment of Pediatric Supracondylar Humerus Fractures: Does Surgeon Training Matter?

INTRODUCTION: National trends reveal increased transfers to referral hospitals for surgical management of pediatric supracondylar humerus (SCH) fractures. This is partly because of the belief that pediatric orthopaedic surgeons (POs) deliver improved outcomes compared with nonpediatric orthopaedic surgeons (NPOs). We compared early outcomes of surgically treated SCH fractures between POs and NPOs at a single center where both groups manage these fractures. METHODS: Patients ages 3 to 10 undergoing surgery for SCH fractures from 2014 to 2020 were included. Patient demographics and perioperative details were recorded. Radiographs at surgery and short-term follow-up assessed reduction. Primary outcomes were major loss of reduction (MLOR) and iatrogenic nerve injury (INI). Complications were compared between PO-treated and NPO-treated cohorts. RESULTS: Three hundred and eleven fractures were reviewed. POs managed 132 cases, and NPOs managed 179 cases. Rate of MLOR was 1.5% among POs and 2.2% among NPOs (P=1). Rate of INI was 0% among POs and 3.4% among NPOs (P=0.041). All nerve palsies resolved postoperatively by mean 13.1 weeks. Rates of reoperation, infection, readmission, and open reduction were not significantly different. Operative times were decreased among POs (38.1 vs. 44.6 min; P=0.030). Pin constructs were graded as higher quality in the PO group, with a higher mean pin spread ratio (P=0.029), lower rate of "C" constructs (only 1 "column" engaged; P=0.010) and less frequent crossed-pin technique (P<0.001). Multivariate analysis revealed minimal positive associations only for operative time with MLOR (odds ratio=1.021; P=0.005) and INI (odds ratio=1.048; P=0.009). CONCLUSIONS: Postsurgical outcomes between POs and NPOs were similar. Rates of MLOR were not different between groups, despite differences in pin constructs. The NPO group experienced a marginally higher rate of INI, though all injuries resolved. Pediatric subspecialty training is not a prerequisite for successfully treating SCH fractures, and overall value of orthopaedic care may be improved by decreasing transfers for these common injuries. LEVEL OF EVIDENCE: Level III-retrospective cohort study.

When Is a Growth-friendly Strategy Warranted? A Matched Comparison of Growing Rods Versus Primary Posterior Spinal Fusion in Juveniles With Early-onset Scoliosis.

BACKGROUND: In 7 to 11-year-old juveniles with severe early-onset scoliosis (EOS) the optimal surgical option remains uncertain. This study compares growing rods (GRs) followed by definitive posterior spinal fusion (PSF) versus primary PSF in this population. We hypothesized that the thoracic height afforded by GRs would be offset by increased rigidity, more complications, and more operations. METHODS: This retrospective comparative study included EOS patients aged 7.0 to 11.9 years at index surgery treated with GR→PSF or primary PSF during 2013 to 2020. Primary outcomes were thoracic height gain (ΔT1-12H), major curve, complications, and total operations. Primary PSFs were matched with replacement 1-to-n to GR→PSFs by age at index, etiology, and major curve. RESULTS: Twenty-eight GR→PSFs met criteria: 19 magnetically controlled GRs and 9 traditional GRs. Three magnetically controlled GRs were definitively explanted without PSF due to complications. The remaining 25 GR→PSFs were matched to 17 primary PSFs with 100% etiology match, mean Δ major curve 1 degree, and mean Δ age at index 0.5 years (PSFs older). Median ΔT1-12H pre-GR to post-PSF was 4.7 cm with median deformity correction of 37%. Median ΔT1-12H among primary PSFs was 1.9 cm with median deformity correction of 62%. GR→PSFs had mean 1.8 complications and 3.4 operations. Primary PSFs had mean 0.5 complications and 1.3 operations. Matched analysis showed adjusted mean differences of 2.3 cm greater ΔT1-12H among GR→PSFs than their matched primary PSFs, with 25% less overall coronal deformity correction, 1.2 additional complications, and 2.2 additional operations per patient. CONCLUSIONS: In juveniles aged 7 to 11 with EOS, on average GRs afford 2 cm of thoracic height over primary PSF at the cost of poorer deformity correction and additional complications and operations. Primary PSF affords an average of 2 cm of thoracic height gain; if an additional 2 cm will be impactful then GRs should be considered. However, in most juveniles the height gained may not warrant the iatrogenic stiffness, complications, and additional operations. Surgeons and families should weigh these benefits and harms when choosing a treatment plan. LEVEL OF EVIDENCE: Level III-retrospective comparative study.

Semiparametric estimation of the proportional rates model for recurrent events data with missing event category.

Proportional rates models are frequently used for the analysis of recurrent event data with multiple event categories. When some of the event categories are missing, a conventional approach is to either exclude the missing data for a complete-case analysis or employ a parametric model for the missing event type. It is well known that the complete-case analysis is inconsistent when the missingness depends on covariates, and the parametric approach may incur bias when the model is misspecified. In this paper, we aim to provide a more robust approach using a rate proportion method for the imputation of missing event types. We show that the log-odds of the event type can be written as a semiparametric generalized linear model, facilitating a theoretically justified estimation framework. Comprehensive simulation studies were conducted demonstrating the improved performance of the semiparametric method over parametric procedures. Multiple types of Pseudomonas aeruginosa infections of young cystic fibrosis patients were analyzed to demonstrate the feasibility of our proposed approach.