New Bivariate MS Copula via Ru ̈schendorf method

Copula study is growing field which used for constructing families of bivariate and multivariate distributions also a measure of dependence structure. There are several methods for constructing copulas, one of these methods is a Ru ̈schendorf method. A new bivariate copula called MS copula is introduced based on Ru ̈schendorf method. Several properties concerning dependence concepts and concordance ordering are studied and also fitting a copula using maximum likelihood. Finally, an application is presented to show applicability of the proposed MS copula

Cholestasis in patients with Cockayne syndrome and suggested modified criteria for clinical diagnosis

<p>Abstract</p> <p>Background</p> <p>Cockayne syndrome is a rare autosomal recessive neurodegenerative disease characterized by low-to-normal birth weight; growth failure; brain dysmyelination with calcium deposits, cutaneous photosensitivity; pigmentary retinopathy, cataract, and sensorineural hearing loss. To the best of our knowledge, cholestatic liver disease was not previously reported in these patients.</p> <p>Aim</p> <p>To highlight the presence of cholestasis and liver dysfunction in this group of patients and to suggest modified criteria for clinical diagnosis.</p> <p>Methods</p> <p>The study included nine patients with Cockayne from four different families (five males and four females) in which Cockayne was suspected clinically. In all patients chromosomal breakage studies revealed mild (45%) to moderate (60%) increase in frequency of chromatid and chromosome gaps and breaks versus 25% in normal controls. Diagnosis was confirmed by DNA repair assay.</p> <p>Results</p> <p>During routine follow up of these patients, seven of them had evident liver affection ranging from mild elevation in liver enzymes to cholestatic liver disease and liver cell failure. The attacks were recurrent in two patients and were sometimes preceded by infection. The attack may lead to deterioration of neurological and/or liver condition. It may end in liver cell failure that either recovers completely or may lead to death.</p> <p>Conclusions</p> <p>liver disease could be considered common in Egyptian patients with Cockayne with the cholestatic form being the most evident. The syndrome should be included in the list of causes of cholestatic liver disease. Chromosomal breakage study and positive family history should be included as major criteria for clinical diagnosis of Cockayne especially in a population like ours where consanguineous marriage is very high and molecular testing and UV sensitivity tests are considered unaffordable.</p

Factor V G1691A (Leiden) is a major etiological factor in Egyptian Budd-Chiari syndrome patients

Objective: Budd-Chiari syndrome is a multifactorial disease in which several prothrombotic disorders may predispose patients to the development of thrombosis at this uncommon location (hepatic veins). The aim of this study was to determine the prevalence and characteristics of inherited thrombophilia in Egyptian Budd-Chiari syndrome patients.Materials and Methods: The study included 47 Budd-Chiari syndrome patients (20 children and 27 adults). Genotyping of Factor V G1691A (Leiden), prothrombin G20210A (PT), and methylenetetrahydrofolate reductase C677T were performed using real-time PCR and fluorescence melting curve detection analysis.Results: Factor V Leiden was observed in 29 patients (61.7%). It is the only factor that caused Budd-Chiari syndrome in 18 of the patients and in 5 of the patients with inferior vena cava involvement. Myeloproliferative disease was noted in 12 (25.5%) patients, antiphospholipid syndrome in 5 (10.6%), and Behcet’s disease in 3 (6.4%). Interestingly, 3 of the children with Budd-Chiari syndrome had lipid storage disease.Conclusion: Factor V Leiden was a major etiological factor in Egyptian Budd-Chiari syndrome patients, which may have been related to the high frequency of this mutation in the study region. Factor V Leiden was also a strong thrombophilic factor and the leading cause of inferior vena cava thrombosis in these patients. Lipid storage disease should be included as a risk factor for Budd-Chiari syndrome

A Machine Learning Application to Classify Patients at Differing Levels of Risk of Opioid Use Disorder: Clinician-Based Validation Study.

Despite restrictive opioid management guidelines, opioid use disorder (OUD) remains a major public health concern. Machine learning (ML) offers a promising avenue for identifying and alerting clinicians about OUD, thus supporting better clinical decision-making regarding treatment. This study aimed to assess the clinical validity of an ML application designed to identify and alert clinicians of different levels of OUD risk by comparing it to a structured review of medical records by clinicians. The ML application generated OUD risk alerts on outpatient data for 649,504 patients from 2 medical centers between 2010 and 2013. A random sample of 60 patients was selected from 3 OUD risk level categories (n=180). An OUD risk classification scheme and standardized data extraction tool were developed to evaluate the validity of the alerts. Clinicians independently conducted a systematic and structured review of medical records and reached a consensus on a patient's OUD risk level, which was then compared to the ML application's risk assignments. A total of 78,587 patients without cancer with at least 1 opioid prescription were identified as follows: not high risk (n=50,405, 64.1%), high risk (n=16,636, 21.2%), and suspected OUD or OUD (n=11,546, 14.7%). The sample of 180 patients was representative of the total population in terms of age, sex, and race. The interrater reliability between the ML application and clinicians had a weighted kappa coefficient of 0.62 (95% CI 0.53-0.71), indicating good agreement. Combining the high risk and suspected OUD or OUD categories and using the review of medical records as a gold standard, the ML application had a corrected sensitivity of 56.6% (95% CI 48.7%-64.5%) and a corrected specificity of 94.2% (95% CI 90.3%-98.1%). The positive and negative predictive values were 93.3% (95% CI 88.2%-96.3%) and 60.0% (95% CI 50.4%-68.9%), respectively. Key themes for disagreements between the ML application and clinician reviews were identified. A systematic comparison was conducted between an ML application and clinicians for identifying OUD risk. The ML application generated clinically valid and useful alerts about patients' different OUD risk levels. ML applications hold promise for identifying patients at differing levels of OUD risk and will likely complement traditional rule-based approaches to generating alerts about opioid safety issues

Non-manifesting AHI1 truncations indicate localized loss-of-function tolerance in a severe Mendelian disease gene

Determination of variant pathogenicity represents a major challenge in the era of high-throughput sequencing. Erroneous categorization may result if variants affect genes that are in fact dispensable. We demonstrate that this also applies to rare, apparently unambiguous truncating mutations of an established disease gene. By whole-exome sequencing (WES) in a consanguineous family with congenital non-syndromic deafness, we unexpectedly identified a homozygous nonsense variant, p.Arg1066*, in AHI1, a gene associated with Joubert syndrome (JBTS), a severe recessive ciliopathy. None of four homozygotes expressed any signs of JBTS, and one of them had normal hearing, which also ruled out p.Arg1066* as the cause of deafness. Homozygosity mapping and WES in the only other reported JBTS family with a homozygous C-terminal truncation (p.Trp1088Leufs*16) confirmed AHI1 as disease gene, but based on a more N-terminal missense mutation impairing WD40-repeat formation. Morpholinos against N-terminal zebrafish Ahi1, orthologous to where human mutations cluster, produced a ciliopathy, but targeting near human p.Arg1066 and p.Trp1088 did not. Most AHI1 mutations in JBTS patients result in truncated protein lacking WD40-repeats and the SH3 domain; disease was hitherto attributed to loss of these protein interaction modules. Our findings indicate that normal development does not require the C-terminal SH3 domain. This has far-reaching implications, considering that variants like p.Glu984* identified by preconception screening (‘Kingsmore panel') do not necessarily indicate JBTS carriership. Genomes of individuals with consanguineous background are enriched for homozygous variants that may unmask dispensable regions of disease genes and unrecognized false positives in diagnostic large-scale sequencing and preconception carrier screenin

Day-case open reduction for developmental dysplasia of the hip.

AIMS: Open reduction in developmental dysplasia of the hip (DDH) is regularly performed despite screening programmes, due to failure of treatment or late presentation. A protocol for open reduction of DDH has been refined through collaboration between surgical, anaesthetic, and nursing teams to allow same day discharge. The objective of this study was to determine the safety and feasibility of performing open reduction of DDH as a day case. METHODS: A prospectively collected departmental database was visited. All consecutive surgical cases of DDH between June 2015 and March 2020 were collected. Closed reductions, bilateral cases, cases requiring corrective osteotomy, and children with comorbidities were excluded. Data collected included demographics, safety outcome measures (blood loss, complications, readmission, reduction confirmation), and feasibility for discharge according to the Face Legs Activity Cry Consolidability (FLACC) pain scale. A satisfaction questionnaire was filled by the carers. Descriptive statistics were used for analysis. RESULTS: Out of 168 consecutive DDH cases, 16 patients fit the inclusion criteria (age range 10 to 26 months, 13 female). Intraoperative blood loss ranged from "minimal" to 120 ml, and there were no complications or readmissions. The FLACC score was 0 for all patients. The carers satisfaction questionnaire expressed high satisfaction from the experience with adequate information and support provided. CONCLUSION: Open reduction in DDH, without corrective osteotomy, is safe and feasible to be managed as a day case procedure. It requires a clear treatment pathway, analgesia, sufficient counselling, and communication with carers. It is even more important during the COVID-19 pandemic when reduced length of hospital stay is likely to be safer for both patient and their parents. Cite this article: Bone Joint Open 2021;2(4):271-277

Laparoscopy in management of appendicitis in high-, middle-, and low-income countries: a multicenter, prospective, cohort study.

BACKGROUND: Appendicitis is the most common abdominal surgical emergency worldwide. Differences between high- and low-income settings in the availability of laparoscopic appendectomy, alternative management choices, and outcomes are poorly described. The aim was to identify variation in surgical management and outcomes of appendicitis within low-, middle-, and high-Human Development Index (HDI) countries worldwide. METHODS: This is a multicenter, international prospective cohort study. Consecutive sampling of patients undergoing emergency appendectomy over 6 months was conducted. Follow-up lasted 30 days. RESULTS: 4546 patients from 52 countries underwent appendectomy (2499 high-, 1540 middle-, and 507 low-HDI groups). Surgical site infection (SSI) rates were higher in low-HDI (OR 2.57, 95% CI 1.33-4.99, p = 0.005) but not middle-HDI countries (OR 1.38, 95% CI 0.76-2.52, p = 0.291), compared with high-HDI countries after adjustment. A laparoscopic approach was common in high-HDI countries (1693/2499, 67.7%), but infrequent in low-HDI (41/507, 8.1%) and middle-HDI (132/1540, 8.6%) groups. After accounting for case-mix, laparoscopy was still associated with fewer overall complications (OR 0.55, 95% CI 0.42-0.71, p < 0.001) and SSIs (OR 0.22, 95% CI 0.14-0.33, p < 0.001). In propensity-score matched groups within low-/middle-HDI countries, laparoscopy was still associated with fewer overall complications (OR 0.23 95% CI 0.11-0.44) and SSI (OR 0.21 95% CI 0.09-0.45). CONCLUSION: A laparoscopic approach is associated with better outcomes and availability appears to differ by country HDI. Despite the profound clinical, operational, and financial barriers to its widespread introduction, laparoscopy could significantly improve outcomes for patients in low-resource environments. TRIAL REGISTRATION: NCT02179112

Global economic burden of unmet surgical need for appendicitis

Background: There is a substantial gap in provision of adequate surgical care in many low-and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods: Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results: Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion: For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p&lt;0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p&lt;0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised