Osteonecrosis of the jaw: surgical treatment results before and during the COVID-19 pandemic in one of the reference hospitals in Poland.

OBJECTIVE: The COVID-19 pandemic has had a huge impact not only on everyday life but, above all, on the functioning of medical entities. During its duration, there were problems with access to health care, including maxillofacial surgery departments. The aim of the study is to analyze how the pandemic affected the surgical results of the treatment of osteonecrosis of the jaws at the Clinic of Maxillofacial Surgery in Poznan which delivers services in maxillofacial surgery for almost 4.5 million inhabitants in Poland. PATIENTS AND METHODS: We conducted a retrospective analysis of patients' medical records before and during the pandemic restrictions. The data was obtained by entering the appropriate passwords and ICD-10 diagnoses (e.g., M87) in the hospital's IT system. The obtained information was subjected to statistical analysis. RESULTS: The number of patients before and during the pandemic did not differ significantly. During the COVID-19 pandemic, the waiting time of patients after admission to the hospital for surgery and the total time of hospitalization were shortened. The number of complications was similar in both groups. However, the waiting time for a follow-up visit was longer during restriction time. CONCLUSIONS: The COVID-19 pandemic had an impact on the course of surgical treatment in patients with osteonecrosis of the jaws. The outcomes of the medical procedure remained consistent with the ones observed before the implementation of restrictions. This is likely due to the urgency of the illness. Despite the pandemic, a critical condition called osteonecrosis of the jaw was treated promptly.

First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year outcomes from CheckMate 743.

BACKGROUND: In the phase III CheckMate 743 study (NCT02899299), first-line nivolumab plus ipilimumab significantly improved overall survival (OS) versus chemotherapy in patients with unresectable malignant pleural mesothelioma (MPM). We report updated data with 3-year minimum follow-up. PATIENTS AND METHODS: Adults with previously untreated, histologically confirmed, unresectable MPM and Eastern Cooperative Oncology Group performance status of ≤1 were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks) for up to 2 years, or six cycles of platinum plus pemetrexed chemotherapy. This report includes updated efficacy and safety outcomes, exploratory biomarker analyses including four-gene inflammatory expression signature score, and a post hoc efficacy analysis in patients who discontinued treatment due to treatment-related adverse events (TRAEs). RESULTS: With a median follow-up of 43.1 months, nivolumab plus ipilimumab continued to prolong OS versus chemotherapy. Median OS was 18.1 versus 14.1 months [hazard ratio (95% confidence interval), 0.73 (0.61-0.87)], and 3-year OS rates were 23% versus 15%, respectively. Three-year progression-free survival rates were 14% versus 1%, and objective response rates were 40% versus 44%. At 3 years, 28% versus 0% of responders had an ongoing response. Improved survival benefit with nivolumab plus ipilimumab versus chemotherapy was observed across subgroups, including histology. A high score of the four-gene inflammatory signature appeared to correlate with improved survival benefit with nivolumab plus ipilimumab. No new safety signals were observed with nivolumab plus ipilimumab, despite patients being off therapy for 1 year. In patients who discontinued nivolumab plus ipilimumab due to TRAEs, median OS was 25.4 months, and 34% of responders maintained their responses for ≥3 years after discontinuation. CONCLUSIONS: With 3 years' minimum follow-up, nivolumab plus ipilimumab continued to provide long-term survival benefit over chemotherapy and a manageable safety profile, supporting the regimen as standard-of-care treatment for unresectable MPM, regardless of histology.

Comorbidities Associated with Worse Outcomes Among Inpatients Admitted for Acute Gastrointestinal Bleeding.

BACKGROUND: Multimorbidity increases healthcare resource utilization. Little is known on specific comorbidity combinations. AIMS: To identify comorbidities associated with increased resource utilization among inpatients admitted for gastrointestinal bleeding (GIB). METHODS: This retrospective cross-sectional study, 1/2010-5/2018 at the University Hospital Zurich, Switzerland, analyzed electronic health records of patients with upper (UGIB) and lower (LGIB) GIB, focusing on length of stay (LOS) and 30-day readmissions for resource use and clinical outcomes, investigated by multivariable regression adjusted for antithrombotics. RESULTS: Of 1101 patients, 791 had UGIB and 310 LGIB, most often melena and bleeding diverticula, respectively. In UGIB, thromboembolic events showed a trend toward 27% increased LOS (1.27; 95% confidence interval [CI] 1.00-1.61), antithrombotics independently associated with 46% increased LOS (1.46; 95% CI 1.32-1.62). Cancer (odds ratio [OR] 2.86; 95% CI 1.68-4.88) independently associated with 30-day readmissions, anemia showed a trend (OR 1.68; 95% CI 1.00-2.84). In LGIB, none of the investigated comorbidities associated with increased LOS, but antithrombotics independently associated with 25% increased LOS (1.25; 95% CI 1.07-1.46). Atrial fibrillation/flutter (OR 2.69; 95% CI 1.06-6.82) and cancer (OR 4.76; 95% CI 1.40-16.20) associated strongly with 30-day readmissions. CONCLUSIONS: In both groups, cancer associated with 30-day readmissions, antithrombotics with increased LOS. Thromboembolic events and anemia showed clinically important trends in UGIB. Atrial fibrillation/flutter associated with 30-day readmissions in LGIB. Prospective studies are needed to investigate these complex multimorbid populations and establish appropriate guidelines.

Outcomes from the use of computerized neurocognitive testing in a recurrent glioblastoma clinical trial.

Assessment of neurocognitive function (NCF) is important in brain tumor clinical trials, however there are varying methodologies available. We used the Cogstate computerized NCF testing battery and the mini-mental state examination (MMSE) to prospectively assess cognition in adult patients with recurrent glioblastoma (GBM) enrolled in the CABARET randomized phase II clinical trial of bevacizumab versus bevacizumab plus carboplatin chemotherapy. We determined completion rates; compared NCF results between trial arms; and assessed baseline NCF as a predictor of survival outcome. 93 of 103 eligible patients completed baseline Cogstate NCF testing. Completion rates were between 60 and 100% across each timepoint, and 38% at disease progression. There was no evidence of difference between arms in time to deterioration in NCF using either test. Prior to disease progression, deterioration on the Cogstate tests was substantially more common (90%) than deterioration on the MMSE (37%), and decline in the Cogstate composite score within the first 8 weeks was associated with shorter overall survival. This testing methodology may be useful when determining net clinical benefit for therapies in patients with recurrent GBM.

Standardising clinical outcomes measures for adult clinical trials in Fabry disease: A global Delphi consensus.

BACKGROUND: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD. METHODS AND FINDINGS: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial. CONCLUSION: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.

Sexual function in women with androgen excess disorders: classic forms of congenital adrenal hyperplasia and polycystic ovary syndrome.

PURPOSE: We compared the sexual function in women with classic forms of congenital adrenal hyperplasia (CAH) and polycystic ovary syndrome (PCOS) to find if the cause of androgen excess determines sexual functioning. METHODS: Hundred and four women (21 with CAH, 63 with PCOS and 20 healthy controls) aged 18-40 years were included into the study. All participants completed a questionnaire regarding their sociodemographic background and underwent anthropometric and basic biochemical measurements. Plasma levels of total testosterone, androstenedione, and 17-hydroxyprogesterone were measured with immunoassay. To assess the sexual functions, the Female Sexual Function Index (FSFI) questionnaire was applied. RESULTS: Apart from the higher physical activity in PCOS patients (P = 0.017), we found no significant sociodemographic differences between the studied groups. In clinical assessment, women with CAH had a lower incidence of acne (P = 0.006). Their plasma levels of 17OHP (P = 0.005) and insulin resistance index (P = 0.0248) were higher, while total testosterone (P = 0.0495) and glucose (P = 0.0061) was lower compared to the PCOS group. Significantly more women with CAH were homosexual (P = 0.003) and bisexual (P = 0.006). CAH group showed a lower total FSFI score (P = 0.0043) and lower scores in three domains: lubrication (P = 0.0131), sexual satisfaction (P = 0.0006), and dyspareunia (P < 0.0001). Higher physical activity was associated in all women with higher total FSFI score (P = 0.009) and scores in the domain of desire (P = 0.034) and sexual satisfaction (P = 0.01), while in CAH women apart from the total score (P = 0.03) and sexual satisfaction (P = 0.002) also in the domains of orgasm (P = 0.005), and pain (P = 0.03). CONCLUSIONS: CAH women present more often homosexual and bisexual orientation, while their sexual functions are impaired compared to PCOS patients.

Clinical experience and results with a Rhombic Plate for transoral endoscopically-assisted osteosynthesis of fractures of the condylar neck.

The intraoral approach is favoured by many patients and surgeons for the treatment of fractures of the condylar neck, but the limited space offered by this approach can make positioning and fixation of the osteosynthesis plate difficult. A rhombic-shaped plate was designed specifically for use with the intraoral approach, and introduced into our clinical practice in 2012. We present the clinical and functional results in 81 patients with 98 fractures of the condylar neck who we have treated with this technique. Of these six required surgical revision, and ultimately all but two had satisfactory occlusion and mandibular function. Our complication rate of 6/81 (7.4%) compares favourably with those reported elsewhere, and confirms that open reduction and internal fixation of condylar fractures using the Rhombic plate through an intra-oral approach provides good outcomes.

The urine podocin/creatinine ratio as a novel biomarker of cardiorenal syndrome in dogs due to degenerative mitral valve disease.

Dysfunction of heart leads inevitable to the dysfunction of kidney which is termed as the cardiorenal syndrome (CRS). Previous studies have confirmed existence of CRS in dogs with degenerative mitral valve disease (DMVD). The goal of the study was to assess the usefulness of commercial test to measure podocyturia in dogs and test the urine podocine/creatinine ratio (UPoC) as an early marker of kidney injury. Urine podocine/creatinine ratio was calculated because numbers of podocytes is dependent on the urine concentration. Fifty dogs was divided into three groups: fifteen healthy (control group), twenty nine with DMVD class C-chronic according to ACVIM (heart group) and six with chronic kidney disease (kidney group). Each dog underwent a clinical examination: electrocardiography, echocardiography, chest radiograph, abdominal ultrasound, blood haematological and biochemical analysis including symmetric dimethylarginine (SDMA) and cystatin C (Cyst C), routine urine analysis and analysis of podocytes using an ELISA test. UPoC was calculated. Mean value ± standard deviation for UPoC was respectively 9.7 ± 4.8 x 10-10 for control group, 49.0 ± 80.0 x 10-10 for heart group, 33.7 ± 18.0 x 10-10 for kidney group. The UPoC in the heart and kidney group was significantly higher than in the control group (P < 0.0001, sensivity 0.83, specyfity 0.20). Commercial ELISA tests may be used to assess podocyturia in dogs. An UPoC increase exceeding 12.93 x 10-10 indicates glomerular damage in DMVD dogs. Based on UPoC, 79.3% of dogs with C-chronic stage of DMVD developed CRS.

Demonstration of differences in colonic volumes, transit, chyme consistency, and response to psyllium between healthy and constipated subjects using magnetic resonance imaging.

BACKGROUND: In functional gastrointestinal disorders a lack of objective biomarkers limits evaluation of underlying mechanisms. We aimed to demonstrate the utility of magnetic resonance imaging for this task using psyllium, an effective constipation treatment, in patients and controls. METHODS: Two crossover studies: (i) adults without constipation (controls, n = 9) took three treatments in randomized order for 6 days - maltodextrin (placebo), psyllium 3.5 g t.d.s and 7 g t.d.s., (ii) adults with chronic constipation (patients, n = 20) took placebo and psyllium 7 g t.d.s. for 6 days. MRI was performed fasting and postprandially on day 6. Measurements included small bowel and ascending colon water content, colonic volume, transit time, and MR relaxometry (T1, T2) to assess colonic chyme. Stool water percentage was measured. RESULTS: 7 g psyllium t.d.s. increased fasting colonic volumes in controls from median 372 mL (IQR 284-601) to 578 mL (IQR 510-882), and in patients from median 831 mL (IQR 745-934) to 1104 mL (847-1316), P < .05. Mean postprandial small bowel water was higher in controls and patients after 7 g psyllium t.d.s. vs placebo. Whole gut transit was slower in patients than controls (P < .05). T1 of the descending colon chyme (fasting) was lower in patients (213 ms, 176-420) than controls (440 ms, 352-884, P < .05) on placebo, but increased by 7 g psyllium t.d.s. (590 ms, 446-1338), P < .001. Descending colon T1 correlated with baseline stool water content and stool frequency on treatment. CONCLUSIONS AND INFERENCES: MRI measurements can objectively demonstrate the mode of action of therapy targeting intestinal fluid content in constipation.

[Perioperative onset of sarcoidosis : Rare differential diagnosis of a difficult airway]. / Perioperative Erstmanifestation der Sarkoidose : Seltene Differenzialdiagnose des schwierigen Atemwegs.

Sarcoidosis is a rare multisystemic chronic inflammatory condition. Typically, there is a big discrepancy between the patient's subjectively perceived symptoms and the presence of clinical signs. Due to the high number of potential sites of onset (e. g. larynx, lungs, heart, liver, kidneys) the affected organs may show functional restrictions that are relevant for decisions related to anesthesia. Therefore, an anesthetists working in a clinical setting should be familiar with the special needs of this patient collective. This article describes the onset of sarcoidosis in a case of an unexpected difficult airway.

Do carer's levels of unmet needs change over time when caring for patients diagnosed with high-grade glioma and how are these needs correlated with distress?

PURPOSE: The aim of the current study was to determine how carer needs changed longitudinally and understand associations between unmet needs and distress. METHODS: Family carers of patients with high-grade glioma (HGG) were recruited. Carers completed questionnaires during patients' chemoradiotherapy (T1), 3 months (T2) and 6 months (T3) including the following: the Distress Thermometer, the General Health Questionnaire-12, the Partner and Carer Supportive Care (PCS) Needs Scale and its supplement the Access to Services Needs Scale and the Brain Tumour Specific Supportive Care Needs Scale. Linear latent growth models were applied. RESULTS: The time 1 questionnaire was completed by 118 carers; 70 carers provided responses at time 3. While the mean numbers of elevated (moderate to high) needs remained stable over time, the specific needs changed. The most frequently reported PCS needs included the impact of caring on the carer's working life or usual activities, finding more accessible parking, making life decisions in the context of uncertainty, reducing stress in the patient's life and understanding the patient's experience. The most frequently reported need unique to carers of a brain tumour patient was for information on adjusting to cognitive changes in the patient. Other prominent needs included managing difficult aspects of the patient's behaviour and adjusting to changes in the patient's personality, both of which increased over time. Higher numbers of unmet needs were associated cross-sectionally with higher distress levels. CONCLUSION: Carers of people with HGG remain highly distressed and their needs evolve over time, indicating a requirement for ongoing evaluation of unmet needs and interventions to address carer psychological morbidities.

MRI assessment of the postprandial gastrointestinal motility and peptide response in healthy humans.

BACKGROUND: Feeding triggers inter-related gastrointestinal (GI) motor, peptide and appetite responses. These are rarely studied together due to methodological limitations. Recent MRI advances allow pan-intestinal, non-invasive assessment of motility in the undisturbed gut. This study aimed to develop a methodology to assess pan-intestinal motility and transit in a single session using MRI and compare imaging findings to GI peptide responses to a test meal and symptoms in a healthy volunteer cohort. METHODS: Fifteen healthy volunteers (29.3±2.7 years and BMI 20.1±1.2 kg m-2 ) underwent baseline and postprandial MRI scans, symptom questionnaires, and blood sampling (for subsequent GI peptide analysis, Glucagon-like peptide-1 [GLP-1], Polypeptide YY [PYY], Cholecystokinin [CCK]) at intervals for 270 minutes following a 400 g soup meal (204 kcal, Heinz, UK). Gastric volume, gall bladder volume, small bowel water content, small bowel motility, and whole gut transit were measured from the MRI scans. KEY RESULTS: (mean±SEM) Small bowel motility index increased from fasting 39±3 arbitrary units (a.u.) to a maximum of 87±7 a.u. immediately after feeding. PYY increased from fasting 98±10 pg mL-1 to 149±14 pg mL-1 at 30 minutes and GLP-1 from fasting 15±3 µg mL-1 to 22±4 µg mL-1 . CCK increased from fasting 0.40±0.06 pmol mL-1 to 0.94±0.1 pmol mL-1 . Gastric volumes declined with a T1/2 of 46±5 minute and the gallbladder contracted from a fasting volume of 19±2 mL-1 to 12±2 mL-1 . Small bowel water content increased from 39±2 mL-1 to 51±2 mL-1 postprandial. Fullness VAS score increased from 9±5 mm to 41±6 mm at 30 minutes postprandial. CONCLUSIONS AND INFERENCES: The test meal challenge was effective in inducing a change in MRI motility end-points which will improve understanding of the pathophysiological postprandial GI response.

A systematic review and meta-analysis of utility estimates in melanoma.

BACKGROUND: Health-related quality of life (HRQOL) in melanoma is affected by cancer stage. Previous studies have reported limited data on utility-based HRQOL. OBJECTIVES: To determine pooled estimates of utility-based HRQOL (utilities) for people with American Joint Cancer Committee stage I/II, III or IV melanoma for use in economic evaluations. METHODS: We performed a systematic review, meta-analysis and metaregression of utilities for patients with melanoma. HRQOL scores reported with the QLQ-C30, SF-36, SF-12, FACT-G and FACT-M instruments were converted to utilities using published mapping algorithms. Meta-analysis was used to calculate mean utilities. Metaregression was used to examine the effects of baseline patient and study characteristics. RESULTS: We identified 33 studies reporting 213 utilities. From meta-analyses, the mean utility for stage I/II melanoma was 0·97 [95% confidence interval (CI) 0·90-0·98]; for stage III melanoma it was 0·77 (95% CI 0·70-0·83); for stage III/IV 0·76 (95% CI 0·76-0·77); and for stage IV melanoma 0·76 (95% CI 0·71-0·81). The difference in utility between stage III and stage IV was not statistically significant (P = 0·52). For patients with stage I/II, the utility estimate at the time of surgery was 0·77 (95% CI 0·75-0·79), and at 3-12 months postsurgery it was 0·85 (95% CI 0·84-0·86). Utility estimates for patients with stage IV melanoma were 0·65 (95% CI 0·62-0·69) during the first 3 months of treatment and 0·83 (95% CI 0·81-0·86) at 4-12 months on treatment. For patients with stage IV melanoma treated with chemotherapy, the utility estimate was 0·52 (95% CI 0·51-0·52), while for those treated with targeted therapy it was 0·83 (95% CI 0·82-0·85). CONCLUSIONS: These robust, evidence-based estimates of health state utility can be used in economic evaluations of new treatments for patients with early-stage or advanced-stage melanoma.

BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against mantle cell lymphoma cells.

Bromodomain extraterminal protein (BETP) inhibitors transcriptionally repress oncoproteins and nuclear factor-κB (NF-κB) target genes that undermines the growth and survival of mantle cell lymphoma (MCL) cells. However, BET bromodomain inhibitor (BETi) treatment causes accumulation of BETPs, associated with reversible binding and incomplete inhibition of BRD4 that potentially compromises the activity of BETi in MCL cells. Unlike BETi, BET-PROTACs (proteolysis-targeting chimera) ARV-825 and ARV-771 (Arvinas, Inc.) recruit and utilize an E3-ubiquitin ligase to effectively degrade BETPs in MCL cells. BET-PROTACs induce more apoptosis than BETi of MCL cells, including those resistant to ibrutinib. BET-PROTAC treatment induced more perturbations in the mRNA and protein expressions than BETi, with depletion of c-Myc, CDK4, cyclin D1 and the NF-κB transcriptional targets Bcl-xL, XIAP and BTK, while inducing the levels of HEXIM1, NOXA and CDKN1A/p21. Treatment with ARV-771, which possesses superior pharmacological properties compared with ARV-825, inhibited the in vivo growth and induced greater survival improvement than the BETi OTX015 of immune-depleted mice engrafted with MCL cells. Cotreatment of ARV-771 with ibrutinib or the BCL2 antagonist venetoclax or CDK4/6 inhibitor palbociclib synergistically induced apoptosis of MCL cells. These studies highlight promising and superior preclinical activity of BET-PROTAC than BETi, requiring further in vivo evaluation of BET-PROTAC as a therapy for ibrutinib-sensitive or -resistant MCL.

Impact of cardio-renal syndrome on adverse outcomes in patients with Fabry disease in a long-term follow-up.

AIMS: Fabry disease (FD) is a rare X-linked lysosomal storage disease with a deficiency of α-galactosidase A leading to progressive sphingolipid accumulation in different organs, among them heart and kidney. We evaluated the impact of cardio-renal syndrome (CRS) on the incidence of major cardiovascular complications and death in a prospective FD cohort. METHODS AND RESULTS: A total of 104 genetically proven FD patients were annually followed at the University Hospitals Zurich and Bern. The main outcome was a composite of incident renal replacement therapy (RRT), hospitalisation due to decompensated Heart Failure, new onset atrial fibrillation, pacemaker/ICD implantation, stroke/TIA and death. Estimated glomerular filtration rate (eGFR) and left ventricular myocardial mass index (LVMMI) where explored as the primary exposure variables. During the median follow-up of 103 [59-155] months, events occurred in 27 patients. In a Cox regression analysis, both higher LVMMI and lower eGFR were independently associated with a greater risk of developing adverse events after adjustment for multiple confounders (HR 1.67 [1.04-2.73] P=0.03 per SD increase in LVMMI, HR 0.45 [0.25-0.83], P=0.01 per SD decrease in eGFR). In patients with CRS, the risk to develop events was significantly increased if adjusted for demographics and RRT (HR 4.46 [1.07-18.62], P=0.04), approaching significance if additionally adjusted for hypertension (HR 4.05 [0.95-17.29], P=0.06). In Kaplan-Meier-Analysis, the poorest event-free survival was observed among patients with CRS. CONCLUSIONS: CRS was associated with a high risk to develop cardiovascular complications and death, emphasizing the importance of its prevention and early recognition. A focus on cardio-reno-protective therapies is crucial.

Impact of immunosuppressive therapy on therapy-neutralizing antibodies in transplanted patients with Fabry disease.

BACKGROUND: Inhibitory antibodies towards enzyme replacement therapy (ERT) are associated with disease progression and poor outcome in affected male patients with lysosomal disorders such as Fabry disease (FD). However, little is known about the impact of immunosuppressive therapy on ERT inhibition in these patients with FD. METHODS: In this retrospective study, we investigated the effect of long-term immunosuppression on ERT inhibition in male patients with FD (n = 26) receiving immunosuppressive therapy due to kidney (n = 24) or heart (n = 2) transplantation. RESULTS: No ERT-naïve transplanted patient (n = 8) developed antibodies within follow-up (80 ±72 months) after ERT initiation. Seven (26.9%) patients were tested ERT inhibition positive prior to transplantation. No de novo ERT inhibition was observed after transplantation (n = 18). In patients treated with high dosages of immunosuppressive medication such as prednisolone, tacrolimus and mycophenolate-mofetil/mycophenolate acid, ERT inhibition decreased after transplantation (n = 12; P = 0.0160). Tapering of immunosuppression (especially prednisolone) seemed to re-increase ERT inhibition (n = 4, median [range]: 16.6 [6.9; 36.9] %; P = 0.0972) over time. One ERT inhibition-positive patient required interventions with steroid therapy and increased doses of tacrolimus, which also lowered ERT inhibition. CONCLUSION: We conclude that the immunosuppressive maintenance therapy after transplantations seems to be sufficient to prevent de novo ERT inhibition in ERT-naïve patients. Intensified high dosages of immunosuppressive drugs are associated with decreased antibody titres and decreased ERT inhibition in affected patients, but did not result in long-term protection. Future studies are needed to establish ERT inhibition-specific immunosuppressive protocols with long-term modulating properties to warrant an improved disease course in ERT inhibition-positive males.

Functional recovery following early mobilization after middle third clavicle osteosynthesis for acute fractures or nonunion: A case-control study.

BACKGROUND: Good outcomes have been reported after surgical treatment for acute or nonunion of displaced midshaft clavicle fractures. However, the postoperative rehabilitation and timeline for a complete functional recovery are poorly documented. The purpose of the current study was to evaluate the efficacy of an immediate motion protocol following plate fixation of a midshaft clavicle fracture and to compare functional recovery between acute and nonunion cases. METHODS: Between October 2011 and July 2015, all patients above the age of 18, having either an acute or a nonunion of the midshaft clavicle fracture, were considered as potentially eligible for inclusion in this prospective case-control study. Postoperatively, no immobilization was recommended and patients were to undergo rehabilitation protocol consisting of hourly stretching. RESULTS: Forty-two patients were included (31 with acute and 11 with delayed fixation) at a mean follow-up of 33months (range, 12 to 78months). Surgical complications consisted of one transient frozen shoulder, one delayed union, and two superficial infections. All patients returned to work, retrieved full shoulder range of motion (ROM), and returned to heavy sports and activities. Function returned faster in the acute group compared to the nonunion group based on the SANE score at 2weeks (73±21 vs. 45±26 respectively, P=0.01), SANE score at 6weeks (89±15 vs. 66±23 respectively, P=0.01), SANE score at 3months (96±10 vs. 85±14 respectively, P=0.03), and based on return of full ROM (17±25 vs. 44±31 days respectively, P=0.01). A trend was observed for nonunion cases needing more time to return to work and sports activities. CONCLUSION: Functional outcome is excellent following the treatment of both acute and non-united clavicle fractures, but recovery occurs earlier following acute treatment. An early mobilization rehab protocol can be safely recommended for both types of conditions and may result in substantial healthcare cost-savings, without increasing complication rate and decreasing patient satisfaction. LEVEL OF EVIDENCE: Level III; case-control study; treatment study.

Fixation of fractures of the condylar head of the mandible with a new magnesium-alloy biodegradable cannulated headless bone screw.

It is difficult to fix fractures of the condylar head of the mandible. Several techniques have been described which show satisfactory outcomes, but stability can be questionable, and some can cause irritation of the soft tissues. We describe a technique and first results of treating such fractures with resorbable magnesium-based headless bone screws (Magnezix® 2.7mm CS; Syntellix AG, Hanover, Germany).

Molecular Basis of Human Diseases and Targeted Therapy Based on Small-Molecule Inhibitors of ER Stress-Induced Signaling Pathways.

The Endoplasmic Reticulum (ER) provides a conserved protein quality control system and plays a fundamental role in cell growth and homeostasis. Disturbances in the ER homeostasis may originate especially from hypoxia, glucose deficiency, presence of mutant proteins, that directly impair protein folding capacity and after deposition of unfolded and misfolded proteins within ER lumen trigger ER stress conditions. This subsequently activates the Unfolded Protein Response (UPR) branches, which have a dual pro-adaptive or pro-apoptotic role depending on the severity and time of duration of ER stress conditions. This review is the first to offer a detailed overview on molecular mechanisms of all major ER stress-dependent signaling branches, that are activated through three specific ER transmembrane receptors of impaired protein folding: Protein kinase RNA (PKR)-like ER kinase (PERK), Inositol-requiring enzyme-1 (IRE1) and Activating transcription factor 6 (ATF6). Molecular crosstalk among ER transmembrane receptors-dependent pathways determines a final UPR response, but the recent data reported that especially PERK over-activation has a significant impact on the development and progression of a wide spectrum of disease entities. Based on these findings, small-molecules, highly specific PERK inhibitors may provide effective, groundbreaking treatment strategy against human diseases. However, after foregoing in vitro cellular and in vivo animal models conducted examination, supplementary investigations of PERK inhibitors are required for their further clinical use. Future research may answer the question of how to minimize toxicity and side effects of characterized small-molecule PERK inhibitors, that may be used, as breakthrough drugs, alone or in combination with currently known models of therapy.