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BACKGROUND Early-onset scoliosis (EOS) is common in children with cerebral palsy (CP). The effectiveness of magnetically controlled growing rods (MCGR) and the risk for unplanned return to the operating room (UPROR) remain to be studied in this patient population. The primary outcome of this study was to examine the frequency of UPROR between MCGRs as compared with traditional growth friendly (TGF) surgeries for children with EOS secondary to CP. METHODS Patients with EOS secondary to CP were prospectively identified from an international database, with data retrospectively analyzed. Scoliosis, kyphosis, T1-S1, and T1-T12 height were measured preoperation, immediate postoperation, and at minimum 2-year follow-up. The risk and etiology of UPRORs were compared between MCGR and TGF. RESULTS Of the 120 patients that met inclusion criteria, 86 received TGF (age 7.5±0. 1.8 y; mean follow-up 7.0±2.9 y) and 34 received MCGR (age 7.1±2.2 y, mean follow-up 2.8±0.0.5 y). Compared with TGF, MCGR resulted in significant improvements in maintenance of scoliosis (P=0.007). At final follow-up, UPRORs were 8 of 34 patients (24%) for MCGR and 37 of 86 patients (43%) for TGF (P=0.05). To minimize the influence of follow-up period, UPRORs within the first 2 years postoperation were evaluated: MCGR (7 of 34 patients, 21%) versus TGF (20 of 86 patients, 23%; P=0.75). Within the first 2 years, etiology of UPROR as a percentage of all patients per group were deep infection (13% TGF, 6% MCGR), implant failure/migration (12% TGF, 9% MCGR), dehiscence (4% TGF, 3% MCGR), and superficial infection (4% TGF, 3% MCGR). The most common etiology of UPROR for TGF was deep infection and for MCGR was implant failure/migration. CONCLUSION For patients with EOS secondary to CP, there was no difference in the risk of UPROR within the first 2 years postoperatively whether treated with TGF surgery or with MCGRs (23% TGF, 21% MCGR). LEVEL OF EVIDENCE Level III-retrospective cohort, therapeutic study.

Previous studies associated plasma cathepsin D (CTSD) activity with hepatic insulin resistance in overweight and obese humans. Insulin resistance is a major feature of non-alcoholic fatty liver disease (NAFLD) and is one of the multiple hits determining the progression towards non-alcoholic steatohepatitis (NASH). In line, we have previously demonstrated that plasma CTSD levels are increased in NASH patients. However, it is not known whether insulin resistance associates with plasma CTSD activity in NAFLD. To increase our understanding regarding the mechanisms by which insulin resistance mediates NAFLD, fifty-five liver biopsy or MRI-proven NAFLD patients (BMI>25kg/m2) were included to investigate the link between plasma CTSD activity to insulin resistance in NAFLD. We concluded that HOMA-IR and plasma insulin levels are independently associated with plasma CTSD activity in NAFLD patients (standardized coefficient β: 0.412, 95% Cl: 0.142~0.679, p=0.004 and standardized coefficient β: 0.495, 95% Cl: 0.236~0.758, p=0.000, respectively). Together with previous studies, these data suggest that insulin resistance may link to NAFLD via elevation of CTSD activity in plasma. As such, these data pave the way for testing CTSD inhibitors as a pharmacological treatment of NAFLD. ispartof: Biomol Concepts vol:12 issue:1 pages:110-115 ispartof: location:Germany status: Published online

Background The prevalence of duodenogastroesophageal reflux (DGER) and its effect on symptoms and oesophageal lesions in gastroesophageal reflux disease (GERD) is unclear. Aims To conduct a systematic review to determine the prevalence of DGER among patients with GERD, the effect of DGER on symptoms and oesophageal lesions, and the treatment of DGER. Methods We searched Pubmed and MEDLINE for full text, English language articles until October 2020 that evaluated DGER prevalence among patients with GERD, the effect of DGER on symptoms and oesophageal lesions, and the treatment of DGER. Results We identified 3891 reports and included 35 which analysed DGER prevalence in GERD, 15 which evaluated its effect in non-erosive reflux disease (NERD), 17 on erosive oesophagitis, 23 in Barrett's, and 13 which evaluated the treatment of DGER. The prevalence of DGER, when evaluated by Bilitec, among all GERD patients ranged from 10% to 97%, in NERD 10%-63%, in erosive oesophagitis 22%-80% and in Barrett's 50%-100%. There were no differences in the presence or degree of DGER among patients who were asymptomatic or symptomatic on proton pump inhibitors (PPI). The most commonly evaluated treatments for DGER were PPIs and DGER reduced post-PPI therapy in all studies. Conclusions The prevalence of DGER increased with more advanced oesophageal lesions and did not explain persisting symptoms among patients taking PPI therapy. PPIs appear to be effective in the treatment of DGER. DGER remains an important consideration in patients with GERD and future therapies deserve more study.

The best treatment and rehabilitation of Achilles tendon ruptures remains controversial. Current literature focuses mainly on objective outcomes despite possible incongruity with patient-reported functional outcomes. Therefore, we aimed to identify the course of patient-reported symptoms, function and quality of life during the early rehabilitation period. In this prospective cohort study, 33 patients with an acute Achilles tendon rupture treated with minimally invasive tendon repair were included in this study. They were followed up at 6, 12, 18 and 24 weeks after surgery with the Foot and Ankle Outcome Score questionnaire. At 6 weeks, patient-reported outcomes were poor regarding quality of life and sports. They however were quite high in the domains activities of daily living, symptoms and pain. All scores improved over the course of 6 months (symptoms (p = .03), activities of daily living (p = .001), sports (p = .002) and quality of life (p = .001). Pain did not improve significantly (p = .12), but patients had good pain scores from the start. There were no significant differences between patients with or without physical therapy. There were 3 minor complications and no re-ruptures in this cohort. In conclusion, patient-reported outcomes improve significantly during the first 6 months after surgery, except for pain. Scores for sports and quality of life remain suboptimal.

BACKGROUND Prescribing opioids for patients with chronic noncancer pain (CNCP) remains controversial. This study surveyed Taiwanese physicians who were clinically treating CNCP outpatients with long-term opioids. METHODS Anonymous questionnaires investigating the clinical practices, opioid knowledge, attitude, and barriers regarding the prescription of long-term opioids were delivered to 66 physicians treating CNCP outpatients who were officially registered and monitored by the Taiwan Food and Drug Administration in 2011. RESULTS All 66 (100%) physicians responded to the survey, comprising 41 (62%) board-certified pain specialists and 25 (38%) nonpain board-certified physicians. Pain specialists treated a greater number of CNCP outpatients and attended more CNCP training courses than nonpain board-certified physicians (97.6% vs. 56.0%, p < 0.001). Most of pain specialists stated that they were familiar with the Taiwan's narcotic regulations for CNCP patients (92.7% vs. 68.0%, p = 0.015). In addition, pain specialists were less likely to skip or reduce the dosage and duration of opioid prescriptions (22.0% vs. 36.0%, p < 0.001). By contrast, nonpain board-certified physicians had significantly less knowledge and a more negative attitude toward opioid prescription. The major perceived barriers were physician's reluctance to prescribe opioids (78% vs. 92%) and an inadequate knowledge of pain management (73% vs. 84%) among all physicians. CONCLUSION Among the Taiwanese physicians treating the officially registered CNCP patients, nonpain board-certified physicians had fewer patients, less knowledge, and an increased negative attitude toward long-term opioid prescriptions. Better education on chronic pain management is needed for improvement of clinical practice.

Introduction Integrase inhibitors (INI) and especially dolutegravir (DTG) are placed as a first-line antiretroviral treatment for their efficacy and safety. Although in the pivotal trials the rate of adverse effects (AEs) was low (2–3%), in real-life studies it appears to be higher, especially neuropsychiatric AEs. The objective is to determine the percentage of AEs and discontinuation of DTG in our site and the relationship with the psychiatric background. Methods Retrospective descriptive study of patients starting DTG from 2015 to 2017. Discontinuation of treatment, adverse effects and previous psychiatric pathology were recorded. Follow-up is carried out since the beginning of the treatment and hospitalizations, emergency room (ER) visits and primary care (PC) were registered. The study was authorizedby the Ethics Committee for Clinical Research of Aragon. Results 283 patients were included, between 11 and 87 years old, 70% male. 21% were naive. 24% of the patients discontinued treatment with DTG, 10% due to AEs. Neuropsychiatric AEs were was detected in 5%. This group of patients had a more frequent previous psychiatric history (62 vs 41%; p = 0.002) than the ongoing treatment group and they needed more visits to PC (18.8 vs 8.4% p = 0.016), ER (8,7 vs 3.3% p = 0.061) and in one case even hospitalization due to AE. Conclusion Patients who discontinued treatment with DTG had more psychiatric history. Although more studies are required, it is necessary to assess this background before starting treatment with INI. Symptoms such as anxiety, insomnia, depression can be DTG AEs more frequently than expected. Being identified by PC and emergency physicians could avoid the unnecessary prescription of other medications.

Ectopic adipose tissues (EAT) are present adjacent to many organs and have predominantly been described in overweight and obesity. They have been suggested to be related to fatty acid overflow and to have harmful effects. The objective of this semi-comprehensive review is to explore whether EAT may play a supportive role rather than interfering with its function, when the adjacent organ is challenged metabolically and functionally. EAT are present adhered to different tissues or organs, including lymph nodes, heart, kidney, ovaries and joints. In this review, we only focused on epicardial, perinodal, and peritumoral fat since these locations have been studied in more detail. Evidence was found that EAT volume significantly increased, associated with chronic metabolic challenges of the corresponding tissue. In vitro evidence revealed transfer of fatty acids from peritumoral and perinodal fat to the adjacent tissue. Cytokine expression in these EAT is upregulated when the adjacent tissue is challenged. In these tissues, glycolysis is enhanced, whereas fatty acid oxidation is increased. Together with more direct evidence, this shows that glucose is oxidized to a lesser degree, but used to support anabolic metabolism of the adjacent tissue. In these situations, browning occurs, resulting from upregulation of anabolic metabolism, stimulated by uncoupling proteins 1 and 2 and possibly 3. In conclusion, the evidence found is fragmented but the available data support the view that accumulation and browning of adipocytes adjacent to the investigated organs or tissues may be a normal physiological response promoting healing and (patho)physiological growth.

Previously, we have shown that hepatic lipid accumulation induces the secretion of cathepsin D (CTSD), and that plasma CTSD levels are associated with increased inflammation and disease severity in nonalcoholic fatty liver disease (NAFLD). Although it is clear that the liver is a major source of plasma CTSD, it is unknown whether other metabolically active organs such as the muscle, also associate with plasma CTSD levels in NAFLD patients. Therefore, the aim of this study was to explore the relation between lipid accumulation in the muscle (myosteatosis) and plasma CTSD levels in forty-five NAFLD patients. We observed that hepatic steatosis positively associated with plasma CTSD levels, confirming the previously established link between plasma CTSD and the liver. Furthermore, a positive association between myosteatosis and plasma CTSD levels was observed, which was independent of sex, age, BMI, waist circumference and hepatic steatosis. By establishing a positive association between myosteatosis and plasma CTSD levels, our findings suggest that, in addition to the liver, the muscle is also linked to plasma CTSD levels in NAFLD patients. The observed link between myosteatosis and plasma CTSD levels supports the concept of a significant role of the skeletal muscle in metabolic disturbances in metabolic syndrome-related disorders. ispartof: Biomol Concepts vol:12 issue:1 pages:27-35 ispartof: location:Germany status: Published online

Phlebotomies are performed in hereditary hemochromatosis (HH) to maintain normal iron concentrations. Proton-pump inhibitors (PPIs) can reduce the number of phlebotomies in patients with HH. However, in patients without HH, the iron concentrations do not appear to be compromised when using PPIs. Therefore, we aim to explain the differences in iron absorption between patients with and without HH. In 10 p.cysteine282tyrosine (p.C282Y) homozygous HH patients with normalized iron stores and 10 healthy control subjects (HCs), the iron parameters and hepcidin concentrations were determined before ingestion of a pharmacological dose of 50 mg iron [ferric iron (Fe3 thorn )] polymaltose and hourly for 4 h afterward. This was repeated after 7 days of treatment with pantoprazole 40 mg once daily. Serum iron concentrations and transferrin saturation percentages dropped significantly during PPI use in the patients with HH, whereas no changes were observed in the HCs. Hepcidin concentrations were lower in the patients with HH compared with the HCs both before and during PPI use. In both groups, hepcidin levels did not significantly decrease during the treatment. Seven-day PPI use significantly reduces iron absorption in patients with HH but not in HCs. Changes in hepcidin concentrations could not explain these different PPI effects on iron absorption probably due to a small sample size. NEW & NOTEWORTHY This study confirms that lowering gastric acidity by proton pump inhibitors results in a reduction in iron absorption in patients with hemochromatosis and not in healthy control subjects. The presupposition that a decrease in hepcidin concentration in healthy control subjects in response to lowering gastric acidity can explain the difference in iron absorption between these groups could not be confirmed probably because of a small sample size.

BACKGROUND: The gut-liver axis is considered to play a critical role in the development and progression of nonalcoholic fatty liver disease (NAFLD). The integrity of the epithelial barrier is crucial to protect the liver against the invasion of microbial products from the gut, although its exact role in NAFLD onset and progression is not clear. METHODS: We performed a systematic review and meta-analysis of studies that addressed the intestinal permeability (IP) in association with NAFLD presence or severity as defined by the presence of nonalcoholic steatohepatitis (NASH) and the degree of steatosis, hepatic inflammation or fibrosis. A total of 14 studies were eligible for inclusion. RESULTS: Studies investigating IP in adult (n = 6) and paediatric (n = 8) NAFLD showed similar results. Thirteen of the included studies focussed on small IP, two studies on whole gut permeability and none on colonic permeability. In the pooled analysis, NAFLD patients showed an increased small intestinal permeability compared to healthy controls based on dual sugar tests (standardized mean difference 0.79, 95% CI 0.49-1.08) and serum zonulin levels (standardized mean difference 1.04 ng/mL, 95% CI 0.40-1.68). No clear difference in IP was observed between simple steatosis and NASH patients. Furthermore, whole gut and small intestinal permeability increased with the degree of hepatic steatosis in 4/4 studies, while no association with hepatic inflammation or fibrosis was observed. CONCLUSION: Based on the limited number of studies available, IP appears to be increased in NAFLD patients compared to healthy controls and is associated with the degree of hepatic steatosis. ispartof: LIVER INTERNATIONAL vol:40 issue:12 pages:2906-2916 ispartof: location:United States status: published

ZusammenfassungMit der Entwicklung von Checkpointinhibitoren gelang in den letzten Jahren ein Durchbruch in der Tumortherapie. Checkpointinhibitoren aktivieren die Immunabwehr gegen Tumoren, indem sie die immunhemmende Wirkung spezifischer, als Kontrollpunkte agierender Zelloberflächenproteine, der sogenannten Checkpoints, aufheben. Dieser Artikel gibt einen Überblick über die Wirkweise und den Stand der derzeitigen klinischen Entwicklung zugelassener Checkpointinhibitoren.Die bisher zugelassenen Checkpointinhibitoren, gegen die Checkpoints CTLA‑4 und PD-1/PD-L1 gerichtete monoklonale Antikörper, werden in verschiedenen Tumorentitäten wie Melanom, Lungen‑, Nieren‑, Urothelkarzinom oder Kopf-Hals-Tumoren sowie dem Hodgkin-Lymphom eingesetzt. Bei einem Teil dieser Patienten mit fortgeschrittenen Tumoren konnte erstmals ein Langzeitüberleben erzielt werden. In Abhängigkeit von der Tumorindikation ist diese charakteristische lange Wirksamkeit jedoch nur bei einem geringen Anteil der behandelten Patienten zu beobachten, was man durch eine Patientenselektion über prädiktive Biomarker und die Entwicklung von Kombinationstherapien zu überwinden versucht. Für manche Indikationen wurde bereits mit der Checkpointinhibitorzulassung eine Einschränkung hinsichtlich des prädiktiven PD-L1-Status vorgeschrieben.

Preeclampsia (PE) is a pregnancy-related disorder characterized by hypertension and proteinuria that affects 3-10% of all pregnancies. Although its pathophysiology remains obscure, placental hypoxia-induced oxidative stress and alterations in vascular function, morphology, and endothelial barrier integrity are considered to play a key role in the development of preeclampsia. In this study, placental villous explants of noncomplicated placentae and BeWo cells were subjected to hypoxia. The effect of placental hypoxic-conditioned medium (HCM) on intraluminal-induced contraction and endothelial barrier integrity in chorionic arteries was investigated using pressure myography. The impact of BeWo cell HCM on endothelial cell viability, reactive oxygen species formation and inflammation was also determined. Alterations in arterial morphology and contractile responsiveness to the thromboxane A2 analog (U46619) after exposure to placental HCM were examined immunohistochemically and by wire myography, respectively. Intraluminal administration of placental HCM induced vasoconstriction and increased the endothelial permeability for KCl, which was concentration-dependently prevented by quercetin. Placental and BeWo cell HCMs decreased endothelial cell viability, increased the production of reactive oxygen species and enhanced the secretion of IL-6 and IL-8. The cross-sectional area of the arterial media was increased upon exposure to placental HCM, which was associated with increased vascular proliferation and contractile responsiveness to U46619, and all of these effects were prevented by the antioxidants quercetin and RRR-alpha-tocopherol. This study is the first to comprehensively demonstrate the link between factors secreted by placental cells in response to hypoxia and vascular abnormalities and paves the way for new diagnostic approaches and therapies to better protect the maternal vasculature during and after a preeclampsia-complicated pregnancy.

Key summary points Aim A comprehensive collateral history is a standard of care recommended both in Ireland, by the Irish National Audit of Dementia Care in Acute Hospitals (INAD) and internationally, by the EuGMS. We sought to establish if this standard was being met. Findings Only 44% of patients with cognitive impairment had a collateral history. The level of detail attained was often inadequate and assessment of patients’ current and premorbid cognition was poor. Message Obtaining a comprehensive collateral history is imperative to the diagnosis of delirium and dementia. It is not possible to make a competent clinical assessment or a management plan without exercising this core clinical skill., Purpose Patients with cognitive impairment are often unable to provide information relating to their pre-morbid cognition and function. Such information is essential to correctly identifying delirium and dementia, as well as making an accurate diagnosis and planning appropriate treatment. It is the standard of care recommended by the EuGMS. Methods We reviewed medical notes and administered a short questionnaire to nursing staff of a convenience sample of 100 patients aged ≥ 75 years admitted to medical wards in a tertiary teaching hospital. Results There were 100 patients with a mean age of 82.3 years, 49% of whom were female. Of 43 patients with cognitive impairment, 19 (44%) had a collateral history. Half of the patients described as having dementia did not have any further detail on the severity of dementia documented. Among those for whom a collateral history was obtained, the level of detail regarding pre-morbid cognition, function, mobility, and continence was sparse. Of the total sample, 13% had formal cognitive testing. Conclusion Acute illness characteristically causes significant impairments in cognition and function in frail older patients. Identifying and reversing these impairments is impossible without a comprehensive collateral history. It is alarming that such an essential component of clinical assessment is so often disregarded and highlights the lack of awareness from clinicians of the importance of collateral history in the management of patients with dementia and delirium. This must be emphasised in both undergraduate and postgraduate teaching.

Triaging patients into and away from preoperative assessment clinics remains a challenge. Anaesthesia Preoperative Assessment Tool (APAT) is a web application that delivers an online 22 question survey to patients at home, and uses an artificially intelligent algorithm to stratify patient risk and identify the need for non routine preoperative investigation and intervention. We assess APATs accuracy and patient acceptability in this prospective observational study. Patients were recruited at preoperative assessment clinic, where they were assessed by a consultant anaesthetist. Anaesthetist (ASA) grade, need for nonstandard investigation and intervention were recorded (gold standard). Patients were invited to complete an APAT assessment on their PC or smartphone at home, and the results of both assessments compared. 22 patients completed conventional clinical assessment by consultant anaesthetist and online assessment by APAT. APAT score correlates with clinicians ASA grade (rτ=0.6075, p=0.0008). APAT predicts patient risk group (misclassification rate of 0%, Area Under the Curve (AUC)=0.9825). APAT predicts the need for additional investigation (AUC=0.8077) and preoperative intervention (AUC=0.7193). Online assessment was acceptable to 92% of patients. Our findings support the hypothesis that APAT accurately predicts patients perioperative risk and predicts the need for investigation and intervention. Further studies are needed to confirm that APAT may be used to identify ASA 1 and 2 patients who could safely bypass preoperative assessment clinic.

The link between psoriasis and obstructive sleep apnea (OSA) has not been confirmed. We aimed to investigate the relationship between psoriasis and OSA. We conducted a systematic review and meta-analysis of case-control, cross-sectional, and cohort studies on the association between psoriasis and OSA. We searched MEDLINE and Embase for relevant studies on May 11, 2019. The Newcastle-Ottawa Scale was used to evaluate the risk of bias of included studies. We performed random-effects model meta-analysis to calculate pooled odds ratio (ORs) with 95% confidence intervals (CIs) for case-control and cross-sectional studies as well as pooled incidence rate ratio (IRR) with 95% CIs for cohort studies in association between psoriasis and OSA. A total of 4 case-control or cross-sectional studies and 3 cohort studies with a total of 5,840,495 subjects were included. We identified a significantly increased odds for OSA in psoriasis patients (pooled OR 2.60; 95% CI 1.07–6.32), and significantly increased risk for psoriasis in OSA patients (pooled IRR 2.52; 95% CI 1.89–3.36). In conclusion, our study identified a bidirectional association between psoriasis and OSA. Sleep quality should be inquired in patients with psoriasis. Respirologist consultation or polysomnography may be indicated for those presenting with night snoring, recurrent awaking, and excessive daytime sleepiness.

Introduction: This review analyzes the efficacy of pneumococcal vaccinations in lung transplant patients before and after transplantation.Areas covered: This review addresses the risk for respiratory infections, in particular pneumococcal infections, in lung transplantation patients in the context of immunodeficiency and immunosuppressive medication. Vaccination is recommended to counteract the increased risk of pneumococcal infection, and the relevant guidelines are discussed in this review. The design of specific vaccination schedules is required because of the impaired antibody response in specific patient categories.Expert opinion: Lung transplantation candidates should be vaccinated with pneumococcal vaccines prior to transplantation. Currently, the 23-valent pneumococcal polysaccharide vaccine offers the broadest coverage, but the antibody response should be monitored. New generation pneumococcal conjugate vaccines with equally broad serotype coverage could be used in the future. During the post-transplantation period, the immune status of the patients should be monitored regularly, and vaccination should be repeated when indicated.

The Alberta Stroke Program Early Computed Tomography Score (ASPECTs) on noncontrast CT (NCCT) is widely used for the decision of endovascular therapy (ET) in randomized controlled trials. CT angiography source images (CTA-SI) is another method to evaluate ischemic brain damage. We aimed to evaluate the association between pretreatment ASPECTs on CTA-SI and post-treatment clinical and radiological outcomes in acute stroke patients treated with ET. The association between both scores along with final infarct and outcome were analyzed. A total of 90 patients with successful recanalization were included in the study. The mean age was 59 ± 11.8. According to the results, CTA-SI ASPECTs was better correlated with final infarct than NCCT ASPECTs (p 0.001). In univariate analyzes, factors associated with good outcome were age, baseline NIHSS score, and presence of diabetes mellitus (p = 0.001, p = 0.002, p = 0.034, respectively). On the other hand, when an analysis differentiating patients by age was performed, 40 patients below 60 years of age had significantly better outcomes despite having higher baseline NIHSS scores (p = 0.002). Finally, in multivariate analyzes, only age and baseline NIHSS score were found to be independent predictors of good outcome (p = 0.003 for both). In conclusion, CTA-SI ASPECTs in patient selection for ET seems to be more useful than NCCT ASPECTs. However, both scoring modalities were not found to be independent predictors of good outcome. Outcomes are changeable for the younger population who could continue their lives with mild or no deficits despite having a relatively low initial ASPECTs.

INTRODUCTION[|]Cerebral amyloid angiopathy (SAA) is a cerebrovascular pathology that develops due to the accumulation of amyloid beta-peptide (Aβ) in the media and adventisia layer of small and large cerebral arteries. Ischemic or hemorrhagic stroke, dementia and encephalopathy can be seen. In our study, we aimed to investigate the frequency of convexal subarachnoid hemorrhage and its effect on prognosis. [¤]METHODS[|]Twenty-four patients diagnosed with cerebral amyloid angiopathy who were examined and treated in the neurology clinic between 2016 and 2017, and who received gradient ECO and SWI MR imaging were included in our study. Patients with a history of trauma and recent surgery were excluded from the study. Demographic features, vascular risk factors, antithrombotic or anticoagulant use, neuroimaging findings, application NIHSS and mRS values after 3 months were recorded. [¤]RESULTS[|]24 patients were included in the study. Eleven (45.8%) were women. The average age was 72.5 +- 8.79. 17% of our patients had convex subarachnoid hemorrhage and 21% had lobar hemorrhage. In 42%, both lobar hemorrhage and convex subarachnoid hemorrhage were observed. There was no significant difference between the groups in terms of prognosis and mortality.[¤]DISCUSSION AND CONCLUSION[|]In our study, it was concluded that convexal subarachnoid hemorrhage did not have a significant effect on prognosis and was not related to hypertension, diabetes, smoking and anticoagulant use.[¤]

Aim This study aims to determine, based on existing data, whether the mechanism resulting in liver dysfunction in HELLP syndrome resembles that in Sinusoidal Obstruction Syndrome (SOS). Background HELLP syndrome is a serious pregnancy disorder with high maternal and perinatal morbidity and mortality rates. Because of poor insight in its pathophysiology, particularly that of the liver involvement, clinical management is limited to symptomatic treatment, often followed by termination of pregnancy. SOS is a rare, potentially life-threatening complication of radio and/ or chemotherapy in the preparation of hematopoietic cell transplantation. The etiology of liver dysfunction in SOS is - unlike that in HELLP syndrome - better-understood and seems to be initiated by direct toxic damage and demise of endothelial cells, causing hepatic sinusoidal obstruction and ischemia. Methods We searched Pubmed, Embase and Cochrane for reports on the etiology of HELLP and SOS. This yielded 73 articles, with 14 additional reports from the references listed in these articles. Results The dysfunctional placenta in women developing HELLP initiates a cascade of events that eventually results in liver dysfunction. The placenta releases, besides anti-angiogenetic factors, also necrotic debris and cell-free DNA, a mixture that not only induces systemic endothelial dysfunction as in preeclampsia, but also a systemic inflammatory response. The latter aggravates the endothelio-toxic effects in the systemic cardiovascular bed, amplifying the already increased pro-thrombotic conditions. Particularly in microcirculations with extremely low shear forces, such as in the hepatic sinusoids, this will facilitate microthrombi formation and fibrin deposition eventually resulting in obstruction of the sinusoids similar as in SOS. The latter causes ischemic damage and progressive demise of hepatocytes. Conclusion The available information supports the concept that the liver damage in HELLP and SOS results from sinusoidal ischemia, presumably resulting from partially overlapping pathophysiological mechanisms.

Valved allografts and xenografts for reconstruction of the right ventricular outflow tract (RVOT) lack durability and do not grow. We report the first clinical use of a completely bioabsorbable valved conduit (Xeltis pulmonary valve - XPV) in children. Twelve children (six male), median age five (two to twelve) years and median weight 17 (10 to 43) kg, underwent RVOT reconstruction with the XPV. Diagnoses were: pulmonary atresia with ventricular septal defect (VSD) (n = 4), tetralogy of Fallot (n = 4), common arterial trunk (n = 3), and transposition of the great arteries with VSD and pulmonary stenosis (n = 1). All had had previous surgery, including prior RVOT conduit implantation in six. Two diameters of conduit 16mm (n = 5) and 18mm (n = 7) were used. At 24 months none of the patients has required surgical re-intervention, 9 of the 12 are in NYHA functional class I and three patients in NYHA class II. None of the conduits has shown evidence of progressive stenosis, dilation or aneurysm formation. Residual peak gradient of >40 mm Hg was observed in three patients, caused by kinking of the conduit at implantation in 1 and distal stenosis in the peripheral pulmonary arteries in 2 patients. Five patients developed severe pulmonary valve insufficiency (PI); the most common mechanism was prolapse of at least one of the valve leaflets. The XPV conduit is a promising innovation for RVOT reconstruction. Progressive PI requires however an improved design (geometry, thickness) of the valve leaflets.

Background Reliable testing for SARS-CoV-2 is key for the management of the COVID-19 pandemic. Aim We estimate diagnostic accuracy for nucleic acid and antibody tests 5 months into the COVID-19 pandemic, and compare with manufacturer-reported accuracy. Methods We reviewed the clinical performance of SARS-CoV-2 nucleic acid and antibody tests based on 93,757 test results from 151 published studies and 20,205 new test results from 12 countries in the European Union and European Economic Area (EU/EEA). Results Pooling the results and considering only results with 95% confidence interval width ≤ 5%, we found four nucleic acid tests, including one point-of-care test and three antibody tests, with a clinical sensitivity ≥ 95% for at least one target population (hospitalised, mild or asymptomatic, or unknown). Nine nucleic acid tests and 25 antibody tests, 12 of them point-of-care tests, had a clinical specificity of ≥ 98%. Three antibody tests achieved both thresholds. Evidence for nucleic acid point-of-care tests remains scarce at present, and sensitivity varied substantially. Study heterogeneity was low for eight of 14 sensitivity and 68 of 84 specificity results with confidence interval width ≤ 5%, and lower for nucleic acid tests than antibody tests. Manufacturer-reported clinical performance was significantly higher than independently assessed in 11 of 32 and four of 34 cases, respectively, for sensitivity and specificity, indicating a need for improvement in this area. Conclusion Continuous monitoring of clinical performance within more clearly defined target populations is needed.

Perilipin 2 (PLIN2) is a lipid droplet protein with various metabolic functions. However, studies investigating PLIN2 in the context of inflammation, especially in systemic and acute inflammation, are lacking. Hence, we assessed the relevance of serum PLIN2 in critically ill patients. We measured serum PLIN2 serum in 259 critically ill patients (166 with sepsis) upon admission to a medical intensive care unit (ICU) compared to 12 healthy controls. A subset of 36 patients underwent computed tomography to quantify body composition. Compared to controls, serum PLIN2 concentrations were elevated in critically ill patients at ICU admission. Interestingly, PLIN2 independently indicated multiple organ dysfunction (MOD), defined as a SOFA score &gt, 9 points, at ICU admission, and was also able to independently predict MOD after 48 h. Moreover, serum PLIN2 levels were associated with severe respiratory failure potentially reflecting a moribund state. However, PLIN2 was neither a predictor of ICU mortality nor did it reflect metabolic dysregulation. Conclusively, the first study assessing serum PLIN2 in critical illness proved that it may assist in risk stratification because it is capable of independently indicating MOD at admission and predicting MOD 48 h after PLIN2 measurement. Further evaluation regarding the underlying mechanisms is warranted.

C-C chemokine receptor 5 (CCR5) and polymorphisms in CCR5 gene are associated with sarcoidosis and Löfgren’s syndrome. Löfgren’s syndrome is an acute and usually self-remitting phenotype of sarcoidosis. We investigated whether the single nucleotide polymorphism (SNP) rs1799987 is associated with susceptibility for Löfgren’s syndrome and has an effect on CCR5 expression on monocytes and function of CCR5. A total of 106 patients with Löfgren’s syndrome and 257 controls were genotyped for rs1799987. Expression of CCR5 on monocytes was measured by flowcytometry. We evaluated calcium influx kinetics following stimulation upon N-formylmethionyl-leucyl-phenylalanine (fMLP) and macrophage inflammatory protein-1α (MIP-1α) on monocytes by measuring the median fluorescence intensity (MFI). The frequency of the G allele of rs1799987 was significantly higher in Löfgren’s syndrome than in healthy controls (p = 0.0015, confidence interval (CI) 1.22–2.32, odds ratio (OR) 1.680). Patients with a GG genotype showed higher CCR5 expression on monocytes than patients with the AA genotype (p = 0.026). A significantly (p = 0.027) lower count of patients with the GG genotype showed a calcium influx reaction to simulation upon MIP-1 α, compared with patients with the AA genotype. The rs1799987 G allele in CCR5 gene is associated with susceptibility to Löfgren’s syndrome and with quantitative and qualitative changes in CCR5, potentially effecting the inflammatory response.

Summary Background Awake prone positioning has been reported to improve oxygenation for patients with COVID-19 in retrospective and observational studies, but whether it improves patient-centred outcomes is unknown. We aimed to evaluate the efficacy of awake prone positioning to prevent intubation or death in patients with severe COVID-19 in a large-scale randomised trial. Methods In this prospective, a priori set up and defined, collaborative meta-trial of six randomised controlled open-label superiority trials, adults who required respiratory support with high-flow nasal cannula for acute hypoxaemic respiratory failure due to COVID-19 were randomly assigned to awake prone positioning or standard care. Hospitals from six countries were involved: Canada, France, Ireland, Mexico, USA, Spain. Patients or their care providers were not masked to allocated treatment. The primary composite outcome was treatment failure, defined as the proportion of patients intubated or dying within 28 days of enrolment. The six trials are registered with ClinicalTrials.gov , NCT04325906 , NCT04347941 , NCT04358939 , NCT04395144 , NCT04391140 , and NCT04477655 . Findings Between April 2, 2020 and Jan 26, 2021, 1126 patients were enrolled and randomly assigned to awake prone positioning (n=567) or standard care (n=559). 1121 patients (excluding five who withdrew from the study) were included in the intention-to-treat analysis. Treatment failure occurred in 223 (40%) of 564 patients assigned to awake prone positioning and in 257 (46%) of 557 patients assigned to standard care (relative risk 0·86 [95% CI 0·75−0·98]). The hazard ratio (HR) for intubation was 0·75 (0·62−0·91), and the HR for mortality was 0·87 (0·68−1·11) with awake prone positioning compared with standard care within 28 days of enrolment. The incidence of prespecified adverse events was low and similar in both groups. Interpretation Awake prone positioning of patients with hypoxaemic respiratory failure due to COVID-19 reduces the incidence of treatment failure and the need for intubation without any signal of harm. These results support routine awake prone positioning of patients with COVID-19 who require support with high-flow nasal cannula. Funding Open AI inc, Rice Foundation, Projet Hospitalier de Recherche Clinique Interregional, Appel d'Offre 2020, Groupement Interregional de Recherche Clinique et d'Innovation Grand Ouest, Association pour la Promotion a Tours de la Reanimation Medicale, Fond de dotation du CHRU de Tours, Fisher & Paykel Healthcare Ltd.

Lung transplant patients are immunocompromised because of the medication they receive to prevent rejection, and as a consequence are susceptible to (respiratory) infections. Adequate vaccination strategies, including COVID-19 vaccination, are therefore needed to minimize infection risks.The international vaccination guidelines for lung transplant patients are reviewed, including the data on immunogenicity and effectivity of the vaccines. The impact on response to vaccination of the various categories of immunosuppressive drugs, used in the posttransplant period, on response to vaccination is described. A number of immunosuppressive and/or anti-inflammatory drugs also is used for controlling the immunopathology of severe COVID-19. Current available COVID-19 vaccines, both mRNA or adenovirus based are recommended for lung transplant patients.In order to improve survival and quality of life, infections of lung transplant patients should be prevented by vaccination. When possible, vaccination should start already during the pre-transplantation period when the patient is on the waiting list. Booster vaccinations should be given post-transplantation, but only when immunosuppression has been tapered. Vaccine design based on mRNA technology could allow the design of an array of vaccines against other respiratory viruses, offering a better protection for lung transplant patients.

Several anatomic plates for fixation of the olecranon after a fracture or an osteotomy are commercially available. They serve as an alternative for tension band wiring, which is associated with a relatively high complication rate. Plating of the olecranon reportedly might result in nonunion or malunion and eventually may require revision surgery or plate removal because of skin irritation. The authors describe a proximal periprosthetic avulsion fracture of the tip of the olecranon as a unique complication associated with the use of an anatomic plate for fixation of an olecranon osteotomy. This retrospective case series included 35 patients with comminuted distal humerus fractures treated by open reduction and internal fixation through an olecranon osteotomy with an anatomic olecranon plate. Of the 35 patients, 6 (17.1%) had postoperative olecranon tip fracture, just proximal to the osteotomy site. In all cases, the fracture line coursed through the proximal cluster of screws situated on the proximal part of the plate. Avulsion fractures of the tip of the olecranon after plating of the olecranon osteotomy could have occurred as a result of biomechanical factors. The short design of the proximal part of the plate and the high screw density in the proximal part of the olecranon could lead to increased mechanical stress during contraction of the triceps. This complication should prompt further biomechanical evaluation of the plate design. [ Orthopedics . 2021;44(4):e583–e587.]

En ningún caso debe llevarse a cabo la automedicación, por lo que se desarrollaron estrategias educativas para prevenir la automedicación y sus efectos adversos como parte de las complicaciones en el adulto joven, donde se analizó las diversas investigaciones y se evidenció que hay algunos casos sobre dicho problema. Se emplearon las modalidades cualitativa y cuantitativa para así complementar y tener un amplio contexto, tomándose en cuenta la investigación de tipo exploratoria, descriptiva y correlacional. En los resultados, el 76% de la población adulta optó por automedicarse, una de las complicaciones fue la dependencia que tienen a los medicamentos que han ingerido en un 47% implicando riesgos en la salud por el desconocimiento de los medicamentos.

The association between vitiligo and hearing loss has been noted but the specific frequencies and degrees of hearing impairment remain unclear. The objective of this systematic review was to investigate the relationship between vitiligo and hearing thresholds at various specific frequencies. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched MEDLINE and Embase for relevant studies from inception to 10th April 2021. Case-control studies, cross-sectional, or cohort studies that compared the frequency-specific hearing thresholds between vitiligo patients and age-matched non-vitiligo controls were included. There were neither language nor geographic limitations. We used the Newcastle-Ottawa Scale to assess the risk of bias of included studies. The DerSimonian and Laird random-effects model was utilized in meta-analyses due to expected clinical heterogeneity. We included 9 case-control studies with 371 vitiligo patients and 349 controls, which were rated with low or unclear risk. We found neither relevant cross-sectional nor cohort studies. The meta-analysis showed that when compared with controls, vitiligo patients had significantly higher pure-tone hearing thresholds at 2000, 4000, and 8000 Hz. In conclusions, vitiligo patients are prone to high-frequency sensorineural hearing loss.

Contains fulltext : 234969.pdf (Publisher’s version ) (Open Access) BACKGROUND AND AIMS: Standard treatment for naïve hereditary hemochromatosis patients consists of phlebotomy or a personalized erythrocytapheresis. Erythrocytapheresis is more efficient, but infrequently used because of perceived costs and specialized equipment being needed. The main aim of our study was to develop a model that predicts the number of initial treatment procedures for both treatment methods. This information may help the clinician to select the optimal treatment modality for the individual patient. METHODS: We analyzed retrospective data of 125 newly diagnosed patients (C282Y homozygous), treated either with phlebotomy (n = 54) or erythrocytapheresis (n = 71) until serum ferritin (SF) reached levels ≤100 μg/L. To estimate the required number of treatment procedures multiple linear regression analysis was used for each treatment method separately. RESULTS: The linear regression model with the best predictive quality (R(2) = 0.74 and 0.73 for erythrocytapheresis and phlebotomy respectively) included initial SF, initial hemoglobin (Hb) level, age, and BMI, where initial SF was independently related to the total number of treatment procedures for both treatment methods. The prediction error expressed in RMSPE and RMSDR was lower for erythrocytapheresis than for phlebotomy (3.8 and 4.1 vs 7.0 and 8.0 respectively), CONCLUSIONS: Although the prediction error of the developed model was relatively large, the model may help the clinician to choose the most optimal treatment method for an individual patient. Generally erythrocytapheresis halves the number of treatment procedures for all patients, where the largest reduction (between 55% and 64%) is reached in patients with an initial Hb level ≥ 9 mmol/L (14.5 g/dL). ClinicalTrials.gov number NCT00202436.

Survival rates from pancreatic cancer have remained stagnant for decades due to the heterogenic nature of the disease. This study aimed to find a new advanced biomarker and evaluate its clinical capabilities, thus enabling more individualised pancreatic cancer management. Between 2013 and 2020, 267 patients were included in the study. Surgically collected pancreatic tissue samples were analysed via high-definition mass spectrometry. Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) was discovered as a possible promising pancreatic cancer biomarker. The predominance of CEACAM6 to pancreatic cancer was validated using antibodies in tissue samples. CEACAM6, carbohydrate antigen 19-9 (CA19-9), and carcinoembryonic antigen (CEA) blood serum concentrations were evaluated for clinical evaluation and comparison. Kaplan–Meier survival analyses were used to evaluate disease-free survival (DFS) and overall survival (OS). Poorer overall survival was significantly dependent on increased CEACAM6 blood serum concentrations (17.0 vs. 12.6 months, p = 0.017) in pancreatic cancer patients after radical treatment and adjuvant chemotherapy. Increased CEA and CA19-9 concentrations showed no significant dependencies with survival. Thus, CEACAM6 is a promising new biomarker with significant prognostic value and prediction of chemoresistance properties, enabling the improvement of individualised approaches to patients with pancreatic cancer.

BACKGROUND Buccal mucosal squamous cell carcinoma (BMSCC) is an aggressive oral cancer. Moreover, reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is a well-known tumor suppressor in many cancers. Our aim was to investigate the association of RECK expression with prognosis in BMSCC patients with different clinicopathological features. MATERIALS AND METHODS The expression level of RECK was determined by immunohistochemistry using tissue microarrays containing specimens from 193 BMSCC patients. The association of RECK expression with outcomes in BMSCC patients stratified by different clinicopathological features was analyzed by Cox proportional hazards models. RESULTS The low expression level of RECK was associated with shorter disease-specific survival, especially in patients with age >40 years, moderate or poor cell differentiation, advanced pathological stage, and history of postoperative radiotherapy. However, the low expression level of RECK was not associated with poor disease-free survival, except in BMSCC patients with age ≦40 years, advanced pathological stage and lymph node metastasis. Furthermore, RECK-knockdowned cells showed higher cell viability and abilities of invasion/migration, indicating that RECK might be a tumor suppressor for tumor progression in oral cancer. CONCLUSION The low expression of RECK might be a potential prognostic biomarker for pathological outcome-dependent BMSCC patients.

Context There is an ongoing debate about whether and how fructose is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A recent experimental study showed an increased intrahepatic triglyceride (IHTG) content in mice deficient for aldolase B (aldo B−/−), the enzyme that converts fructose-1-phosphate to triose phosphates. Objective To translate these experimental findings to the human situation. Design Case-control study. Setting Outpatient clinic for inborn errors of metabolism. Patients or Other Participants Patients with hereditary fructose intolerance, a rare inborn error of metabolism caused by a defect in aldolase B (n = 15), and healthy persons matched for age, sex, and body mass index (BMI) (n =15). Main Outcome Measure IHTG content, assessed by proton magnetic resonance spectroscopy. Results IHTG content was higher in aldo B−/− patients than controls (2.5% vs 0.6%; P = 0.001) on a background of lean body mass (median BMI, 20.4 and 21.8 kg/m2, respectively). Glucose excursions during an oral glucose load were higher in aldo B−/− patients (P = 0.043). Hypoglycosylated transferrin, a surrogate marker for hepatic fructose-1-phosphate concentrations, was more abundant in aldo B−/− patients than in controls (P < 0.001). Finally, plasma β-hydroxybutyrate, a biomarker of hepatic β-oxidation, was lower in aldo B−/− patients than controls (P = 0.009). Conclusions This study extends previous experimental findings by demonstrating that aldolase B deficiency also results in IHTG accumulation in humans. It suggests that the accumulation of fructose-1-phosphate and impairment of β-oxidation are involved in the pathogenesis.

Background The older inpatient population is a particularly frail cohort with high rates of delirium, falls and immobility. These patients require skilled gerontological nursing with high levels of supervision. Despite this, restraints such as bed rails continue to be common. Tethering through intravenous drips and urinary catheters are another form of restraint. Methods We performed a chart review and a bedside observation of patients aged ≥75 on medical wards admitted for ≥72 hours. We excluded patients who were critically unwell or imminently dying. We used the open source software package PSPP to complete the statistical analysis. Results We reviewed 100 patients, of whom 25 were restrained in some way (most commonly by bed rails 80%), 10 were tethered (through intravenous drips, oxygen tubing, urinary catheters and others), 7 were in isolation for infection control reasons. Restraint was associated with greater dependence in mobility and function, reduced time out of bed (Mann Whitney, P< 0.05), delirium and incontinence (chi square, p Conclusion Patients who are restrained are clearly frailer, more dependent, spend more time in bed, have higher rates of delirium and incontinence. These are particularly vulnerable patients who need high levels of attention from both medical and nursing staff. Supervision is always superior to restraint but requires investment in staff and resources. Patients who are isolated are also more physically dependent. Tethering should be minimised. Simple measures such as leg bags are underused.

BACKGROUND/AIM Long-term exposure to betel quid (BQ)-, cigarette-, and alcohol-induced chronic inflammation is a crucial risk factor for oral and pharyngeal squamous cell carcinoma (OPSCC) progression. We analyzed the genotypes of stromal-cell-derived factor-1 (SDF-1) and CXC-chemokine receptor-4 (CXCR4) and determined the association between their polymorphisms and the risk of OPSCC. MATERIALS AND METHODS This study consisted of 452 patients with pathologically proved OPSCC and 424 sex- and age-matched cancer-free controls. The genotypes of SDF-1 and CXCR4 were detected through the TaqMan real-time polymerase chain reaction (PCR) method. RESULTS Our data indicated that the C allele and C/C genotypes of CXCR4 were significantly associated with OPSCC [adjusted odds ratio (AOR)=1.41, 95% confidence interval (CI):1.02-1.96, p=0.037 and AOR=1.51, 95% CI:1.05-2.17, p=0.028, respectively] and OSCC (AOR=1.41, 95%CI:1.00-2.00, p=0.049 and AOR=1.49, 95%CI:1.01-2.20, p=0.044, respectively) risk. Patients with genetic polymorphisms of the genotype combination SDF-1/CXCR4 had a higher risk of OSCC (p trend=0.033). We analyzed the effects of CXCR4 genetic variants on susceptibility to OPSCC in patients with different risk habits of BQ chewing, tobacco smoking and alcohol consumption, and revealed that C/T+T/T genotypes exerted an increased risk only in patients with one (AOR=2.68, p=0.036) or two risk habits (AOR=2.02, p=0.027) compared to patients with the C/C genotype. CONCLUSION We concluded that CXCR4 C>T can be used as a genetic marker of susceptibility to OPSCC, particularly in OPSCC patients with one or two types of risk habits with a synergistic effect.

BACKGROUND Type V collagen (COL5), in the functional heterotrimer [α1(V)2 α2(V)] isoform, participates in the malignancies of various cancers. However, its role in tongue squamous cell carcinoma (TSCC) remains unclear. MATERIALS AND METHODS The expression levels of COL5A1 and COL5A2 polypeptide chains were examined using the tissue microarray from 245 TSCC patients with immunohistochemistry. Paired t test and Wilcoxon signed-rank test were performed for comparisons among the groups. Survival rates were estimated by using the Kaplan-Meier method and compared with log-rank tests. A Cox proportional hazards model was used to evaluate the impact of protein expression level on survival rate. RESULTS Expression level of COL5A1 was significantly increased in tumor tissues (P

C6orf141 (Chromosome 6 open reading frame 141) is a novel gene, and its role in oral cancer progression remains unclear. C6orf141 expression in oral squamous cell carcinoma (OSCC) and adjacent normal tissues from 428 patients was examined through immunohistochemistry (IHC). Our results revealed that C6orf141 expression was significantly reduced in OSCC compared with adjacent normal tissues. Low C6orf141 expression was significantly associated with a poor American Joint Committee on Cancer pathological stage (P P = 0.002), and pN stage (P = 0.032). Kaplan–Meier curves revealed that low C6orf141 expression was significantly associated with shorter disease-specific survival (DSS) in patients with OSCC (log-rank P = 0.007). Multivariate analysis indicated that low C6orf141 expression was an independent prognostic biomarker for DSS (adjusted hazard ratio = 1.34; 95% confidence interval = 1.10–1.81; P = 0.05). Additionally, ectopic C6orf141 expression could significantly suppress oral cancer cell proliferation, colony formation, and migratory and invasive abilities. Xenograft tumor growth assay revealed that C6orf141 could significantly suppress oral tumor growth in vivo. Our results suggest that C6orf141 plays a novel tumor-suppressive role in oral cancer cell growth and motility. Furthermore, C6orf141 dysfunction could be a potential prognostic biomarker for OSCC and provide new therapeutic strategies in the future.

Background Neuregulin 4 (Nrg4), a novel adipokine enriched in brown adipose tissue has been observed to negatively regulate de novo hepatic lipogenesis and limit nonalcoholic fatty liver disease (NAFLD) progression to nonalcoholic steatohepatitis (NASH) in rodents. However, the role of Nrg4 in human NAFLD remains unclear to date. We analysed Nrg4 plasma levels and its association with liver disease severity together with the transcriptional profile of the Nrg4 pathway in liver and visceral adipose tissue (VAT) of NAFLD patients. Methods Plasma Nrg4 levels were measured in 65 NAFLD patients and 43 healthy controls (HC). Hepatic steatosis and fibrosis were diagnosed and quantified with chemical shift MRI and transient elastography respectively. Furthermore, blood lipid levels, HOMA-IR and systemic pro-inflammatory cytokines (TNF-α, IL-6 and IFN-γ) were analysed. Microarray analyses to assess differences in the Nrg4 and its receptor family ErbB pathway in liver and VAT from an independent patient group with biopsy proven NAFL (simple steatosis) (n = 4), NASH (n = 5) and normal liver (n = 6) were performed. Results Plasma Nrg4 levels were not significantly different between NAFLD patients and HC (p = 0.622). Furthermore, plasma Nrg4 levels did not correlate with the hepatic fat fraction (r = -0.028, p = 0.829) and were not significantly different between NAFLD patients with or without hepatic fibrosis (p = 0.087). Finally, the expression profile of 82 genes related to the Nrg4-ErbB pathway in liver and VAT was not significantly different between NAFL, NASH or obese controls. Conclusion Our study does not support a role for Nrg4 in the pathophysiology of human NAFLD.

Background and aim: Insulin resistance (IR) plays a central role in the complex pathophysiology of nonalcoholic fatty liver disease (NAFLD). IR is linked to fat infiltration in skeletal muscle (myosteatosis) and loss of skeletal muscle mass and function (sarcopenia). The clinical significance of myosteatosis in NAFLD is not well investigated. In this exploratory study we aimed to investigate the association between myosteatosis and NAFLD related hepatic and systemic variables in a well characterized NAFLD cohort.Methods: We cross-sectionally studied forty-five NAFLD patients. The muscle fat fraction (MFF) was measured with chemical shift gradient echo MRI. In addition, the hepatic fat fraction (MRI), liver stiffness (FibroScan) and appendicular skeletal muscle mass (Dual-energy X-ray absorptiometry) were analyzed.Results: The median hepatic fat fraction was 15.64% (IQR 12.05-25.13) and significant (F2-F3) liver fibrosis (liver stiffness >= 7 kPa) was diagnosed in 18 NAFLD patients (40%). MFF was not correlated with hepatic fat fraction (r = -0.035, P = 0.823) and did not differ between subjects with or without significant fibrosis (P = 0.980). No patient was diagnosed with sarcopenia based on the skeletal muscle mass index. In a linear regression model, anthropometric parameters, including body mass index (BMI) (P = 0.018) and total body fat percentage (P = 0.005), were positively associated with MFF while no association with insulin resistance (HOMA-IR) was observed.Conclusion: Myosteatosis did not correlate with the degree of hepatic steatosis or fibrosis in this well characterized NAFLD cohort, but was positively correlated with total body fat percentage and BMI. (C) 2020 Elsevier Masson SAS. All rights reserved.

An increasing percentage of people have or are at risk to develop non-alcoholic fatty liver disease (NAFLD) worldwide. NAFLD comprises different stadia going from isolated steatosis to non-alcoholic steatohepatitis (NASH). NASH is a chronic state of liver inflammation that leads to the transformation of hepatic stellate cells to myofibroblasts. These cells produce extra-cellular matrix that results in liver fibrosis. In a normal situation, fibrogenesis is a wound healing process that preserves tissue integrity. However, sustained and progressive fibrosis can become pathogenic. This process takes many years and is often asymptomatic. Therefore, patients usually present themselves with end-stage liver disease e.g., liver cirrhosis, decompensated liver disease or even hepatocellular carcinoma. Fibrosis has also been identified as the most important predictor of prognosis in patients with NAFLD. Currently, only a minority of patients with liver fibrosis are identified to be at risk and hence referred for treatment. This is not only because the disease is largely asymptomatic, but also due to the fact that currently liver biopsy is still the golden standard for accurate detection of liver fibrosis. However, performing a liver biopsy harbors some risks and requires resources and expertise, hence is not applicable in every clinical setting and is unsuitable for screening. Consequently, different non-invasive diagnostic tools, mainly based on analysis of blood or other specimens or based on imaging have been developed or are in development. In this review, we will first give an overview of the pathogenic mechanisms of the evolution from isolated steatosis to fibrosis. This serves as the basis for the subsequent discussion of the current and future diagnostic biomarkers and anti-fibrotic drugs.

Objective Liver injury has frequently been reported in COVID-19 patients. The clinical relevance of liver injury related to SARS-CoV-2 infection remains unclear with a need for prospective studies on the impact of liver function test (LFT) abnormalities at baseline. Design Data of 217 patients without pre-existing liver disease prospectively included in the COVID-19 registry of the LMU university hospital were analysed in order to assess the association of abnormal LFT at admission and course of the disease. Severe course was defined as admission to the intensive care unit (ICU) or as COVID-19-related death. Results Abnormal LFT at baseline was present in 58% of patients, with a predominant elevation of aspartate aminotransferase (AST) (42%), gamma-glutamyltransferase (GGT) (37%) and alanine aminotransferase (ALT) (27%), hypoalbuminaemia was observed in 33%. Elevation of ALT and GGT, as well as hypoalbuminaemia, was associated with higher proportions of patients requiring ICU treatment and mechanical ventilation. After adjusting for age, gender and comorbidities, hypoalbuminaemia combined with abnormal AST or GGT at hospital admission was a highly significant independent risk factor for ICU admission (OR 46.22 and 38.8, respectively) and for a composite endpoint of ICU admission and/or COVID-19-related death (OR 42.0 and 26.9, respectively). Conclusion Abnormal LFTs at hospital admission, in particular GGT and albumin, are associated with a severe course of SARS-CoV-2 infection.

Whole body vibration (WBV) has been suggested to improve athletes’ neuromuscular strength and power. This study investigated the effect of single WBV stimulation on volleyball-specific performance. The participants were 20 elite male volleyball players who performed a 1-min warm-up exercise on a vibration platform at a frequency of 30 Hz and peak-to-peak displacement of 2 mm. After the warm-up exercise, the participants performed a blocking agility test (BAT), 10-m sprinting test, agility T-test, and counter movement jump test. We compared the participants’ performance at four time points (Pretest, Post 0, Post 1, and Post 2). The results revealed that the participants’ BAT performance and maximum rate of force development improved significantly 1 min after the vibration stimulation (p

Giant mitochondria are peculiarly shaped, extremely large mitochondria in hepatic parenchymal cells, the internal structure of which is characterised by atypically arranged cristae, enlarged matrix granules and crystalline inclusions. The presence of giant mitochondria in human tissue biopsies is often linked with cellular adversity, caused by toxins such as alcohol, xenobiotics, anti-cancer drugs, free-radicals, nutritional deficiencies or as a consequence of high fat Western diets. To date, non-alcoholic fatty liver disease is the most prevalent liver disease in lipid dysmetabolism, in which mitochondrial dysfunction plays a crucial role. It is not well understood whether the morphologic characteristics of giant mitochondria are an adaption or caused by such dysfunction. In the present study, we employ a complementary multimodal imaging approach involving array tomography and transmission electron tomography in order to comparatively analyse the structure and morphometric parameters of thousands of normal- and giant mitochondria in four patients diagnosed with non-alcoholic fatty liver disease. In so doing, we reveal functional alterations associated with mitochondrial gigantism and propose a mechanism for their formation based on our ultrastructural findings.

Non-alcoholic fatty liver disease (NAFLD) is a widespread liver disease in Western society, but its multifactorial pathogenesis is not yet fully understood. Ultrastructural analysis of liver sinusoidal endothelial cells (LSECs) in animal models and in vitro studies shows defenestration early in the course of NAFLD, promoting steatosis. LSECs and fenestrae are important in the transport of lipids across the sinusoids. However, human ultrastructural data, especially on LSECs and fenestrae, are scarce. This study aimed to explore the ultrastructural changes in perfusion type fixed liver biopsies of NAFLD patients with and without non-alcoholic steatohepatitis (NASH), with a special focus on LSECs and their fenestration. Liver biopsies from patients with NAFLD were fixed using two perfusion techniques, jet and injection fixation, for needle and wedge biopsies, respectively. Ultrastructural changes were studied using transmission electron microscopy. NASH was diagnosed by bright-field microscopy using the SAF score (steatosis, activity, fibrosis). Thirty-seven patients were included, of which 12 (32.4%) had NASH. Significantly less defenestration was found in NASH compared to noNASH samples (p=0.002). Other features, i.e., giant mitochondria and fenestrae size did not differ between groups. Furthermore, we described new structures, i.e., single cell steatonecrosis and inflammatory fat follicles (IFF) that were observed in both groups. Concluding, defenestration was more common in noNASH compared to NASH in human liver samples. Defenestration was not related to the degree of steatosis or fibrosis. We speculate that defenestration can be a protective mechanism in simple steatosis which is lacking in NASH.

Digital, Non-alcoholic fatty liver disease (NAFLD) is a potentially serious liver disease that affects approximately one-quarter of the global adult population, causing a substantial burden of ill health with wide-ranging social and economic implications. It is a multisystem disease and is considered the hepatic component of metabolic syndrome. Unlike other highly prevalent conditions, NAFLD has received little attention from the global public health community. Health system and public health responses to NAFLD have been weak and fragmented, and, despite its pervasiveness, NAFLD is largely unknown outside hepatology and gastroenterology. There is only a nascent global public health movement addressing NAFLD, and the disease is absent from nearly all national and international strategies and policies for non-communicable diseases, including obesity. In this global Delphi study, a multidisciplinary group of experts developed consensus statements and recommendations, which a larger group of collaborators reviewed over three rounds until consensus was achieved. The resulting consensus statements and recommendations address a broad range of topics — from epidemiology, awareness, care and treatment to public health policies and leadership — that have general relevance for policy-makers, health-care practitioners, civil society groups, research institutions and affected populations. These recommendations should provide a strong foundation for a comprehensive public health response to NAFLD., Ciencias Médicas y de la Salud

PURPOSE: To investigate the effect and potential predictors of corneal transplantation on patient-reported outcomes such as quality of life, visual functioning, and mental health by systematically reviewing the literature. METHODS: Studies with 1 preoperative and at least 1 postoperative measurement were searched for in relevant literature databases. Methodological quality was assessed using the Quality Assessment Tool for Quantitative Studies, and effect sizes were calculated. RESULTS: Of 1445 unique publications, 14 studies, including 15 study designs, were described in 16 publications. Four randomized controlled trials, 1 controlled clinical trial, 1 cohort study, and 1 before-after study (BA) were of good quality; 6 BAs were of moderate quality; and 2 BAs were of weak quality. Patients generally improved 12 months after transplantation on health-related quality of life (effect size between 0.08 and -3.06), vision-related quality of life (-0.67 and -6.65), visual functioning (-0.55 and -0.63), and subjective visual symptoms (-0.31 and -0.86). Patient satisfaction was high (-0.95). Patients improved on depression (-0.31) but remained stable on anxiety (-0.05) 4 months after transplantation. Predictors of positive outcomes were lower preoperative visual acuity and visual functioning, better postoperative visual factors, younger age, and male sex. CONCLUSIONS: Corneal transplantation showed overall beneficial effects on patient-reported outcomes. Knowledge of these effects and predictors might result in better treatment, more patient-centered care, and more realistic expectations on the part of patients and ophthalmologists. Future studies should focus on not only health- and vision-related quality of life but also mental health and labor participation using longitudinal study designs.

Simple Summary In Glioblastoma (GB), a malignant tumor of the central nervous system, diagnosis can currently only be obtained via tissue biopsy. In this study we were able to isolate GB derived extracellular vesicles (EVs) in the blood, after patients received 5-aminolevulinic acid (5-ALA) before surgery. This isolation is based on fluorescence caused by the accumulation of fluorescent protoporphyrin IX (PpIX) in these EVs. We show that these EVs contain various GB-related micro RNAs. While there are many ways in which our technique needs to be improved before being able to be implemented in the clinic, this study shows that detecting and analyzing circulating GB-derived EVs based on PpIX fluorescence is feasible. In the future, our technique could be developed to diagnose and monitor GB via blood samples instead of a brain biopsy. Abstract Background: In glioblastoma (GB), tissue is required for accurate diagnosis and subtyping. Tissue can be obtained through resection or (stereotactic) biopsy, but these invasive procedures provide risks for patients. Extracellular vesicles (EVs) are small, cell-derived vesicles that contain miRNAs, proteins, and lipids, and possible candidates for liquid biopsies. GB-derived EVs can be found in the blood of patients, but it is difficult to distinguish them from circulating non-tumor EVs. 5-aminolevulinic acid (5-ALA) is orally administered to GB patients to facilitate tumor visualization and maximal resection, as it is metabolized to fluorescent protoporphyrin IX (PpIX) that accumulates in glioma cells. In this study, we assessed whether PpIX accumulates in GB-derived EVs and whether these EVs could be isolated and characterized to enable a liquid biopsy in GB. Methods: EVs were isolated from the conditioned media of U87 cells treated with 5-ALA by differential ultracentrifugation. Blood samples were collected and processed from healthy controls and patients undergoing 5-ALA guided surgery for GB. High-resolution flow cytometry (hFC) enabled detection and sorting of PpIX-positive EVs, which were subsequently analyzed by digital droplet PCR (ddPCR). Results: PpIX-positive EVs could be detected in conditioned cell culture media as well as in patient samples after administration of 5-ALA. By using hFC, we could sort the PpIX-positive EVs for further analysis with ddPCR, which indicated the presence of EVs and GB-associated miRNAs. Conclusion: GB-derived EVs can be isolated from the plasma of GB patients by using 5-ALA induced fluorescence. Although many challenges remain, our findings show new possibilities for the development of blood-based liquid biopsies in GB patients.