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Clostridium difficile infection (CDI) is the most common infectious disease related to antibiotic-associated diarrhoea and is a current leading cause of morbidity/mortality, with substantial consequences for healthcare services and overall public health. Thus, we performed a retrospective epidemiological study of CDI for a long period (8 years), in an infectious hospital located in north-western Romania, which serves an entire county of the country (617,827 inhabitants). From 2011 to 2018, 877 patients were diagnosed with CDI; the mean incidence of this disease was 2.76 cases/10,000 patient-days, with an increasing trend in the annual incidence until 2016, at which point there was a decrease. The most commonly afflicted were patients in the 75–84 age group, observed in winter and spring. The results show that the antibiotics were administered in 679 (77.42%) subjects, within the last 3 months before CDI, statistically significant more than proton-pump inhibitors (PPIs)—128 (14.60%) and antidepressant medications—60 (6.84%), which were administered during the same period (p < 0.001). No medication was reported in 10 (6.84%) cases of CDI, in the last 3 months of the study. The fatality rate attained 4.1%, tripling in 2018 vs. 2011. CDI became a significant public health conundrum that can, nevertheless, be combatted through a judicious use of antibiotics.

ObjectiveTo examine trends in end-of-life communication with people with cancer in general practice.MethodsMortality follow-back survey among general practitioners (GPs) in representative epidemiological surveillance networks in Belgium (BE), the Netherlands (NL) and Spain (ES) in 2009–2010 (ES: 2010–2011) and 2013–2014. Using a standardised form, GPs registered all deceased adult patients in their practice and reported for five end-of-life care topics whether they had been discussed with the patient. Non-sudden cancer deaths were included (n=2306; BE: 1233; NL: 729; ES: 344).ResultsA statistically significant increase was found between 2009/2010 and 2014 in the prevalence of communication about diagnosis (from 84% to 94%) and options for end-of-life care (from 73% to 90%) in BE, and in GPs’ awareness of patients’ preferences for medical treatment and a proxy decision-maker in BE (from 41% and 20% up to 53% and 28%) and the NL (from 62% and 32% up to 70% and 52%). Communication about options for end-of-life care and psychosocial problems decreased in the NL (from 88% and 91% down to 73%) and ES (from 76% and 77% down to 26% and 39%).ConclusionConsiderable change in GP–patient communication seems possible in a relatively short time span, but communication cannot be assumed to increase over time. Increasing specialisation of care and task differentiation may lead to new roles in communication for healthcare providers in primary and secondary care. Improved information sharing between GPs and other healthcare providers may be necessary to ensure that patients have the chance to discuss important end-of-life topics.

Palliative care is increasingly confronted with cultural diversity. This can lead to various problems in practice. In this perspective article, the authors discuss in more detail which issues play a role in culture-sensitive palliative care, why naive culturalism will not solve such problems and in which direction research into this aspect of care can be further elaborated.

CTGrepeat expansion (CTGexp) is associated with aberrant alternate splicing that contributes to cardiac dysfunction in myotonic dystrophy type 1 (DM1). Excision of thisCTGexprepeat using CRISPR-Cas resulted in the disappearance of punctate ribonuclear foci in cardiomyocyte-like cells derived from DM1-induced pluripotent stem cells (iPSCs). This was associated with correction of the underlying spliceopathy as determined byRNA sequencingand alternate splicing analysis. Certain genes were of particular interest due to their role in cardiac development, maturation, and function (TPM4,CYP2J2,DMD,MBNL3,CACNA1H,ROCK2,ACTB) or their association with splicing (SMN2,GCFC2,MBNL3). Moreover, while comparing isogenic CRISPR-Cas9-corrected versus non-corrected DM1 cardiomyocytes, a prominent difference in the splicing pattern for a number of candidate genes was apparent pertaining to genes that are associated with cardiac function (TNNT,TNNT2,TTN,TPM1,SYNE1,CACNA1A,MTMR1,NEBL,TPM1),cellular signaling(NCOR2,CLIP1,LRRFIP2,CLASP1,CAMK2G), and other DM1-related genes (i.e.,NUMA1,MBNL2,LDB3) in addition to the disease-causingDMPKgene itself. Subsequent validation using a selected gene subset, includingMBNL1,MBNL2,INSR,ADD3, andCRTC2, further confirmed correction of the spliceopathy followingCTGexprepeat excision. To our knowledge, the present study provides the first comprehensive unbiased transcriptome-wide analysis of the differential splicing landscape in DM1 patient-derived cardiac cells after excision of theCTGexprepeat using CRISPR-Cas9, showing reversal of the abnormal cardiac spliceopathy in DM1.

Lyophilization is commonly used in the production of pharmaceutical compounds to increase the stability of the Active Pharmaceutical Ingredient (API) by removing solvents. This study investigates the possibility to lyophilize an anti-HER2 and an anti-MMR single-domain antibody fragment (sdAb)-based precursor as a first step in the development of a diagnostic kit for PET imaging. Methods NOTA-sdAb precursors have been lyophilized with the following formulation: 100 µg NOTA-sdAb in 0.1 M NaOAc (NaOAc), 5% (w/v%) mannitol-sucrose mix at a 2:1 ratio and 0.1 mg/mL polysorbate 80. During development of the formulation and drying cycle, factors such as cake appearance, glass transition temperature and residual moisture were analyzed to ensure qualitative and stable lyophilized samples. Stability studies of lyophilized precursor were conducted up to 18 months after storage at 2–8 °C by evaluating the precursor integrity, aggregation, functionality and 68Ga-labeling efficiency. A comparative biodistribution study (lyophilized vs non-lyophilized precursor) was conducted in wild type mice (n = 3) and in tumor bearing mice (n = 6). Results The lyophilized NOTA-anti-HER2 precursor shows consistent stability data in vitro for up to 12 months at 2–8 °C in three separate batches, with results indicating stability even for up to T18m. No aggregation, degradation or activity loss was observed. Radiochemical purity after 68Ga-labeling is consistent over a period of 12 months (RCP ≥ 95% at T12m). In vivo biodistribution analyses show a typical [68Ga]Ga-NOTA-anti-HER2 sdAb distribution profile and a comparable tumor uptake for the lyophilized compound vs non-lyophilized (5.5% vs 5.7 %IA/g, respectively). In vitro results of lyophilized NOTA-anti-MMR precursor indicates stability for up to 18 months, while in vivo data show a comparable tumor uptake (2.5% vs 2.8 %IA/g, respectively) and no significant difference in kidney retention (49.4% vs 47.5 %IA/g, respectively). Conclusion A formulation and specific freeze-drying cycle were successfully developed to lyophilize NOTA-sdAb precursors for long-term storage at 2–8 °C. In vivo data show no negative impact of the lyophilization process on the in vivo behavior or functionality of the lyophilized precursor. These results highlight the potential to develop a kit for the preparation of 68Ga-sdAb-based radiopharmaceuticals.

Objectives The purpose of this study was to determine the relationship between the changes in diastolic function and their association with cardiac biomarkers in the perioperative period in patients undergoing complex endovascular aortic repair. Design Prospective observational study. Setting Single-center academic hospital, central teaching hospital in Warsaw, Poland. Participants The study comprised 27 high-risk patients scheduled for elective endovascular repair of aortic aneurysm. Interventions Complex endovascular procedure using branched endograft of the thoracoabdominal aorta. Branches of the stent grafts included renal arteries, the superior mesenteric artery, and the celiac trunk. Measurements and Main Results The primary outcome was to evaluate changes in diastolic function parameters assessed with transthoracic echocardiography at two and 24 hours postoperatively. The major secondary outcomes were changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) and troponin I concentrations, systolic function parameters, hemodynamic parameters at two and 24 hours, length of hospital stay, and 30-day mortality. There was a reduction in e’ wave velocity on both the septal and lateral sides at two hours compared with the baseline (p = 0.041 and p = 0.05, respectively). There was an increase in both NT-proBNP and troponin I concentrations after surgery (p = 0.002 and p = 0.034, respectively), with troponin I peaking two hours after surgery and NT-proBNP peaking 24 hours after surgery. Conclusions Patients undergoing a branched endovascular aortic repair of a thoracoabdominal aortic aneurysm experience a cardiac insult that manifests with deterioration in diastolic parameters and concomitant increases of troponin and NT-proBNP concentrations. Additional large-scale prospective studies are required to confirm this phenomenon.

Haplophyllum tuberculatum is a plant commonly used in folk medicine to treat several diseases including vomiting, nausea, infections, rheumatism, and gastric pains. In the current study, H. tuberculatum essential oils, hydrosols, the pure compounds R-(+)-limonene, S-(−)-limonene, and 1-octanol, as well as their combinations R-(+)-limonene/1-octanol and S-(−)-limonene/1-octanol, were screened for their cytotoxicity on HEp-2 cells after 24, 48, and 72 h, and then tested for their activity against Coxsackievirus B3 and B4 (CV-B3 and CV-B4) at 3 different moments: addition of the plant compounds before, after, or together with virus inoculation. Results showed that the samples were more cytotoxic after 72 h than after 24 h or 48 h cell contact. However, the combinations R-(+)-limonene/1-octanol and S-(−)-limonene/1-octanol showed less effect on HEp-2 cells than pure R-(+)-limonene and S-(−)-limonene after 24 h, 48 h, and 72 h. 1-octanol exhibited the highest concentration causing 50% cytotoxicity (CC50) on HEp-2 cells after 24 h (CC50 = 93 µg/mL) and 48 h (CC50 = 83 µg/mL). The antiviral assays showed that the tested samples exhibited potent inhibition of CV-B. IC50 values ranged from 0.66 µg/mL to 28.4 µg/mL. In addition, CV-B3 was more sensitive than CV-B4. Both CV-B strains are more inhibited when cells were pretreated with the plant compounds. The hydrosols have no effect, neither on HEp-2 cells nor on the virus. 1-octanol, S-(−), and R-(+)-limonene/1-octanol had important selectivity indexes over time. Although essential oils had potent antiviral activity, they can be considered for application in the pretreatment of cells. However, 1-octanol and the combinations are within the safety limits, and thus, they can be used as an active natural antiviral agent for CV-B3 and CV-B4 inhibition.

Background Several volar plating techniques exist to treat distal radial fractures. Question We investigated minimally invasive plate osteosynthesis (MIPO) with pronator quadratus (PQ) sparing versus conventional flexor carpi radialis approach for volar plating with PQ repair after distal radial fractures during the first postoperative year. Patients and Methods Prospective data of two consecutive cohorts were compared: 62 patients in MIPO group with an average age of 61.2 years and 66 patients in PQ repair group with an average age of 61.4 years completed the entire follow-up period. Results Range of motion was not significantly different, except flexion–extension that was significantly higher in the MIPO group. Quick Disabilities of the Arm, Shoulder and Hand was significantly lower in the MIPO group. Pain visual analogue scale was only significantly lower at 6 weeks. Grip strength measurements and patient satisfaction were not significantly different. Conclusions MIPO volar plating with PQ sparing is a surgical technique that can be chosen according to surgeon's preference and expertise, resulting in a better flexion–extension mobility and function score according to our study. Level of evidence This is a Level 3 study.

Introduction: In patients with metastatic melanoma, progression of a single tumour lesion (solitary progression) after response to immune checkpoint inhibition (ICI) is increasingly treated with local therapy. We evaluated the role of local therapy for solitary progression in melanoma.Patients and methods: Patients with metastatic melanoma treated with ICI between 2010 and 2019 with solitary progression as first progressive event were included from 17 centres in 9 countries. Follow-up and survival are reported from ICI initiation.Results: We identified 294 patients with solitary progression after stable disease in 15%, partial response in 55% and complete response in 30%. The median follow-up was 43 months; the median time to solitary progression was 13 months, and the median time to subsequent progression after treatment of solitary progression (TTSP) was 33 months. The estimated 3-year overall survival (OS) was 79%; median OS was not reached. Treatment consisted of systemic therapy (18%), local therapy (36%), both combined (42%) or active surveillance (4%). In 44% of patients treated for solitary progression, no subsequent progression occurred. For solitary progression during ICI (n = 143), the median TTSP was 29 months. Both TTSP and OS were similar for local therapy, ICI continuation and both combined. For solitary progression post ICI (n = 151), the median TTSP was 35 months. TTSP was higher for ICI recommencement plus local therapy than local therapy or ICI recommencement alone (p = 0.006), without OS differences.Conclusion: Almost half of patients with melanoma treated for solitary progression after initial response to ICI had no subsequent progression. This study suggests that local therapy can benefit patients and is associated with favourable long-term outcomes. & ordf;2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Background Quality human resources constitute an essential pillar of an effective health system. This paper analyzes the outcomes of blended learning for post-Ebola capacity strengthening of health professionals in Guinea. Methods Two courses lasting 3 months each (7–8 modules) were developed and implemented: one in Primary Health Care (eSSP) and the other in Sexual and Reproductive Health Services Management (eSSR). Both eSSP and eSSR courses were offered online on the Moodle platform, followed by a face-to-face capacity-building workshop. A cross-sectional study using a mixed-methods approach was conducted in 2018–19. As outcomes, we described learners’ sociodemographic characteristics, course completion and success, and perceptions of the courses and support from the instructors, analyzed the factors associated with learners’ successful completion and reported on learners’ feedback on their blended learning experience. Quantitative data were analyzed using the STATA 15 software, and qualitative data were analyzed through content analysis. Results Overall, 282 health professionals were enrolled for both eSSP and eSSR courses. The completion rate was 69.5% (196/282). The success rate for learners who completed the courses was 80% (156/196), and the overall success rate for enrollees was 55% (156/282). The dropout and abstention rates were 22 and 9%, respectively. On both eSSP and eSSR courses, the success rate of women enrolled was higher than or equal to men’s. The success rate of medical doctors enrolled (53% for eSSP and 67% for eSSR) was higher than for other health professionals, in particular nurses (9% for eSSP) and midwives (40% for eSSR). Course type was associated with success (AOR = 1.93; 95% CI = 1.15–3.24). Most learners strongly agreed that the courses are relevant for targeted health professionals (81 to 150/150), pdf course materials are well-structured and useful (105/150), the content of the modules is relevant, comprehensible, and clear (90/150), self-assessment quizzes are helpful (105/150), summative assessment assignments are relevant (90/150), the course administrators and IT manager were responsive to learners’ concerns (90/150), they will recommend the courses to colleagues and friends (120/150). Conclusion Two blended courses for capacity strengthening of health professionals were successfully developed and implemented in Guinea.

There are multiple imaging modalities in primary hyperparathyroidism. Ultrasound examination and subtraction scintigraphy are usually the first-line imaging techniques. When these results are negative or inconsistent, additional [11C]-methionine PET/CT (MET-PET/CT) or 4-dimensional computed tomography can be performed. ​This study aims to evaluate MET-PET/CT in comparison with other imaging techniques in primary hyperparathyroidism. This is a retrospective cohort study. Eighty-four patients with primary hyperparathyroidism, who underwent parathyroid surgery, were included. ​Imaging results have been correlated to the perioperative drop in parathyroid hormone level and to the pathological analysis. ​Descriptive statistics are used, supplemented with 95% Clopper–Pearson confidence intervals for sensitivity and specificity and a sub-analysis with the McNemar test on paired data only. The per-lesion sensitivity of MET-PET/CT seems higher than that of [99mTc]-sestamibi or [99mTc]-tetrofosmin and [99mTc]-pertechnetate subtraction scintigraphy. The McNemar test, on paired data only, shows significantly higher sensitivity of MET-PET/CT compared to ultrasound (p=0.039) and significantly higher specificity of ultrasound compared to subtraction scintigraphy (p=0.035).​ MET-PET/CT after inconclusive or negative ultrasound and/or subtraction scintigraphy has an additional value in 70% of the cases.​ Preoperative parathyroid hormone levels were higher in patients in whom MET-PET/CT correctly predicted the pathological parathyroid glands, compared to those where MET-PET/CT missed at least one adenoma. The same trend was seen for 4-dimensional computed tomography. In conclusion, MET-PET/CT seems a valuable imaging modality in primary hyperparathyroidism, at least as second line imaging approach, with a higher per-lesion sensitivity than ultrasound in such setting. Especially when ultrasound and/or subtraction scintigraphy are inconclusive or negative, MET-PET/CT directs the surgeon to the correct localization of the parathyroid adenoma.

INTRODUCTION: 13 C-breath tests are valuable, noninvasive diagnostic tests that can be widely applied for the assessment of gastroenterological symptoms and diseases. Currently, the potential of these tests is compromised by a lack of standardization regarding performance and interpretation among expert centers. METHODS: This consensus-based clinical practice guideline defines the clinical indications, performance, and interpretation of 13 C-breath tests in adult and pediatric patients. A balance between scientific evidence and clinical experience was achieved by a Delphi consensus that involved 43 experts from 18 European countries. Consensus on individual statements and recommendations was established if ≥ 80% of reviewers agreed and

Objective:To compare actual patient presentation rates from Belgium’s largest public open-air cultural festival with predictions provided by existing models and the Belgian Plan Risk Manifestations model.Methods:Retrospectively, actual patient presentation rates gathered from the Ghent Festivities (Belgium) during 2013–2019 were compared to predicted patient presentation rates by the Arbon, Hartman, and PRIMA models.Results:During 7 editions, 8673000 people visited the Ghent Festivities; 9146 sought medical assistance resulting in a mean patient presentation rate (PPR) of 1.05. The PRIMA model overestimated the number of patient encounters for each occasion. The other models had a high rate of underprediction. When comparing deviations in predictions between the PRIMA model to the other models, there is a significant difference in the mean deviation (Arbon: T = 0.000, P < 0.0001, r = −0.8701; Hartman: T = 0.000, P < 0.0001, r = −0.869).Conclusion:Despite the differences between the predictions of all 3 models, our results suggest that the PRIMA model is a valid tool to predict patient presentations to IEHS during public cultural MG. However, to substantiate the PRIMA model even further, more research is needed to further validate the model for a broad range of MG.

Item does not contain fulltext BACKGROUND: Catheter ablation for persistent atrial fibrillation (persAF) is associated with less favorable outcomes than for paroxysmal AF. To improve success rates, left atrial (LA) substrate modification is frequently performed in addition to pulmonary vein isolation (PVI). The purpose of the study was to compare 4 different ablation approaches using radiofrequency catheter ablation (RFCA) or cryoballoon ablation (CB-A) for persAF and to evaluate the respective outcomes on a midterm follow-up of 12 months. METHODS: We did a propensity score-matched comparison of 30 patients undergoing PVI + LA posterior wall isolation (LAPWI) with CB-A, 30 patients who underwent PVI + linear ablation (roof and mitral lines) using RFCA, 60 patients with PVI alone using CB-A, and 60 patients who had PVI alone using RFCA. The endpoint was recurrence of documented atrial tachyarrhythmias (ATas) > 30 s at 1-year follow-up. RESULTS: After 12 months, freedom from ATas after a single procedure was 83.3% in the PVI + LAPWI group, 46.7% in the PVI + linear ablation group, 58.3% in the PVI-alone CB-A group, and 61.6% PVI-alone RFCA (p = 0.03). Moreover, freedom from ATas was significantly higher comparing the PVI + LAPWI group with each of the other groups. CONCLUSIONS: In this propensity-matched comparison of strategies for persAF, LAPW ablation in addition to PVI with CB-A seems to improve 1-year outcome in comparison to PVI + linear ablation using RFCA and to PVI alone using RFCA or CB-A. Randomized comparisons are eagerly awaited.

Parasitic leiomyomas are a rare subtype of subserosal uterine leiomyomas and are mostly found incidentally. Diagnosis is challenging and treatment consists out of complete surgical resection. Cases are few in women without history of uterine surgery. In this extraordinary case, a 56-year-old menopausal female suffering from backache and abdominal swelling, was suspected to have a huge malignant ovarian tumor. She underwent a resection of the mass along with hysterectomy and bilateral salpingo-oöphorectomy. Histopathology revealed a gigantic leiomyoma of 19.1 kg in the broad ligament. This unique case suggests taking this diagnosis into account in future clinical cases presenting with large abdominal masses even without previous uterine surgery.

Multiple myeloma (MM) is an (epi)genetic highly heterogeneous plasma cell malignancy that remains mostly incurable. Deregulated expression and/or genetic defects in epigenetic-modifying enzymes contribute to high-risk disease and MM progression. Overexpression of the histone methyltransferase G9a was reported in several cancers, including MM, correlating with disease progression, metastasis, and poor prognosis. However, the exact role of G9a and its interaction partner G9a-like protein (GLP) in MM biology and the underlying mechanisms of action remain poorly understood. Here, we report that high G9a RNA levels are associated with a worse disease outcome in newly diagnosed and relapsed MM patients. G9a/GLP targeting using the specific G9a/GLP inhibitors BIX01294 and UNC0638 induces a G1-phase arrest and apoptosis in MM cell lines and reduces primary MM cell viability. Mechanistic studies revealed that G9a/GLP targeting promotes autophagy-associated apoptosis by inactivating the mTOR/4EBP1 pathway and reducing c-MYC levels. Moreover, genes deregulated by G9a/GLP targeting are associated with repressive histone marks. G9a/GLP targeting sensitizes MM cells to the proteasome inhibitors (PIs) bortezomib and carfilzomib, by (further) reducing mTOR signaling and c-MYC levels and activating p-38 and SAPK/JNK signaling. Therapeutic treatment of 5TGM1 mice with BIX01294 delayed in vivo MM tumor growth, and cotreatment with bortezomib resulted in a further reduction in tumor burden and a significantly prolonged survival. In conclusion, we provide evidence that the histone methyltransferases G9a/GLP support MM cell growth and survival by blocking basal autophagy and sustaining high c-MYC levels. G9a/GLP targeting represents a promising strategy to improve PI-based treatment in patients with high G9a/GLP levels.

Necrotizing enterocolitis (NEC) is a disease with high morbidity and mortality that occurs mainly in premature born infants. The pathophysiologic mechanisms indicate that gastrointestinal dysbiosis is a major risk factor. We searched for relevant articles published in PubMed and Google Scholar in the English language up to October 2020. Articles were extracted using subject headings and keywords of interest to the topic. Interesting references in included articles were also considered. Network meta-analysis suggests the preventive efficacy of Bifidobacterium and Lactobacillus spp., but even more for mixtures of Bifidobacterium, Streptococcus, and Bifidobacterium, and Streptococcus spp. However, studies comparing face-to-face different strains are lacking. Moreover, differences in inclusion criteria, dosage strains, and primary outcomes in most trials are major obstacles to providing evidence-based conclusions. Although adverse effects have not been reported in clinical trials, case series of adverse outcomes, mainly septicemia, have been published. Consequently, systematic administration of probiotic bacteria to prevent NEC is still debated in literature. The risk-benefit ratio depends on the incidence of NEC in a neonatal intensive care unit, and evidence has shown that preventive measures excluding probiotic administration can result in a decrease in NEC.

Background Guinea undertook health workforce reform in 2016 following the Ebola outbreak to overcome decades-long shortages and maldistribution of healthcare workers (HCWs). Specifically, over 5000 HCWs were recruited and deployed to rural health districts and with a signed 5-year commitment for rural medical practice. Governance structures were also established to improve the supervision of these HCWs. This study assessed the effects of this programme on local health systems and its influence on HCWs turnover in rural Guinea. Methods An exploratory study design using a mixed-method approach was conducted in five rural health districts. Data were collected through semi-structured questionnaires, in-depth interview guides, and documentary reviews. Results Of the 611 HCWs officially deployed to the selected districts, 600 (98%) took up duties. Female HCWs (64%), assistant nurses (39%), nurses (26%), and medical doctors (20%) represented the majority. Findings showed that 69% of HCWs were posted in health centres and the remaining in district hospitals and the health office (directorate); the majority of which were medical doctors, nurses, and midwives. The deployment has reportedly enhanced quality and timely data reporting. However, challenges were faced by local health authorities in the posting of HCWs including the unfamiliarity of some with primary healthcare delivery, collaboration conflicts between HCWs, and high feminization of the recruitment. One year after their deployment, 31% of the HCWs were absent from their posts. This included 59% nurses, 29% medical doctors, and 11% midwives. The main reasons for absenteeism were unknown (51%), continuing training (12%), illness (10%), and maternity leave (9%). Findings showed a confusion of roles and responsibilities between national and local actors in the management of HCWs, which was accentuated by a lack of policy documents. Conclusion The post-Ebola healthcare workers policy appears to have been successfully positive in the redistribution of HCWs, quality improvement of staffing levels in peripheral healthcare facilities, and enhancement of district health office capacities. However, greater attention should be given to the development of policy guidance documents with the full participation of all actors and a clear distinction of their roles and responsibilities for improved implementation and efficacy of this programme.

PD-1 Immune checkpoint inhibitors, such as Pembrolizumab, can have a durable beneficial therapeutic effect in patients with advanced melanoma. However, not all patients will benefit equally from these therapies, and (potentially life-threatening) immune-related adverse events may occur. In this study, we investigate the value of early response assessment by FDG-PET/CT as a biomarker for predicting survival. We identified all patients with advanced melanoma who were treated with Pembrolizumab in our medical center and underwent a baseline and at least one follow-up FDG-PET/CT. The total metabolic tumor volume (TMTV) was calculated, and the evolution was compared to survival parameters. A total of 77 patients underwent a baseline and at least one follow-up FDG-PET/CT, 36 patients had follow-up imaging within 2–4 months, and 21 patients an FDG-PET/CT 5–6 months after baseline. When the TMTV evolution was categorized into two subgroups (stable/decrease versus increase), an association was found between stability or decrease in TMTV and better PFS and OS. A similar trend, however non-significant, was observed at 5–6 months. The evolution in TMTV as assessed by FDG-PET/CT 2–4 months after treatment initiation is associated with long-term outcomes in patients with advanced melanoma treated with Pembrolizumab.

Background: Secondary lymphedema (LE) can occur after breast cancer (BC) therapy with axillary lymph node surgery and/or radiotherapy. Reported incidence varies around 20%. The aim of this study was to see whether low-energy extracorporeal shockwave therapy (ESWT) is a therapeutic option in end-stage secondary upper limb fibro-LE. Methods and Results: A pilot study was performed on 10 adult patients who presented with an end-stage LE after BC treatment. They were all treated with usual physical therapy and all had lymphatic surgery before. Eight sessions of ESWT were applied, 2600 shocks at 0.1 mJ/mm2, 2/week during 4 weeks. Upper limb volume decreased nonsignificantly, from 3086.4 ± 539.47 to 2909.1 ± 471.60 mL. Mean circumference of the upper limb was significantly decreased from 32.3 ± 3.01 to 31.4 ± 2.71 cm at the height of the upper arm, from 29.1 ± 2.89 to 28.1 ± 2.71 cm at the height of the elbow, and from 27.5 ± 4.08 to 26.8 ± 3.75 cm at the height of the forearm. Subjective measurements by visual analog scale showed significant decrease in both hardness from 57.3 ± 15.84 to 24.4 ± 21.89 mm and subjective feeling of edema from 44.2 ± 16.90 to 23.2 ± 21.16 mm. No adverse features were reported. Conclusion: We added some evidence that low-energy ESWT is well supported and has additional benefits also in longstanding fibro-lipo-LE on swelling of the arm leading to more subjective comfort for the patients.

Graph-theoretical analysis is a novel tool to understand the organisation of the brain.We assessed whether altered graph theoretical parameters, as observed in multiple sclerosis (MS), reflect pathology-induced restructuring of the brain's functioning or result from a reduced signal quality in functional MRI (fMRI). In a cohort of 49 people with MS and a matched group of 25 healthy subjects (HS), we performed a cognitive evaluation and acquired fMRI. From the fMRI measurement, Pearson correlation-based networks were calculated and graph theoretical parameters reflecting global and local brain organisation were obtained. Additionally, we assessed metrics of scanning quality (signal to noise ratio (SNR)) and fMRI signal quality (temporal SNR and contrast to noise ratio (CNR)). In accordance with the literature, we found that the network parameters were altered in MS compared to HS. However, no significant link was found with cognition. Scanning quality (SNR) did not differ between both cohorts. In contrast, measures of fMRI signal quality were significantly different and explained the observed differences in GTA parameters. Our results suggest that differences in network parameters between MS and HS in fMRI do not reflect a functional reorganisation of the brain, but rather occur due to reduced fMRI signal quality.

Background: Trauma-based psychotherapy is a first line treatment for post-traumatic stress disorder (PTSD) but not all patients achieve long-term remission. Transcranial direct current stimulation (tDCS) received considerable attention as a neuromodulation method that may improve trauma-based psychotherapy. Objective: We explored the effects of repeated anodal tDCS over the prefrontal cortex (PFC) on fear extinction in mice as a preclinical model for trauma-based psychotherapy. Methods: We performed auditory fear conditioning with moderate or high shock intensity on C57BL6/J mice. Next, mice received anodal tDCS (0.2 mA, 20 min) or sham stimulation over the PFC twice daily for five consecutive days. Extinction training was performed by repeatedly exposing mice to the auditory cue the day after the last stimulation session. Early and late retention of extinction were evaluated one day and three weeks after extinction training respectively. Results: We observed no significant effect of tDCS on the acquisition or retention of fear extinction in mice subjected to fear conditioning with moderate intensity. However, when the intensity of fear con-ditioning was high, tDCS significantly lowered freezing during the acquisition of extinction, regardless of the extinction protocol. Moreover, when tDCS was combined with a strong extinction protocol, we also observed a significant improvement of early extinction recall. Finally, we found that tDCS reduced generalized fear induced by contextual cues when the intensity of conditioning is high and extinction training limited. Conclusions: Our data provide a rationale to further explore anodal tDCS over the PFC as potential support for trauma-based psychotherapy for PTSD. (c) 2021 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Little is known about the association between terrorism and suicide. This study investigates suicide numbers in Flanders, Belgium before and after the Paris-attacks (13/11/2015) and Brussels-attacks (22/03/2016). Population mortality data for suicide were gathered from the Agency for healthcare. Suicides in Flanders, Belgium, were higher after both attacks. The increase was higher after the Paris-attacks, compared to the attacks in Brussels, Belgium. The effect of a close-by, but still foreign attack (the Paris-attacks in France) on suicide numbers is larger than that of an attack inside the country (the Brussels-attacks), possibly due to a difference in threat experience and coping possibilities.

Background An increasing number of women wish breast implant removal whilst maintaining an acceptable projection and form were possible. Objectives The authors propose a technique to remodel the breast after implant removal utilizing internal suture loops to project the breast, recruit abdominal and axillary tissue cranially and medially, and provide a matrix for lipofilling. Methods A prospective analysis was performed of consecutive patients undergoing implant extraction followed by power-assisted liposuction loops and lipofilling. Patient characteristics were measured. The aesthetic results were evaluated by 2 independent raters. Patient-reported satisfaction was measured by standardized questionnaires. Results Implants in 52 patients with an average age of 55 and body mass index of 23.7 were extracted followed by breast remodeling. A total of 73% of patients had implants for aesthetic reasons, 41% were smokers, and 43% of the reconstruction cases received radiotherapy. A total of 28% had implant extraction for rupture, 58% for capsular contracture, and 14% due to pain and migration. The average volume of the implants removed was 292 cc, followed by an average lipofilling of 223 cc, yielding a ratio of 0.76 to 1. The average tissue recruited by loops was 82.5 cc. Independent raters measured 79% of results as good, 13% as acceptable, and 8% as requiring improvement; 80% of patients were satisfied to very satisfied. Conclusions The authors propose implant extraction followed by power-assisted liposuction loops and lipofilling can provide footprint definition, sustained projection, and high patient satisfaction. Moreover, the recruitment of a vascularized adipo-cutaneous flap by loops allows a reduced ratio of fat grafting to implant volume. Level of Evidence: 4

Objectives: The number of electronic prescriptions (ePrescriptions) grows steadily in Belgium as in other European countries. In the future, Belgium wants to dematerialize the ePrescription flow, removing all paper trails. A quality check of the digital content and implementation of national ePrescription guidelines in the field was conducted, comparing the content at both prescription and pharmacy side. Methods: An explanatory mixed-methods design was applied. In a first phase, potential problems (warning flags) were identified by consulting stakeholders. Secondly, the warning flags were validated to problems (errors) in a random set of ePrescriptions collected in April 2019. In a third phase, explanatory interviews were held with various stakeholders in order to find explanations and to identify the initiators of these errors. Results: In the first phase, 15 warning flags were identified to evaluate the quality of an ePrescription. In the second phase, a random selection of 11,798 ePrescriptions was validated. The most prevalent errors found, were the digital construction of the messages (18.88%), combined with lots of necessarily deemed substitutions by the pharmacist (3.39%) not following what was prescribed originally. In the third phase, stakeholders indicated that software of the prescriber and the use of inconsistent databases between prescriber and pharmacy can often be seen as the cause and initiator of these problems. Conclusions: Use of authentic medication databases and well-designed software systems have the potential to solve ePrescription problems. Focus should go to prevention instead of detection.

PURPOSE: Tibial plateau fractures with the involvement of the posterior column are an important prognostic factor towards poor functional outcome. We aimed to assess the sporting abilities postoperatively with special emphasis on the type of sports and sport-specific movements, as well as time needed to resume sports, restricting factors in sports engagement, and patient satisfaction. We aimed to provide prognostic information on return to sports. METHODS: Demographic, clinical and radiological variables were retrospectively collected from 82 multicentric patients between 2014 and 2016. Prospectively, sporting abilities before and after surgery were determined using questionnaires at a mean follow-up of 33 months postoperatively. RESULTS: Involvement in sports significantly decreased, with only 68.4% of patients resuming sports (p

Aims Malformations of cortical development (MCD) include a heterogeneous spectrum of clinical, imaging, molecular and histopathological entities. While the understanding of genetic causes of MCD has improved with the availability of next‐generation sequencing modalities, genotype‐histopathological correlations remain limited. This is the first systematic review of molecular and neuropathological findings in patients with MCD to provide a comprehensive overview of the literature. Methods A systematic review was performed between November 2019 and February 2020. A MEDLINE search was conducted for 132 genes previously linked to MCD in order to identify studies reporting macroscopic and/or microscopic findings in patients with a confirmed genetic cause. Results Eighty‐one studies were included in this review reporting neuropathological features associated with pathogenic variants in 46 genes (46/132 genes, 34.8%). Four groups emerged, consisting of (1) 13 genes with well‐defined histological‐genotype correlations, (2) 27 genes for which neuropathological reports were limited, (3) 5 genes with conflicting neuropathological features, and (4) 87 genes for which no histological data were available. Lissencephaly and polymicrogyria were reported most frequently. Associated brain malformations were variably present, with abnormalities of the corpus callosum as most common associated feature. Conclusions Neuropathological data in patients with MCD with a defined genetic cause are available only for a small number of genes. As each genetic cause might lead to unique histopathological features of MCD, standardised thorough neuropathological assessment and reporting should be encouraged. Histological features can help improve the understanding of the pathogenesis of MCD and generate hypotheses with impact on further research directions.

Psychological stress is a risk factor for primary polydipsia in adolescents without psychiatric comorbidity. Taking a detailed family and social history can help to distinguish primary polydipsia from diabetes insipidus in adolescents with challenging presentations of polydipsia and polyuria.

Trapeziometacarpal instability is a well-known condition that could lead to trapeziometacarpal osteoarthritis. With the focus in the literature being on ligament insufficiency, bony deformity has received much less attention. Although trapezial tilt is currently used to measure trapezial dysplasia, we believe trapezial inclination is a more reliable measurement. The purpose of this study is to compare these two methods for evaluating trapezial dysplasia and to define the most reproducible measurement. Fifty patients were identified who had three consecutive radiographs of the trapeziometacarpal joint. Eaton views with little to no signs of osteoarthritis (Eaton stage I or II) were used. Both trapezial tilt and trapezial inclination were measured by two independent observers on three radiographs for every patient. Intra-observer variation, absolute agreement and consistency, and intra-observer variation and consistency were assessed for both measurements. Mean trapezial tilt was 135° and mean trapezial inclination was 10°. For both observers, intra-observer variation of trapezial inclination was significantly less than for trapezial tilt. Our study shows that mean trapezial inclination in a middle-aged adult population is approximately 10°. This measurement is more reproducible than the more frequently used trapezial tilt and may be a better parameter to define trapezial dysplasia and to guide its treatment.

OBJECTIVES: This health-economic evaluation aimed to assess the cost-effectiveness of a number of alternatives for preventive and curative oral health care in institutionalised older people in Flanders. METHODS: A six-state Markov model was used to compare expected costs and healthy oral years (HOYs) of four alternatives: (1) usual care; (2) on-site preventive care; (3) on-site preventive care + curative care in the community; and (4) on-site preventive care + on-site curative care. A healthcare payer perspective was adopted, and the time horizon was 10 years. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: Incremental cost-effectiveness ratios (ICERs) of alternatives 2, 3 and 4 (all compared to alternative 1) were as follows: (2) 7944 €/HOY gained; (3) 1576 €/HOY gained; and (4) 1132 €/HOY gained. Hence, alternatives 2 and 3 were not cost-effective compared to alternative 4. The probability that oral care interventions are more effective and cost-saving than usual care was

In vitro maturation (IVM) is an assisted reproduction technique with reduced hormone-related side-effects. Several attempts to implement IVM in routine practice have failed, primarily due to its relatively low efficiency compared with conventional in vitro fertilization (IVF). Recently, capacitation (CAPA)-IVM—a novel two-step IVM method—has improved the embryology outcomes through synchronizing the oocyte nuclear and cytoplasmic maturation. However, the efficiency gap between CAPA-IVM and conventional IVF is still noticeable especially in the numerical production of good quality embryos. Considering the importance of glucose for oocyte competence, its metabolization is studied within both in vivo and CAPA-IVM matured mouse cumulus-oocyte-complexes (COCs) through direct measurements in both cellular compartments, from transcriptional and translational perspectives, to reveal metabolic shortcomings within the CAPA-IVM COCs. These results confirmed that within in vivo COC, cumulus cells (CCs) are highly glycolytic, whereas oocytes, with low glycolytic activity, are deviating their glucose towards pentose phosphate pathway. No significant differences were observed in the CAPA-IVM oocytes compared with their in vivo counterparts. However, their CCs exhibited a precocious increase of glycolytic activity during the pre-maturation culture step and activity was decreased during the IVM step. Here, specific alterations in mouse COC glucose metabolism due to CAPA-IVM culture were characterized using direct measurements for the first time. Present data show that, while CAPA-IVM CCs are able to utilize glucose, their ability to support oocytes during final maturation is impaired. Future CAPA-IVM optimization strategies could focus on adjusting culture media energy substrate concentrations and/or implementing co-culture strategies.Summary sentence Pre-maturation culture conditions for immature oocytes from small antral follicles affect glycolytic activity and antioxidant defense capacity in mouse CCs during IVM.

Background The disease course of adult immunoglobulin A (IgA) vasculitis (IgAV; Henoch–Schönlein purpura) has not been well defined. Methods In a retrospective survey, we studied 85 adult IgAV patients with extended follow-up (median 43 months) for 67 patients. Results Only 33 of 67 (49%) achieved complete remission. Ongoing renal disease was the most common persistent organ manifestation, but extra-renal disease activity was also present in >50% of patients not achieving complete remission. Twenty-nine of 67 (43%) had relapsing disease, with 18/67 (27%) experiencing several relapses. Skin disease was the most common feature in relapsing patients, followed by nephritis. At 4 years of follow-up, 6 of 29 (21%) experienced progressive disease and 10/29 (34%) relapsing disease. Five of 67 (7%) developed nephritis after diagnosis, within the first 6 months of follow-up. At final follow-up, 10 of 67 (15%) had chronic kidney disease Stage ≥G3a, 18 (27%) haematuria and 13 (19%) proteinuria. No therapy appeared particularly effective and only 6/17 patients treated with mycophenolate mofetil experienced a good response. Conclusions The disease course of adult IgAV is different from that seen in children, with higher frequency of persisting and relapsing disease. Renal disease is the main determinant of ongoing disease activity, but extra-renal features were seen in >50% of patients with chronic disease activity. No clear conclusions on use or choice of immunosuppressive agent could be made based on our experience.

Background Pituitary carcinomas are rare but aggressive and require maximally coordinated multimodal therapies. For refractory tumors, unresponsive to temozolomide (TMZ), therapeutic options are limited. Immune checkpoint inhibitors (ICI) may be considered for treatment as illustrated in the present case report. Case We report a patient with ACTH-secreting pituitary carcinoma, progressive after multiple lines of therapy including chemotherapy with TMZ, who demonstrated disease stabilization by a combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) ICI therapy. Discussion Management of pituitary carcinoma beyond TMZ remains ill-defined and relies on case reports. TMZ creates, due to hypermutation, more immunogenic tumors and subsequently potential candidates for ICI therapy. This case report adds support to the possible role of ICI in the treatment of pituitary carcinoma. Conclusion ICI therapy could be a promising treatment option for pituitary carcinoma, considering the mechanisms of TMZ-induced hypermutation with increased immunogenicity, pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy.

Background Paroxysmal atrial fibrillation (PAF) can be triggered by non-pulmonary vein foci, like the superior vena cava (SVC). The latter is correlated with improved result in terms of freedom from atrial tachycardias (ATs), when electrical isolation of this vessel utilizing radiofrequency energy (RF) is achieved. Objectives Evaluate the clinical impact, in patients with PAF, of the SVC isolation (SVCi) in addition to ordinary pulmonary vein isolation (PVI) by means of the second-generation cryoballoon (CB) Methods A total of 100 consecutive patients that underwent CB ablation for PAF were retrospectively selected. Fifty consecutive patients received PVI followed by SVCi by CB application, and the following 50 consecutive patients received standard PVI. All patients were followed 12 months. Results The mean time to SVCi was 36.7 ± 29.0 s and temperature at SVC isolation was − 35 (− 18 to − 40) °C. Real-time recording (RTR) during SVCi was observed in 42 (84.0%) patients. At the end of 12 months of follow-up, freedom from ATs was achieved in 36 (72%) patients in the PVI only group and in 45 (90%) patients of the SVC and PV isolation group (Fisher’s exact test p = 0.039, binary logistic regression: p = 0.027, OR = 0.28, 95%CI = 0.09–0.86). In survival analysis, SVC and PV isolation group was also associated with improved freedom from ATs (log-rank test: p = 0.017, Cox regression: p = 0.026, HR = 0.31, 95%CI = 0.11–0.87). Conclusion Superior vena cava isolation with the CB in addition to PVI might improve freedom from ATs if compared to PVI alone at 1-year follow-up.

Purpose This study aimed to investigate the spatial relationship between low-voltage areas (LVAs) in bipolar voltage mapping (BVM) and localized complex conduction (LCC)-cores in a global, non-contact, charge-density-based imaging, and mapping system (AcM). Methods Patients with history of index PVI for PsAF and scheduled for a repeat ablation procedure for recurrence of the same arrhythmia were enrolled between August 2018 and February 2020. All patients underwent both substrate mappings of the left atrium (LA) with the CARTO 3D map-ping system and with AcM. Results Ten patients where included in our analysis. All presented with persistency of PVI in all veins at the moment of repeat procedure. There was no linear relationship in BVM maps between SR and CSd (correlation coefficient 0.31 ± 0.15), SR and CSp (0.36 ± 0.12) and CSd and CSp (0.43 ± 0.10). The % overlap of localized irregular activation (LIA), localized rotational activation (LRA) and Focal (F) regions with LVA was lower at 0.2 mV compared to 0.5 mV (4.97 ± 7.39%, 3.27 ± 5.25%, 1.09 ± 1.92% and 12.59 ± 11.81%, 7.8 ± 9.20%, 4.62 ± 5.27%). Sensitivity and specificity are not significantly different when comparing composite maps with different LVA cut-offs. AURC was 0.46, 0.48, and 0.39 for LIA, LRA, and Focal, respectively. Conclusion Due to wave front direction dependency, LVAs mapped with BVM in sinus rhythm and during coronary sinus pacing only partially overlap in patients with PsAF. LCC-cores mapped during PsAF partially co-localize with LVAs.

Currently, there is no doubt that the first choice of treatment for alarming infantile haemangiomas (IHs) is oral beta-blockers. However, research in this field remains active, as the pathogenesis of IH is still not completely elucidated. Furthermore, there are different approaches to the management of IHs with beta-blockers. In Part 1 of this review we will discuss the state-of-the-art evidence for IH with regard to (i) the definition, epidemiology, course, risk factors and sequelae, and (ii) the pathogenesis, focusing on genetic studies. This review will update the reader on the latest developments in the pathogenesis of IH. Furthermore, we hope this review will give more insight into risk factors and sequelae of IH, thereby contributing to better decisions in the clinical management of patients with IH. The therapy and evaluation of IHs will be discussed in Part 2 of this review.

Background: The glenoid track is a useful tool to predict engagement and therefore the risk of recurrence of dislocation in the presence of Hill-Sachs and/or bony Bankart lesions. To assess the glenoid track preoperatively, only methods using 3-dimensional reconstruction (3DR) have been described, but these lack a standardized, reliable, and easy description. Purpose/Hypothesis: The purpose was to evaluate a new method for determining the glenoid track using computed tomography (CT) scan with multiplanar reconstruction (MPR) in comparison with using 3DR images. Our hypothesis was that the MPR method would be easier to standardize and more reproducible. Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: A total of 52 patients whose arthro-CT scan revealed a Hill-Sachs lesion, whether in combination with a bony Bankart lesion or not, were included. Digital Imaging and Communications in Medicine data from the 52 CT scans were all analyzed using open source image analysis software. Glenoid width, with or without associated bony defect, and the Hill-Sachs interval (HSI) were measured on MPR as well as on 3DR images. All measurements obtained using both methods were directly compared and evaluated for intra- and interobserver reliability. Results: In absolute values, only small differences were seen between the MPR and 3DR methods, amounting to a maximal difference of 0.07 cm for the HSI and 0.04 cm for the glenoid width. For glenoid measurements, both methods were similar. For humeral measurements, the MPR method demonstrated higher inter- and intraobserver reliability than did the 3DR method. Conclusion: The newly described MPR method for the assessment of the glenoid track and HSI is at least as accurate as the published 3DR method, with better intra- and interobserver reliability. Because MPRs are also easier to obtain, this method could be recommended in daily practice.

Patients with heterotaxy syndrome (HS) can present with an associated complete dorsal pancreas agenesis (DPA). They are considered to be at increased risk for developing diabetes due to a reduced functional beta cell mass (FBM) as well as for chronic pancreatitis leading to unmanageable pain. We report the case of a young woman with chronic pancreatitis due to HS and associated DPA. She presented with a severe persisting upper abdominal pain refractory to nonsurgical treatment. Unlike in previously reported cases, she had a high FBM (ie, 150% of normoglycemic controls) as determined by hyperglycemic clamp. She underwent a total pancreatectomy followed within 24 hours by an intraportal autologous islet cell transplant containing 4 × 106 beta cells (4700 islet equivalent)/kg body weight. After surgery, the pain resolved, eliminating the need for analgesics. The intraportal implant established an adequate FBM (72% of controls at posttransplant month 2), achieving glycemic control without need for insulin administration. A hyperglycemic clamp can assess the utility and efficacy of an intraportal islet cell autotransplant following total pancreatectomy in patients with HS and complete DPA.

Summary Background and aims: Caloric prescription based on resting energy expenditure (REE) measured with indirect calorimetry (IC) improves outcome and is the gold standard in nutritional therapy of critically ill patients. Until now continuous renal replacement therapy (CRRT) precluded the use of IC due to several mechanisms. We investigated the impact of CRRT on VCO2, VO2 and REE to facilitate indirect calorimetry during CRRT. Methods In 10 critically ill ventilated patient in need of continuous veno-venous hemofiltration (CVVH) using citrate predilution we performed IC in 4 different states: baseline, high dose, baseline with NaCl predilution and without CVVH. CO2 content of effluent fluid was measured by a point of care blood gas analyzer. Carbon dioxide production (VCO2) measured with IC was adapted by adding the CO2 flow of effluent and deducing CO2 flow in postdilution fluid to calculate a true VCO2. True REE was calculated with the Weir equation using the true VCO2. Results CO2 removal in effluent during baseline, high dose and NaCl predilution was respectively 24 mL/min, 38 mL/min and 23 mL/min. Together with the CO2 delivery by the postdilution fluid this led to an adaptation of REE respectively by 34 kcal/d or 2% (p = 0,002), 44 kcal/d or 3% (p = 0,002) and 33 kcal/d or 2% (p = 0,002). Compared to the true REE during baseline of 1935 ± 921 kcal/d, true REE during high dose was 1723 ± 752 kcal/d (p = 0.65), during NaCl predilution it was 1604 ± 633 kcal/d (p = 0.014) and without CRRT it was 1713 ± 704 kcal/d (p = 0.193). Conclusions CO2 alterations due to CVVH are clinically of no importance so no correction factor of REE is needed with or without CVVH. IC must be performed during CVVH as CVVH seems to alter metabolism. These changes may be mainly explained by the use of citrate predilution.

ObjectivesVitamin D deficiency was previously correlated with incidence and severity of coronavirus disease 2019 (COVID-19). We investigated the association between serum 25-hydroxyvitamin D (25(OH)D) level on admission and radiologic stage and outcome of COVID-19 pneumonia.MethodsA retrospective observational trial was done on 186 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–infected individuals hospitalized from March 1, 2020, to April 7, 2020, with combined chest computed tomography (CT) and 25(OH)D measurement on admission. Multivariate regression analysis was performed to study if vitamin D deficiency (25(OH)D ResultsOf the patients with COVID-19, 59% were vitamin D deficient on admission: 47% of females and 67% of males. In particular, male patients with COVID-19 showed progressively lower 25(OH)D with advancing radiologic stage, with deficiency rates increasing from 55% in stage 1 to 74% in stage 3. Vitamin D deficiency on admission was not confounded by age, ethnicity, chronic lung disease, coronary artery disease/hypertension, or diabetes and was associated with mortality (odds ratio [OR], 3.87; 95% confidence interval [CI], 1.30-11.55), independent of age (OR, 1.09; 95% CI, 1.03-1.14), chronic lung disease (OR, 3.61; 95% CI, 1.18-11.09), and extent of lung damage expressed by chest CT severity score (OR, 1.12; 95% CI, 1.01-1.25).ConclusionsLow 25(OH)D levels on admission are associated with COVID-19 disease stage and mortality.

INTRODUCTION: Gastro-esophageal reflux disease (GERD) in infants is worldwide diagnosed with increasing frequency, resulting in an increasing number of infants exposed to treatment. In this review, we focus on the safety of therapeutic options. AREAS COVERED: English articles were searched from 1990 until May 2020 in PubMed and Google Scholar. Evidence suggests that non-pharmacological treatment is often effective and safe. Guidelines restrict pharmacological treatment to acid-suppressive medication, which is associated with adverse effects, often related to gastro-intestinal dysbiosis and consequences of the latter. Aluminum-free alginates have some efficacy and are not associated with relevant adverse effects. Especially in infants, GERD is often non-acid related. Prokinetics are not recommended because of lack of efficacy and numerous adverse effects. EXPERT OPINION: Pediatric trials are underpowered regarding adverse effects. The number of infants exposed to anti-secretory agents is increasing worldwide, often without indication. Informing healthcare providers about adverse effects of acid-secretory medication may contribute to a more rational use. Acid inhibiting agents such as alginates are a drug class associated with limited efficacy and devoid of serious adverse effects. Regarding prokinetics, the risk of adverse effects outweighs the benefit. Reassurance of parents and nutritional management of GERD in infants is effective and safe.

BACKGROUND: Fat graft ischemia impedes us from having satisfying long-term results. The quality and quantity culture is a 1-week cell culture that increases the vasculogenic potential of peripheral blood mononuclear cells (PBMNC). This in vivo murine model investigates whether enrichment with quality and quantity-cultured human mononuclear cells (MNC-QQ) improves the vascularization in the human fat graft and whether this decreases the tissue loss. METHODS: Human adipose tissue, PBMNC, MNC-QQ, and stromal vascular fraction were prepared. First, PBMNC, MNC-QQ, and stromal vascular fraction were compared in vitro for vasculogenic potential by endothelial progenitor cell colony-forming and culture assays. Second, 0.25-g fat grafts were created with 1 × 106 PBMNC (n = 16), 1 × 106 MNC-QQ (n = 16), 1 × 106 stromal vascular fraction (n = 16), or phosphate-buffered saline as control (n = 16) before grafting in BALB/c nude mice. Grafts were analyzed for weight persistence, vessel formation by CD31 immunohistochemistry, and angiogenic markers by quantitative polymerase chain reaction. RESULTS: MNC-QQ develop more definitive endothelial progenitor cell colonies and more functional endothelial progenitor cells compared to PBMNC and stromal vascular fraction. Weight persistence after 7 weeks was significantly higher in grafts with MNC-QQ (89.8 ± 3.5 percent) or stromal vascular fraction (90.1 ± 4.2 percent) compared with control (70.4 ± 6.3 percent; p < 0.05). MNC-QQ-enriched grafts had the highest vessel density (96.6 ± 6.5 vessels/mm2; control, 70.4 ± 5.6 vessels/mm2; p < 0.05). MNC-QQ exerted a direct vasculogenic effect through vascular integration and a potential paracrine vascular endothelial growth factor-mediated effect. CONCLUSION: Quality and quantity-cultured human mononuclear cells containing endothelial progenitor cells stimulate fat graft vascularization and enhance graft survival in a rodent recipient.

Objective Despite the clinical effectiveness of Spinal Cord Stimulation (SCS), potential structural brain modifications have not been explored. Our aim was to identify structural volumetric changes during subsensory SCS, in patients with Failed Back Surgery Syndrome (FBSS). Methods In this cohort study, twenty-two FBSS patients underwent a magnetic resonance imaging protocol before SCS and 3 months after SCS. Clinical parameters were correlated with volumetric changes, calculated with voxel-based morphometry. Results After 3 months, a significant volume decrease was found in the inferior frontal gyrus, precuneus, cerebellar posterior lobe and middle temporal gyrus. Significant increases were found in the inferior temporal gyrus, precentral gyrus and the middle frontal gyrus after SCS. Additionally, significant increases in volume of superior frontal and parietal white matter and a significant decrease in volume of white matter underlying the premotor/middle frontal gyrus were revealed after SCS. A significant correlation was highlighted between white matter volume underlying premotor/middle frontal gyrus and leg pain relief. Conclusions This study revealed for the first time that SCS is able to induce volumetric changes in gray and white matter, suggesting the reversibility of brain alterations after chronic pain treatment. Significance Volumetric brain alterations are observable after 3 months of subsensory SCS in FBSS patients.

It has been suggested that trapeziometacarpal total joint arthroplasty be combined with complete release of the joint capsule to prevent ligament tethering and implant dislocation. Our goal was to evaluate the consequences of capsular release on range of motion. Trapeziometacarpal joint motion was measured with a 3D motion tracking system in seven fresh frozen human cadaver hands before and after capsular release and total joint arthroplasty with subsequently longer neck lengths. Relative to the native trapeziometacarpal joint with intact joint capsule, mean flexion–extension was significantly increased after the arthroplasty with released capsule and lengthening up to 6 mm. Mean abduction–adduction did not increase significantly. Total joint replacement combined with capsular release increases the trapeziometacarpal joint's range of motion, but not beyond the limits of most trapeziometacarpal implant designs. Lengthening of the implant neck progressively decreases the excess motion.

Objective This study assessed the rate of maxillary osteotomies after cleft palate surgery following a standardized two-stage palatoplasty protocol. In order to improve our treatment strategy, the results were compared with the data extracted from the literature by means of a systematic review. Design Retrospective cohort study. Patients Non-syndromic cleft lip, alveolus, and palate patients with complete records who underwent primary cleft palate surgery. Intervention The incidence of midface hypoplasia after primary cleft surgery that required surgical intervention was retrospectively evaluated. Results Of the final 51 patients included in our retrospective analysis, two required a maxillary repositioning osteotomy. The frequency was lower than reported in the literature. In the literature, there was no difference between patients treated according to a one-stage protocol (21%) and patients treated according to a two-stage protocol (20.8%), but a higher incidence of pharyngeal surgery was noted in the two-stage closure group. Only the cleft type, timing of hard palate closure, and orthodontic treatment proved to influence the need for maxillary osteotomy. Conclusion Our protocol shows promising results and needs more validation.

Adeno-associated virus (AAV) forms the basis for several commercial gene therapy products and for countless gene transfer vectors derived from natural or synthetic viral isolates that are under intense preclinical evaluation. Here, we report a versatile pipeline that enables the direct side-by-side comparison of pre-selected AAV capsids in high-throughput and in the same animal, by combining DNA/RNA barcoding with multiplexed next-generation sequencing. For validation, we create three independent libraries comprising 183 different AAV variants including widely used benchmarks and screened them in all major tissues in adult mice. Thereby, we discover a peptide-displaying AAV9 mutant called AAVMYO that exhibits superior efficiency and specificity in the musculature including skeletal muscle, heart and diaphragm following peripheral delivery, and that holds great potential for muscle gene therapy. Our comprehensive methodology is compatible with any capsids, targets and species, and will thus facilitate and accelerate the stratification of optimal AAV vectors for human gene therapy., Adeno-associated virus is the basis of many gene therapies and gene transfer vectors. Here the authors report a pipeline to enable side-by-side comparison of pre-selected capsids in a high throughput manner.

Patients with neurofibromatosis type 1 (NF1) have an increased lifetime risk for the development of nervous system tumors, including high-grade gliomas (glioblastoma). NF1 is associated with the loss of expression of neurofibromin 1 (NF1 gene product). This hyperactivates the mitogen-activated protein kinase pathway, leading to cellular proliferation and survival. MEK-inhibitor monotherapy is a promising treatment strategy in this setting, but is associated with distinct adverse events, most prominently cutaneous toxicity. We report the case of a young NF1 patient with a recurrent, heavily pretreated mesencephalic glioblastoma who was treated with the MEK-inhibitor trametinib (2 mg once daily). A partial response was documented, but unfortunately, he developed dose-limiting cutaneous toxicity (rash, paronychia). Based on interim results of a phase 2 trial in advanced BRAFV600 wild-type melanoma indicating that a low dose of the BRAF-inhibitor dabrafenib is able to counter trametinib-related cutaneous toxicity, dabrafenib 50 mg twice daily was added. The cutaneous adverse events gradually recovered after addition of dabrafenib to trametinib. The patient eventually achieved a durable complete response, has excellent tolerance of his treatment and remains fully active.

The use of high-dose spinal cord stimulation (HD-SCS) has increased drastically during the past few years, with positive results. However, there remains a deficit of real-world data of the effectiveness of HD-SCS. Therefore, the primary aim was to evaluate the effectiveness of HD-SCS in patients with failed back surgery syndrome (FBSS). The second aim was to develop a prediction model for a holistic responder. One hundred ninety-four patients were recruited to a multicenter real-world registry. Self-reporting outcome variables were evaluated at baseline (before SCS) and at 1, 3, and 12 months of HD-SCS implant. Outcome measures were the mean pain intensity over time, sleep quality, disability, health-related quality of life, and medication use. Besides the effectiveness, logistic regression and decision tree analysis were performed to define a holistic responder (pain intensity reduction, medication reduction, Oswestry disability index reduction, and EQ5D improvement) after 12 months of HD-SCS. Of 185 FBSS patients who underwent a baseline visit, 75.13% had a successful HD trial. At 12 months, 92 patients were still receiving HD-SCS. Both low back and leg pain significantly decreased at 12 months. All outcome measures revealed a significant time-dependent effect from baseline to 12 months. Holistic responders could be predicted with a sensitivity and specificity of 90%. Clinically significant and sustained pain relief over a period of 12 months was achieved with HD-SCS in patients with FBSS. In addition, HD-SCS also achieved an improvement in sleep quality, functionality, and a decrease in pain medication.

Objective: We aimed to analyze oncologic outcomes and identify patterns of failure and negative prognostic factors in patients who underwent salvage total laryngectomy (STL) for residual, recurrent, and second primary squamous cell carcinoma (SCC) of the larynx and hypopharynx. Methods: This was a retrospective cohort study of patients who underwent STL in four major Belgian reference hospitals between 2002 and 2018 for residual/recurrent/second primary SCC in the larynx or hypopharynx after initial (chemo)radiation. Prognostic factors for oncologic outcomes were identified using univariable and multivariable analysis. Results: A total of 405 patients were included in the final analysis. Five-year overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), and locoregional relapse-free survival (LRFS) estimates were 47.7% (95% confidence interval [CI] 42.0–53.2%), 68.7% (95% CI 63.7–73.7%), 42.1% (95% CI 36.7–47.4%), and 44.3% (95% CI 38.8–49.7%), respectively. In a multivariable model, increasing clinical tumor stage of the residual/recurrent/second primary tumor, increasing number of metastatic cervical lymph nodes retrieved during neck dissection, hypopharyngeal and supraglottic tumor location, positive section margin status and perineural invasion were independent negative prognostic variables for OS, DSS, DFS, and LRFS. The type of second tumor was identified as an additional independent prognosticator for DSS, with local recurrences and second primary tumors having a better prognosis than residual tumor. Conclusions and Relevance: Favorable oncologic outcomes are reported after STL. Increasing clinical tumor stage, increasing number of metastatic cervical lymph nodes, hypopharyngeal and supraglottic tumor location, positive section margins, and perineural invasion are identified as independent negative prognosticators for all oncologic outcome measures.

ObjectiveVolunteers are an important resource in bridging palliative care (PC) services and communities. However, no studies have systematically mapped volunteers’ actual contributions to PC provision and how well they are supported by healthcare services at the volunteer level. Such insights are important to shape and optimise supportive environments for volunteering in PC. This study aimed to describe organised volunteering practices in PC across dedicated PC services and healthcare services providing generalist PC, in terms of tasks, training, supervision and how volunteers evaluate these.MethodsA cross-sectional postal survey of 2273 volunteers from healthcare organisations providing care for people with serious illnesses in the Flemish healthcare system (Belgium) was conducted between June and November 2018. A two-step cluster randomised sample was used. Volunteers were recruited through their respective volunteering organisations.ResultsResponse was obtained for 801 (35.2%) volunteers. Volunteers were predominantly women (75.5%), retired (70.8%) and aged 60–69 years (43.4%). Almost all volunteers provided psychosocial care (96.3%). Volunteers were found to provide either (1) broad volunteer support, emphasising psychosocial and existential care and signposting tasks or (2) narrow volunteer support, emphasising nursing care tasks. Nursing home volunteers had the lowest prevalence of PC training (7.7% vs 53.7% total, pConclusionsMultidimensional support was most prevalent among dedicated PC volunteers, while practical support was most prevalent among sitting service volunteers. Results indicate that volunteers can offer complementary support for patients with serious illnesses, although this requires training and consistent supervision. This is currently suboptimal for volunteers in nursing homes and community home care.