Repurposing SGLT2 inhibitors: Treatment of renal proximal tubulopathy in Fanconi-Bickel syndrome with empagliflozin.

Renal proximal tubulopathy in Fanconi-Bickel syndrome is caused by impaired basolateral glucose transport via GLUT2 and consequently, intracellular accumulation of glucose and glycogen. SGLT2 inhibitors act on apical glucose reabsorption of renal proximal tubular cells. The purpose of this study was to retrospectively describe the first experiences with repurposing the SGLT2 inhibitor empagliflozin to treat the generalized tubulopathy in Fanconi-Bickel syndrome. A case series was conducted of seven persons from five families (five males, two females; three children, who were 14y5m, 2y9m, and 1y6m old) with genetically confirmed Fanconi-Bickel syndrome, off-label treated with empagliflozin. Median (range) age at start of empagliflozin was 27 years (1y6m - 61y) and duration of follow-up under empagliflozin treatment was 169 days (57-344). Under empagliflozin (up to 25 mg/d), biochemical parameters of tubular cell integrity (urinary N-acetyl-glucosaminidase) and/or tubular functions (including urinary α1-microglobulin) improved in all persons with Fanconi-Bickel syndrome, albeit to varying degrees. Clinically, supplementations (i.e., phosphate, alkali, carnitine, and alfacalcidol) could be completely discontinued in the three children, whereas results in the four adult patients were more variable and not as significant. Empagliflozin was well-tolerated and no symptomatic hypoglycemia was observed. In conclusion, SGLT2 inhibitors such as empagliflozin shift the metabolic block in Fanconi-Bickel syndrome, that is, they intervene specifically in the underlying pathophysiology and can thus attenuate renal proximal tubulopathy, especially when started in early childhood.

Methylation Analysis to Detect CIN3+ in High-Risk Human Papillomavirus-Positive Self-Samples From the Population-Based Cervical Cancer Screening Program.

Since 2017, a self-sampling device has been introduced to the Dutch population-based screening program to enable higher participation rates. However, routine triage cytology cannot be performed on self-sampling material. Methylation is an alternative triage method that can be performed directly on DNA extracted from self-samples. Recently, we tested a set of 15 published cervical intraepithelial neoplasia grade 3 or worse (CIN3+)-specific methylation markers and found a panel of 3 markers with a sensitivity of 82% and a specificity of 74%. In this study, we determined the sensitivity and specificity of 2 commercial assays using quantitative methylation-specific PCR. DNA from the same cohort of high-risk human papillomavirus-positive self-sampled material obtained through the population-based screening program in the North of the Netherlands from women with CIN2 or less (

Timing of acute carotid artery stenting for tandem lesions in patients with acute ischemic stroke: A Maastricht Stroke Quality Registry (MaSQ-Registry) study.

BACKGROUND: To better understand the influence of treatment strategies on outcomes for patients with tandem lesions undergoing acute internal carotid artery (ICA) stenting during endovascular treatment (EVT), this study compared clinical, technical, and safety outcomes in patients with acute ischemic stroke due to a large vessel occlusion (LVO) who underwent ICA stenting before versus after intracranial thrombectomy. METHODS: This single-center retrospective cohort study included patients who underwent EVT due to a LVO and periprocedural ICA stenting for significant ICA stenosis or occlusion between September 2020 and January 2023. Data were extracted from the Maastricht Stroke Quality Registry (MaSQ-Registry). Primary outcome was the modified Rankin Scale (mRS) at 3 months. Secondary outcomes included procedure times, number of total thrombectomy attempts, first-attempt excellent recanalization rates (extended Thrombolysis In Cerebral Infarction (eTICI) ≥ 2C after one thrombectomy attempt), and safety outcomes. RESULTS: This study included 50 patients. Thirty-one patients (62%) underwent ICA stenting before intracranial thrombectomy. No significant differences between both groups were found regarding mRS, total procedure time, number of total thrombectomy attempts, first-attempt excellent recanalization, or complications. Time between groin puncture and recanalization (reperfusion time) was significantly longer in patients who had ICA stenting before intracranial thrombectomy versus after intracranial thrombectomy (45 min versus 28 min, P = 0.004). CONCLUSION: ICA stenting after intracranial thrombectomy in patients with tandem lesions undergoing EVT did not lead to better patient outcomes compared to stenting before intracranial thrombectomy, despite shorter reperfusion times.

Access to cancer clinical trials for racialised older adults: an equity-focused rapid scoping review protocol.

BACKGROUND: The intersection of race and older age compounds existing health disparities experienced by historically marginalised communities. Therefore, racialised older adults with cancer are more disadvantaged in their access to cancer clinical trials compared with age-matched counterparts. To determine what has already been published in this area, the rapid scoping review question are: what are the barriers, facilitators and potential solutions for enhancing access to cancer clinical trials among racialised older adults? METHODS: We will use a rapid scoping review methodology in which we follow the six-step framework of Arksey and O'Malley, including a systematic search of the literature with abstract and full-text screening to be conducted by two independent reviewers, data abstraction by one reviewer and verification by a second reviewer using an Excel data abstraction sheet. Articles focusing on persons aged 18 and over who identify as a racialised person with cancer, that describe therapies/therapeutic interventions/prevention/outcomes related to barriers, facilitators and solutions to enhancing access to and equity in cancer clinical trials will be eligible for inclusion in this rapid scoping review. ETHICS AND DISSEMINATION: All data will be extracted from published literature. Hence, ethical approval and patient informed consent are not required. The findings of the scoping review will be submitted for publication in a peer-reviewed journal and presentation at international conferences.

Fibroblast growth factor 23 and calcium-phosphate metabolism in relation to cardiovascular risk factors in patients with type 1 diabetes.

BACKGROUND: Cardiovascular disease (CVD) is the major cause of mortality in type 1 diabetes (T1D). The objective of this study is to evaluate fibroblast growth factor 23 (FGF23) and calcium-phosphate metabolism in relation to cardiovascular risk factors in adults with and without T1D. METHODS: A case-control study was conducted using data from patients with T1D and age- and sex matched controls without T1D from the Lifelines Cohort Study. RESULTS: We included 302 adults in the T1D group and 302 adults in the control group. Median age was 42 years. Median glycosylated hemoglobin (HbA1c) in the T1D group was 7.8%. FGF23 of all patients with T1D was not significantly different from controls. Females with T1D had significantly higher FGF23 than males with T1D (83.3 vs 69.3 U/mL, p = 0.002), this was not observed in controls. Serum phosphate, calcium, and alkaline phosphatase were higher and parathyroid hormone was lower in patients with T1D, compared to controls (all p < .001), all within normal range. In the T1D group, FGF23 was positively correlated with serum phosphate (p < .001), alkaline phosphatase (p = .01), and calcium (p = .030), these correlations were not observed in controls. Median FGF23 was significantly higher in current smokers than in nonsmokers with T1D (84.9 vs 73.5 U/mL, p < .05). CONCLUSIONS: Serum calcium, phosphate, and alkaline phosphatase were higher in patients with T1D than in controls and were positively correlated to FGF23 in patients with T1D. Current smokers with T1D had higher FGF23 than nonsmokers with T1D. These findings may contribute to the increased risk of CVD in patients with T1D.

A multicenter retrospective study of calcineurin inhibitors in nephrotic syndrome secondary to podocyte gene variants.

While 44-83% of children with steroid-resistant nephrotic syndrome (SRNS) without a proven genetic cause respond to treatment with a calcineurin inhibitor (CNI), current guidelines recommend against the use of immunosuppression in monogenic SRNS. This is despite existing evidence suggesting that remission with CNI treatment is possible and can improve prognosis in some cases of monogenic SRNS. Herein, our retrospective study assessed response frequency, predictors of response and kidney function outcomes among children with monogenic SRNS treated with a CNI for at least three months. Data from 203 cases (age 0-18 years) were collected from 37 pediatric nephrology centers. Variant pathogenicity was reviewed by a geneticist, and 122 patients with a pathogenic and 19 with a possible pathogenic genotype were included in the analysis. After six months of treatment and at last visit, 27.6% and 22.5% of all patients respectively, demonstrated partial or full response. Achievement of at least partial response at six months of treatment conferred a significant reduction in kidney failure risk at last follow-up compared to no response (hazard ratio [95% confidence interval] 0.25, [0.10-0.62]). Moreover, risk of kidney failure was significantly lower when only those with a follow-up longer than two years were considered (hazard ratio 0.35, [0.14-0.91]). Higher serum albumin level at CNI initiation was the only factor related to increased likelihood of significant remission at six months (odds ratio [95% confidence interval] 1.16, [1.08-1.24]). Thus, our findings justify a treatment trial with a CNI also in children with monogenic SRNS.

Prevalence and risk factors of nonalcoholic fatty liver disease in a general population, the HUNT study.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and the metabolic syndrome is the main risk factor. Alanine aminotransferase (ALT) is widely used to screen for NAFLD, and the aims of this study were to assess the prevalence and risk factors of NAFLD in a general population. METHODS: The study was based on the third population-based Trøndelag Health Study (HUNT3), Norway, performed 2006-2008. In HUNT3, ALT and lipids were analyzed, anthropometric measures done, and comorbidity and risk factors reported. Elevated ALT was used to define NAFLD and participants with other diagnosed liver diseases and excessive alcohol consumption were excluded. Multivariable logistic regression reporting odds ratio (OR) and 95% confidence interval (CI) was used to assess risk factors. RESULTS: In HUNT3, 2373 (4.7%) of 50,006 participants were diagnosed with NAFLD. The risk increased with obesity (OR 1.73, 95% CI 1.46-2.05) and very increased waist circumference (OR 1.97, 95% CI 1.65-2.35), and the risk increased dose-dependently (p for trend <0.001). Hypertension (OR 1.58, 95% CI 1.42-1.76), diabetes mellitus (OR 1.48, 95% CI 1.30-1.68), high triglycerides (OR 1.55, 95% CI 1.41-1.71), high total cholesterol (OR 1.52, 95% CI 1.29-1.81) and low high-density lipoproteins (OR 1.33, 95% CI 1.21-1.47) also increased the risk of NAFLD. The risk was lower in men (OR 0.71, 95% CI 0.64-0.79) and among current smokers (OR 0.79, 95% CI 0.70-0.89). CONCLUSION: NAFLD is a common condition in the general population. NAFLD should be suspected in individuals with abdominal obesity, hypertension, diabetes mellitus and dyslipidemias.

The impact of facility-based transitional care programs on function and discharge destination for older adults with cognitive impairment: a systematic review.

BACKGROUND: Older adults with cognitive impairment are frequently hospitalized and discharged to facility-based transitional care programs (TCPs). However, it is unknown whether TCPs are effective in improving their functional status and promoting discharge home rather than to long-term care. The aims of this systematic review were to examine the effectiveness of facility-based TCPs on functional status, patient and health services outcomes for older adults (≥ 65 years) with cognitive impairment and to determine what proportion post TCP are discharged home compared to long-term care. METHODS: The Joanna Briggs Institute Critical Appraisal Manual for Evidence Synthesis was used to guide the methodology for this review. The protocol was published in PROSPERO (registration number CRD42021257870). MEDLINE, CINAHL, PsycINFO, the Cochrane Library, and EMBASE databases, and ClinicalTrials.gov and the World Health Organization Trials Registry were searched for English publications. Studies that met the following criteria were included: community-dwelling older adults ≥ 65 years who participated in facility-based TCPs and included functional status and/or discharge destination outcomes. Studies with participants from nursing homes and involved rehabilitation programs or transitional care in the home or in acute care, were excluded. Risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklists. Results are in narrative form. RESULTS: Twenty-two studies (18 cohort and four cross sectional studies) involving 4,013,935 participants met inclusion criteria. The quality of the studies was mostly moderate to good. Improvement in activities of daily living (ADLs) was reported in eight of 13 studies. Between 24.4%-68% of participants were discharged home, 20-43.9% were hospitalized, and 4.1-40% transitioned to long-term care. Review limitations included the inability to perform meta-analysis due to heterogeneity of outcome measurement tools, measurement times, and patient populations. CONCLUSIONS: Facility-based TCPs are associated with improvements in ADLs and generally result in a greater percentage of participants with cognitive impairment going home rather than to long-term care. However, gains in function were not as great as for those without cognitive impairment. Future research should employ consistent outcome measurement tools to facilitate meta-analyses. The level of evidence is level III-2 according to the National Health and Medical Research Council for cohort and cross-sectional studies.

Carotid Plaque Characteristics Predict Recurrent Ischemic Stroke and TIA: The PARISK (Plaque At RISK) Study.

BACKGROUND: Patients with symptomatic carotid stenosis are at high risk for recurrent stroke. The decision for carotid endarterectomy currently mainly relies on degree of stenosis (cutoff value >50% or 70%). Nevertheless, also, patients with mild-to-moderate stenosis still have a considerable recurrent stroke risk. Increasing evidence suggests that carotid plaque composition rather than degree of stenosis determines plaque vulnerability; however, it remains unclear whether this also provides additional information to improve clinical decision making. OBJECTIVES: The PARISK (Plaque At RISK) study aimed to improve the identification of patients at increased risk of recurrent ischemic stroke using multimodality carotid imaging. METHODS: The authors included 244 patients (71% men; mean age, 68 years) with a recent symptomatic mild-to-moderate carotid stenosis in a prospective multicenter cohort study. Magnetic resonance imaging (carotid and brain) and computed tomography angiography (carotid) were performed at baseline and after 2 years. The clinical endpoint was a recurrent ipsilateral ischemic stroke or transient ischemic attack (TIA). Cox proportional hazards models were used to assess whether intraplaque hemorrhage (IPH), ulceration, proportion of calcifications, and total plaque volume in ipsilateral carotid plaques were associated with the endpoint. Next, the authors investigated the predictive performance of these imaging biomarkers by adding these markers (separately and simultaneously) to the ECST (European Carotid Surgery Trial) risk score. RESULTS: During 5.1 years follow-up, 37 patients reached the clinical endpoint. IPH presence and total plaque volume were associated with recurrent ipsilateral ischemic stroke or TIA (HR: 2.12 [95% CI: 1.02-4.44] for IPH; HR: 1.07 [95% CI: 1.00-1.15] for total plaque volume per 100 µL increase). Ulcerations and proportion of calcifications were not statistically significant determinants. Addition of IPH and total plaque volume to the ECST risk score improved the model performance (C-statistics increased from 0.67 to 0.75-0.78). CONCLUSIONS: IPH and total plaque volume are independent risk factors for recurrent ipsilateral ischemic stroke or TIA in patients with mild-to-moderate carotid stenosis. These plaque characteristics improve current decision making. Validation studies to implement plaque characteristics in clinical scoring tools are needed. (PARISK: Validation of Imaging Techniques [PARISK]; NCT01208025).

Frailty assessment tools for use by surgeons when evaluating older adults prior to surgery: a scoping review protocol.

INTRODUCTION: Despite growing evidence, uncertainty persists about which frailty assessment tools are best suited for routine perioperative care. We aim to understand which frailty assessment tools perform well and are feasible to implement. METHODS AND ANALYSIS: Using a registered protocol following Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA), we will conduct a scoping review informed by the Joanna Briggs Institute Guide for Scoping Reviews and reported using PRISMA extension for Scoping Reviews recommendations. We will develop a comprehensive search strategy with information specialists using the Peer Review of Electronic Search Strategies checklist, and implement this across relevant databases from 2005 to 13 October 2021 and updated prior to final review publication. We will include all studies evaluating a frailty assessment tool preoperatively in patients 65 years or older undergoing intracavitary, non-cardiac surgery. We will exclude tools not assessed in clinical practice, or using laboratory or radiologic values alone. After pilot testing, two reviewers will independently assess information sources for eligibility first by titles and abstracts, then by full-text review. Two reviewers will independently chart data from included full texts using a piloted standardised electronic data charting. In this scoping review process, we will (1) index frailty assessment tools evaluated in the preoperative clinical setting; (2) describe the level of investigation supporting each tool; (3) describe useability of each tool and (4) describe direct comparisons between tools. The results will inform ready application of frailty assessment tools in routine clinical practice by surgeons and other perioperative clinicians. ETHICS AND DISSEMINATION: Ethic approval is not required for this secondary data analysis. This scoping review will be published in a peer-review journal. Results will be used to inform an ongoing implementation study focused on geriatric surgery to overcome the current lack of uptake of older adult-oriented care recommendations and ensure broad impact of research findings.

Infraspinatus Muscle Fiber Moment Arms During Abduction: A Biomechanical Comparison of Values for Intact Rotator Cuff, Supraspinatus Tear, Superior Capsular Reconstruction, and Reverse Total Shoulder Arthroplasty.

Background: Lines of action of the superior, middle, and inferior infraspinatus muscle fibers work together to produce moment arms that change throughout abduction in an intact shoulder, after a supraspinatus tear, and after superior capsular reconstruction (SCR) and reverse total shoulder arthroplasty (rTSA). Purpose: To use moment arm values to indicate the efficacy of SCR and rTSA to restore infraspinatus function during shoulder abduction. Study Design: Descriptive laboratory study. Methods: A total of 5 human cadaveric shoulders placed in a testing apparatus were each actively abducted (0°-90°) under the following 4 conditions: intact, complete supraspinatus tear, SCR, and rTSA. The 3-dimensional coordinates of points were tracked along the origin and insertion of the superior, middle, and inferior infraspinatus fibers during abduction. Moment arm values were calculated using the origin-insertion method to determine abduction contribution of infraspinatus fiber sections. Analysis of variance and post hoc Tukey testing were used to compare differences in moment arms between the 4 conditions and between fiber sections. Results: In the intact condition, the superior infraspinatus fibers had an abduction moment that decreased with elevation until shifting to adduction. Conversely, the middle and inferior fibers had an adduction moment that turned to abduction (mean moment arm values from 0° to 90°: inferior, from -5.9 to 19.4 mm; middle, from -4.7 to 15.9 mm; superior, from 5.6 to -5.1 mm; P < .05). After a supraspinatus tear, superior fibers lacked any torque, and inferior and middle fibers lost adduction potential (inferior, from 4.8 to 14.0 mm; middle, from -0.2 to 9.6 mm; superior, from 1.0 to 0.7 mm; P < .05). SCR restored the initial superior fiber abduction moment (5.6 mm at 0°; P < .05); middle and inferior fibers had some restoration but were weaker than intact fibers. Loss of abduction moment in all fibers was seen with rTSA (inferior, from -9.6 to -1.6 mm; middle, from -10.5 to -3.6 mm; superior, from -1.7 to -4.6 mm; P < .05). Conclusion: Infraspinatus fiber groups had different and inverse moment arms during scapular plane elevation. SCR most closely resembled the intact shoulder, whereas rTSA transformed the infraspinatus into an adductor. Clinical Relevance: These results support the efficacy of SCR at restoring biomechanical muscle function and suggest that the changes in moment arms for each fiber group be considered when choosing treatment modalities and rehabilitation protocols after rotator cuff tear.

Functional Improvement Trajectories After Surgery (FIT After Surgery) study: protocol for a multicentre prospective cohort study to evaluate significant new disability after major surgery in older adults.

INTRODUCTION: Older adults prioritise surviving surgery, but also preservation of their functional status and quality of life. Current approaches to measure postoperative recovery, which focus on death, complications and length of hospitalisation, may miss key relevant domains. We propose that postoperative disability is an important patient-centred outcome to measure intermediate-to-long recovery after major surgery in older adults. METHODS AND ANALYSIS: The Functional Improvement Trajectories After Surgery (FIT After Surgery) study is a multicentre cohort study of 2000 older adults (≥65 years) having major non-cardiac surgery. Its objectives are to characterise the incidence, trajectories, risk factors and impact of new significant disability after non-cardiac surgery. Disability is assessed using WHO Disability Assessment Schedule (WHODAS) 2.0 instrument and participants' level-of-care needs. Disability assessments occur before surgery, and at 1, 3, 6, 9 and 12 months after surgery. The primary outcome is significantly worse WHODAS score or death at 6 months after surgery. Secondary outcomes are (1) significantly worse WHODAS score or death at 1 year after surgery, (2) increased care needs or death at 6 months after surgery and (3) increased care needs or death at 1 year after surgery. We will use multivariable logistic regression models to determine the association of preoperative characteristics and surgery type with outcomes, joint modelling to characterise longitudinal time trends in WHODAS scores over 12 months after surgery, and longitudinal latent class mixture models to identify clusters following similar trajectories of disability. ETHICS AND DISSEMINATION: The FIT After Surgery study has received research ethics board approval at all sites. Recruitment began in December 2019 but was placed on hold in March 2020 because of the COVID-19 pandemic. Recruitment was gradually restarted in October 2020, with 1-year follow-up expected to finish in 2023. Publication of the primary results is anticipated to occur in 2024.

Safety and efficacy of aspirin, unfractionated heparin, both, or neither during endovascular stroke treatment (MR CLEAN-MED): an open-label, multicentre, randomised controlled trial.

BACKGROUND: Aspirin and unfractionated heparin are often used during endovascular stroke treatment to improve reperfusion and outcomes. However, the effects and risks of anti-thrombotics for this indication are unknown. We therefore aimed to assess the safety and efficacy of intravenous aspirin, unfractionated heparin, both, or neither started during endovascular treatment in patients with ischaemic stroke. METHODS: We did an open-label, multicentre, randomised controlled trial with a 2 × 3 factorial design in 15 centres in the Netherlands. We enrolled adult patients (ie, ≥18 years) with ischaemic stroke due to an intracranial large-vessel occlusion in the anterior circulation in whom endovascular treatment could be initiated within 6 h of symptom onset. Eligible patients had a score of 2 or more on the National Institutes of Health Stroke Scale, and a CT or MRI ruling out intracranial haemorrhage. Randomisation was done using a web-based procedure with permuted blocks and stratified by centre. Patients were randomly assigned (1:1) to receive either periprocedural intravenous aspirin (300 mg bolus) or no aspirin, and randomly assigned (1:1:1) to receive moderate-dose unfractionated heparin (5000 IU bolus followed by 1250 IU/h for 6 h), low-dose unfractionated heparin (5000 IU bolus followed by 500 IU/h for 6 h), or no unfractionated heparin. The primary outcome was the score on the modified Rankin Scale at 90 days. Symptomatic intracranial haemorrhage was the main safety outcome. Analyses were based on intention to treat, and treatment effects were expressed as odds ratios (ORs) or common ORs, with adjustment for baseline prognostic factors. This trial is registered with the International Standard Randomised Controlled Trial Number, ISRCTN76741621. FINDINGS: Between Jan 22, 2018, and Jan 27, 2021, we randomly assigned 663 patients; of whom, 628 (95%) provided deferred consent or died before consent could be asked and were included in the modified intention-to-treat population. On Feb 4, 2021, after unblinding and analysis of the data, the trial steering committee permanently stopped patient recruitment and the trial was stopped for safety concerns. The risk of symptomatic intracranial haemorrhage was higher in patients allocated to receive aspirin than in those not receiving aspirin (43 [14%] of 310 vs 23 [7%] of 318; adjusted OR 1·95 [95% CI 1·13-3·35]) as well as in patients allocated to receive unfractionated heparin than in those not receiving unfractionated heparin (44 [13%] of 332 vs 22 [7%] of 296; 1·98 [1·14-3·46]). Both aspirin (adjusted common OR 0·91 [95% CI 0·69-1·21]) and unfractionated heparin (0·81 [0·61-1·08]) led to a non-significant shift towards worse modified Rankin Scale scores. INTERPRETATION: Periprocedural intravenous aspirin and unfractionated heparin during endovascular stroke treatment are both associated with an increased risk of symptomatic intracranial haemorrhage without evidence for a beneficial effect on functional outcome. FUNDING: The Collaboration for New Treatments of Acute Stroke consortium, the Brain Foundation Netherlands, the Ministry of Economic Affairs, Stryker, Medtronic, Cerenovus, and the Dutch Heart Foundation.

Majority of patients find sleep patterns return to normal 6 months following rotator cuff repair.

BACKGROUND AND HYPOTHESIS: Rotator cuff tears have a wide variability in presentation, with some causing pain and reduced function but others remaining completely asymptomatic. Sleep disturbances are a primary driver for patients with rotator cuff tears to see a physician, and one of the main goals of rotator cuff repair (RCR) surgery is to restore normal sleep patterns in these patients. The primary purpose of this study aimed to determine the percentage of patients undergoing RCR who report preoperative sleep disturbances. Second, this study sought to identify at what postoperative follow-up intervals patients stopped reporting sleep disturbances and how the percentages change over time. It was hypothesized that the majority of patients undergoing arthroscopic RCR would report preoperative and initial postoperative sleep disturbances and that 75% of patients would report resolution of sleep disturbances by 1 year postoperatively. METHODS: A total of 326 patients undergoing primary arthroscopic RCR were prospectively enrolled in this study. Validated patient-reported outcome measures were obtained preoperatively and postoperatively, including the visual analog pain scale score, American Shoulder and Elbow Surgeons score, Single Assessment Numeric Evaluation score, Simple Shoulder Test (SST) score, and Veterans RAND 12-Item Health Survey physical and mental component scores. RESULTS: According to question 2 of the SST, 291 patients (89%) reported preoperative sleep disturbances. Within the cohort of patients who reported resolution of sleep disturbances, 46% reported resolution by 3 months postoperatively; an additional 31%, by 6 months; a further 14%, by 12 months; and the final 8%, by 24 months. Age ≥ 65 years was significantly associated with increased reporting of resolution compared with age < 65 years. All patient-reported outcome measures, including the visual analog pain scale score, American Shoulder and Elbow Surgeons score, Single Assessment Numeric Evaluation score, SST score, and Veterans RAND 12-Item Health Survey (physical component) score, showed statistically significant improvements after surgery. CONCLUSIONS: Eighty-nine percent of patients reported preoperative sleep disturbances. Seventy-seven percent of patients reported resolution of sleep disturbances by 6 months postoperatively, and 81% of patients reported resolution of sleep disturbances by 2 years postoperatively.

Strategies in Rapid Genetic Diagnostics of Critically Ill Children: Experiences From a Dutch University Hospital.

Background: Genetic disorders are a substantial cause of infant morbidity and mortality and are frequently suspected in neonatal intensive care units. Non-specific clinical presentation or limitations to physical examination can result in a plethora of genetic testing techniques, without clear strategies on test ordering. Here, we review our 2-years experiences of rapid genetic testing of NICU patients in order to provide such recommendations. Methods: We retrospectively included all patients admitted to the NICU who received clinical genetic consultation and genetic testing in our University hospital. We documented reasons for referral for genetic consultation, presenting phenotypes, differential diagnoses, genetic testing requested and their outcomes, as well as the consequences of each (rapid) genetic diagnostic approach. We calculated diagnostic yield and turnaround times (TATs). Results: Of 171 included infants that received genetic consultation 140 underwent genetic testing. As a result of testing as first tier, 13/14 patients received a genetic diagnosis from QF-PCR; 14/115 from SNP-array; 12/89 from NGS testing, of whom 4/46 were diagnosed with a small gene panel and 8/43 with a large OMIM-morbid based gene panel. Subsequent secondary or tertiary analysis and/or additional testing resulted in five more diagnoses. TATs ranged from 1 day (QF-PCR) to a median of 14 for NGS and SNP-array testing, with increasing TAT in particular when many consecutive tests were performed. Incidental findings were detected in 5/140 tested patients (3.6%). Conclusion: We recommend implementing a broad NGS gene panel in combination with CNV calling as the first tier of genetic testing for NICU patients given the often unspecific phenotypes of ill infants and the high yield of this large panel.

Evaluation of rotator cuff abduction moment arms for superior capsular reconstruction and reverse total shoulder arthroplasty.

PURPOSE: The rotator cuff (RC) muscles contribute to dynamic stability and rotational actions of the glenohumeral joint. Moment arm can be used to demonstrate the potential work a muscle contributes to a musculoskeletal joint rotation. This study aimed to understand the moment arm contributions of the RC muscles and explore changes following a complete supraspinatus tear treated with either superior capsular reconstruction (SCR) or reverse total shoulder arthroplasty (rTSA). METHODS: Five fresh-frozen cadaveric specimens were prepared and mounted in an apparatus where each intact RC muscle was held in tension with a line of action toward its origin on the scapula. Mean moment arms for each muscle were determined experimentally based on Optotrak data collected during cadaveric shoulder arm abduction. RESULTS: Using ANOVA testing, our analysis demonstrated significant differences (p < 0.001) in infraspinatus and teres minor moment arms after rTSA compared to the intact shoulder model. After SCR, significant differences (p < 0.001) were seen in teres minor, with these differences being statistically similar to the changes seen in teres minor after rTSA. Subscapularis showed no significant difference in moment arm values between the models (p = 0.148). CONCLUSION: Our results illustrate that mean moment arms were preserved in the RC muscles after complete supraspinatus tear. This study also shows evidence that subscapularis function may be maintained after SCR or rTSA. After SCR, infraspinatus may maintain similar abduction ability compared to the anatomical shoulder, while teres minor ability may increase. Infraspinatus may have decreased abduction ability after rTSA while teres minor may have increased ability.

Abnormal Coagulation as a Risk Factor for Postoperative Complications After Primary and Revision Total Hip and Total Knee Arthroplasty.

BACKGROUND: Patients undergoing total joint arthroplasty (TJA) have an increased likelihood of having an abnormal coagulation profile compared with the general population. Coagulation abnormalities are often screened for before surgery and considered during perioperative planning. This study assesses a preoperative abnormal coagulation profile as a risk factor for postoperative complications after total hip arthroplasty (THA), revision THA (rTHA), total knee arthroplasty (TKA), and revision TKA (rTKA) and then examines specific coagulopathies to determine their influence on complication rates. METHODS: Patients who underwent THA, rTHA, TKA, or rTKA from 2011 to 2017 were identified in the American College of Surgeons National Surgical Quality Improvement Program database and then assessed for preoperative abnormal coagulation profiles. Various postoperative complications were analyzed for each cohort, and two separate multivariate regression analyses were used to assess the relationship between abnormal coagulation and postoperative complications. RESULTS: 403,566 THA, rTHA, TKA, or rTKA cases were identified, and 40,466 (10.0%) of patients were found to have an abnormal coagulation profile. Patients with preoperative coagulation abnormalities had higher likelihoods of postoperative complications after primary TJA than in revision TJA. An international normalized ratio>1.2 was associated with the most types of postoperative complications, followed by a bleeding disorder diagnosis. A partial thromboplastin time>35 seconds was associated with only one type of postoperative complication, while a platelet count <150,000 per µL was associated with postoperative complications only after TKA. CONCLUSION: TJA in patients with abnormal coagulation profiles may result in adverse outcomes. These patients may benefit from preoperative intervention. Prophylactic care needs to be personalized to the specific coagulation abnormalities present.

Flucloxacillin decreases tacrolimus blood trough levels: a single-center retrospective cohort study.

PURPOSE: Tacrolimus and everolimus are widely used to prevent allograft rejection. Both are metabolized by the hepatic cytochrome P450 (CYP) enzyme CYP3A4 and are substrate for P-glycoprotein (P-gp). Drugs influencing the activity or expression of CYP enzymes and P-gp can cause clinically relevant changes in the metabolism of immunosuppressants. Several case reports have reported that flucloxacillin appeared to decrease levels of drugs metabolized by CYP3A4 and P-gp. The magnitude of this decrease has not been reported yet. METHODS: In this single-center retrospective cohort study, we compared the tacrolimus and everolimus blood trough levels (corrected for the dose) before, during, and after flucloxacillin treatment in eleven transplant patients (tacrolimus n = 11 patients, everolimus n = 1 patient, flucloxacillin n = 11 patients). RESULTS: The median tacrolimus blood trough level decreased by 37.5% (interquartile range, IQR 26.4-49.7%) during flucloxacillin treatment. After discontinuation of flucloxacillin, the tacrolimus blood trough levels increased by a median of 33.7% (IQR 22.5-51.4%). A Wilcoxon signed-rank test showed statistically significantly lower tacrolimus trough levels during treatment with flucloxacillin compared with before (p = 0.009) and after flucloxacillin treatment (p = 0.010). In the only available case with concomitant everolimus and flucloxacillin treatment, the same pattern was observed. CONCLUSIONS: Flucloxacillin decreases tacrolimus trough levels, possibly through a CYP3A4 and/or P-gp-inducing effect. It is strongly recommended to closely monitor tacrolimus and everolimus trough levels during flucloxacillin treatment and up to 2 weeks after discontinuation of flucloxacillin.