FRACTION: protocol of a phase II study of Fedratinib and Nivolumab combination in patients with myelofibrosis and resistance or suboptimal response to JAK-inhibitor treatment of the German MPN study group (GSG-MPN).

Development of Janus-kinase (JAK) inhibitors has revolutionized the therapeutic landscape for patients with myeloproliferative neoplasia (MPN). Following approval of the first JAK1/2-inhibitor Ruxolitinib, symptoms of this inflammatory disease, characterized by splenomegaly, release of inflammatory cytokines and appearance of thrombosis, could be effectively reduced for the first time. However, JAK-inhibitor treatment is limited in several aspects: 1) duration of response: 3 years after initiation of therapy more than 50% of patients have discontinued JAK-inhibitor treatment due to lack of efficacy or resistance; 2) reduction of disease burden: while effective in reducing inflammation and constitutional symptoms, JAK-inhibitors fail to reduce the malignant clone in the majority of patients and therefore lack long-term efficacy. Early clinical trials for patients with myelofibrosis (MF) have tried to address these issues for patients with suboptimal response to Ruxolitinib therapy while combination therapies with Fedratinib are rare. Recent reports provided first evidence on how the JAK2-V617F mutated myeloid cells may influence T-cell responses. JAK2-V617F promoted the synthesis of PD-L1 in MPN cells leading to limited anti-neoplastic T-cell responses, metabolic changes in T-cells and eventually JAK2-V617F-driven immune-escape of MPN cells. These findings may facilitate the use of immunotherapeutic approaches for JAK-mutated clones. Immune checkpoints refer to a variety of inhibitory pathways that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. The FRACTION study is a single arm, open label Phase II trial investigating the combination of Fedratinib with the PD-1 inhibitor Nivolumab in patients with myelofibrosis and suboptimal or lack of response to JAK-inhibitor therapy. Over a 12 months period the trial assesses longer term outcomes, particularly the effects on clinical outcomes, such as induction of clinical remissions, quality of life and improvement of anemia. No prospective clinical trial data exist for combinations of JAK- and immune-checkpoint-inhibitors in the planned MF study population and this study will provide new findings that may contribute to advancing the treatment landscape for MF patients with suboptimal responses and limited alternatives.

Effects of robotic-assisted early mobilization versus conventional mobilization in intensive care unit patients: prospective interventional cohort study with retrospective control group analysis.

BACKGROUND: Approximately one in three survivors of critical illness suffers from intensive-care-unit-acquired weakness, which increases mortality and impairs quality of life. By counteracting immobilization, a known risk factor, active mobilization may mitigate its negative effects on patients. In this single-center trial, the effect of robotic-assisted early mobilization in the intensive care unit (ICU) on patients' outcomes was investigated. METHODS: We enrolled 16 adults scheduled for lung transplantation to receive 20 min of robotic-assisted mobilization and verticalization twice daily during their first week in the ICU (intervention group: IG). A control group (CG) of 13 conventionally mobilized patients after lung transplantation was recruited retrospectively. Outcome measures included the duration of mechanical ventilation, length of ICU stay, muscle parameters evaluated by ultrasound, and quality of life after three months. RESULTS: During the first week in the ICU, the intervention group received a median of 6 (interquartile range 3-8) robotic-assisted sessions of early mobilization and verticalization. There were no statistically significant differences in the duration of mechanical ventilation (IG: median 126 vs. CG: 78 h), length of ICU stay, muscle parameters evaluated by ultrasound, and quality of life after three months between the IG and CG. CONCLUSION: In this study, robotic-assisted mobilization was successfully implemented in the ICU setting. No significant differences in patients' outcomes were observed between conventional and robotic-assisted mobilization. However, randomized and larger studies are necessary to validate the adequacy of robotic mobilization in other cohorts. TRIAL REGISTRATION: This single-center interventional trial was registered in clinicaltrials.gov as NCT05071248 on 27/08/2021.

Trends in cancer incidence by socioeconomic deprivation in Germany in 2007 to 2018: An ecological registry-based study.

Age-standardized cancer incidence has decreased over the last years for many cancer sites in developed countries. Whether these trends led to narrowing or widening socioeconomic inequalities in cancer incidence is unknown. Using cancer registry data covering 48 million inhabitants in Germany, the ecological association between age-standardized total and site specific (colorectal, lung, prostate and breast) cancer incidence in 2007 to 2018 and a deprivation index on district level (aggregated to quintiles) was investigated. Incidence in the most and least deprived districts were compared using Poisson models. Average annual percentage changes (AAPCs) and differences in AAPCs between deprivation quintiles were assessed using Joinpoint regression analyses. Age-standardized incidence decreased strongly between 2007 and 2018 for total cancer and all cancer sites (except female lung cancer), irrespective of the level of deprivation. However, differences in the magnitude of trends across deprivation quintiles resulted in increasing inequalities over time for total cancer, colorectal and lung cancer. For total cancer, the incidence rate ratio between the most and least deprived quintile increased from 1.07 (95% confidence interval: 1.01-1.12) to 1.23 (1.12-1.32) in men and from 1.07 (1.01-1.13) to 1.20 (1.14-1.26) in women. Largest inequalities were observed for lung cancer with 82% (men) and 88% (women) higher incidence in the most vs the least deprived regions in 2018. The observed increase in inequalities in cancer incidence is in alignment with trends in inequalities in risk factor prevalence and partly utilization of screening. Intervention programs targeted at socioeconomically deprived and urban regions are highly needed.

Step-in dosing of bosutinib in pts with chronic phase chronic myeloid leukemia (CML) after second-generation tyrosine kinase inhibitor (TKI) therapy: results of the Bosutinib Dose Optimization (BODO) Study.

The approved dose of bosutinib in chronic phase CML is 400 mg QD in first-line and 500 mg QD in later-line treatment. However, given that gastrointestinal (GI) toxicity typically occurs early after treatment initiation, physicians often tend to start therapy with lower doses although this has never been tested systematically in prospective trials in the Western world. The Bosutinib Dose Optimization (BODO) Study, a multicenter phase II study, investigated the tolerability and efficacy of a step-in dosing concept of bosutinib (starting at 300 mg QD) in chronic phase CML patients in 2nd or 3rd line who were intolerant and/or refractory to previous TKI treatment. Of 57 patients included until premature closure of the study due to slow recruitment, 34 (60%) reached the targeted dose level of 500 mg QD following the 2-weekly step-in dosing regimen. While the dosing-in concept failed to reduce GI toxicity (grade II-IV, primary study endpoint) to < 40% (overall rate of 60%; 95% CI: 45-74%), bosutinib treatment (mean dosage: 403 mg/day) showed remarkable efficacy with a cumulative major molecular remission (MMR) rate of 79% (95% CI: 66 to 88%) at month 24. Of thirty patients refractory to previous therapy and not in MMR at baseline, 19 (64%) achieved an MMR during treatment. GI toxicity did not significantly impact on patient-reported outcomes (PRO) and led to treatment discontinuation in only one patient. Overall, the results of our trial support the efficacy and safety of bosutinib after failure of second-generation TKI pre-treatment. Trial registration: NCT02577926.

[Regional and Temporal Trends in SARS-CoV-2-Associated Mortality in Bavaria: An Age-Stratified Analysis Over 5 Quarters for Persons Aged 50 and Older]. / Regionale und zeitliche Trends der SARS-CoV-2 assoziierten Sterblichkeit in Bayern: Eine altersstratifizierte Analyse über 5 Quartale für Personen ab 50 Jahren.

OBJECTIVE: The aim of this study was to investigate the influence of regional factors such as incidence rate, hospitalizations, socio-economic status and nursing homes on the regional and temporal heterogeneity of SARS-CoV-2-associated mortality in Bavaria. METHODOLOGY: Official Bavarian SARS-CoV-2 reporting data were considered for three age groups (50-64, 65-74,>74 years) between March 2020 and April 2021. Maps of regional standardized mortality rates were spatially smoothed using a Bayesian hierarchical model. RESULTS: The picture of regional mortality was heterogeneous with an increasing gradient toward the northeast. Adjustment for standardized incidence rates, hospitalizations of infected persons, and availability of care homes for the elderly levelled the heterogeneity. CONCLUSION: The north-east gradient in Bavarian SARS-CoV-2-specific mortality rates is clearly explained by the comparable gradient in regional incidence rates. Other regional factors show a less clear influence.

[Mapping Regional Differences in Infection Rates for the Coronavirus (COVID-19): Results of a Bayesian Approach to Administrative Districts of Bavaria]. / Kartografische Darstellung regionaler Unterschiede der Infektionsraten beim Coronavirus (COVID-19): Ergebnisse einer bayesianischen Glättung über Landkreise Bayerns.

BACKGROUND: Since the beginning of the COVID-19 pandemic, thematic maps showing the spread of the disease have been of great public interest. From the perspective of risk communication, those maps can be problematic, since random variation or extreme values may occur and cover up the actual regional patterns. One potential solution is applying spatial smoothing methods. The aim of this study was to show changes in incidence ratios over time in Bavarian districts using spatially smoothed maps. METHODS: Data on SARS-CoV-2 were provided by the Bavarian Health and Food Safety Authority on 29.10.2021 and 17.02.2022. The demographic data per district are derived from the Statistical Report of the Bavarian State Office for Statistics for 2019. Four age groups per sex (<18, 18-29, 30-64,>64 years) divided into 16 time periods (01/28/2020 to 12/31/2021) were included. Maps show standardized incidence ratios (SIR) spatially smoothed by Bayesian hierarchical modelling. RESULTS: The SIR varied remarkably between districts. Variations occurred for each time period, showing changing regional patterns over time. CONCLUSION: Smoothed health maps are suitable for showing trends in incidence ratios over time for COVID-19 in Bavaria and offer the advantage over traditional maps in giving more realistic estimates by including neighborhood relationships. The methodological approach can be seen as a first step to explain the regional heterogeneity in the pandemic, and to support improved risk communication.

[Regional monitoring of infections by means of standardized case fatality rates using the example of SARS-CoV-2 in Bavaria]. / Regionales Monitoring von Infektionen mittels standardisierter Fallfatalitätsraten am Beispiel von SARS-CoV-2 in Bayern.

BACKGROUND: Maps of the temporal evolution of the regional distribution of a health-related measure enable public health-relevant assessments of health outcomes. OBJECTIVES: The paper introduces the concept of standardized case fatality rate (sCFR). It describes the ratio of the regional variation in mortality to the regional variation in the documented infection process. The regional sCFR values are presented in maps and the time-varying regional heterogeneity observed in them is interpreted. MATERIALS AND METHODS: The regional sCFR is the quotient of the regional standardized mortality and case rate. It is estimated using a bivariate model. The sCFR values presented in maps are based on SARS-CoV­2 reporting data from Bavaria since the beginning of April 2020 until the end of March 2021. Four quarters (Q2/20, Q3/20, Q4/20, and Q1/21) are considered. RESULTS: In the quarters considered, the naïve CFR values in Bavaria are 5.0%, 0.5%, 2.5%, and 2.8%. In Q2/20, regional sCFR values are irregularly distributed across the state. This heterogeneity weakens in the second wave of the epidemic. In Q1/21, only isolated regions with elevated sCFR (> 1.25) appear in southern Bavaria. Clusters of regions with sCFR > 1.25 form in northern Bavaria, with Oberallgäu being the region with the lowest sCFR (0.39, 95% credibility interval: 0.25-0.55). CONCLUSIONS: In Bavaria, heterogeneous regional SARS-CoV-2-specific sCFR values are shown to change over time. They estimate the relative risk of dying from or with COVID-19 as a documented case. Strong small-scale variability in sCFR suggests a preference for regional over higher-level measures to manage the incidence of infection.

The Impact of the Opioid Antagonist Naloxone on Experimentally Induced Craving in Nicotine-Dependent Individuals.

OBJECTIVE: Preclinical and clinical findings suggest a substantial association of the endogenous opioid system in nicotine dependence. The present study investigates the possible dose-dependent influence of naloxone, an unspecific opioid-receptor-antagonist, combined with cue exposure on the physiological state, locomotor activity, craving and the hypothalamic-pituitary-adrenal axis in nicotine-dependent humans. METHODS: Twenty nicotine-dependent, outpatient participants were deprived of nicotine for over 4 h, before receiving challenges with naloxone (1.6 mg or 3.2 mg q70 kg IV) or the placebo. Additionally, following drug administration, either smoking-related cues or neutral images were presented. Nicotine withdrawal was monitored by evaluating the following objective signs - skin conductance, heart rate, temperature, respiration, locomotor activity, cortisol, prolactin and ACTH levels as well as craving. RESULTS: With respect to subjective effects, participants administered a higher dosage of naloxone and those who were shown smoking-related cues were significantly less pleased (p = 0.019), felt more depressed (p = 0.033) and thought smoking would make them feel better (p = 0.028) than participants given naloxone and shown neutral cues. Participants given no naloxone but with smoking-related cues felt a higher urge to smoke than participants given naloxone and shown neutral cues (p = 0.042). Naloxone - in both dosages - also decreased the desire and intention to smoke in comparison to placebo. Compared to the placebo group, significantly higher cortisol, prolactin and ACTH values were observed after administration of lower and higher dosage of naloxone followed by smoking-related cues. CONCLUSION: Naloxone influenced nicotine withdrawal and strengthened significantly by cue exposure, both on objective measurement and on craving scales. These findings suggest an involvement of the endogenous opioid system in the development and maintenance of nicotine dependence.

Preventing Atrophic Long-Bone Nonunion: Retrospective Analysis at a Level I Trauma Center.

Background: Among the risk factors for nonunion are unchangeable patient factors such as the type of injury and comorbidities, and factors that can be influenced by the surgeon such as fracture treatment and the postoperative course. While there are numerous studies analyzing unchangeable factors, there is poor evidence for factors that can be affected by the physician. This raises the need to fill the existing knowledge gaps and lay the foundations for future prevention and in-depth treatment strategies. Therefore, the goal of this study was to illuminate knowledge about nonunion in general and uncover the possible reasons for their development; Methods: This was a retrospective analysis of 327 patients from 2015 to 2020 from a level I trauma center in Germany. Information about patient characteristics, comorbidities, alcohol and nicotine abuse, fracture classification, type of osteosynthesis, etc., was collected. Matched pair analysis was performed, and statistical testing performed specifically for atrophic long-bone nonunion; Results: The type of osteosynthesis significantly affected the development of nonunion, with plate osteosynthesis being a predictor for nonunion. The use of wire cerclage did not affect the development of nonunion, nor did the use of NSAIDs, smoking, alcohol, osteoporosis and BMI; Conclusion: Knowledge about predictors for nonunion and strategies to avoid them can benefit the medical care of patients, possibly preventing the development of nonunion.

Quality of Life and Patient Satisfaction After the Provision of an Orthopedic Knee Scooter­a Multicenter Randomized Controlled Trial.

BACKGROUND: Partial or total avoidance of weight-bearing by a lower limb is regularly needed after trauma and surgery. There are approximately 200 such cases per 100 000 persons per year. Underarm crutches have mainly been used in Germany until now to keep these patients mobile. For those who lack the strength or coordination needed to use crutches, a wheelchair may become necessary, or they might find themselves forced to continue weight-bearing on the affected limb, with possible impending adverse consequences and complications. METHODS: The supplementary use of a new type of orthopedic scooter by patients who must avoid weight-bearing by a lower limb, wholly or in part, was studied in a multicenter randomized controlled trial involving 88 subjects. The endpoints were improvement in quality of life (EQ5D, SF36) and improved abilities in everyday life (retrospective registration: DRKS00032980). RESULTS: Patients who used orthopedic knee scooters (KS) reported a better overall state of health more frequently than those who used underarm crutches (UC) (SF-36 score: 67 [KS group], 95% CI [61; 73]; 59 [UC group], [53; 64]). They also reported less anxiety and depressed mood, greater mobility, and more independence than the patients who used crutches. In addition, they more frequently reported being able to transport themselves 4 x 500 meters in less than 20 minutes (n = 30 [KS], 63.8% [48.5; 77.3]; n = 6 [UC], 14.6% [5.6, 29.2]). CONCLUSION: The supplementary use of an orthopedic knee scooter can improve these patients' mobility and independence and prolong the distance over which they can transport themselves. For many patients, this form of treatment may well shorten the time of their total or partial inability to work and thus lower the socioeconomic costs of lower limb injuries and surgery.

Robot-assisted early mobilization for intensive care unit patients: Feasibility and first-time clinical use.

BACKGROUND: Early mobilization is only carried out to a limited extent in the intensive care unit. To address this issue, the robotic assistance system VEMOTION® was developed to facilitate (early) mobilization measures more easily. This paper describes the first integration of robotic assistance systems in acute clinical intensive care units. OBJECTIVE: Feasibility test of robotic assistance in early mobilization of intensive care patients in routine clinical practice. SETTING: Two intensive care units guided by anesthesiology at a German university hospital. PARTICIPANTS: Patients who underwent elective surgery with postoperative treatment in the intensive care unit and had an estimated ventilation time over 48 h. METHODS: Participants underwent robot-assisted mobilization, scheduled for twenty-minute sessions twice a day, ten times or one week, conducted by nursing staff under actual operational conditions on the units. No randomization or blinding took place. We assessed data regarding feasible cutoff points (in brackets): the possibility of enrollment (x ≥ 50 %), duration (pre- and post-setup (x ≤ 25 min), therapy duration (x = 20 min), and intervention-related parameters (number of mobilizing professionals (x ≤ 2), intensity of training, events that led to adverse events, errors or discontinuation). Mobilizing professionals rated each mobilization regarding their physical stress (x ≤ 3) and feasibility (x ≥ 4) on a 7 Point Likert Scale. An estimated sample size of at least twenty patients was calculated. We analyzed the data descriptively. RESULTS: Within 6 months, we screened thirty-two patients for enrollment. 23 patients were included in the study and 16 underwent mobilization using robotic assistance, 7 dropped out (enrollment eligibility = 69 %). On average, 1.9 nurses were involved per therapy unit. Participants received 5.6 robot-assisted mobilizations in mean. Pre- and post-setup had a mean duration of 18 min, therapy a mean of 21 min. The robot-assisted mobilization was started after a median of 18 h after admission to the intensive care unit. We documented two adverse events (pain), twelve errors in handling, and seven unexpected events that led to interruptions or discontinuation. No serious adverse events occurred. The mobilizing nurses rated their physical stress as low (mean 2.0 ±â€¯1.3) and the intervention as feasible (mean 5.3 ±â€¯1.6). CONCLUSIONS: Robot-assisted mobilization was feasible, but specific safety measures should be implemented to prevent errors. Robotic-assisted mobilization requires process adjustments and consideration of unit staffing levels, as the intervention does not save staff resources or time. REGISTRATION: clinicaltrials.org TRN: NCT05071248; Date: 2021/10/08; URL https://clinicaltrials.gov/ct2/show/NCT05071248. TWEETABLE ABSTRACT: Robot-assisted early mobilization in intensive care patients is feasible and no adverse event occurred.

Quality of long standing radiographs assessment of the patella position.

BACKGROUND: The gold standard for evaluating leg alignment is a long leg standing radiograph (LSR). The research states that a correct LSR should have a patella that is centered and facing forward as well as a fibula head superimposition (FHS) with a tibia that is 1/3 larger than the fibula. The purpose of this study was to determine levels of quality for LSR by quantifying and correlating the patella position and fibular head superimposition. METHOD: 741 lower limbs were included using two distinct measurement techniques, we calculated the patella position's (PD) departure from the center of the knee joint (M1 and M2). To measure the inter-rater dependability in assessing PD and FHS, intraclass correlation coefficients were determined. The Bland-Altman approach was used to compare M1 with M2's performance. We created three quality groups based on the average quantity of PD. RESULTS: The mean PD was 3.5 mm for M1 and 4.1 mm for M2, respectively. Three quality categories were created: group A for PD ≤ 5 mm, group B for PD 5-10 mm, and group C for PD of ≥10 mm. Group A takes up 70.9% of the LSR. Interestingly, group A's FHS was 21.3% than the typical value of 1/3. CONCLUSIONS: The patella's center should be centered within a 5 mm range and the fibular head should be 1/5 covered from the tibia. This study is the first to define quantitative metrics based on LSR analysis. LEVEL OF EVIDENCE: Level IV (diagnostic retrospective case series).

Binding potential changes of SERT in patients with depression are associated with remission: A prospective [¹²³I]ß-CIT-SPECT study.

The status of remission in patients with major depressive disorder treated with selective serotonin reuptake inhibitors (SSRIs) is mostly evaluated with clinical rating scales. Morphological correlates of the remission status remain a rare event. Addressing this challenge, we investigated functional correlates of remission by assessment of serotonin and dopamine transporter availability (SERT and DAT) using single-photon emission computed tomography (SPECT). Our purpose was to identify changes in the SERT/DAT binding potential in accordance with the clinical improvement. Nineteen drug-naïve patients with a Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) diagnosis of major depression were included. [¹²³I]2ß-carbomethoxy-3ß-(4-iodophenyl)tropane(ß-CIT) SPECT was obtained from each participant before (baseline) and after 6 weeks (follow-up) of standardized treatment with escitalopram. The [¹²³I]ß-CIT-SPECT recordings were acquired 4 hr (SERT-weighted) and 20-24 hr p.i (DAT-weighted), and binding potentials (˜BPND: baseline, follow-up, and rate of change) were calculated for thalamus, midbrain, pons (SERT), and striatum (DAT). From all study participants, neuropsychiatric symptoms were assessed using Hamilton depression (HAM-D) and Beck Depression Inventory scores. At follow-up, patients were divided into responders and nonresponders (as well as remitters and nonremitters). Compared to nonremitted, remitted patients showed over the course of 6 weeks a significantly higher loss of SERT binding potential in the thalamus (p = .036) and in the midbrain (p = .019). Additionally, the correlation of HAM-D with SERT binding potential in the thalamus showed a trend toward significance (p = .057) with higher HAM-D scores (at baseline) leading to lower SERT binding potential. No significant associations were identified for the analysis of baseline prediction of therapy response with SERT and DAT. Our results suggest that patients who remit from their depressive symptoms under escitalopram are characterized by stronger decreases of SERT, indicating that escitalopram blocking of SERT leads to clinical improvement. Therefore, this study shows that measuring SERT availability with SPECT could be an efficient and applicable technique to illustrate a possible underlying pathophysiology of symptom remission in response to treatment. In addition, the present results could help to stimulate new treatment approaches based on SERT and DAT binding. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Area Deprivation and COVID-19 Incidence and Mortality in Bavaria, Germany: A Bayesian Geographical Analysis.

Background: Area deprivation has been shown to be associated with various adverse health outcomes including communicable as well as non-communicable diseases. Our objective was to assess potential associations between area deprivation and COVID-19 standardized incidence and mortality ratios in Bavaria over a period of nearly 2 years. Bavaria is the federal state with the highest infection dynamics in Germany and demographically comparable to several other European countries. Methods: In this retrospective, observational ecological study, we estimated the strength of associations between area deprivation and standardized COVID-19 incidence and mortality ratios (SIR and SMR) in Bavaria, Germany. We used official SARS-CoV-2 reporting data aggregated in monthly periods between March 1, 2020 and December 31, 2021. Area deprivation was assessed using the quintiles of the 2015 version of the Bavarian Index of Multiple Deprivation (BIMD 2015) at district level, analyzing the overall index as well as its single domains. Results: Deprived districts showed higher SIR and SMR than less deprived districts. Aggregated over the whole period, the SIR increased by 1.04 (95% confidence interval (95% CI): 1.01 to 1.07, p = 0.002), and the SMR by 1.11 (95% CI: 1.07 to 1.16, p < 0.001) per BIMD quintile. This represents a maximum difference of 41% between districts in the most and least deprived quintiles in the SIR and 110% in the SMR. Looking at individual months revealed clear linear association between the BIMD quintiles and the SIR and SMR in the first, second and last quarter of 2021. In the summers of 2020 and 2021, infection activity was low. Conclusions: In more deprived areas in Bavaria, Germany, higher incidence and mortality ratios were observed during the COVID-19 pandemic with particularly strong associations during infection waves 3 and 4 in 2020/2021. Only high infection levels reveal the effect of risk factors and socioeconomic inequalities. There may be confounding between the highly deprived areas and border regions in the north and east of Bavaria, making the relationship between area deprivation and infection burden more complex. Vaccination appeared to balance incidence and mortality rates between the most and least deprived districts. Vaccination makes an important contribution to health equality.

Treatment outcome, cognitive function, and psychopathology in methamphetamine users compared to other substance users.

BACKGROUND: The rising number of people using methamphetamine leads to an increasing need for treatment options for this patient group. Evidence-based research on the efficacy of treatment programs for methamphetamine users is limited. Due to specific characteristics of methamphetamine users, the question arises whether established treatment methods for individuals using other substances can be effective for the treatment of methamphetamine dependence as well. We hypothesize that there are significant differences between the two groups that may affect the effectiveness of treatment and worsen the prognosis of treatment outcomes for methamphetamine users compared to consumers of other substances. AIM: To investigate potential differences in cognitive functioning and psychopathology between methamphetamine users and other substance users and possible correlations with treatment outcomes. METHODS: A total of 110 subjects were recruited for an observational, longitudinal study from a German inpatient addiction treatment center: 55 patients with methamphetamine dependence and 55 patients with dependence of other substances ("OS group"). Both groups were examined at beginning (baseline) and end of treatment (after 6 mo) with regard to treatment retention, craving, cognitive functioning, psychosocial resources, personality traits, depression, and other psychiatric symptoms. Instruments used were Raven's IQ test, Mannheimer craving scale, cognitrone cognitive test battery, NEO personality factors inventory, Hamilton depression scale, Becks depression inventory, and a symptom checklist. The statistical methods used were χ 2-test, t-test and multiple mixed ANOVAs. RESULTS: A total drop-out rate of 40% (methamphetamine-group: 36.4%; OS-group: 43.6%) was observed without significant differences between groups. At baseline, methamphetamine-group subjects significantly differed from OS-group individuals in terms of a lower intelligence quotient, fewer years of education, slower working speed, and decreased working accuracy, as well as less cannabinoid and cocaine use. Methamphetamine-group subjects further showed a significantly lower score of conscientiousness, depressive, and psychiatric symptoms than subjects from the OS-group. In both groups, a reduction of craving and depressive symptoms and an improvement of working speed and working accuracy was noted after treatment. CONCLUSION: There are differences between methamphetamine users and users of other drugs, but not with regard to the effectiveness of treatment in this inpatient setting. There are differences in cognitive function and psychopathology between methamphetamine and other drugs users. The existing treatment options seem to be an effective approach in treating methamphetamine dependence.

Inequality indices to monitor geographic differences in incidence, mortality and fatality rates over time during the COVID-19 pandemic.

BACKGROUND: It is of interest to explore the variability in how the COVID-19 pandemic evolved geographically during the first twelve months. To this end, we apply inequality indices over regions to incidences, infection related mortality, and infection fatality rates. If avoiding of inequality in health is an important political goal, a metric must be implemented to track geographical inequality over time. METHODS: The relative and absolute Gini index as well as the Theil index are used to quantify inequality. Data are taken from international data bases. Absolute counts are transformed to rates adjusted for population size. RESULTS: Comparing continents, the absolute Gini index shows an unfavorable development in four continents since February 2020. In contrast, the relative Gini as well as the Theil index support the interpretation of less inequality between European countries compared to other continents. Infection fatality rates within the EU as well as within the U.S. express comparable improvement towards more equality (as measured by both Gini indices). CONCLUSIONS: The use of inequality indices to monitor changes in geographic inequality over time for key health indicators is a valuable tool to inform public health policies. The absolute and relative Gini index behave complementary and should be reported simultaneously in order to gain a meta-perspective on very complex dynamics.

Psychiatric Comorbidity and Stress in Medical Students Using Neuroenhancers.

Background: Pharmacological neuroenhancement (PN) is a common healthcare problem at least among students. PN seems to be associated with stressful situations. There is a lack of data about personal characteristics, comorbidities, and coping strategies regarding stress and factors of resilience in students and medical staff. Methods: A web-based survey about the non-medical use of PN drugs with a focus on neuroenhancement was developed and distributed among medical students throughout Germany; the questionnaire was open in April and May of 2020. The survey contained questions about the use of well-known PN drugs, frequency, special purposes, reasons for the use, psychiatric disorders, use of psychotropic drugs apart from PN purposes, and factors of resilience using the brief resilience scale. Results: Data of 1,159 students of medicine were analyzed. The most frequently used substances for PN were coffee (78.8% lifetime prevalence rate), energy drinks (45.7%), caffeine tablets (24.3%), methylphenidate (5.2%), illicit amphetamines (2.0%), and cocaine (1.7%). 98.4% suspected that PN drug use could lead to addiction. PN drug use specifically for PN was significantly associated with the use of (a) any psychotropic drug (other than neuroenhancers), (b) any psychiatric disorder, and (c) higher values of feeling pressure to perform in professional/students' life and in private life as well as (d) the subjective feeling of pressure to perform to be burdening and (e) harmful to one's own health. PN drug use in general was significantly associated with being less resilient. The use of illicit PN drugs, over the counter drugs and prescription drugs was associated with being less resilient. Conclusion: This study indicates that PN with legal and illegal drugs is a widespread phenomenon among German medical students. Users seem to be more often burdened by psychiatric disorders, especially addictive disorders, the perception of stress, pressure to perform and low levels of resilience. These aspects should be considered in further investigation of PN drug use.

CXCL13 and CXCL9 CSF Levels in Central Nervous System Lymphoma-Diagnostic, Therapeutic, and Prognostic Relevance.

Background: Diagnostic delay and neurologic deterioration are still a problem for the treatment of rapidly progressing CNS lymphoma (CNSL); there is an unmet need for a diagnostic test with a high diagnostic yield and limited risk, minimizing the time to the initiation of effective treatment. Methods: In this prospective monocentric study, we analyzed the utility of CXCL13 and CXCL9 as diagnostic, therapeutic and prognostic biomarkers for CNSL. Cerebrospinal fluid (CSF) from 155 consecutive patients admitted with brain lesions of various origins was collected. Levels of CXCL13 and CXCL9 were analyzed by ELISA. Additionally, CSF was analyzed during CNSL disease course (relapse, remission, progress) in 17 patients. Results: CXCL13 and CXCL9 CSF levels were significantly increased in patients with CNSL compared to control patients with lesions of other origin. Using logistic regression and a minimal-p-value approach, a cut-off value of 80 pg/ml for CXCL13 shows high sensitivity (90.7%) and specificity (90.1%) for the diagnosis of active CNSL. CXCL9 at a cut-off value of 84 pg/ml is less sensitive (61.5%) and specific (87.1%). Both cytokines correlate with the clinical course and response to therapy. Conclusions: Our results confirm the excellent diagnostic potential of CXCL13 and introduce CXCL9 as a novel albeit less powerful marker for PCNSL.

Stapes and Stapes Revision Surgery: Preoperative Air-Bone Gap Is a Prognostic Marker.

OBJECTIVE: Stapes surgery is considered an effective treatment in otosclerosis, but controversy remains regarding predictors of surgical outcome. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary referral center. PATIENTS: One hundred sixty three cases of stapes surgery between 2012 and 2019 were reviewed. MAIN OUTCOME MEASURES: Primary outcome measures were relative hearing improvement (relHI), defined as preoperative minus postoperative air conduction divided by preoperative air-bone gap (ABG), as well as relative ABG closure (relABGc), defined as preoperative ABG minus postoperative ABG divided by preoperative ABG. Univariate and multivariate linear regression analyses were performed to determine independent predictors for these outcomes. RESULTS: Higher preoperative bone conduction (BC) and primary surgery (compared with revision) were independently associated with increased relHI (p = 0.001 and p = 0.004, respectively). Lower preoperative BC, higher preoperative ABG, primary surgery, and age were independently associated with increased relABGc (p = 0.0030, p < 0.001, p = 0.0214, and p = 0.0099, respectively). Sex did not predict surgical outcome. In patients with less than 20 dB preoperative ABG, likelihood of negative relABGc was increased (compared with 20-30 dB or >30 dB preoperative ABG, p = 0.0292, Fisher's exact test). This tendency was not significant for relHI (p = 0.074). CONCLUSIONS: Our findings demonstrate that calculating HI and ABGc in relation to preoperative ABG can reliably predict outcomes of stapes surgery. Both primary and revision stapes surgery are effective treatment options, but relative improvement is higher in primary cases. Preoperative BC, preoperative ABG, and age predict surgical outcomes as well. Otosclerosis patients with low preoperative ABG, especially less than 20 dB, should be counseled and selected cautiously regarding stapes surgery.

Just "Like Coffee" or Neuroenhancement by Stimulants?

Introduction: Pharmacological neuroenhancement (PN) is a topic of increasing importance and prevalence among students. However, there is a lack of differentiating PN substances, according to their psychoactive effects. In particular, there is a lack of data about PN by caffeinated drinks, even if coffee is a common and broadly used Neuroenhancer because of its cognitively enhancing effects regarding wakefulness, alertness and concentration. Materials and Methods: A web-survey was developed for German students and alumni about the non-medical use of caffeine for PN contained questions about coffee, caffeinated drinks and energy drinks, caffeine pills and methylxanthine tea regarding frequency and further contextual factors. Results: Six hundred and eighty-three participants completed the survey. Nearly all participants knew about PN (97.7%). 88.1% admitted using some over-the-counter substances. For PN purposes, coffee was used by 72.9% followed by energy drinks (68.2%) and cola drinks (62.4%). Methylxanthine containing tea was used for PN purposes, too (black tea 52.3%, green tea 51.7%). 1.8% admitted using illegal substances or prescription drugs, too. Discussion: Using legal methylxanthine containing drinks for PN seems to be extremely common with coffee and energy drinks being the preferred substances, while illegal and prescription drugs are only minimally used. Further studies should investigate the awareness of methylxanthine containing drinks as well as its character to be a flavoring drink or a neuroenhancer.