Comprehensive Diagnostic Services Research Articles

A comprehensive diagnostic service to clarify intervention needs when work participation is at risk: study protocol of a randomized controlled trial (GIBI, DRKS00027577)

BackgroundEffective care services for people whose work participation is at risk require low-threshold access, a comprehensive diagnostic clarification of intervention needs, a connection to the workplace and job demands, and interdisciplinary collaboration between key stakeholders at the interface of rehabilitation and occupational medicine. We have developed a comprehensive diagnostic service to clarify intervention needs for employees with health restrictions and limited work ability: this service is initiated by occupational health physicians.Methods/designOur randomized controlled trial tests the effectiveness of a comprehensive diagnostic service for clarifying intervention needs (GIBI: Comprehensive clarification of the need for intervention for people whose work participation is at risk). The comprehensive intervention comprises three elements: initial consultation, two-day diagnostics at a rehabilitation center and follow-up consultations. We will include 210 employees with health restrictions and limited work ability, who are identified by occupational health physicians. All individuals will receive an initial consultation with their occupational health physician to discuss their health, work ability and job demands. After this, half the individuals are randomly assigned to the intervention group and the other half to the waiting-list control group. Individuals in the intervention group start two-day diagnostics, carried out by a multi-professional rehabilitation team in a rehabilitation center, shortly after the initial consultation. The diagnostics will allow first recommendations for improving work participation. The implementation of these recommendations is supported by an occupational health physician in four follow-up consultations. The control group will receive the comprehensive two-day diagnostic service and subsequent follow-up consultations six months after the initial consultation. The primary outcome of the randomized controlled trial is self-rated work ability assessed using the Work Ability Score (0 to 10 points) six months after study inclusion. Secondary outcomes include a range of patient-reported outcomes regarding physical and mental health, impairment, and the physical and mental demands of jobs.DiscussionThis randomized controlled trial is designed to test the effects of a new complex intervention involving a comprehensive clarification of intervention needs in order to promote work participation and prevent the worsening of health and work disability.Trial registrationGerman Clinical Trials Register (DRKS00027577, February 01, 2022).

Demographic, clinical and laboratory features of leptospirosis-malaria co-infections in Peninsular Malaysia.

Introduction. Co-infection of leptospirosis-malaria is not uncommon due to their overlapping geographical distribution in the tropics.Aim. This study aimed to describe and compare the demographic, clinical and laboratory features of leptospirosis-malaria co-infection (LMCI) against leptospirosis mono-infection (LMI) in Peninsular Malaysia.Methodology. Data of patients admitted to various hospitals in Peninsular Malaysia from 2011 to 2014 diagnosed with leptospirosis in our laboratory were obtained from their admission records. Co-infections with malaria were identified via blood film for malaria parasites (BFMP). Description with inferential statistics analysis and multiple logistic regressions were used to distinguish features between dual and mono-infections.Results. Of 111 leptospirosis-positive patients, 26 (23.4 %) tested positive for malaria. Co-infections were predominant among male patients with a mean age of 33 years and were prevalent among immigrant populations who had settled in high-density suburban areas. Chills and rigor with splenomegaly were the only significant distinguishing clinical features of LMCI while leukocytosis and raised transaminases were significant laboratory parameters. Only chills and rigor demonstrated a predictive value for LMCI from analysis of multiple logistic regressions. No death was attributed to co-infection in this study, in contrast to LMI (11.8 %, n=10).Conclusion. The significant prevalence of LMCI found in this study with overlapping demographic, clinical and laboratory parameters makes diagnosis of co-infection challenging. It is essential to evaluate co-infection in endemic areas. Strengthened awareness of LMCI, comprehensive diagnostic services and further prospective studies are warranted.

Placental Molar Disease: What are the Benefits and Barriers to the Adoption of a Comprehensive Diagnostic Service?

The molecular cytogenetic analysis of specimens (genotyping) suspicious for hydatidiform mole (HM) significantly improves diagnostic accuracy over histopathology and immunohistochemical analysis alone, particularly in the classification of partial mole. However, the implementation of this advance in diagnostics has been slow. This study sought to identify the major benefit and potential barriers to the adoption of genotyping. A pilot Placental Molar Diagnostic (PMD) Service was established combining histopathology, p57 immunohistochemistry, and molecular genotyping analysis for both in-house and referred-in cases suspicious for HM or with a preliminary diagnosis of HM. A retrospective analysis of 117 cases received in the first 16 mo was conducted to identify the utility of the PMD Service and factors or barriers which precluded optimal results. A final diagnosis of HM was made in 73 cases (37 complete HMs and 36 partial HMs). The remaining 44 cases were hydropic abortuses. Three potential barriers were identified that could lead to less than optimal results from a PMD Service: prevalence of noninformative genotyping, lack of any available or appropriate paraffin blocks, and inappropriate deferral of genotyping. The major utility of this pilot PMD Service was to increase the specificity of a diagnosis of HM, and avoid unnecessary clinical follow-up in 37% of cases with an initial suspicion or diagnosis of HM. Measures can be undertaken to address potential barriers to the implementation of a comprehensive placental diagnostic platform. Underutilization of molecular genotyping in the diagnosis of HM likely leads to inappropriate management and "downstream" costs in a significant proportion of patients suspected of having HM.

Screening for duplications, deletions and a common intronic mutation detects 35% of second mutations in patients with USH2A monoallelic mutations on Sanger sequencing

BackgroundUsher Syndrome is the leading cause of inherited deaf-blindness. It is divided into three subtypes, of which the most common is Usher type 2, and the USH2A gene accounts for 75-80% of cases. Despite recent sequencing strategies, in our cohort a significant proportion of individuals with Usher type 2 have just one heterozygous disease-causing mutation in USH2A, or no convincing disease-causing mutations across nine Usher genes. The purpose of this study was to improve the molecular diagnosis in these families by screening USH2A for duplications, heterozygous deletions and a common pathogenic deep intronic variant USH2A: c.7595-2144A>G.MethodsForty-nine Usher type 2 or atypical Usher families who had missing mutations (mono-allelic USH2A or no mutations following Sanger sequencing of nine Usher genes) were screened for duplications/deletions using the USH2A SALSA MLPA reagent kit (MRC-Holland). Identification of USH2A: c.7595-2144A>G was achieved by Sanger sequencing. Mutations were confirmed by a combination of reverse transcription PCR using RNA extracted from nasal epithelial cells or fibroblasts, and by array comparative genomic hybridisation with sequencing across the genomic breakpoints.ResultsEight mutations were identified in 23 Usher type 2 families (35%) with one previously identified heterozygous disease-causing mutation in USH2A. These consisted of five heterozygous deletions, one duplication, and two heterozygous instances of the pathogenic variant USH2A: c.7595-2144A>G. No variants were found in the 15 Usher type 2 families with no previously identified disease-causing mutations. In 11 atypical families, none of whom had any previously identified convincing disease-causing mutations, the mutation USH2A: c.7595-2144A>G was identified in a heterozygous state in one family. All five deletions and the heterozygous duplication we report here are novel. This is the first time that a duplication in USH2A has been reported as a cause of Usher syndrome.ConclusionsWe found that 8 of 23 (35%) of ‘missing’ mutations in Usher type 2 probands with only a single heterozygous USH2A mutation detected with Sanger sequencing could be attributed to deletions, duplications or a pathogenic deep intronic variant. Future mutation detection strategies and genetic counselling will need to take into account the prevalence of these types of mutations in order to provide a more comprehensive diagnostic service.

Usher syndrome type 2 caused by activation of an USH2A pseudoexon: Implications for diagnosis and therapy

USH2A sequencing in three affected members of a large family, referred for the recessive USH2 syndrome, identified a single pathogenic alteration in one of them and a different mutation in the two affected nieces. As the patients carried a common USH2A haplotype, they likely shared a mutation not found by standard sequencing techniques. Analysis of RNA from nasal cells in one affected individual identified an additional pseudoexon (PE) resulting from a deep intronic mutation. This was confirmed by minigene assay. This is the first example in Usher syndrome (USH) with a mutation causing activation of a PE. The finding of this alteration in eight other individuals of mixed European origin emphasizes the importance of including RNA analysis in a comprehensive diagnostic service. Finally, this mutation, which would not have been found by whole-exome sequencing, could offer, for the first time in USH, the possibility of therapeutic correction by antisense oligonucleotides (AONs).

Mutation detection rate and spectrum in familial hypercholesterolaemia patients in the UK pilot cascade project

Cascade testing using DNA-mutation information is now recommended in the UK for patients with familial hypercholesterolaemia (FH). We compared the detection rate and mutation spectrum in FH patients with a clinical diagnosis of definite (DFH) and possible (PFH) FH. Six hundred and thirty-five probands from six UK centres were tested for 18 low-density lipoprotein receptor gene (LDLR) mutations, APOB p.Arg3527Gln and PCSK9 p.Asp374Tyr using a commercial amplification refractory mutation system (ARMS) kit. Samples with no mutation detected were screened in all exons by single strand conformation polymorphism analysis (SSCP)/denaturing high performance liquid chromatography electrophoresis (dHPLC)/direct-sequencing, followed by multiplex ligation-dependent probe amplification (MLPA) to detect deletions and duplications in LDLR.The detection rate was significantly higher in the 190 DFH patients compared to the 394 PFH patients (56.3% and 28.4%, p > 0.00001). Fifty-one patients had inadequate information to determine PFH/DFH status, and in this group the detection rate was similar to the PFH group (25.5%, p = 0.63 vs PFH). Overall, 232 patients had detected mutations (107 different; 6.9% not previously reported). The ARMS kit detected 100 (44%) and the MLPA kit 11 (4.7%). Twenty-eight (12%) of the patients had the APOB p.Arg3527Gln and four (1.7%) had the PCSK9 p.Asp374Tyr mutation. Of the 296 relatives tested from 100 families, a mutation was identified in 56.1%. In 31 patients of Indian/Asian origin 10 mutations (two previously unreported) were identified. The utility of the ARMS kit was confirmed, but sequencing is still required in a comprehensive diagnostic service for FH. Even in subjects with a low clinical suspicion of FH, and in those of Indian origin, mutation testing has an acceptable detection rate.

Home sleep testing

Sleep disordered breathing, also known as obstructive sleep apnea (OSA), is a highly prevalent disease occurring with a variety of life threatening comorbidities. For years, polysomnography has been considered the gold standard in diagnosis, consequently resulting in high costs and difficulty for head and neck surgeons to participate in the practice of sleep medicine. The development of multichannel home sleep testing by a variety of manufacturers offers a cost-effective and highly reliable method of screening for and diagnosing OSA. To complete the head and neck surgery sleep medicine practice, surgeons should provide sleep consultations and comprehensive diagnostic services out of their offices utilizing multichannel home sleep testing.