Challenges of Loss to Follow-up in Tuberculosis Research.

In studies evaluating methods for diagnosing tuberculosis (TB), follow-up to verify the presence or absence of active TB is crucial and high dropout rates may significantly affect the validity of the results. In a study assessing the diagnostic performance of the QuantiFERON®-TB Gold In-Tube test in TB suspect children in Tanzania, factors influencing patient adherence to attend follow-up examinations and reasons for not attending were examined. In 160 children who attended and 102 children who did not attend scheduled 2-month follow-up baseline health characteristics, demographic data and risk factors for not attending follow-up were determined. Qualitative interviews were used to understand patient and caretakers reasons for not returning for scheduled follow-up. Being treated for active tb in the dots program (OR: 4.14; 95% CI:1.99-8.62;p-value<0.001) and receiving money for the bus fare (OR:129; 95% CI 16->100;P-value<0.001) were positive predictors for attending follow-up at 2 months, and 21/85(25%) of children not attending scheduled follow-up had died. Interviews revealed that limited financial resources, i.e. lack of money for transportation and poor communication, were related to non-adherence. Patients lost to follow-up is a potential problem for TB research. Receiving money for transportation to the hospital and communication is crucial for adherence to follow-up conducted at a study facility. Strategies to ensure follow-up should be part of any study protocol

Dysregulation of Mitochondrial Dynamics and the Muscle Transcriptome in ICU Patients Suffering from Sepsis Induced Multiple Organ Failure

BACKGROUND: Septic patients treated in the intensive care unit (ICU) often develop multiple organ failure including persistent skeletal muscle dysfunction which results in the patient's protracted recovery process. We have demonstrated that muscle mitochondrial enzyme activities are impaired in septic ICU patients impairing cellular energy balance, which will interfere with muscle function and metabolism. Here we use detailed phenotyping and genomics to elucidate mechanisms leading to these impairments and the molecular consequences. METHODOLOGY/PRINCIPAL FINDINGS: Utilising biopsy material from seventeen patients and ten age-matched controls we demonstrate that neither mitochondrial in vivo protein synthesis nor expression of mitochondrial genes are compromised. Indeed, there was partial activation of the mitochondrial biogenesis pathway involving NRF2alpha/GABP and its target genes TFAM, TFB1M and TFB2M yet clearly this failed to maintain mitochondrial function. We therefore utilised transcript profiling and pathway analysis of ICU patient skeletal muscle to generate insight into the molecular defects driving loss of muscle function and metabolic homeostasis. Gene ontology analysis of Affymetrix analysis demonstrated substantial loss of muscle specific genes, a global oxidative stress response related to most probably cytokine signalling, altered insulin related signalling and a substantial overlap between patients and muscle wasting/inflammatory animal models. MicroRNA 21 processing appeared defective suggesting that post-transcriptional protein synthesis regulation is altered by disruption of tissue microRNA expression. Finally, we were able to demonstrate that the phenotype of skeletal muscle in ICU patients is not merely one of inactivity, it appears to be an actively remodelling tissue, influenced by several mediators, all of which may be open to manipulation with the aim to improve clinical outcome. CONCLUSIONS/SIGNIFICANCE: This first combined protein and transcriptome based analysis of human skeletal muscle obtained from septic patients demonstrated that losses of mitochondria and muscle mass are accompanied by sustained protein synthesis (anabolic process) while dysregulation of transcription programmes appears to fail to compensate for increased damage and proteolysis. Our analysis identified both validated and novel clinically tractable targets to manipulate these failing processes and pursuit of these could lead to new potential treatments

The association between pregnancy, pelvic girdle pain and health-related quality of life – a comparison of two instruments

Background The main purposes in this cross-sectional study were to study the impact of pregnancy and pelvic girdle pain (PGP) on health related quality of life (HRQoL), by comparing the scores on different domains of two HRQoL instruments in pregnant women with population norms as well as in women with severe and less severe PGP. Further, to explore the association between PGP and HRQoL and whether the two instruments differ in the way they assess the influence of PGP on HRQoL. Methods Pregnant women in gestation week 30 completed questionnaires containing the Short Form Health Survey (SF-36) and the Nottingham Health Profile (NHP). Additional variables, self-reported PGP, pain location in the pelvis and response on clinical tests were also collected. HRQoL scores were compared with expected age adjusted mean scores and comparisons between groups with different severity of PGP were made, using Mann-Whitney U, t-tests and Hodges-Lehman method. Results Two hundred eighty-three pregnant women, mean age 31.3 (SD 4.2) years, participated. We found statistical significant differences in all domains of both HRQoL instruments in late pregnancy compared to the expected age-adjusted means of the reference populations (p ≤ 0.003) except for Social isolation (p = 0.775). Women with PGP had lower HRQoL than women without, and the most affected women scored lowest. SF-36 detected a deficit in Social Function compared to norms whereas the NHP showed no evidence of Social Isolation. Conclusions Both instruments revealed changes in HRQoL in pregnant women compared with population norms. Pregnancy itself influences HRQoL and having PGP gave an additional impact. The consistency of the correlations between SF-36 and NHP domains across the sub-groups found in this study suggests convergent validity across levels of impairment. The results in social domains vary between SF-36 and NHP in pregnant women and might be due to the basic design (construction) of the tools

The association between different outcome measures and prognostic factors in patients with neck pain: a cohort study

Background Health domains like pain, disability, and health-related quality of life are commonly used outcomes for musculoskeletal disorders. Most prognostic studies include only one outcome, and it is unknown if prognostic factors and models may be generic across different outcomes. The objectives of this study were to examine the correlation among commonly used outcomes for neck pain (pain intensity, disability, and health-related quality of life) and to explore how the predictive performance of a prognostic model differs across commonly used outcomes. Methods We conducted an observational prospective cohort study with data from patients with neck pain aged 18–84 years consulting Norwegian chiropractors. We used three different outcomes: pain intensity (Numeric Pain Rating Scale), the Neck Disability Index (NDI), and health-related quality of Life (EQ-5D). We assessed associations between change in outcome scores at 12-weeks follow-up with Pearson’s correlation coefficient. We used multivariable linear regression models to explore differences in explained variance and relationship between predictors and outcomes. Results The study sample included 1313 patients and 941 (72%) completed follow-up at 12 weeks. The strongest correlation was between NDI and EQ-5D (r = 0.57) while the weakest correlation was between EQ-5D and pain intensity (r = 0.39). The correlation between NDI and pain intensity was moderate (r = 0.53) In the final regression models, the explained variance ranged from adjusted R2 of 0.26 to 0.60, highest with NDI and lowest with pain intensity as outcome. The predictive contributions of the included predictors were similar across outcomes. Among the investigated predictors, pain patterns and the baseline measure of the corresponding outcome measure contributed the most to explained variance across all outcomes. Conclusions The highest correlation was found between NDI and EQ-5D and the lowest with pain intensity. The same prognostic model showed highest predictive performance with NDI as outcome and poorest with pain intensity as outcome. These results suggest that we need more knowledge on the reasons for the differences in predictive performance variation across outcomes

Exploring visual pain trajectories in neck pain patients, using clinical course, SMS-based patterns, and patient characteristics: a cohort study

Background The dynamic nature of neck pain has so far been identified through longitudinal studies with frequent measures, a method which is time-consuming and impractical. Pictures illustrating different courses of pain may be an alternative solution, usable in both clinical work and research, but it is unknown how well they capture the clinical course. The aim of this study was to explore and describe self-reported visual trajectories in terms of details of patients’ prospectively reported clinical course, their SMS-based pattern classification of neck pain, and patient’s characteristics. Methods Prospective cohort study including 888 neck pain patients from chiropractic practice, responding to weekly SMS-questions about pain intensity for 1 year from 2015 to 2017. Patients were classified into one of three clinical course patterns using definitions based on previously published descriptors. At 1-year follow-up, patients selected a visual trajectory that best represented their retrospective 1-year course of pain: single episode, episodic, mild ongoing, fluctuating and severe ongoing. Results The visual trajectories generally resembled the 1-year clinical course characteristics on group level, but there were large individual variations. Patients selecting Episodic and Mild ongoing visual trajectories were similar on most parameters. The visual trajectories generally resembled more the clinical course of the last quarter. Discussion The visual trajectories reflected the descriptors of the clinical course of pain captured by weekly SMS measures on a group level and formed groups of patients that differed on symptoms and characteristics. However, there were large variations in symptoms and characteristics within, as well as overlap between, each visual trajectory. In particular, patients with mild pain seemed predisposed to recall bias. Although the visual trajectories and SMS-based classifications appear related, visual trajectories likely capture more elements of the pain experience than just the course of pain. Therefore, they cannot be seen as a proxy for SMS-tracking of pain over 1 year

DOORS syndrome and a recurrent truncating ATP6V1B2 variant

PURPOSE: Biallelic variants in TBC1D24, which encodes a protein that regulates vesicular transport, are frequently identified in patients with DOORS (deafness, onychodystrophy, osteodystrophy, intellectual disability [previously referred to as mental retardation], and seizures) syndrome. The aim of the study was to identify a genetic cause in families with DOORS syndrome and without a TBC1D24 variant. METHODS: Exome or Sanger sequencing was performed in individuals with a clinical diagnosis of DOORS syndrome without TBC1D24 variants. RESULTS: We identified the same truncating variant in ATP6V1B2 (NM_001693.4:c.1516C>T; p.Arg506*) in nine individuals from eight unrelated families with DOORS syndrome. This variant was already reported in individuals with dominant deafness onychodystrophy (DDOD) syndrome. Deafness was present in all individuals, along with onychodystrophy and abnormal fingers and/or toes. All families but one had developmental delay or intellectual disability and five individuals had epilepsy. We also describe two additional families with DDOD syndrome in whom the same variant was found. CONCLUSION: We expand the phenotype associated with ATP6V1B2 and propose another causal gene for DOORS syndrome. This finding suggests that DDOD and DOORS syndromes might lie on a spectrum of clinically and molecularly related conditions