A comprehensive introduction to the genetic basis of non-syndromic hearing loss in the Saudi Arabian population

<p>Abstract</p> <p>Background</p> <p>Hearing loss is a clinically and genetically heterogeneous disorder. Mutations in the <it>DFNB1 </it>locus have been reported to be the most common cause of autosomal recessive non-syndromic hearing loss worldwide. Apart from <it>DFNB1</it>, many other loci and their underlying genes have also been identified and the basis of our study was to provide a comprehensive introduction to the delineation of the molecular basis of non-syndromic hearing loss in the Saudi Arabian population. This was performed by screening <it>DFNB1 </it>and to initiate prioritized linkage analysis or homozygosity mapping for a pilot number of families in which <it>DFNB1 </it>has been excluded.</p> <p>Methods</p> <p>Individuals from 130 families of Saudi Arabian tribal origin diagnosed with an autosomal recessive non-syndromic sensorineural hearing loss were screened for mutations at the <it>DFNB1 </it>locus by direct sequencing. If negative, genome wide linkage analysis or homozygosity mapping were performed using Affymetrix GeneChip^®Human Mapping 250K/6.0 Arrays to identify regions containing any known-deafness causing genes that were subsequently sequenced.</p> <p>Results</p> <p>Our results strongly indicate that <it>DFNB1 </it>only accounts for 3% of non-syndromic hearing loss in the Saudi Arabian population of ethnic ancestry. Prioritized linkage analysis or homozygosity mapping in five separate families established that their hearing loss was caused by five different known-deafness causing genes thus confirming the genetic heterogeneity of this disorder in the kingdom.</p> <p>Conclusion</p> <p>The overall results of this study are highly suggestive that underlying molecular basis of autosomal recessive non-syndromic deafness in Saudi Arabia is very genetically heterogeneous. In addition, we report that the preliminary results indicate that there does not seem to be any common or more prevalent loci, genes or mutations in patients with autosomal recessive non-syndromic hearing loss in patients of Saudi Arabian tribal origin.</p

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Training in robotic thoracic surgery-the European way

The increasing demand for robot-assisted thoracic surgery (RATS) in Europe requires a structured and standardized training module. Until now, Intuitive Surgical Inc. (Sunnyvale, CA, USA) has delivered the only available robotic surgery platform. Although the training program that is organized by Intuitive is divided in an initial and an advanced course, the success of the training depends on many external factors. Until now the training focused on experienced thoracic surgeons. The aim of this article is to offer a stepwise training module, which can be adopted by experienced open (thoracotomy) surgeons or video-assisted thoracic (VATS) surgeons but is primarily meant for thoracic surgery fellows and residents, as it is our sincere opinion that we should focus on training for this type of surgery as early in their careers as possible. In order to maintain surgical technique and minimize the chance of complications, on-going training and certification of the surgeons and the team is deemed necessary

Robot-assisted thoracic surgery for stages IIB-IVA non-small cell lung cancer: retrospective study of feasibility and outcome

Robot-assisted thoracic surgery (RATS) for higher stages non-small cell lung carcinoma (NSCLC) remains controversial. This study reports the feasibility of RATS in patients with stages IIB-IVA NSCLC. A single-institute, retrospective study was conducted with patients undergoing RATS for stages IIB-IVA NSCLC, from January 2015 until January 2020. Unforeseen N2 disease was excluded. Data were collected from the Dutch Lung Cancer Audit database. Conversion rate, radical (R0) resection rate, local recurrence rate and complications were analyzed, as were risk factors for conversion. RATS was performed in 95 patients with NSCLC clinical or pathological stages IIB (N = 51), IIIA (N = 39), IIIB (N = 2) and IVA (N = 3). 10.5% had received neoadjuvant chemoradiotherapy. Pathological staging was T3 in 33.7% and T4 in 34.7%. RATS was completed in 77.9% with a radical resection rate of 94.8%. Lobectomy was performed in 67.4% of the total resections. Conversion was for strategic (18.9%) and emergency (3.2%) reasons. Pneumonectomy (p = 0.001), squamous cell carcinoma (p < 0.001), additional resection of adjacent structures (p = 0.025) and neoadjuvant chemoradiation (p = 0.017) were independent risk factors for conversion. Major post-operative complications occurred in ten patients (10.5%) including an in-hospital mortality of 2.1% (n = 2). Median recurrence-free survival was estimated at 39.4 months (CI 16.4-62.5). Two- and 5-year recurrence-free survival rates were 53.8% and 36.7%, respectively. This study concludes that RATS is safe and feasible in higher staged NSCLC tumors after exclusion of unforeseen N2 disease. It brings new perspective on the potential of RATS in higher stages, dealing with larger and more invasive tumors

Robot-assisted thoracic surgery for stages IIB–IVA non-small cell lung cancer: retrospective study of feasibility and outcome

Robot-assisted thoracic surgery (RATS) for higher stages non-small cell lung carcinoma (NSCLC) remains controversial. This study reports the feasibility of RATS in patients with stages IIB–IVA NSCLC. A single-institute, retrospective study was conducted with patients undergoing RATS for stages IIB–IVA NSCLC, from January 2015 until January 2020. Unforeseen N2 disease was excluded. Data were collected from the Dutch Lung Cancer Audit database. Conversion rate, radical (R0) resection rate, local recurrence rate and complications were analyzed, as were risk factors for conversion. RATS was performed in 95 patients with NSCLC clinical or pathological stages IIB (N = 51), IIIA (N = 39), IIIB (N = 2) and IVA (N = 3). 10.5% had received neoadjuvant chemoradiotherapy. Pathological staging was T3 in 33.7% and T4 in 34.7%. RATS was completed in 77.9% with a radical resection rate of 94.8%. Lobectomy was performed in 67.4% of the total resections. Conversion was for strategic (18.9%) and emergency (3.2%) reasons. Pneumonectomy (p = 0.001), squamous cell carcinoma (p < 0.001), additional resection of adjacent structures (p = 0.025) and neoadjuvant chemoradiation (p = 0.017) were independent risk factors for conversion. Major post-operative complications occurred in ten patients (10.5%) including an in-hospital mortality of 2.1% (n = 2). Median recurrence-free survival was estimated at 39.4 months (CI 16.4–62.5). Two- and 5-year recurrence-free survival rates were 53.8% and 36.7%, respectively. This study concludes that RATS is safe and feasible in higher staged NSCLC tumors after exclusion of unforeseen N2 disease. It brings new perspective on the potential of RATS in higher stages, dealing with larger and more invasive tumors

Comparison of EUS-guided fine needle aspiration and integrated PET-CT in restaging after treatment for locally advanced non-small cell lung cancer

Background: After induction treatment restaging of mediastinal disease in patients with stage III non-small cell lung cancer (NSCLC) may lead to selection of candidates for further surgical treatment. Nodal down-staging is the best predictive characteristic for proceeding with surgery. We report our experience in restaging with endoscopic ultrasound-guided fine needle aspirations (EUS-FNA) and with repeated integrated positron emission tomography and computed tomography (PET-CT). Methods: Twenty-eight patients with stage III NSCLC were staged with integrated PET-CT, cerebral magnetic resonance imaging (MRI) and pathologically proven nodal disease. Restaging was performed with PET-CT and EUS-FNA on the same nodes that showed initially metastatic disease provided these nodal sites determined the tumor stage. Cerebral MRI was not repeated. When restaging EUS-FNA revealed no malignant cells anymore, patients were operated. The postoperative pathologic results were compared with the preoperative restaging EUS-FNA results. Also, patterns of decreased fluoro-2-deoxyglucose (FDG) uptake were compared with the postoperative pathologic results. Results: Restaging EUS-FNA was well tolerated in all patients even in those with clinical signs of radiation esophagitis. Of the 28 patients 15 were down-staged based on cytologic findings with restaging EUS-FNA and in one patient the cytology was not conclusive. Of these 15 patients, down-staging was histologically confirmed after mediastinal exploration in 11 patients and 1 patient had persistent nodal disease at resection. In 3 patients no mediastinal tissue verification was performed. Two subjects were not fit for operation, and in the other patient intraoperative nodal staging was omitted. The negative predictive value for restaging EUS-FNA was 91.6%. The accuracy of EUS-FNA was 92.3%. Concordance between findings of restaging EUS-FNA and metabolic response of lymph node metastases occurred in 17 out of 27 patients. Conclusion: Restaging with EUS-FNA after induction chemo(-radiotherapy) is well tolerated and predicts the absence of nodal metastasis reliably. Although changes in mediastinal FDG-PET uptake show a high concordance with EUS-FNA, pathological confirmation is still superior and therefore necessary. EUS-FNA is the procedure of first choice for mediastinal restaging. (C) 2009 Elsevier Ireland Ltd. All rights reserved

The usefulness of preoperative exercise therapy in patients scheduled for lung cancer surgery;:a survey among Dutch pulmonologists and cardiothoracic surgeons

Background Preoperative exercise training (PET) studies show promising results in various patient populations. However, the lack of standardised programmes and uniformity in practice guidelines are barriers for implementation. Aim of this study was to assess the current opinions of pulmonologists and cardiothoracic surgeons on the clinical applicability of PET in patients scheduled for lung cancer surgery. Methods Dutch pulmonologists and cardiothoracic surgeons were asked to complete a 29-question survey regarding PET as an additional option to further optimise the health status of patients scheduled for lung cancer surgery. Results In total, 47 respondents (63% response rate), including 30 pulmonologists and 11 cardiothoracic surgeons and 6 residents in training completed the survey. A vast majority of the respondents had a positive attitude towards PET. Home-based exercise was considered less useful, as well as unsupervised exercise. Patient's motivation, improvements in physical capacity and quality of life, and lifestyle adjustments are important factors for the success of PET. The programme should at least contain inspiratory muscle training (95.7%), lifestyle interventions (95.7%), and supervised exercise training (91.5%). Cardiac and pulmonary risk assessment and medication assessment and optimisation were found less important. Conclusion Among pulmonologists and cardiothoracic surgeons, there is a tendency that PET can be a valuable addition to the perioperative care of lung surgery patients. Points of discussion are the contents of PET programmes, and there seems to be a lack of awareness among chest physicians

The usefulness of preoperative exercise therapy in patients scheduled for lung cancer surgery;: a survey among Dutch pulmonologists and cardiothoracic surgeons

Background Preoperative exercise training (PET) studies show promising results in various patient populations. However, the lack of standardised programmes and uniformity in practice guidelines are barriers for implementation. Aim of this study was to assess the current opinions of pulmonologists and cardiothoracic surgeons on the clinical applicability of PET in patients scheduled for lung cancer surgery. Methods Dutch pulmonologists and cardiothoracic surgeons were asked to complete a 29-question survey regarding PET as an additional option to further optimise the health status of patients scheduled for lung cancer surgery. Results In total, 47 respondents (63% response rate), including 30 pulmonologists and 11 cardiothoracic surgeons and 6 residents in training completed the survey. A vast majority of the respondents had a positive attitude towards PET. Home-based exercise was considered less useful, as well as unsupervised exercise. Patient's motivation, improvements in physical capacity and quality of life, and lifestyle adjustments are important factors for the success of PET. The programme should at least contain inspiratory muscle training (95.7%), lifestyle interventions (95.7%), and supervised exercise training (91.5%). Cardiac and pulmonary risk assessment and medication assessment and optimisation were found less important. Conclusion Among pulmonologists and cardiothoracic surgeons, there is a tendency that PET can be a valuable addition to the perioperative care of lung surgery patients. Points of discussion are the contents of PET programmes, and there seems to be a lack of awareness among chest physicians

A Randomized Controlled Trial of Postthoracotomy Pulmonary Rehabilitation in Patients with Resectable Lung Cancer

<p>Introduction: Little is known about the effects of rehabilitation for patients with lung cancer after thoracotomy. The primary objective of this study was to evaluate the effect of a multidisciplinary rehabilitation program on quality of life (QOL) and secondary objectives were to determine its effects on pain and exercise capacity and the feasibility of combining rehabilitation with adjuvant chemotherapy.</p><p>Methods: Patients who had undergone a thoracotomy for lung cancer were randomized between rehabilitation and usual care. Rehabilitation consisted of twice-weekly training for 12 weeks starting 1 month after hospital discharge, scheduled visits to pain specialists, and medical social work. QOL and pain were measured with validated questionnaires at baseline and after 1, 3, 6, and 12 months. Exercise tolerance was assessed at baseline and after 3 months with a 6-minute walking distance test.</p><p>Results: The study closed prematurely because of the introduction of video-assisted thoracoscopic surgery. Of 57 randomized patients, 49 patients (23 active and 26 control) were analyzed. QOL was not significantly different between groups, although, the active group reported more pain after 3 and 6 months and more limitations because of physical problems after 3 months. In the active group, 6-minute walking distance improved by 35 m from preoperative baseline, as opposed to the control group that showed a decline by 59 m (p = 0.024 for difference). Patients treated with adjuvant chemotherapy showed decreased attendance at training sessions.</p><p>Conclusion: Rehabilitation did not result in a better QOL. Exercise tolerance improved at the cost of more pain and more limitations because of physical problems. We suggest that rehabilitation is better postponed for 3 to 4 months after hospital discharge.</p>

Outcomes from the Delphi process of the Thoracic Robotic Curriculum Development Committee

OBJECTIVES: As the adoption of robotic procedures becomes more widespread, additional risk related to the learning curve can be expected. This article reports the results of a Delphi process to define procedures to optimize robotic training of thoracic surgeons and to promote safe performance of established robotic interventions as, for example, lung cancer and thymoma surgery. METHODS: In June 2016, a working panel was spontaneously created by members of the European Society of Thoracic Surgeons (ESTS) and European Association for Cardio-Thoracic Surgery (EACTS) with a specialist interest in robotic thoracic surgery and/or surgical training. An e-consensus-finding exercise using the Delphi methodology was applied requiring 80% agreement to reach consensus on each question. Repeated iterations of anonymous voting continued over 3 rounds. RESULTS: Agreement was reached on many points: a standardized robotic training curriculum for robotic thoracic surgery should be divided into clearly defined sections as a staged learning pathway; the basic robotic curriculum should include a baseline evaluation, an e-learning module, a simulation-based training (including virtual reality simulation, Dry lab and Wet lab) and a robotic theatre (bedside) observation. Advanced robotic training should include e-learning on index procedures (right upper lobe) with video demonstration, access to video library of robotic procedures, simulation training, modular console training to index procedure, transition to full-procedure training with a proctor and final evaluation of the submitted video to certified independent examiners. CONCLUSIONS: Agreement was reached on a large number of questions to optimize and standardize training and education of thoracic surgeons in robotic activity. The production of the content of the learning material is ongoing