Radical vaginal trachelectomy: long-term oncologic and fertility outcomes in patients with early cervical cancer.

OBJECTIVE: Radical vaginal trachelectomy is a fertility-preserving treatment for patients with early cervical cancer. Despite encouraging oncologic and fertility outcomes, large studies on radical vaginal trachelectomy are lacking. METHOD: Demographic, histological, fertility, and follow-up data of consecutive patients who underwent radical vaginal trachelectomy between March 1995 and August 2021 were prospectively recorded and retrospectively analyzed. RESULTS: A total of 471 patients of median age 33 years (range 21-44) were included. 83% (n=390) were nulliparous women. Indications were International Federation of Gynecology and Oncology (FIGO, 2009) stages IA1 with lymphvascular space involvement (LVSI) in 43 (9%) patients, IA1 multifocal in 8 (2%), IA2 in 92 (20%), IB1 in 321 (68%), and IB2/IIA in 7 (1%) patients, respectively. LVSI was detected in 31% (n=146). Lymph node staging was performed in 151 patients (32%) by the sentinel node technique with a median of 7 (range 2-14) lymph nodes and in 320 (68%) by systematic lymphadenectomy with a median of 19 (range 10-59) lymph nodes harvested. Residual tumor was histologically confirmed in 29% (n=136). In total, 270 patients (62%) were seeking pregnancy of which 196 (73%) succeeded. There were 205 live births with a median fetal weight of 2345 g (range 680-4010 g). Pre-term delivery occurred in 94 pregnancies (46%). After a median follow-up of 159 months (range 2-312), recurrences were detected in 16 patients (3.4%) of which 43% occurred later than 5 years after radical vaginal trachelectomy. Ten patients (2.1%) died of disease (five more than 5 years after radical vaginal trachelectomy). Overall survival, disease-free survival, and cancer-specific survival were 97.5%, 96.2%, and 97.9%, respectively. CONCLUSION: Our study confirms oncologic safety of radical vaginal trachelectomy associated with a high chance for childbearing. High rate of pre-term delivery may be due to cervical volume loss. Our long-term oncologic data can serve as a benchmark for future modifications of fertility-sparing surgery.

FusionVAC22_01: a phase I clinical trial evaluating a DNAJB1-PRKACA fusion transcript-based peptide vaccine combined with immune checkpoint inhibition for fibrolamellar hepatocellular carcinoma and other tumor entities carrying the oncogenic driver fusion.

The DNAJB1-PRKACA fusion transcript was identified as the oncogenic driver of tumor pathogenesis in fibrolamellar hepatocellular carcinoma (FL-HCC), also known as fibrolamellar carcinoma (FLC), as well as in other tumor entities, thus representing a broad target for novel treatment in multiple cancer entities. FL-HCC is a rare primary liver tumor with a 5-year survival rate of only 45%, which typically affects young patients with no underlying primary liver disease. Surgical resection is the only curative treatment option if no metastases are present at diagnosis. There is no standard of care for systemic therapy. Peptide-based vaccines represent a low side-effect approach relying on specific immune recognition of tumor-associated human leucocyte antigen (HLA) presented peptides. The induction (priming) of tumor-specific T-cell responses against neoepitopes derived from gene fusion transcripts by peptide-vaccination combined with expansion of the immune response and optimization of immune function within the tumor microenvironment achieved by immune-checkpoint-inhibition (ICI) has the potential to improve response rates and durability of responses in malignant diseases. The phase I clinical trial FusionVAC22_01 will enroll patients with FL-HCC or other cancer entities carrying the DNAJB1-PRKACA fusion transcript that are locally advanced or metastatic. Two doses of the DNAJB1-PRKACA fusion-based neoepitope vaccine Fusion-VAC-XS15 will be applied subcutaneously (s.c.) with a 4-week interval in combination with the anti-programmed cell death-ligand 1 (PD-L1) antibody atezolizumab starting at day 15 after the first vaccination. Anti-PD-L1 will be applied every 4 weeks until end of the 54-week treatment phase or until disease progression or other reason for study termination. Thereafter, patients will enter a 6 months follow-up period. The clinical trial reported here was approved by the Ethics Committee II of the University of Heidelberg (Medical faculty of Mannheim) and the Paul-Ehrlich-Institute (P-00540). Clinical trial results will be published in peer-reviewed journals. Trial registration numbers: EU CT Number: 2022-502869-17-01 and ClinicalTrials.gov Registry (NCT05937295).

Characteristics Associated with COVID-19 Breakthrough Infections after Booster Vaccinations in Healthcare Workers: Insights from the TüSeRe:exact Study.

Background: The prevalence of COVID-19 breakthrough infections in healthcare workers (HCWs) remains an issue of concern. This study examines the different characteristics associated with breakthrough infections in HCWs. Methods: From the total participants in the TüSeRe:exact study (n = 1046), we specifically included study participants who had received three vaccinations and were not infected prior to the third vaccination. Participants were invited to complete an online questionnaire, which included inquiries about any breakthrough infections they might have experienced. Univariate Cox regression analysis was used to investigate the association between participant characteristics and breakthrough infections. Results: Among 629 HCWs (497 female and 132 male), 241 (38%) experienced breakthrough infections during the follow-up period. The frequency of breakthrough infections was 39.2% (195/497) among female participants and 34.8% (46/132) among male participants (p = 0.357). The Cox regression model adjusted for age and sex showed that participants with cardiovascular disease (hazard ratio (95%CI) = 0.621 (0.392-0.985); p = 0.043) and those taking antihypertensives (hazard ratio (95%CI) = 0.551 (0.331-0.915); p = 0.021) had a significantly lower hazard ratio for breakthrough infections. The use of analgesics after the first vaccine (hazard ratio (95%CI) = 1.343 (1.025-1.759); p = 0.032) was associated with an increased risk of breakthrough infections. Conclusions: These findings can inform targeted preventive measures and risk management strategies to protect frontline workers and maintain a resilient healthcare system during the ongoing pandemic.

Apixaban versus Aspirin for Embolic Stroke of Undetermined Source.

Apixaban versus Aspirin for Embolic StrokeIn a trial of 352 patients with embolic stroke of undetermined source, 5 mg of apixaban administered twice daily was compared with 100 mg of aspirin administered once daily for the prevention of recurrent ischemic strokes. At 12 months, 13.6% of patients given apixaban had new ischemic lesions on magnetic resonance imaging compared with 16.0% of patients given aspirin, and the rates of clinically relevant bleeding were also comparable.

Isolated melanoma cells in sentinel lymph node in stage IIIA melanoma correlate with a favorable prognosis similar to stage IB.

BACKGROUND: The American Joint Committee on Cancer 8th edition (AJCC v8) defines sentinel lymph nodes (SLN) containing any tumor cells as positive SLN. Consequently, even thin melanomas with isolated tumor cells (ic) in SLN are classified as stage IIIA, making them candidates for adjuvant therapy. OBJECTIVES AND ENDPOINTS: We aimed to evaluate survival outcomes of melanoma stage IIIA (ic) and compare them with stage IIIA with lymph node (LN) metastases > 0.1 mm. Primary endpoints were relapse-free survival (RFS) and distant metastases-free survival (DMFS). Secondary endpoint was melanoma specific survival (MSS). RESULTS: The discovery cohort from the Department of Dermatology, University Hospital Tuebingen, included 237 patients; confirmation cohort included 143 patients from the DeCOG trial. The Tuebingen cohort included 95 patients with stage IIIA (ic) and 142 patients with stage IIIA. The DeCOG trial included 39 patients with stage IIIA (ic) and 104 patients with stage IIIA. In the Tuebingen cohort, 10-year RFS rates for stage IIIA (ic) and IIIA were 84% (95% CI 75-94) and 49% (95% CI 39-59), respectively (p < 0.001). 10-year DMFS rates for stage IIIA (ic) and IIIA were 89% (95% CI 81-97) and 56% (95% CI 45-67), respectively; (p < 0.001). In the DeCOG cohort, 10-year RFS for stage IIIA (ic) and stage IIIA were 88% (95% CI 78-99) and 35% (95% CI 7-62), respectively; (p = 0.009). 10-year DMFS for stage IIIA (ic) and IIIA was 88% (95% CI 77-99) and 60% (95% CI 39-80), respectively (p = 0.061). CONCLUSION: Stage IIIA (ic) melanoma exhibits a prognosis similar to stage IB. Recommendation of adjuvant therapy in Stage IIIA (ic) warrants thorough discussion.

SARS-CoV-2 infection is associated with physical but not mental fatigue - Findings from a longitudinal controlled population-based study.

OBJECTIVE: Fatigue has been identified as the core symptom of long-Covid, however, putative pandemic-related influences remain largely unclear. We investigated trajectories of total, physical and mental fatigue and the factors associated with it in previously infected and non-infected individuals up to one year post- infection. METHODS: We used data from a longitudinal cohort study of German adults with two samples: A representative probability sample and a sample of individuals with proven SARS-CoV-2 infection. Surveys were conducted in spring 2020(T1), autumn 2020(T2) and summer 2021(T3). Fatigue was assessed using the FAS, distinguishes between physical and mental fatigue. Depression, anxiety and stress were assessed using PHQ-4 and PSQ. RESULTS: 1990 participants [mean age 47.2 (SD = 17.0), 30.5% previously infected] were included in the survey at T1 (n = 1118 at T2, n = 692 at T3). Total and physical fatigue, but not mental fatigue were significantly higher in the previously infected compared to the non-infected sample at T2, but this group difference disappeared at T3. We identified Covid-infection as a factor associated with transient total and physical fatigue at T2. Depression, anxiety and stress at T1 were associated with total, physical and mental fatigue at both follow-ups. CONCLUSIONS: Our results highlight the importance of considering physical and mental fatigue as separate entities, while suggesting a greater relevance of the physical signs of fatigue in understanding long-Covid. The results further showed that baseline mental health symptoms were the most strongly associated with fatigue trajectories.

Effectiveness of an 11-week exercise intervention for patients with hip or knee osteoarthritis: results of a quasi-experimental pragmatic trial.

OBJECTIVE: To assess the effectiveness of exercise and education in addition to standard care (SC) compared to SC alone in patients with hip or knee osteoarthritis (OA) during 24 months follow-up. DESIGN: We conducted a quasi-experimental pragmatic clinical trial in care centers of a health insurance company. Overall, 1,030 subjects with hip and/or knee OA were included. The intervention group was recruited from clients participating in a hip/knee training (HKT, n = 515) in addition to SC. The control group (CO, n = 515) receiving SC only was recruited from the insurance database. HKT comprised 8 group sessions (1/week) of exercise and education, complemented by a 11-week structured home-exercise program (2/week). Primary endpoints were change of joint-related pain and function (WOMAC Index, score 0-10) after 3 months. Secondary endpoints related to follow-ups at 6, 12 and 24 months. All patient reported outcome measures were analyzed using linear mixed models (LMMs) investigating a time x treatment effect. A multivariable cox proportional hazards regression model was used to identify differences of joint replacement during follow-up between groups. RESULTS: LMMs revealed statistically significant differences in favor of HKT for the primary outcomes WOMAC pain = 0.47 (CI 0.27-0.66; Effect Size (ES) = 0.22, p < 0.001) and WOMAC function = 0.27 (CI 0.11-0.44; ES = 0.13, p < 0.001). HKT was superior to CO for 6, 12, and 24 months as well (ES < 0.2, p ≤ 0.006). HKT was inferior regarding the first incidence of hip or knee AJR during follow-up in comparison to CO (adjusted hazard ratio, HR = 1.57; CI 1.08-2.30; p = 0.020). CONCLUSIONS: This trial demonstrated short-, mid- and long-term superiority of exercise versus control. However, differences were smaller than those reported in previous efficacy trials, raising questions regarding clinical importance. Responder analysis will follow to identify possible predictors for patient responsiveness on an individual level. Further studies should investigate the frequency and reasons for joint replacement following exercise therapy. TRIAL REGISTRATION: German Clinical Trial Register (DRKS00009251). Registered 10 September 2015.

Tübingen model study: large-scale introduction of rapid antigen testing in the population and the viral dynamics of SARS-CoV-2.

Despite of contact restrictions, population mobility remains the main reason for the spread of SARS-CoV-2. The state of Baden-Württemberg (BW), Germany, approved a model study in Tübingen (TÜMOD) to evaluate how mandatory rapid diagnostic tests (RDT) could reduce transmission. Between 16 March and 24 April 2021, approximately 165,000 residents and visitors to the city were screened for SARS CoV-2 infection using Abbott Panbio™ COVID-19 Antigen rapid test device. We assessed incidences and recorded epidemiological characteristics in a subset of 4,118 participants recruited at three of the nine testing stations. PCR tests were performed in RDT-positives to determine the positive predictive value (PPV), and circulating variants of SARS-CoV-2 were identified by whole-genome sequencing. 2,282 RDT-negative samples were tested by pooled PCR to calculate the false negative rate (FNR). Viral load was compared between variants. 116 (3%) participants were positive by RDT, and of these, 57 (49%) were positive by PCR, 55 (47%) were negative. This resulted in a PPV of 51%. Of the 57 positives, 52 SARS-CoV-2 genomes were successfully sequenced. Of these, 50 belonged to the B.1.1.7 lineage, which had a high viral load (average Ct = 19). Of the 2,282 RDT negatives tested, all were PCR negative (FNR 0%). At the end of TÜMOD, the incidence in Tübingen, which was initially lower, had reached the incidence in the state of BW. While it is difficult to assess the impact of TÜMOD on incidence independent of confounding factors, further studies are needed to identify the effect of close-meshed testing on infection rates.

Stress and Depressive and Anxiety Symptoms in the General Population and in SARS-CoV-2-Infected Patients-Findings from a Population-Based Three-Wave Study.

Objective: Understanding factors that impaired mental health during the COVID-19 pandemic is extremely relevant in order to mitigate long-term consequences of the pandemic and to promote resilience in future crises. Method: Data were collected in southern Germany in a population-based survey study (CoKoS) with three times of measurement in May 2020, November 2020 and July 2021. Predictors of depressive and anxiety symptoms were measured with a short version of the Patient Health Questionnaire (PHQ-4) in the general population (N = 758) and individuals who were infected with SARS-CoV-2 in the beginning of the pandemic (N = 412). We investigated differences between both samples and how stress components (worry, tension, demands and joy) measured with the Perceived Stress Questionnaire (PSQ) varied with depressive and anxiety symptoms over time. Three linear mixed models (GLMMs) were fitted to predict the PHQ-4 stepwise, including sociodemographic variables and stress (PSQ). Results: Depressive and anxiety symptoms increased from May 2020 to November 2020 and remained stable until July 2021. There were no differences between people with SARS-CoV-2 infection and the general population. Those with a pre-existing disease and lower education reported higher levels of depressive and anxiety symptoms. Stress explained a substantial fraction of variance in depressive and anxiety symptoms. The stress component worry emerged as the strongest predictor of depressive and anxiety symptoms, whereas joy seemed to buffer these symptoms. Conclusions: The results suggest that mitigating people's worry and increasing joy may promote resilience in future crises. Future studies should assess mental health interventions targeted at vulnerable groups, such as those with lower socioeconomic status and poorer health.

Early vvECMO implantation may be associated with lower mortality in ARDS.

BACKGROUND: Venovenous extracorporeal membrane oxygenation (vvECMO) is used to treat hypoxia in patients with severe acute respiratory distress syndrome (ARDS). Nevertheless, uncertainty exists regarding the optimal timing of initiation of vvECMO therapy. We aimed to investigate the association between number of days of invasive mechanical ventilation (IMV) prior to vvECMO implantation and mortality. METHODS: In this retrospective observational study, we included patients treated at an academic intensive care unit with vvECMO for severe ARDS. The primary outcome was all-cause 28-day mortality. We conducted a multivariate logistic regression analysis to estimate the association between number of days of IMV prior to vvECMO implantation and mortality after adjustment for confounders. RESULTS: Out of 274 patients who underwent ECMO for severe ARDS, 158 patients (median age: 58 years) with relevant data were included in the analysis. The mean duration of IMV prior to vvECMO was significantly shorter in survivors than in nonsurvivors [survivors median: 1; interquartile range: 1-3; non-survivors median 4; interquartile range: 1-5.75; p = 0.0001). Logistic regression showed an association between the duration of ventilation prior to vvECMO and patient mortality. The odds ratio for the all-cause 28-day mortality and in-hospital mortality was significantly reduced in patients who received vvECMO within the first 5 days of IMV. CONCLUSIONS: Early vvECMO implantation may be associated with lower mortality in ARDS.

Daratumumab, Bortezomib, and Dexamethasone for Treatment of Patients with Relapsed or Refractory Multiple Myeloma and Severe Renal Impairment: Results from the Phase 2 GMMG-DANTE Trial.

Renal function impairment (RI) is a common complication in multiple myeloma (MM). However, limited data exist on the safety and efficacy of anti-MM regimens in patients with severe RI, as these patients are frequently excluded from clinical trials. This investigator-initiated multicentric phase II GMMG-DANTE trial evaluated daratumumab, bortezomib, and dexamethasone (DVd) in relapsed or refractory (r/r) MM patients with severe RI. r/rMM patients with ≥1 prior treatment line and a GFR <30 mL/min/1.73 m2 or undergoing hemodialysis were eligible and received eight cycles of DVd followed by daratumumab maintenance. The trial closed prematurely after 22/36 planned patients. The primary endpoint was overall response rate (ORR). Median age of patients was 70 (range 55-89) years, with a median GFR of 20.1 mL/min/1.73 m2 (interquartile range, 9.4-27.3 mL/min/1.73 m2), and eight patients under hemodialysis. Median number of prior lines was two (range 1-10). The trial was successful, albeit with premature termination, as it met its primary endpoint, with an ORR of 67% (14/21). The rates of partial response, very good partial response, and complete response were 29%, 29%, and 10%, respectively (n = 6, 6, and 2). Fourteen patients (67%) achieved renal response. After median follow-up of 28 months, median progression-free survival was 10.4 months; median overall survival was not reached. Higher-grade toxicity was mainly hematologic, and non-hematologic toxicities ≥Grade 3 were mostly infections (24%). The prospective GMMG-DANTE trial investigating DVd exclusively in r/rMM patients with severe RI showed efficacy and safety to be comparable to data from patients without RI.

Amantadine for NeuroenhaNcement in acutE patients Study - a protocol for a prospective pilot proof of concept phase IIb study in intensive and intermediate care unit patients (ANNES).

BACKGROUND: Persisting coma is a common complication in (neuro)intensive care in neurological disease such as acute ischemic stroke, intracerebral hemorrhage or subarachnoid hemorrhage. Amantadine acts as a nicotinic receptor antagonist, dopamine receptor agonist and non-competitive N-Methyl-D-aspartate receptor antagonist. Amantadine is a long-known drug, originally approved for treatment of influenza A and Parkinson`s Disease. It has been proven effective in improving vigilance after traumatic brain injury. The underlying mechanisms remain largely unknown, albeit anti-glutamatergic and dopaminergic effects might be most relevant. With limited evidence of amantadine efficacy in non-traumatic pathologies, the aim of our study is to assess the effects of amantadine for neuroenhancement in non-traumatic neurointensive patients with persisting coma. METHODS: An investigator-initiated, monocenter, phase IIb proof of concept open-label pilot study will be carried out. Based on the Simon design, 43 adult (neuro)intensive care patients who meet the clinical criteria of persisting coma not otherwise explained and < 8 points on the Glasgow Coma Scale (GCS) will be recruited. Amantadine will be administered intravenously for five days at a dosage of 100 mg bid. The primary endpoint is an improvement of at least 3 points on the GCS. If participants present as non-responders (increase < 3 points or decrease on the GCS) within the first 48 h, the dosage will be doubled from day three to five. Secondary objectives aim to demonstrate that amantadine improves vigilance via alternative scales. Furthermore, the incidence of adverse events will be investigated and electroencephalography (EEG) will be recorded at baseline and end of treatment. DISCUSSION: The results of our study will help to systematically assess the clinical utility of amantadine for treatment of persisting coma in non-traumatic brain injury. We expect that, in the face of only moderate treatment risk, a relevant number of patients will benefit from amantadine medication by improved vigilance (GCS increase of at least 3 points) finally leading to a better rehabilitation potential and improved functional neurological outcome. Further, the EEG data will allow evaluation of brain network states in relation to vigilance and potentially outcome prediction in this study cohort. TRIAL REGISTRATION: NCT05479032.

Enhancing physical activity and reducing symptoms of patients with osteoarthritis of the knee: a randomized controlled trial of the PrevOP-Psychological Adherence Program.

BACKGROUND: This primary analysis evaluated the "PREVenting the impairment of primary Osteoarthritis by high-impact long-term Physical exercise regimen-Psychological Adherence Program" (PrevOP-PAP), designed to support patients with osteoarthritis of the knee (OAK) to engage in regular moderate-to-vigorous physical activity (MVPA) to reduce OAK symptoms (WOMAC scores). Theory-based on the health action process approach (HAPA), the intervention targeted volitional precursors of MVPA change: action and coping planning, maintenance and recovery self-efficacy, action control, and social network formation. We hypothesized that compared to an active control condition, increases in MVPA at the end of the 12-month intervention would translate into lower WOMAC scores at 24 months in the intervention condition. METHODS: Participants with radiographically verified moderate OAK (N = 241; 62.66% female; M(SD) = 65.60(7.61) years) were randomly assigned to the intervention (51%) or the active control condition. WOMAC scores (24 months) were the primary -, accelerometer-assessed MVPA (12 months) the key secondary outcomes. The PrevOP-PAP was a 12-month intervention with computer-assisted face-to-face and phone-based sessions designed to increase HAPA-proposed volitional precursors of MVPA change (up to 24 months; secondary outcomes). Intent-to-treat analyses included multiple regression and manifest path models. RESULTS: MVPA (12 months) did not mediate effects of the PrevOP-PAP on WOMAC scores (24 months). Compared to the active control condition, WOMAC scores (24 months) were lower in the intervention condition, but this effect did not remain stable in sensitivity analyses (b(SE) = -8.41(4.66), 95%-CI [-17.53; 0.71]). However, exploratory analyses revealed significantly stronger reductions in WOMAC-pain (24 months) in the intervention condition (b(SE) = -2.99(1.18), 95%-CI [-5.36; -0.63]). Groups did not differ in MVPA at 12 months (b(SE) = -3.78(3.42), 95%-CI [-10.80; 2.58]). Of the proposed precursors of MVPA change, action planning was higher in the intervention than in the control condition (24 months; b(SE) = 0.64(0.26), 95%-CI [0.14; 1.15]). CONCLUSIONS: Compared to an active control condition, the PrevOP-PAP did not produce reliable effects on WOMAC scores and none on preceding MVPA. Of the HAPA-proposed volitional precursors, only action planning was sustainably increased. Future interventions should use m-health applications to digitally support long-term changes in proposed volitional precursors of MVPA change. TRIAL REGISTRATION: German Clinical Trials Register; https://drks.de/search/de/trial/DRKS00009677 ; also available at http://apps.who.int/trialsearch/ ; registration number: DRKS00009677; date of registration: 26/01/2016.

Acylated- and unacylated ghrelin during an oral glucose tolerance test in humans at risk for type 2 diabetes mellitus.

BACKGROUND/OBJECTIVES: The orexigenic peptide hormone ghrelin has been implicated in the pathophysiology of obesity and type 2 diabetes mellitus through its effects on nutrient homeostasis. Ghrelin is subject to a unique post-translational acyl modification regulating its biochemical activity. SUBJECTS/METHODS: In this study we aimed to investigate the relation of acylated (AcG) as well as unacylated ghrelin (UnG) with body weight and insulin resistance in the fasting (n = 545) and post-oral glucose tolerance test (oGTT) state (n = 245) in a metabolically well characterized cohort covering a broad range of BMI (17.95 kg/m²-76.25 kg/m²). RESULTS: Fasting AcG (median 94.2 pg/ml) and UnG (median 175.3 pg/ml) were negatively and the AcG/UnG ratio was positively correlated with BMI (all p < 0.0001). Insulin sensitivity (ISI) correlated positively with AcG (p = 0.0014) and UnG (p = 0.0004) but not with the AcG/UnG ratio. In a multivariate analysis, including ISI and BMI, only BMI, but not ISI was independently associated with AcG and UnG concentrations. Significant changes of AcG and UnG concentrations were detectable after oGTT stimulation, with slight decreases after 30 min and increases after 90-120 min. Subject stratification into BMI-divergent groups revealed more pronounced AcG increases in the two groups with BMI < 40 kg/m². CONCLUSION: Our data demonstrate lower concentrations for both AcG and UnG with increasing BMI as well as an increased proportion of the biologically active, acylated form of ghrelin giving point to pharmacologic intervention in ghrelin acylation and/or increase in UnG for treatment of obesity despite decreased absolute AcG levels.

Intraoperative MRI-Guided Resection Is Not Superior to 5-Aminolevulinic Acid Guidance in Newly Diagnosed Glioblastoma: A Prospective Controlled Multicenter Clinical Trial.

PURPOSE: Prospective data suggested a superiority of intraoperative MRI (iMRI) over 5-aminolevulinic acid (5-ALA) for achieving complete resections of contrast enhancement in glioblastoma surgery. We investigated this hypothesis in a prospective clinical trial and correlated residual disease volumes with clinical outcome in newly diagnosed glioblastoma. METHODS: This is a prospective controlled multicenter parallel-group trial with two center-specific treatment arms (5-ALA and iMRI) and blinded evaluation. The primary end point was complete resection of contrast enhancement on early postoperative MRI. We assessed resectability and extent of resection by an independent blinded centralized review of preoperative and postoperative MRI with 1-mm slices. Secondary end points included progression-free survival (PFS) and overall survival (OS), patient-reported quality of life, and clinical parameters. RESULTS: We recruited 314 patients with newly diagnosed glioblastomas at 11 German centers. A total of 127 patients in the 5-ALA and 150 in the iMRI arm were analyzed in the as-treated analysis. Complete resections, defined as a residual tumor ≤0.175 cm³, were achieved in 90 patients (78%) in the 5-ALA and 115 (81%) in the iMRI arm (P = .79). Incision-suture times (P < .001) were significantly longer in the iMRI arm (316 v 215 [5-ALA] minutes). Median PFS and OS were comparable in both arms. The lack of any residual contrast enhancing tumor (0 cm³) was a significant favorable prognostic factor for PFS (P < .001) and OS (P = .048), especially in methylguanine-DNA-methyltransferase unmethylated tumors (P = .006). CONCLUSION: We could not confirm superiority of iMRI over 5-ALA for achieving complete resections. Neurosurgical interventions in newly diagnosed glioblastoma shall aim for safe complete resections with 0 cm³ contrast-enhancing residual disease, as any other residual tumor volume is a negative predictor for PFS and OS.

The spinal cord injury-induced immune deficiency syndrome: results of the SCIentinel study.

Infections are prevalent after spinal cord injury (SCI), constitute the main cause of death and are a rehabilitation confounder associated with impaired recovery. We hypothesize that SCI causes an acquired lesion-dependent (neurogenic) immune suppression as an underlying mechanism to facilitate infections. The international prospective multicentre cohort study (SCIentinel; protocol registration DRKS00000122; n = 111 patients) was designed to distinguish neurogenic from general trauma-related effects on the immune system. Therefore, SCI patient groups differing by neurological level, i.e. high SCI [thoracic (Th)4 or higher]; low SCI (Th5 or lower) and severity (complete SCI; incomplete SCI), were compared with a reference group of vertebral fracture (VF) patients without SCI. The primary outcome was quantitative monocytic Human Leukocyte Antigen-DR expression (mHLA-DR, synonym MHC II), a validated marker for immune suppression in critically ill patients associated with infection susceptibility. mHLA-DR was assessed from Day 1 to 10 weeks after injury by applying standardized flow cytometry procedures. Secondary outcomes were leucocyte subpopulation counts, serum immunoglobulin levels and clinically defined infections. Linear mixed models with multiple imputation were applied to evaluate group differences of logarithmic-transformed parameters. Mean quantitative mHLA-DR [ln (antibodies/cell)] levels at the primary end point 84 h after injury indicated an immune suppressive state below the normative values of 9.62 in all groups, which further differed in its dimension by neurological level: high SCI [8.95 (98.3% confidence interval, CI: 8.63; 9.26), n = 41], low SCI [9.05 (98.3% CI: 8.73; 9.36), n = 29], and VF without SCI [9.25 (98.3% CI: 8.97; 9.53), n = 41, P = 0.003]. Post hoc analysis accounting for SCI severity revealed the strongest mHLA-DR decrease [8.79 (95% CI: 8.50; 9.08)] in the complete, high SCI group, further demonstrating delayed mHLA-DR recovery [9.08 (95% CI: 8.82; 9.38)] and showing a difference from the VF controls of -0.43 (95% CI: -0.66; -0.20) at 14 days. Complete, high SCI patients also revealed constantly lower serum immunoglobulin G [-0.27 (95% CI: -0.45; -0.10)] and immunoglobulin A [-0.25 (95% CI: -0.49; -0.01)] levels [ln (g/l × 1000)] up to 10 weeks after injury. Low mHLA-DR levels in the range of borderline immunoparalysis (below 9.21) were positively associated with the occurrence and earlier onset of infections, which is consistent with results from studies on stroke or major surgery. Spinal cord injured patients can acquire a secondary, neurogenic immune deficiency syndrome characterized by reduced mHLA-DR expression and relative hypogammaglobulinaemia (combined cellular and humoral immune deficiency). mHLA-DR expression provides a basis to stratify infection-risk in patients with SCI.

Influence of Face Masks on Physiological and Subjective Response during 130 Min of Simulated Light and Medium Physical Manual Work-An Explorative Study.

BACKGROUND: Undesirable side effects from wearing face masks during the ongoing COVID-19 pandemic continue to be discussed and pose a challenge to occupational health and safety when recommending safe application. Only few studies examined the effects of continuously wearing a face mask for more than one hour. Therefore, the influence of wearing a medical mask (MedMask) and a filtering facepiece class II respirator (FFP2) on the physiological and subjective outcomes in the course of 130 min of manual work was exploratively investigated. Physical work load and cardiorespiratory fitness levels were additionally considered as moderating factors. METHODS: Twenty-four healthy subjects (12 females) from three different cardiorespiratory fitness levels each performed 130 min of simulated manual work with light and medium physical workload using either no mask, a MedMask or FFP2. Heart rate, transcutaneous oxygen and carbon dioxide partial pressure (PtcO2, PtcCO2) as well as perceived physical exertion and respiratory effort were assessed continuously at discrete time intervals. Wearing comfort of the masks were additionally rated after the working period. RESULTS: There was no difference in time-dependent changes of physiological outcomes when using either a MedMask or a FFP2 compared to not wearing a mask. A stronger increase over time in perceived respiratory effort occurred when the face masks were worn, being more prominent for FFP2. Physical workload level and cardiorespiratory fitness level were no moderating factors and higher wearing comfort was rated for the MedMask. CONCLUSION: Our results suggest that using face masks during light and medium physical manual work does not induce detrimental side effects. Prolonged wearing episodes appeared to increase respiratory effort, but without affecting human physiology in a clinically relevant way.

Platelet versus plasma CXCL14, coronary artery disease, and clinical outcomes.

Background: Platelets express CXCL14, while platelet-derived CXCL14 induces monocyte chemotaxis and exerts an angiostatic effect on endothelial cells. Objectives: This study investigated both platelet surface-associated and circulating levels of CXCL14 in patients with heart disease and associations of this chemokine with myocardial function and outcomes in patients with coronary artery disease (CAD). Methods: This prospective study enrolled 450 patients with symptomatic heart disease. Platelet surface-associated and plasma CXCL14 levels were analyzed. All patients were followed up for 360 days for a primary composite outcome consisting of all-cause mortality, myocardial infarction, and/or ischemic stroke. Secondary outcomes consisted of the single events of all-cause mortality or myocardial infarction. Results: Baseline platelet-associated but not circulating CXCL14 levels were significantly lower in patients with chronic coronary syndrome (mean fluorescence intensity logarithmized, 1.35 ± 0.35) when compared to those with acute coronary syndrome (1.47 ± 0.38) and without CAD (1.51 ± 0.40). Platelet CXCL14 levels were significantly lower (1.37 ± 0.37 vs 1.48 ± 0.39) and circulating CXCL14 levels were significantly higher (lg, 2.88 ± 0.20 pg/mL vs 2.82 ± 0.26 pg/mL) in patients with normal baseline left ventricular ejection fraction (LVEF) when compared to those with impaired LVEF. Low baseline circulating CXCL14 (hazard ratio, 2.33; 1.00-5.46) but not platelet CXCL14 was associated with worse outcome in patients with CAD. Conclusion: Platelet-associated and circulating CXCL14 levels show differential regulation in patients with and without CAD. Although platelet-associated CXCL14 increased and circulating CXCL14 decreased with impairment of LVEF, only lower circulating CXCL14 upon admission was associated with worse prognosis in patients with CAD.