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How does onchocerciasis-related skin and eye disease in africa depend on cumulative exposure to infection and mass treatment?
No full textBackground Onchocerciasis (river-blindness) in Africa is targeted for elimination through mass drug administration (MDA) with ivermectin. Onchocerciasis may cause various types of skin and eye disease. Predicting the impact of MDA on onchocercal morbidity is useful for future policy development. Here, we introduce a new disease module within the established ONCHO-SIM model to predict trends over time in prevalence of onchocercal morbidity. Methods We developed novel generic model concepts for development of symptoms due to cumulative exposure to dead microfilariae, accommodating both reversible (acute) and irreversible (chronic) symptoms. The model was calibrated to reproduce pre-control age patterns and associations between prevalences of infection, eye disease, and various types of skin disease as observed in a large set of population-based studies. We then used the new disease module to predict the impact of MDA on morbidity prevalence over a 30-year time frame for various scenarios. Results ONCHOSIM reproduced observed age-patterns in disease and community-level associations between infection and disease reasonably well. For highly endemic settings with 30 years of annual MDA at 60% coverage, the model predicted a 70% to 89% reduction in prevalence of chronic morbidity. This relative decline was similar with higher MDA coverage and only somewhat higher for settings with lower pre-control endemicity. The decline in prevalence was lowest for mild depigmentation and visual impairment. The prevalence of acute clinical manifestations (severe itch, reactive skin disease) declined by 95% to 100% after 30 years of annual MDA, regardless of pre-control endemicity. Conclusion We present generic model concepts for predicting trends in acute and chronic symptoms due to history of exposure to parasitic worm infections, and apply this to onchocerciasis. Our predictions suggest that onchocercal morbidity, in particular chronic manifestations, will remain a public health concern in many epidemiological settings in Africa, even after 30 years of MDA.</p
Association Between T<sub>2</sub><sup>*</sup> Relaxation Times Derived From Ultrashort Echo Time MRI and Symptoms During Exercise Therapy for Patellar Tendinopathy
No full textBackground: Exercise therapy is considered preferential treatment for patellar tendinopathy (PT). However, there is conflicting evidence for structural patellar tendon adaptation in response to exercise therapy and its association with symptoms is weak. Purpose: To assess the association between 1) T2* relaxation times and symptom severity; 2) baseline T2* and clinical outcome; and 3) longitudinal T2* changes and clinical outcome in athletes with PT performing exercise therapy. Study Type: Randomized controlled clinical trial. Subjects: Seventy-six athletes (18–35 years) with clinically diagnosed and ultrasound-confirmed PT. Field strength/Sequence: 3D gradient echo sequence (3.0 T). Assessment: Patients were enrolled in a randomized trial of progressive tendon-loading exercises (PTLE) versus eccentric exercise therapy (EET). Symptoms were assessed using the Victorian Institute of Sports Assessment (VISA-P) questionnaire. 3D-Ultrashort echo time (UTE)-MRI was acquired at baseline, 12 and 24 weeks. Voxel-wise T2* relaxation times were quantified using mono-exponential and bi-exponential models. T2* analysis was performed in three patellar tendon tissue compartments representing: aligned collagen, degenerative tissue, and interface. Statistical Tests: Adjusted general linear, mixed-linear models, and generalized estimating equations. Results: We included 76 patients with PT (58 men, mean age 24 ± 4 years); 38 in the PTLE-group and 38 in the EET-group, of which 57 subjects remained eligible for analysis. T2* relaxation times were significantly associated with VISA-P in degenerative and interface tissues of the patellar tendon. No association was found between baseline T2* and VISA-P after 24 weeks (P > 0.29). The estimated mean T2* in degenerative tissue decreased from 14 msec (95%CI: 12–16) at baseline to 13 msec (95%CI: 11–15) at 12 weeks and to 13 msec (95%CI: 10–15) at 24 weeks. The significant decrease in T2* from baseline to 24 weeks was associated with improved clinical outcome. Data Conclusion: Tissue-specific T2* relaxation times, identified with 3D-UTE-MRI, decreased significantly in athletes with patellar tendinopathy performing exercise therapy and this decrease was associated with improved clinical outcome. Evidence Level: 1. Technical Efficacy: Stage 4.</p
T cell composition and polygenic multiple sclerosis risk
No full textBackground and purpose: Patients with multiple sclerosis (MS) have altered T cell function and composition. Common genetic risk variants for MS affect proteins that function in the immune system. It is currently unclear to what extent T cell composition is affected by genetic risk factors for MS, and how this may precede a possible disease onset. Here, we aim to assess whether an MS polygenic risk score (PRS) is associated with an altered T cell composition in a large cohort of children from the general population. Methods: We included genotyped participants from the population-based Generation R study in whom immunophenotyping of blood T cells was performed at the age of 6 years. Analyses of variance were used to determine the impact of MS-PRSs on total T cell numbers (n = 1261), CD4+ and CD8+ lineages, and subsets therein (n= 675). In addition, T-cell-specific PRSs were constructed based on functional pathway data. Results: The MS-PRS negatively correlated with CD8+ T cell frequencies (p = 2.92 × 10−3), which resulted in a positive association with CD4+/CD8+ T cell ratios (p = 8.27 × 10−9). These associations were mainly driven by two of 195 genome-wide significant MS risk variants: the main genetic risk variant for MS, HLA-DRB1*15:01 and an HLA-B risk variant. We observed no significant associations for the T-cell-specific PRSs. Conclusions: Our results suggest that MS-associated genetic variants affect T cell composition during childhood in the general population.</p
Identifying persistent somatic symptoms in electronic health records
No full textObjective Persistent somatic symptoms (PSSs) are defined as symptoms not fully explained by well-established pathophysiological mechanisms and are prevalent in up to 10% of patients in primary care. The present study aimed to explore methods to identify patients with a recognisable risk of having PSS in routine primary care data. Design A cross-sectional study to explore four identification methods that each cover part of the broad spectrum of PSS was performed. Cases were selected based on (1) PSS-related syndrome codes, (2) PSS-related symptom codes, (3) PSS-related terminology and (4) Four-Dimensional Symptom Questionnaire scores and all methods combined. Setting Coded electronic health record data were extracted from 76 general practices in the Netherlands. Participants Patients who were registered for at least 1 year during 2014-2018, were included (n=169 138). Outcome measures Identification methods were explored based on (1) PSS sample sizes and demographics, (2) presence of chronic conditions and (3) healthcare utilisation (HCU) variables. Overlap between methods and practice specific differences were examined. Results The percentage of cases identified varied between 0.3% and 7.0% across the methods. Over 58.1% of cases had chronic physical condition(s) and over 33.8% had chronic mental condition(s). HCU was generally higher for cases selected by any method compared with the total cohort. HCU was higher for method B compared with the other methods. In 26.7% of cases, cases were selected by multiple methods. Overlap between methods was low. Conclusions Different methods yielded different patient samples which were general practice specific. Therefore, for the most comprehensive data-based selection of PSS cases, a combination of methods A, C and D would be recommended. Advanced (data-driven) methods are needed to create a more sensitive algorithm for identifying the full spectrum of PSS. For clinical purposes, method B could possibly support screening of patients who are currently missed in daily practice.</p
A phase I/II study of bevacizumab, irinotecan and erlotinib in children with progressive diffuse intrinsic pontine glioma
No full textIntroduction: This study investigates the safety, tolerability, and preliminary efficacy of combined treatment with VEGF inhibitor bevacizumab, topoisomerase I inhibitor irinotecan, and EGFR inhibitor erlotinib in children with progressive diffuse intrinsic pontine glioma (DIPG). Methods: Biweekly bevacizumab (10 mg/kg) and irinotecan (125 mg/m2) were combined with daily erlotinib. Two cohorts received increasing doses of erlotinib (65 and 85 mg/m2) following a 3 + 3 dose-escalation schedule, until disease progression with a maximum of one year. Dose-limiting toxicities (DLT) were monitored biweekly. Secondary progression free survival (sPFS) and overall survival (OS) were determined based on clinical and radiological response measurements. Quality of life (QoL) during treatment was also assessed. Results: Between November 2011 and March 2018, nine patients with disease progression after initial radiotherapy were enrolled. Median PFS at start of the study was 7.3 months (range 3.5–10.0). In the first dose cohort, one patient experienced a DLT (grade III acute diarrhea), resulting in enrollment of three additional patients in this cohort. No additional DLTs were observed in consecutive patients receiving up to a maximum dose of 85 mg/m2. Median sPFS was 3.2 months (range 1.0–10.9), and median OS was 13.8 months (range 9.3–33.0). Overall QoL was stable during treatment. Conclusions: Daily erlotinib is safe and well tolerated in doses up to 85 mg/m2 when combined with biweekly bevacizumab and irinotecan in children with progressive DIPG. Median OS of the study patients was longer than known form literature.</p
Survival in advanced-stage epithelial ovarian cancer patients with cardiophrenic lymphadenopathy who underwent cytoreductive surgery
No full textPurpose: To evaluate the clinical outcomes of enlarged cardiophrenic lymph node (CPLN) in advanced-stage epithelial ovarian cancer (AEOC) patients who underwent cytoreductive sur-gery. Methods: The Embase, Medline, Web of Science, Cochrane Library, and Google Scholar data-bases were searched for articles from the database inception to June 2021. Meta-analysis was conducted to determine the prognostic impact of surgical outcome, postoperative complication, and survival using random-effects models. Results: A total of 15 studies involving 727 patients with CPLN adenopathy and 981 patients without CPLN adenopathy were included. The mean size of preoperative CPLN was 9.1± 3.75 mm. Overall, 82 percent of the resected CPLN were histologically confirmed pathologic nodes. Surgical outcomes and perioperative complications did not differ between both groups. The median OS time was 42.7 months (95% CI 10.8–74.6) versus 47.3 months (95% CI 23.2–71.2), in patients with and without CPLN adenopathy, respectively. At 5 years, patients with CPLN adenopathy had a significantly increased risk of disease recurrence (HR 2.14, 95% CI 1.82–2.52, p < 0.001) and dying from the disease (HR 1.74, 95% CI 1.06–2.86, p = 0.029), compared with those without CPLN adenopathy. CPLN adenopathy was significantly associated with ascites (OR 3.30, 95% CI 1.90–5.72, p < 0.001), pleural metastasis (OR 2.58, 95% CI 1.37–4.82, p = 0.003), abdominal adenopathy (OR 2.30, 95% CI 1.53–3.46, p < 0.001) and extra-abdominal metastasis (OR 2.30, 95% CI 1.61–6.67, p = 0.001). Conclusions: Enlarged CPLN in preoperative imaging is highly associated with metastatic involvement. Patients with CPLN adenopathy had a lower survival rate, compared with patients without CPLN adenopathy. Further randomized controlled trials should be conducted to definitively demonstrate whether CPLN resection at the time of cytoreductive surgery is beneficial.</p
Liquid biopsies in sarcoma clinical practice
No full textSarcomas are rare tumors of bone and soft tissue with a mesenchymal origin. This uncommon type of cancer is marked by a high heterogeneity, consisting of over 70 subtypes. Because of this broad spectrum, their treatment requires a subtype-specific therapeutic approach. Tissue biopsy is currently the golden standard for sarcoma diagnosis, but it has its limitations. Over the recent years, methods to detect, characterize, and monitor cancer through liquid biopsy have evolved rapidly. The analysis of circulating biomarkers in peripheral blood, such as circulating tumor cells (CTC) or circulating tumor DNA (ctDNA), could provide real-time information on tumor genetics, disease state, and resistance mechanisms. Furthermore, it traces tumor evolution and can assess tumor heterogeneity. Although the first results in sarcomas are encouraging, there are technical challenges that need to be addressed for implementation in clinical practice. Here, we summarize current knowledge about liquid biopsies in sarcomas and elaborate on different strategies to integrate liquid biopsy into sarcoma clinical care.</p
Serum mir-373-3p and mir-194-5p are associated with early tumor progression during folfirinox treatment in pancreatic cancer patients
No full textIn this study, we explored the predictive value of serum microRNA (miRNA) expression for early tumor progression during FOLFIRINOX chemotherapy and its association with overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC). A total of 132 PDAC patients of all disease stages were included in this study, of whom 25% showed progressive disease during FOLFIRINOX according to the RECIST criteria. MiRNA expression was analyzed in serum collected before the start and after one cycle of chemotherapy. In the discovery cohort (n = 12), a 352-miRNA RT-qPCR panel was used. In the validation cohorts (total n = 120), miRNA expression was detected using individual RT-qPCR miRNA primers. Before the start of FOLFIRINOX, serum miR-373-3p expression was higher in patients with progressive disease compared to patients with disease control after FOLFIRINOX (Log2 fold difference (FD) 0.88, p = 0.006). MiR-194-5p expression after one cycle of FOLFIRINOX was lower in patients with progressive disease (Log2 FD −0.29, p = 0.044). Both miRNAs were predictors of early tumor progression in a multivariable model including disease stage and baseline CA19-9 level (miR-373-3p odds ratio (OR) 3.99, 95% CI 1.10–14.49; miR-194-5p OR 0.91, 95% CI 0.83–0.99). MiR-373-3p and miR-194-5p did not show an association with OS after adjustment for disease stage, baseline CA19-9, and chemotherapy response. In conclusion, high serum miR-373-3p before the start and low serum miR-194-5p after one cycle are associated with early tumor progression during FOLFIRINOX.</p
Differing time-orders of inflammation decrease between ACPA subsets in RA patients suggest differences in underlying inflammatory pathways
No full textObjectives: Advanced imaging modalities have shown that not only joints but also bones and tendon sheaths can be inflamed at diagnosis of RA. We aimed to better understand the time-order in which the inflamed tissues respond to DMARD treatment. Also, because ACPA status may reflect a different pathophysiology, differences in time-order of inflammation decrease were hypothesized between these disease types. Methods: A total of 216 consecutive patients presenting with RA (n = 176) or undifferentiated arthritis (n = 40), who all started with conventional synthetic DMARD treatment, were studied. 1.5T contrast-enhanced hand and foot MRIs were performed before treatment and after 4, 12 and 24 months. Cross-lagged models evaluated the influence of two time patterns: a simultaneous pattern ('change in one inflammatory feature associated with change in another feature') and a subsequent pattern ('change in one inflammatory feature preceded change in another feature'). ACPA stratification was performed. Results: The median symptom duration at presentation was 13 weeks. Forty-four percent of patients was ACPA-positive. All pairs of inflammatory features decreased simultaneously in all time intervals (0-4/4-12/12-24 months; P < 0.05). Moreover, time-orders were identified: synovitis decrease preceded tenosynovitis decrease (0-4 to >4-12 months; P = 0.02 and 4-12 to >12-24 months; P = 0.03). Largely similar results were obtained in both ACPA subgroups. Additionally, in ACPA-positive but not ACPA-negative patients, synovitis decrease preceded osteitis decrease (4-12 to >12-24 moths; P = 0.002). Conclusion: This study increased the understanding of the response to treatment on the tissue level. In addition to simultaneous decrease of inflammation, synovitis decrease preceded tenosynovitis decrease. Differences in time-order of inflammation decrease between ACPA subgroups suggest differences in underlying inflammatory pathways. </p
Hyponatremia Intervention Trial (HIT)
No full textBackground: Hyponatremia is the most common electrolyte disorder with a prevalence of up to 30% in hospitalized patients. In contrast to acute hyponatremia where the need for immediate treatment is well-recognized, chronic hyponatremia is often considered not clinically relevant. This is illustrated by reports showing that appropriate laboratory tests are ordered in <50% of patients and that up to 75% are still hyponatremic at discharge. At the same time, emerging evidence suggests an association between hyponatremia and adverse events including increased risk of mortality and rehospitalization. Methods: This is a randomized (1:1 ratio) controlled, superiority, parallel-group international multi-center trial with blinded outcome assessment. In total 2,278 participants will be enrolled. Participants will be randomly assigned to undergo either targeted correction of plasma sodium levels or standard of care during hospitalization. The primary outcome is the combined risk of death or re-hospitalization within 30 days. Discussion: All data on hyponatremia and mortality are derived from observational studies and often lack methodologic robustness. Consequently, the direct impact of hyponatremia on mortality and rehospitalization risk is still debated, resulting in a clinical equipoise whether in-hospital chronic hyponatremia should be treated or not. Therefore, a randomized controlled trial is required to study whether targeted plasma sodium correction reduces the risk of mortality and rehospitalization associated with hyponatremia. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03557957.</p