Association of Hormonal Contraceptive Use With Adverse Health Outcomes: An Umbrella Review of Meta-analyses of Randomized Clinical Trials and Cohort Studies.

Importance: Meta-analyses have reported conflicting data on the safety of hormonal contraception, but the quality of evidence for the associations between hormonal contraceptive use and adverse health outcomes has not been quantified in aggregate. Objective: To grade the evidence from meta-analyses of randomized clinical trials (RCTs) and cohort studies that assessed the associations between hormonal contraceptive use and adverse health outcomes among women. Data Sources: MEDLINE, Embase, and the Cochrane Database of Systematic Reviews were searched from database inception to August 2020. Search terms included hormonal contraception, contraceptive agents, progesterone, desogestrel, norethindrone, megestrol, algestone, norprogesterones, and levonorgestrel combined with terms such as systematic review or meta-analysis. Evidence Review: The methodological quality of each meta-analysis was graded using the Assessment of Multiple Systematic Reviews, version 2, which rated quality as critically low, low, moderate, or high. The Grading of Recommendation, Assessment, Development and Evaluations approach was used to assess the certainty of evidence in meta-analyses of RCTs, with evidence graded as very low, low, moderate, or high. Evidence of associations from meta-analyses of cohort studies was ranked according to established criteria as nonsignificant, weak, suggestive, highly suggestive, or convincing. Results: A total of 2996 records were screened; of those, 310 full-text articles were assessed for eligibility, and 58 articles (13 meta-analyses of RCTs and 45 meta-analyses of cohort studies) were selected for evidence synthesis. Sixty associations were described in meta-analyses of RCTs, and 96 associations were described in meta-analyses of cohort studies. Among meta-analyses of RCTs, 14 of the 60 associations were nominally statistically significant (P ≤ .05); no associations between hormonal contraceptive use and adverse outcomes were supported by high-quality evidence. The association between the use of a levonorgestrel-releasing intrauterine system and reductions in endometrial polyps associated with tamoxifen use (odds ratio [OR], 0.22; 95% CI, 0.13-0.38) was graded as having high-quality evidence, and this evidence ranking was retained in the subgroup analysis. Among meta-analyses of cohort studies, 40 of the 96 associations were nominally statistically significant; however, no associations between hormonal contraceptive use and adverse outcomes were supported by convincing evidence in the primary and subgroup analyses. The risk of venous thromboembolism among those using vs not using oral contraception (OR, 2.42; 95% CI, 1.76-3.32) was initially supported by highly suggestive evidence, but this evidence was downgraded to weak in the sensitivity analysis. Conclusions And Relevance: The results of this umbrella review supported preexisting understandings of the risks and benefits associated with hormonal contraceptive use. Overall, the associations between hormonal contraceptive use and cardiovascular risk, cancer risk, and other major adverse health outcomes were not supported by high-quality evidence.

Long-term Outcomes of Minimally Invasive Versus Open Abdominoperineal Resection for Rectal Cancer: A Single Specialized Center Experience.

BACKGROUND: Randomized studies have validated laparoscopic proctectomy for the treatment of rectal cancer as noninferior to an open proctectomy, but most of those studies have included sphincter-preserving resections along with abdominoperineal resection. OBJECTIVE: This study aimed to compare perioperative and long-term oncological outcomes between minimally invasive and open abdominoperineal resection. DESIGN: This study is a retrospective analysis of a prospectively maintained database. SETTINGS: The study was conducted in a single specialized colorectal surgery department. PATIENTS: All patients who underwent abdominoperineal resection for primary rectal cancer between 2000 and 2016 were included. MAIN OUTCOME MEASURES: The primary outcomes measured were the perioperative and long-term oncological outcomes. RESULTS: We included 452 patients, 372 in the open group and 80 in the minimally invasive group, with a median follow-up time of 74 months. There were significant differences between the groups in terms of neoadjuvant radiation treatment (67.5% of the open versus 81.3% of the minimally invasive group, p = 0.01), operative time (mean of 200 minutes versus 287 minutes, p < 0.0001), and mean length of stay (9.5 days versus 6.6 days, p < 0.0001). Overall complication rates were similar between the groups (34.5% versus 27.5%, p = 0.177). There were no significant differences in the mean number of lymph nodes harvested (21.7 versus 22.2 nodes, p = 0.7), circumferential radial margins (1.48 cm versus 1.37 cm, p = 0.4), or in the rate of involved radial margins (10.8% versus 6.3%, p = 0.37). Five-year overall survival was 70% in the open group versus 80% in the minimally invasive group (p = 0.344), whereas the 5-year disease-free survival rate in the open group was 63.2% versus 77.6% in the minimally invasive group (p = 0.09). LIMITATIONS: This study was limited because it describes a single referral institution experience. CONCLUSIONS: Although both approaches have similar perioperative outcomes, the minimally invasive approach benefits the patients with a shorter length of stay and a lower risk for surgical wound infections. Both approaches yield similar oncological technical quality in terms of the lymph nodes harvested and margins status, and they have comparable long-term oncological outcomes. See Video Abstract at http://links.lww.com/DCR/B754.RESULTADOS A LARGO PLAZO DE LA RESECCIÓN ABDOMINOPERINEAL MÍNIMAMENTE INVASIVA VERSUS ABIERTA PARA EL CÁNCER DE RECTO: EXPERIENCIA DE UN SOLO CENTRO ESPECIALIZADOANTECEDENTES:Estudios aleatorizados han validado la proctectomía laparoscópica para el tratamiento del cáncer de recto igual a la proctectomía abierta, pero la mayoría de esos estudios han incluido resecciones con preservación del esfínter junto con resección abdominoperineal.OBJETIVO:Comparar los resultados oncológicos perioperatorios y a largo plazo entre la resección abdominoperineal abierta y mínimamente invasiva.DISEÑO:Análisis retrospectivo de una base de datos mantenida de forma prospectiva.ENTORNO CLINICO:Servicio único especializado en cirugía colorrectal.PACIENTES:Todos los pacientes que se sometieron a resección abdominoperineal por cáncer de recto primario entre 2000 y 2016.PRINCIPALES MEDIDAS DE VALORACION:Resultados oncológicos perioperatorios y a largo plazo.RESULTADOS:Se incluyeron 452 pacientes, 372 en el grupo abierto y 80 en el grupo mínimamente invasivo, con una mediana de seguimiento de 74 meses. Hubo diferencias significativas entre los grupos en términos de tratamiento con radiación neoadyuvante (67,5% del grupo abierto versus 81,3% del grupo mínimamente invasivo, p = 0,01), tiempo operatorio (media de 200 minutos versus 287 minutos, p < 0,0001) y la duración media de la estancia (9,5 días frente a 6,6 días, p < 0,0001). Las tasas generales de complicaciones fueron similares entre los grupos (34,5% versus 27,5%, p = 0,177). No hubo diferencias significativas en el número medio de ganglios linfáticos extraídos (21,7 versus 22,2 ganglios, p = 0,7), márgenes radiales circunferenciales (1,48 cm y 1,37 cm, p = 0,4), ni en la tasa de márgenes radiales afectados (10,8 cm). % versus 6,3%, p = 0,37). La supervivencia general a 5 años fue del 70% en el grupo abierto frente al 80% en el grupo mínimamente invasivo (p = 0,344), mientras que la tasa de supervivencia libre de enfermedad a 5 años en el grupo abierto fue del 63,2% frente al 77,6% en el grupo mínimamente invasivo (p = 0,09).LIMITACIONES:Experiencia en una institución de referencia única.CONCLUSIONES:Si bien ambos tienen resultados perioperatorios similares, el enfoque mínimamente invasivo, beneficia a los pacientes con estadía más corta y menor riesgo de infecciones de la herida quirúrgica. Ambos enfoques, producen una calidad técnica oncológica similar en términos de ganglios linfáticos extraídos y estado de los márgenes, y tienen resultados oncológicos comparables a largo plazo. Consulte Video Resumen en http://links.lww.com/DCR/B754. (Traducción - Dr. Fidel Ruiz Healy).

Cardiac allograft rejection in the current era of continuous flow left ventricular assist devices.

OBJECTIVE: Left ventricular assist device (LVAD) implantation has been shown to increase allosensitization before orthotopic heart transplantation, but the influence of LVAD support on posttransplant rejection is controversial. This study examines the postoperative incidence of acute cellular rejection (ACR) in patients bridged with continuous flow LVAD (CF-LVAD) relative to primary transplant (Primary Tx). METHODS: All patients who underwent orthotopic heart transplantation at our institution between July 2006 and March 2019 were retrospectively reviewed (n = 395). Patients were classified into Primary Tx (n = 145) and CF-LVAD (n = 207) groups. Propensity score matching on 13 covariates implemented a 0.1 caliper logistic model with nearest neighbor 1:1 matching. Development of moderate to severe (ie, 2R/3R) rejection was evaluated using a competing risks model. Potential predictors of 2R/3R ACR were evaluated using Fine-Gray regression on the marginal subdistribution hazard. RESULTS: Propensity score matching yielded 122 patients in each group (n = 244). At 12 and 24 months, the cumulative incidence of 2R/3R ACR was 17% and 23% for the CF-LVAD group and 26% and 31%, respectively, for the Primary Tx group (P = .170). CF-LVAD was not predictive of 2R/3R rejection on multivariable Fine-Gray regression (subdistribution hazard ratio, 0.73; 95% confidence interval, 0.40-1.33; P = .301). There was no difference in the 5-year incidence of antibody mediated rejection (10% [n = 12] vs 9% [n = 11]; P = .827). CONCLUSIONS: After adjusting for covariates, CF-LVAD was not associated with an increased risk of moderate to severe ACR during the 24 months after cardiac transplantation. Further investigation is warranted with larger cohorts, but CF-LVAD may have minimal influence on posttransplant ACR.

Association between type 2 diabetes and long-term outcomes in middle-aged and older trauma patients.

BACKGROUND: Diabetes is associated with increased hospital complications and mortality following trauma. However, there is limited research on the longer-term recovery of trauma patients with diabetes. The aim of this study was to explore the association between type 2 diabetes (T2D) and in-hospital and 24-month outcomes in major trauma patients. METHODS: In this cohort study using the Victorian State Trauma Registry, middle-aged and older adults (≥45 years) with major trauma were followed up at 24 months postinjury. Logistic regression (univariable and multivariable) analyses were used to determine the association between diabetes status and 24-month patient-reported outcomes. In-hospital outcomes were compared between groups using χ2 tests. RESULTS: Of the 11,490 participants who survived to hospital discharge, 8,493 survived to 24 months postinjury and were followed up at that time point: 953 people (11%) with and 7540 (89%) without T2D. People with T2D had a higher in-hospital death rate (19%) compared with people without T2D (16%; p < 0.001). After adjusting for confounders, people with T2D had poorer outcomes 24 months postinjury than people without T2D, with respect to functional recovery (Glasgow Outcome Scale Extended) (adjusted odds ratio [AOR], 0.58; 95% confidence interval [CI], 0.48-0.69) and return to work/study (AOR, 0.51; 95% CI, 0.37-0.71]). People with T2D experienced higher odds of problems with mobility (AOR, 1.92; 95% CI, 1.60-2.30), self-care (AOR, 1.94; 95% CI, 1.64, 2.29), usual activities (AOR, 1.50; 95% CI, 1.26-1.79), pain and discomfort (AOR, 1.75; 95% CI, 1.49-2.07), anxiety and depression (AOR, 1.45; 95% CI, 1.24, 1.70), and self-reported disability (AOR, 1.51; 95% CI, 1.28-1.79) than people without T2D. CONCLUSION: Major trauma patients with T2D have a poorer prognosis than patients without T2D, both during their hospital admission and 24 months postinjury. Patients with T2D may need additional health care and support following trauma to reach their recovery potential. LEVEL OF EVIDENCE: Prognostic, level III.

Endoscopic Management of Low-Grade Upper Tract Urothelial Carcinoma: Characterizing the Long-term Burden of Care in Comparison to Radical Nephroureterectomy.

OBJECTIVE: To compare procedure burden, oncologic, surgical and renal-function outcomes between patients with low-grade upper urothelial cancer (UTUC) who were referred for either radical management (RM) or kidney-sparing endoscopic management (EM). PATIENTS AND METHODS: We retrospectively reviewed data of all patients treated for UTUC at our tertiary medical center between 2000 and 2018 and selected patients diagnosed with unilateral low-grade UTUC. RESULTS: Twenty-four patients were treated with EM and 37 with RM. Surgical and oncologic risk factors were similar between the arms except for tumor size. Mean follow-up was 4.9 ± 3.4 years. The 5-year overall-survival rate was 85% with EM and 84% with RM (P = .707). Metastasis-free and cancer-specific survival were also similar (P = .994, P = .960). End-of-follow-up average glomerular filtration rates were 58.7 ± 21.5 and 49.2 ± 22.1 mL/min/1.73 m2, respectively (P = .12). Ninety-two percent of patients managed endoscopically had local recurrences, with an average of 3.2 recurrences per patient. Four (17%) patients underwent salvage radical nephroureterectomy. Procedure burden was higher with EM, having 6.5 ± 4.4 operations and 344 ± 272 minutes under anesthesia compared with 1.9 ± 0.4 operations (P <.0001) and 213 ± 84 minutes under anesthesia (P = .031) with RM. Cost-of-care analysis revealed higher costs for EM in both private and publicly funded medical insurance plans. CONCLUSION: Patients undergoing endoscopic management had an 83% chance of preserving their kidney and an 81% chance of 5-year metastasis-free survival at a cost of 6.5 ± 4.4 operations during a mean follow-up of 4.9 ± 3.4 years. Our findings support EM for low-grade UTUC as a valid option from oncological aspects but highlight the associated costs.

Long-term pulmonary function, thoracic pain, and quality of life in patients with one or more rib fractures.

BACKGROUND: Long-term outcomes after rib fractures and the effect of treatment modality or chest wall injury severity on these outcomes remains uncertain. This retrospective cohort study evaluated the long-term pulmonary function, thoracic pain, and quality of life in patients admitted with rib fractures. METHODS: Patients admitted with rib fractures between January 1, 2012, and December 1, 2019, were included. Data on long-term outcomes were collected during one follow-up visit. Patients were stratified by chest wall injury severity (one or two rib fractures, ≥3 rib fractures, or a flail chest) and treatment modality (surgical stabilization of rib fractures [SSRF] or nonoperative management). Multivariable analysis was performed to compare outcomes after SSRF with nonoperative treatment in patients with three or more rib fractures. RESULTS: In total, 300 patients were included. The median follow-up was 39 months (P25-P75, 18-65 months). At follow-up, the corrected forced vital capacity returned to 84.7% (P25-P75, 74.3-93.7) and the forced expiratory volume in 1 second to 86.3% (P25-P75, 75.3-97.0) of the predicted reference values. Quality of life was determined using the Short Form-12 version 2 and EuroQoL-5D-5L. The Short Form-12 version 2 physical and mental component summary were 45 (P25-P75, 38-54) and 53 (P25-P75, 43-60), respectively. The EuroQoL-5D-5L utility score was 0.82 (P25-P75 0.66-0.92) and visual analog scale score 75 (P25-P75 70-85). This indicated a quality of life within normal population ranges. Moderate to severe thoracic pain was reported by 64 (21.3%) patients. Long-term outcomes returned to values within population ranges and were similar across chest wall injury severity and for patients treated with SSRF or nonoperatively. CONCLUSION: While long-term pulmonary function and quality of life recover to values considered normal, subjective thoracic complaints, such as pain and dyspnea, remain frequently present following rib fractures. No effect of chest wall injury severity or treatment modality on long-term outcomes was demonstrated. LEVEL OF EVIDENCE: Therapeutic, level III.

Long-term Bisphosphonates for Osteoporosis: A Factor Effecting Fracture Pattern?

BACKGROUND: The incidence of fragility hip fractures, intracapsular and extracapsular, has been increasing worldwide. Fracture stability is important for treatment decision-making and is related to the expected rate of complications. It is unclear whether metabolic therapy explains the increased incidence of unstable fractures. OBJECTIVES: To investigate the possible association between treatment with bisphosphonates and the various patterns encountered with intertrochanteric hip fractures. METHODS: Patients with fragility hip fractures who were treated in our department between 2013 and 2014 were included in this study. They were classified into three groups: group 1 had a stable extracapsular fracture, group 2 had an unstable extracapsular fracture, and group 3 had an intracapsular fracture. Collated data included: osteoporosis preventive therapy and duration, fracture-type, history of previous fractures, and vitamin D levels. RESULTS: Of 370 patients, 87 were previously treated with bisphosphonates (18.3% prior to fracture in group 1, 38.3% in group 2, and 13.8% in group 3). Of those treated with bisphosphonates, 56.3% had an unstable fracture, 21.8% had a stable fracture, and the rest an intracapsular fracture. In contrast, only 27.9% of patients who were not treated with bisphosphonates had an unstable fracture and 30.0% had stable fractures. CONCLUSIONS: Our findings show a higher proportion of complex and unstable fractures among patients with fragility hip-fractures who were treated with bisphosphonates than among those who did not receive this treatment. The risk for complex and unstable fracture may affect the preferred surgical treatment, its complexity, length of surgery, and rehabilitation.

Acute Compartment Syndrome of the Upper Extremity: Clinical Outcomes Following Surgical Treatment. A Retrospective Cohort Study.

BACKGROUND: Acute extremity compartment syndrome is a surgical emergency for which timely diagnosis is essential. OBJECTIVES: To assess whether the time from the initial insult to the fasciotomy of compartment syndrome of the upper extremity affects outcomes and to examine the differences between compartment syndrome secondary to fractures and that resulting from a non-fracture etiology with regard to the time from insult to fasciotomy and the long-term patient outcomes. METHODS: Patients presented with documented fasciotomy treatment following acute upper extremity compartment syndrome and a minimum of 6 months follow-up. Patient information included demographics, cause of compartment syndrome, method of diagnosis, and outcome on follow-up. RESULTS: Our study was comprised of 25 patients. Fasciotomies were performed for compartment syndrome caused by fracture in 11 patients (44%), and due to insults other than fractures in 14 patients (56%). The average time to fasciotomy in patients without a fracture was 10.21 hours and 16.55 hours with a fracture. Fasciotomy performed more than 24 hours from the initial insult was not found to significantly affect long-term sequelae compared to fasciotomy performed earlier than 24 hours from the initial insult. The non-fracture group had more long-term sequelae than the fracture group (13/15 patients and 5/11 patients, respectively). CONCLUSIONS: Most injuries treated for fasciotomy of compartment syndrome were non-fracture related, with more complications found in patients with non-fracture related injuries. Time interval from insult to fasciotomy did not affect outcome and was longer in the fracture group, suggesting longer monitoring in this group and supporting fasciotomy even with late presentation.

Triglyceride-Glukose Index Predicts Adverse Events in Patients with Acute Coronary Syndrome: A Meta-Analysis of Cohort Studies.

The triglyceride-glucose (TyG) index, a recently proposed indicator for insulin resistance, has been related with cardiovascular risks. We aimed to summarize the association between TyG index and incidence of major adverse cardiovascular events (MACEs) in patients with acute coronary syndrome (ACS). Cohort studies demonstrating the association between TyG index and incidence of MACEs in ACS patients with multivariate adjusted analyses were identified by search of PubMed, Embase, and Web of Science databases. A random-effekt model incorporating the heterogeneity was applied to pool the results. Eight cohort studies with 19 611 participants were included. Results showed that compared to those with the lowest category of TyG index, ACS patients with the highest category of TyG index were independently associated with higher risk of MACEs [risk ratio (RR): 1.94, 95% confidence interval (CI): 1.47-2.56, I2=85%, p <0.001). Subgroup analyses showed consistent results in patients with ST-segment elevated myocardial infarction or non-ST segment elevated ACS, in patients with or without diabetes, and in patients after percutaneous coronary intervention. Results were consistent in studies with TyG index analyzed as continuous variable (RR for per standard deviation increment of TyG index: 1.59, 95% CI: 1.38-1.83, I2=24%, p <0.001). In conclusion, higher TyG index may be independently associated with higher incidence of MACEs in patients with ACS.

Outcomes of Percutaneous Coronary Intervention in Patients with Spontaneous Coronary Artery Dissection.

OBJECTIVES: To compare outcomes of percutaneous coronary intervention (PCI) in spontaneous coronary artery dissection (SCAD) patients versus conservative therapy. BACKGROUND: SCAD is an important cause of myocardial infarction (MI) in young-to-middle-aged women. Percutaneous coronary intervention (PCI) is often pursued, but outcomes compared to conservative therapy are unclear. METHODS: 403 nonatherosclerotic SCAD patients were enrolled between 2011 and 2017 and prospectively followed up in our Vancouver General Hospital registries. Detailed baseline, hospital, PCI, and outcomes were recorded. We explored the outcomes of SCAD patients who underwent PCI during their initial presentation. RESULTS: PCI was performed in 75 patients, the average age was 48.9 ± 10.1 yrs, and 94.7% were women. All presented with MI; 50.7% STEMI, 49.3% NSTEMI, and 13.3% had VT/VF. PCI was successful in 34.7%, partially successful in 37.3%, and unsuccessful in 28.0%. Stents were deployed in 73.3%, 16.0% had balloon angioplasty alone, 10.7% had wiring attempts only, and 5.3% required bailout surgery. Major adverse cardiovascular event rates (MACE) were significantly higher with the PCI group in hospital (29.3% versus 2.8%, p < 0.001), and at median follow-up of 3.7 yrs (58.7% versus 22.6% (p < 0.001) compared to the non-PCI group. CONCLUSION: PCI in SCAD patients was associated with high failure rate and MACE in hospital and at long-term follow-up. These findings support the recommendation of conservative therapy as first-line management unless high-risk features are present.

Low recurrence rate after endoscopic resection in non-ampullary duodenal lesions: A 16-year single-center retrospective study.

ABSTRACT: Endoscopic resection (ER) for non-ampullary duodenal lesions (NADLs) is technically more difficult than lesions of the stomach. However, endoscopic treatment of duodenal lesions has been increasingly performed in recent years. This study aimed to evaluate the efficacy and safety of ER for NADLs.Patients who underwent ER for NADLs between 2004 and 2019 were retrospectively reviewed. Clinical and pathologic features of the lesions including the clinical outcomes and adverse events were analyzed.The study included 80 patients with NADLs. The mean age of patients was 59.3 years (22-80 years), the mean size of the lesion was 8.8 ±â€Š7.0 mm, and the mean procedure time was 13.2 ±â€Š11.2 min. Half (40/80) of the lesions were in the duodenal bulb including the superior duodenal angle. Final histological data showed 56 adenomas (70.5%), 13 Brunner gland tumors (16.2%), and 4 pyloric gland tumors (5.0%). The final diagnoses of 5 lesions after ER showed higher-grade dysplasia compared to pre-ER biopsy findings. The en bloc resection rate was 93.8% (75/80), and the complete resection rate with clear margins was 90.0% (72/80). Micro-perforation occurred in 2 of 80 patients and was successfully treated with conservative treatment. There were no cases of delayed bleeding. The mean follow-up period was 27.0 months (2-119 months) with no cases of recurrence.ER may be an effective treatment for NADLs with favorable long-term outcomes. However, the possibility of perforation complications should always be considered during ER.

Early LSD treatment in Denmark from 1960 to 1974: An analysis of possible and long-lasting changes in the adult personality following psychedelic treatment. A historical retrospective cohort study.

ABSTRACT: In view of the renewed interest in psychedelics in psychiatry it is timely to analyze psychedelic treatment in historical cohorts. Recently the therapeutic efficacy of psychedelics has been linked to the so-called phenomenon of "connectedness." The aim of the present study was to explore whether long-lasting personality changes were observed in any of the 151 Danish psychiatric patients who were treated with Lysergic acid diethylamide (LSD) from 1960 to 1974.The exploration included a reanalysis of a subgroup as well from a 1964 Danish historical cohort. Medical records and other case materials of the above mentioned 151 patients are kept in the Danish State Archives. The present author was granted access to the LSD case materials in the Danish State Archives, and respected confidentiality per the Archives Law. According to the LSD Damages Law from 1986, they all received financial compensation for LSD-inflicted harm.Analysis did not reveal any personality changes such as "connectedness;" however, other lasting personality changes were observed in 2 to 4 patients and in quite a few patients unwanted effects persisted for weeks or months following acute treatment. In the present analysis of the 1964 cohort, the same percentage of patients improved with LSD treatment as in the historical analysis. In the latter, however, little attention was given to side effects, such as suicide attempts, suicides, and one homicide.Future psychedelic research with psychiatric patients should respect the potential toxicity of LSD and other psychedelics and meticulously monitor possible side effects.

The use of the fibula flap in post oncologic reconstruction of long bone in pediatric patients: A retrospective cohort study.

BACKGROUND: Pediatric sarcomas are the most common malignancies of bones in childhood. With advances in adjuvant treatment, limb salvage surgery has become common, increasing the demand of skeletal reconstruction. Traditional practice included bone grafting and transport. Recently, microsurgical tissue transfer in pediatric patients has become a well-accepted practice, with the fibula as an ideal biologic construct for long bone reconstruction. We aim to assess the success rate of this operation, including flap survival, bony union, weight-bearing ambulation, and complications. METHODS: We identified 10 pediatric patients who underwent reconstruction of long bones (femur, humerus, or tibia) with a free fibula flap from January 2015 to January 2020. All patients received neoadjuvant chemotherapy 4 weeks prior to the surgical procedure followed by adjuvant chemotherapy. RESULTS: The average follow-up time was 15 months. We had no partial or total flap loss. Three of our patients passed away in the first post-operative year due to metastatic disease. In the remaining 7 patients, we had two long-term complications. The fibula of one patient did not exhibit hypertrophy, yet weight-bearing ambulation was achieved. The other patient had nonunion proximally that required bone grafting at 8 months post-operatively. After that, the same patient fractured her fibula and required surgical fixation. She was eventually able to achieve weight-bearing ambulation. CONCLUSION: The vascularized fibula flap is a reliable tool for reconstruction in children. Flap survival is similar to that of adults. Complication rate is low compared to that for other forms of reconstruction.

Long-term safety and efficacy of sarilumab over 5 years in patients with rheumatoid arthritis refractory to TNF inhibitors.

OBJECTIVE: The objective of this study was to evaluate the long-term safety and efficacy of sarilumab over 5 years in patients with RA refractory to TNF inhibitors (TNFis). METHODS: Patients in the 24-week randomized controlled trial (RCT) TARGET (NCT01709578) who received double-blind placebo or sarilumab 150 or 200 mg every 2 weeks (q2w), plus conventional synthetic DMARDs (csDMARDs), were eligible to receive open-label sarilumab 200 mg q2w plus csDMARDs in the open-label extension (OLE), EXTEND (NCT01146652). OLE dose reduction to 150 mg q2w was permitted per investigators' judgement or protocol-mandated safety concerns. Safety and efficacy were assessed through treatment-emergent adverse events (AEs), laboratory abnormalities and clinical DASs. All statistics are descriptive. RESULTS: Of 546 patients, 454 (83%) were treated with sarilumab in the OLE. The cumulative observation period was 1654.8 patient-years (PY; n = 521); 268 patients (51%) had ≥4 years' exposure. Incidence rates per 100 PY of AEs, and AEs leading to discontinuation, infection and serious infection were 160.4, 8.1, 57.8 and 3.9, respectively. Neutropenia was the most common AE (15.3 per 100 PY). An absolute neutrophil count of <1000 cells/mm3 (Grade 3/4 neutropenia) was observed in 74 patients (14.2%) and normalized on treatment in 48. Clinical efficacy was sustained through 5 years' follow-up. Efficacy was similar for patients with 1 and >1 TNFi failure, and similar for patients who either remained on 200 mg or reduced to 150 mg. CONCLUSION: In patients with RA refractory to TNFi, sarilumab's long-term term safety profile was consistent with previous clinical studies and post-marketing reports. Efficacy was sustained over 5 years. TRIAL REGISTRATION: TARGET, ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01709578, NCT01709578; EXTEND, ClinicalTrials.gov, https://www.clinicaltrials.gov/ct2/show/NCT01146652, NCT01146652.

Long-term all-cause mortality among asymptomatic individuals with 80th percentile of coronary calcium score based on age and gender in the St. Francis Heart Study.

OBJECTIVES: High coronary artery calcium score (CAC) is a significant risk factor for cardiovascular morbidity and mortality. We investigated the long-term outcome of subjects with elevated CAC. METHODS: We studied 1005 participants of The St. Francis Heart Study who were asymptomatic and apparently healthy and had CAC scores at 80th percentile or higher for age and gender. They were randomized to receive atorvastatin 20 mg daily or placebo for up to 5 years. We used an as-treated study design accounting for cross-overs at the end of the original trial. All-cause mortality risk was assessed using adjusted hazard ratios. RESULTS: Mean age was 59 ± 6 years and 26% (N = 263) were female. After 17 ± 3 years follow-up 176 subjects died. High CAC at baseline was associated with increased mortality risk with adjusted hazard ratio for logarithmic transformed CAC at 1.33 and 95% confidence interval 1.06-1.68. The mortality risk associated with CAC was similar between the group with high-sensitivity CRP ≥2 and <2 mg/dL. Those with a family history of premature coronary artery disease exhibited a higher mortality risk in association with high CAC with an adjusted hazard ratio 1.51 (1.09, 2.09). CONCLUSION: Elevated CAC is an independent risk for long-term all-cause mortality. The screening of CAC score in addition to identifying conventional risk factors can differentiate asymptomatic individuals with and without increased long-term mortality risk.

Comparison of the efficacy and safety of cuffed versus uncuffed endotracheal tubes for infants in the intensive care setting: a pilot, unblinded RCT.

OBJECTIVE: To study effectiveness and safety of cuffed versus uncuffed endotracheal tubes (ETTs) in small infants in the intensive care unit (ICU). DESIGN: Pilot RCT. SETTING: Neonatal and paediatric ICUs of children's hospital in Western Australia. PARTICIPANTS: Seventy-six infants ≥35 weeks gestation and infants <3 months of age, ≥3 kg. INTERVENTIONS: Patients randomly assigned to Microcuff cuffed or Portex uncuffed ETT. MAIN OUTCOMES MEASURES: Primary outcome was achievement of optimal ETT leak in target range (10%-20%). Secondary outcomes included: reintubations, ventilatory parameters, ventilatory complications, postextubation complications and long-term follow-up. RESULTS: Success rate (achievement of mean leak in the range 10%-20%) was 13/42 (30.9%) in the cuffed ETT group and 6/34 (17.6%) in uncuffed ETT group (OR=2.09; 95% CI (0.71 to 6.08); p=0.28). Mean percentage time within target leak range in cuffed ETT group 28% (IQR: 9-42) versus 15% (IQR: 0-28) in uncuffed ETT group (p=0.01). There were less reintubations to optimise size in cuffed ETT group 0/40 versus 10/36 (p<0.001). No differences were found in gaseous exchange, ventilator parameters or postextubation complications. There were fewer episodes of atelectasis in cuffed ETT group 0/42 versus 4/34 (p=0.03). No patient had been diagnosed with subglottic stenosis at long-term follow-up. CONCLUSIONS: There was no difference in the primary outcome, though percentage time spent in optimal leak range was significantly higher in cuffed ETT group. Cuffed ETTs reduced reintubations to optimise ETT size and episodes of atelectasis. Cuffed ETTs may be a feasible alternative to uncuffed ETTs in this group of patients. TRIAL REGISTRATION NUMBER: ACTRN12615000081516.

Pulmonary Function and Radiologic Features in Survivors of Critical COVID-19: A 3-Month Prospective Cohort.

BACKGROUND: More than 20% of hospitalized patients with COVID-19 demonstrate ARDS requiring ICU admission. The long-term respiratory sequelae in such patients remain unclear. RESEARCH QUESTION: What are the major long-term pulmonary sequelae in critical patients who survive COVID-19? STUDY DESIGN AND METHODS: Consecutive patients with COVID-19 requiring ICU admission were recruited and evaluated 3 months after hospitalization discharge. The follow-up comprised symptom and quality of life, anxiety and depression questionnaires, pulmonary function tests, exercise test (6-min walking test [6MWT]), and chest CT imaging. RESULTS: One hundred twenty-five patients admitted to the ICU with ARDS secondary to COVID-19 were recruited between March and June 2020. At the 3-month follow-up, 62 patients were available for pulmonary evaluation. The most frequent symptoms were dyspnea (46.7%) and cough (34.4%). Eighty-two percent of patients showed a lung diffusing capacity of less than 80%. The median distance in the 6MWT was 400 m (interquartile range, 362-440 m). CT scans showed abnormal results in 70.2% of patients, demonstrating reticular lesions in 49.1% and fibrotic patterns in 21.1%. Patients with more severe alterations on chest CT scan showed worse pulmonary function and presented more degrees of desaturation in the 6MWT. Factors associated with the severity of lung damage on chest CT scan were age and length of invasive mechanical ventilation during the ICU stay. INTERPRETATION: Three months after hospital discharge, pulmonary structural abnormalities and functional impairment are highly prevalent in patients with ARDS secondary to COVID-19 who required an ICU stay. Pulmonary evaluation should be considered for all critical COVID-19 survivors 3 months after discharge.

Long-Term Outcomes of Patients Undergoing the Ross Procedure.

BACKGROUND: Treatment of aortic-valve disease in young patients still poses challenges. The Ross procedure offers several potential advantages that may translate to improved long-term outcomes. OBJECTIVES: This study reports long-term outcomes after the Ross procedure. METHODS: Adult patients who were included in the Ross Registry between 1988 and 2018 were analyzed. Endpoints were overall survival, reintervention, and major adverse events at maximum follow-up. Multivariable regression analyses were performed to identify risk factors for survival and the need of Ross-related reintervention. RESULTS: There were 2,444 adult patients with a mean age of 44.1 ± 11.7 years identified. Early mortality was 1.0%. Estimated survival after 25 years was 75.8% and did not statistically differ from the general population (p = 0.189). The risk for autograft reintervention was 0.69% per patient-year and 0.62% per patient-year for right-ventricular outflow tract (RVOT) reintervention. Larger aortic annulus diameter (hazard ratio [HR]: 1.12/mm; 95% confidence interval [CI]: 1.05 to 1.19/mm; p < 0.001) and pre-operative presence of pure aortic insufficiency (HR: 1.74; 95% CI: 1.13 to 2.68; p = 0.01) were independent predictors for autograft reintervention, whereas the use of a biological valve (HR: 8.09; 95% CI: 5.01 to 13.08; p < 0.001) and patient age (HR: 0.97 per year; 95% CI: 0.96 to 0.99; p = 0.001) were independent predictors for RVOT reintervention. Major bleeding, valve thrombosis, permanent stroke, and endocarditis occurred with an incidence of 0.15% per patient-year, 0.07% per patient-year, 0.13%, and 0.36% per patient-year, respectively. CONCLUSIONS: The Ross procedure provides excellent survival over a follow-up period of up to 25 years. The rates of reintervention, anticoagulation-related morbidity, and endocarditis were very low. This procedure should therefore be considered as a very suitable treatment option in young patients suffering from aortic-valve disease. (Long-Term Follow-up After the Autograft Aortic Valve Procedure [Ross Operation]; NCT00708409).

Association of Rituximab Use With Adverse Events in Children, Adolescents, and Young Adults.

Importance: Rituximab is among the most frequently used immunotherapies in pediatrics. Few studies have reported long-term adverse events associated with its use for children. Objective: To describe the use of rituximab and to assess whether its use is associated with short- or long-term adverse events, infections, or time to immune reconstitution in a diverse group of young people. Design, Setting, and Participants: This retrospective cohort study included 468 patients aged younger than 21 years who received rituximab for diverse indications between October 1, 2010, and December 31, 2017, at Texas Children's Hospital, a large pediatric referral hospital. Patterns of adverse events, infections, and immune recovery are described. Data analyses were conducted from December 2019 to June 2020. Exposure: One or more doses of rituximab. Main Outcomes and Measures: Adverse drug events (eg, anaphylaxis), incidence of mild and severe infections, and time to recovery of B lymphocyte subset counts and immunoglobulin levels. Survival models and logistic regression analyses and were used to identify associated risk factors of infectious and noninfectious adverse drug events. Results: We identified 468 patients receiving at least 1 dose of rituximab. The total follow-up time was 11 713 person-months. Of the 468 patients, 293 (62.6%) were female, the median (interquartile range) age at receipt of dose was 14.3 (9.9-16.8) years, and 209 (44.7%) were self-reported White Hispanic. Adverse events associated with rituximab infusion occurred in 72 patients (15.4%), and anaphylaxis occurred in 17 patients (3.6%). Long-term adverse events, such as prolonged neutropenia and leukoencephalopathy, were absent. Infections occurred in 224 patients (47.9%); 84 patients (17.9%) had severe infections, and 3 patients (0.6%) had lethal infections. Concurrent use of intravenous chemotherapy, treatment of systemic lupus erythematosus, neutropenia, and use of intravenous immunoglobulin were associated with increased risk of infection. Among 135 patients (28.8%) followed up to B cell count recovery, CD19+ or CD20+ cell numbers normalized in a median of 9.0 months (interquartile range, 5.9-14.4 months) following rituximab use; 48 of 95 patients (51%) evaluated beyond a year had low-for-age B cell counts. Recovery of CD27+ memory B cell number occurred in a median of 15.7 months (interquartile range, 6.0-22.7 months). Among patients with normal baseline values, low immunoglobulin G (IgG) levels developed in 67 of 289 patients (23.2%) and low IgM levels in 118 of 255 patients (40.8%); of these patients evaluated beyond 12 months from rituximab, 16 of 117 (13.7%) had persistently low IgG and 37 (33.9%) of 109 had persistently low IgM. Conclusions and Relevance: Rituximab is well tolerated among young people and is associated with few serious adverse events, but infections are common, corresponding to a prolonged period of B cell count recovery often lasting for longer than a year. Further examination of strategies to prevent infections following rituximab should be pursued.