The causes of retinal dystrophy and the development of more comprehensive screening approach

Inherited retinal diseases (IRDs) are a group of genetically and phenotypically heterogenous disorders caused by variants in around 280 genes. Additional loci have also been localised to chromosomal regions, though the causative genes remain unknown. Recent improvements in screening technologies have increased the detection of pathogenic variants in IRD. This thesis describes the use of next generation sequencing (second (short-read) and third (long-read) generation sequencing) to find missing or hard to find pathogenic variants in IRD patients. The first results chapter describes use of whole exome sequencing to screen 24 individuals with syndromic and non-syndromic IRDs. This identified pathogenic variants in known genes in eight cases; CDHR1 (c.1527T>G, p.Y509*), RHO (c.284T>C, p.L95P), PRPF31 (c.797delC, p.S266*), CNGA3 (c.1088T>C, p.L363P), BBS10 (c.728-731delAAGA, p. K243Ifs*15), USH2A (c.252T>G, p.C84W), ABCA4 (c.2588G>C, p.G863A and c.6089G>A, p.R2030Q), and SLC25A46 (c.670A>G, p.T224A). In addition, several candidate variants were highlighted for further investigation. In the second results chapter, seven patients with late onset macular dystrophy and one with age related macular degeneration were found to carry the same heterozygous ~126 kb deletion encompassing CRX, TPRX1 and SULT2A1. This phenotype has already been documented in patients with heterozygous variants in the gene encoding retinal transcription factor CRX, while there is no known functional or phenotypic link with variants in TPRX1 or SULT2A1. This therefore confirms that CRX haploinsufficiency is pathogenic, a finding that had previously been debated in the ophthalmic literature. The deletion was characterized using a PCR assay followed by cloning and Sanger sequencing or direct Sanger sequencing. Haplotype analysis was done by microsatellite genotyping. The third results chapter describes use of SMRT PacBio and nanopore long-read sequencing to screen the hard-to-sequence mutation hotspot RPGR-ORF15. Both approaches were effective in reading throughout ORF15 and allowed sequencing indexed pooled samples, and 218 IRD patients were screened, detecting known and new variants. Nanopore sequencing on the smaller Flongle flowcell allowed low-cost optimisation, but pores rapidly blocked, probably due to ORF15 secondary structures. Repeated DNase I washes reopened the pores but required use of the more expensive MinION flowcells. Ultimately, the PacBio sequencer proved simpler to use, cheaper, and more scalable

Life after conflict-related amputation trauma: A clinical study from the Gaza Strip

Source at https://doi.org/10.1186/s12914-018-0173-3. © The Author(s). 2018Background: More than 17.000 Palestinians were injured during different Israeli military incursions on the Gaza Strip from 2006 to 2014. Many suffered traumatic extremity amputations. We describe the injuries, complications, living conditions and health among a selection of traumatic amputees in the Gaza Strip. Methods: We included 254 civilian Palestinians who had survived, but lost one or more limb(s) during military incursions from 2006 to 2016. All patients were receiving follow-up treatment at a physical rehabilitation center in Gaza at the time of inclusion. We measured and photographed anatomical location and length of extremity amputations and interviewed the amputees using standard questionnaires on self-reported health, socioeconomic status, mechanism of injury, physical status and medical history. Results: The amputees were young (median age 25,6 years at the time of trauma), well educated (37% above graduate level), males (92%), but also 43 children (17% ≤ 18 years). The greater part suffered major amputations (85% above wrist or ankle). Limb losses were unilateral (35% above-, 29·5% below knee), and bilateral (17%) lower extremity amputations. Pain was the most frequent long-term complaint (in joints; 34%, back; 33% or phantom pain; 40·6%). Sixty-three percent of amputees were their family’s sole breadwinner, 75·2% were unemployed and 46% had lost their home. Only one in ten (11·6%) of the destroyed homes had been rebuilt. Conclusions: The most frequently observed amputees in our study were young, well-educated male breadwinners and almost one in five were children. Conflict-related traumatic amputations have wide-ranging, serious consequences for the amputees and their families

Children perception of inter-parental conflicts and their cognitive emotion regulation

Basic aim of the present study is to explore the effect of inter-parental conflicts on the cognitive emotion regulation of children, based upon their own perception of these conflicts. Convenient sampling has been used to collect data from children age 9-12 years (50 boys and 50 girls) from different areas of Lahore city.For this study, two scales (CPIC and CERQ-k) are used.These scales are translated into Urdu by the researchers themselves.The results of this study suggest that cognitive emotional regulation emerges as significant predictor, =.35, t =.19, p <.00. The outcomes of the study also indicate that gender and SES have significant effect F (2, 99) = 8.38, p <.00 on CERQ-k.It has been observed that girls have no significant effect on children perception of inter-parental conflicts as p >.06 and R is.06, whereas boys have significant effect as p <.00. The 2 results also indicate that there is significant effect of CERQ-k t (98) = 2.69, p <.00.It has been illustrated that high level of interpersonal conflicts among parents may also lead their children and people related to them towards clinical pathologist that may be dangerous for their future lives.Furthermore, the study concludes that socio-economic statuses also have significant effect on the perception of children during conflicts.The results are discussed in the particular cultural context of Pakistan

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Children's participation in child welfare investigations within social services : A qualitative study of how children’s participation is applied in reality

The purpose of this bachelor thesis is to investigate the empowering and limiting factors that social workers are subjected to when they are to involve children in child welfare investigations. The empirical collection for the bachelor thesis is based on qualitative data collected by interviewing five social workers working mainly within the children- and family units and a sample of 17 scientific articles. The articles are international with origins from England, Netherlands, Norway, Sweden and Taiwan. When the empirical collection was compiled we could establish that the term “children’s participation” is in fact a complex field to put into practice by the social workers. Even if the children in some cases showed willingness to participate this could be limited by the social workers' fear to overburden them. Among other factors that limited the children’s participation was the social workers’ ambiguous view on children’s participation, the high workload, the caretakers influence on children’s participation, the child’s age and maturity as well as the social worker’s lack of competence and communication skills. Through the collection of former research, interviewing material, and Harry Shier’s Pathway to Participation model (2001) we could analyze how children’s participation is shaped by forming a thematic analysis. Finally, we can note that the reached stage of participation is relatively limited and does not reach a higher stage than stage two in Shier’s Pathway to Participation model (2001). Due to our limited possibility to conduct more interviews we couldn’t draw any general conclusions. However, we were able to shine a light on the critical and challenging aspects social workers could face when trying to enable child participation

Re-Learning EXP3 Multi-Armed Bandit Algorithm for Enhancing the Massive IoT-LoRaWAN Network Performance

Long-Range Wide Area Network (LoRaWAN) is an open-source protocol for the standard Internet of Things (IoT) Low Power Wide Area Network (LPWAN). This work&rsquo;s focal point is the LoRa Multi-Armed Bandit decentralized decision-making solution. The contribution of this paper is to study the effect of the re-learning EXP3 Multi-Armed Bandit (MAB) algorithm with previous experts&rsquo; advice on the LoRaWAN network performance. LoRa smart node has a self-managed EXP3 algorithm for choosing and updating the transmission parameters based on its observation. The best parameter choice needs previously associated distribution advice (expert) before updating different choices for confidence. The paper proposes a new approach to study the effects of combined expert distribution for each transmission parameter on the LoRaWAN network performance. The successful transmission of the packet with optimized power consumption is the pivot of this paper. The validation of the simulation result has proven that combined expert distribution improves LoRaWAN network&rsquo;s performance in terms of data throughput and power consumption