Pediatric multi-drug-resistant tuberculosis in Germany - diagnostic and therapeutic challenges of an "orphan disease".

Delay in diagnosing multidrug-resistant tuberculosis (MDR-pTB) in children prolongs time to effective treatment. Data on risk factors for pediatric MDR from low-incidence countries are scarce. Retrospective nationwide case-control study to analyze MDR-pTB cases in Germany between 2010 and 2020 in comparison to a drug-susceptible (DS)-pTB group. We included 52 MDR cases (24 tuberculosis (TB), 28 TB infection (TBI); mean age 7.3 years) and 56 DS cases (31 TB, 26 TBI; mean age 7.9 years). Groups were similar for sex, household size, and migration background. Compared to the DS group, more children with MDR were born in the Commonwealth of Independent States (CIS) (22% MDR-pTB vs. 13% DS-pTB, n.s.) and had more MDR index cases (94% MDR-pTB, 5% DS-pTB, p < 0.001). The interval between first healthcare contact and initiation of effective therapy was significantly longer in MDR-pTB (47 days) than in DS-pTB (11 days, p < 0.001), correlating with disease progression. Treatment for MDR-pTB was successful in 74%, but 22% experienced long-term adverse effects (e.g., hepatopathy, hearing loss). CONCLUSIONS: Close contact to MDR cases or birth in MDR-TB-high-incidence countries are risk factors for MDR-pTB. Early identification of potential MDR index cases by contact investigation, and susceptibility testing in children from high-burden MDR-TB countries are essential for timely diagnosis and treatment, reducing the severity of disease and treatment side effects. TRIAL REGISTRATION: Deutsches Register Klinischer Studien ( https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00023817 ), DRKS00023817, 2020-09-08. WHAT IS KNOWN: •Management of children with MDR-TB remains challenging due to difficulties in diagnosing MDR-TB (lack of information on MDR index case, lack of microbiological confirmation in paucibacillary disease). •Choice of treatment regimen and monitoring of side effects. WHAT IS NEW: •Children with an MDR-TB index or born in a MDR-TB-high-incidence country are at higher risk of developing MDR-TB in a low incidence country. •The time lag to initiate treatment in MDR-TB is longer than in DS-TB and MDR-TB treatment involves a higher risk of adverse effects in longer treatment regimens especially with injectables.

Duodenal mast cells and eosinophils in children with celiac disease: occurrence and distribution pattern.

OBJECTIVE: The aim of this study was to characterize duodenal mast cell (MC) and eosinophil (EO) numbers, their distribution within the lamina propria and possible impact on disease severity of paediatric celiac patients compared to children without celiac disease (CD). METHODS: We analysed duodenal samples of 215 children (109 CD, 106 controls) who underwent esophagogastroduodenoscopy from 2010 to 2018. After immunohistochemical staining, average MC and EO counts were histologically examined in ten high-power-fields. Additionally, cell-distribution within the lamina propria was analysed. Possible influence of relevant clinical parameters was evaluated. STATISTICS: Student's-t-test, Mann-Whitney U-test, Chi-square-test, ANOVA, significance-level <.05. Trial registration-number: DRKS00024669. RESULTS: MC-density was higher in CD-patients compared to the control-group (23.7 (±12.1)/HPF versus 19.7 (±9.1)/HPF; p = .008), varying in number interindividually. Eosinophils were also increased in the duodenum of celiac patients (23.3 (±9.3)/HPF versus 12.2 (±6.3)/HPF; p= <.001). MCs were distributed more often homogenously in all parts of CD lamina propria (44 biopsies (40.4%), residing more distant from the intestinal lumen in controls (0 biopsies with homogenous distribution-pattern (0%); p= <.001). Regarding EOs no polarity was observable. Atopic diseases did not occur significantly more often in patients with elevated EO-counts. CONCLUSION: MC- and EO-numbers were increased in the duodenum of CD-patients and MCs showed a different distribution-pattern in the lamina propria of celiac patients. These findings support the concept that both cell-types contribute to disease-pathogenesis. However, functional studies highlighting both cell-types' and their mediators' role regarding mucosal alterations during the course of the inflammatory process in celiac patients are needed. TRIAL REGISTRATION NUMBER AND URL: DRKS00024669; https://www.drks.de/drks_web/.

Effects of leachates from UV-weathered microplastic on the microalgae Scenedesmus vacuolatus.

Plastics undergo successive fragmentation and chemical leaching steps in the environment due to weathering processes such as photo-oxidation. Here, we report the effects of leachates from UV-irradiated microplastics towards the chlorophyte Scenedesmus vacuolatus. The microplastics tested were derived from an additive-containing electronic waste (EW) and a computer keyboard (KB) as well as commercial virgin polymers with low additive content, including polyethylene (PE), polyethylene terephthalate (PET), polypropylene (PP), and polystyrene (PS). Whereas leachates from additive-containing EW and KB induced severe effects, the leachates from virgin PET, PP, and PS did not show substantial adverse effects in our autotrophic test system. Leachates from PE reduced algae biomass, cell growth, and photosynthetic activity. Experimental data were consistent with predicted effect concentrations based on the ionization-corrected liposome/water distribution ratios (Dlip/w) of polymer degradation products of PE (mono- and dicarboxylic acids), indicating that leachates from weathering PE were mainly baseline toxic. This study provides insight into algae toxicity elicited by leachates from UV-weathered microplastics of different origin, complementing the current particle- vs. chemical-focused research towards the toxicity of plastics and their leachates.

How health systems facilitate patient-centered care and care coordination: a case series analysis to identify best practices.

Large- and small-scale transformation of healthcare delivery toward improved patient experience through promotion of patient-centered and coordinated care continues to be at the forefront of health system efforts in the United States. As part of a Quality Improvement (QI) project at a large, midwestern health system, a case series of high-performing organizations was explored with the goal of identifying best practices in patient-centered care and/or care coordination (PCC/CC). Identification of best practices was done through rapid realist review of peer-reviewed literature supporting three PCC/CC interventions per case. Mechanisms responsible for successful intervention outcomes and associated institutional-level facilitators were evaluated, and cross-case analysis produced high-level focus items for health system leadership, including (1) institutional values surrounding PCC/CC, (2) optimization of IT infrastructure to enhance performance and communication, (3) pay structures and employment models that enhance accountability, and (4) organizing bodies to support implementation efforts. Health systems may use this review to gain insight into how institutional-level factors may facilitate small-scale PCC/CC behaviors, or to conduct similar assessments in their own QI projects. Based on our analysis, we recommend health systems seeking to improve PCC/CC at any level or scale to evaluate how IT infrastructure affects provider-provider and provider-patient communication, and the extent to which institutional prioritization of PCC/CC is manifest and held accountable in performance feedback, incentivization, and values shared among departments and settings. Ideally, this evaluation work should be performed and/or supported by cross-department organizing bodies specifically devoted to PCC/CC implementation work.

Endovascular and open surgical options in the treatment of uretero-arterial fistulas.

OBJECTIVE: To report and analyze the indications and results of endovascular and open surgical treatment for uretero-arterial fistula. METHODS: We retrospectively reviewed the clinical data of 25 consecutive patients with uretero-arterial fistulas admitted to our hospital from 2011 to 2020. Endpoints were technical success, freedom from open conversion, stent-graft/graft-related complications, and 30-day and one-year mortality. RESULTS: The study included 25 patients (68% female, n = 17) with 27 uretero-arterial fistulas by bilateral pathologies in two patients. The mean age was 61 ± 11 years (range 35-80). The most common predisposing factors for uretero-arterial fistula were history of pelvic operations for malignancy in 21 patients (84%), radiotherapy in 21 patients (84%), previous pelvic vascular bypass in 2 patients (8%), and iliac aneurysms in 2 patients (8%). On average, the period between the primary pelvic surgery and the diagnosis of uretero-arterial fistulas was 46 months (range 7-255). Twenty patients (80%) underwent endovascular treatment of the uretero-arterial fistulas. The primary technical success of the endovascular treatment was 95%, and the freedom from open conversion was 40% at six months and 30% at one year. Thirteen uretero-arterial fistulas (48%) underwent delayed open conversion due to recurrent bleeding in six cases (46%), stent-graft infection in three cases (23%), or pelvic abscess in four cases (31%). Primary open surgery was applied for five (20%) patients. After a mean follow-up of 34 months, early (<30 days) mortality was 8% (2/25), one-year mortality 16% (4/25), and overall mortality was 24% (6/25). CONCLUSIONS: Uretero-arterial fistula is a late complication of prior pelvic surgery, radiation, and indwelling ureteral stents. Endovascular treatment remains an effective and less invasive modality in controlling the related life-threatening arterial bleeding of the uretero-arterial fistula. Open surgical treatment is still required for patients with local sepsis, previously failed endovascular treatment or infected stent-grafts.

Improvement in Renal Cystic Disease of Tuberous Sclerosis Complex After Treatment with Mammalian Target of Rapamycin Inhibitor.

Renal cysts occur in approximately 50% of patients with tuberous sclerosis complex, but their clinical significance and response to treatment are unknown. Abdominal imaging of 15 patients with tuberous sclerosis complex-associated renal cystic disease who had received mammalian target of rapamycin inhibitor therapy for other tuberous sclerosis complex-related indications was evaluated. Reductions in cyst number, sum diameter, and volume were observed.

The Effects of Mitral Valve Repair on Memory Performance, Executive Function, and Psychological Measures in Patients With Heart Failure.

OBJECTIVES: Heart failure (HF) is a prevalent disease that remains costly and associated with a high mortality rate. HF is also associated with poor neurocognitive functioning. For the treatment for HF patients with severe mitral regurgitation, the MitraClip device has emerged as a promising interventional tool that reduces the mitral valve leakage and thus increases cardiac output. Currently, there is only limited knowledge on changes in cognitive and psychosocial functioning before and after the MitraClip intervention. METHODS: Cognitive function (memory and executive function) and psychosocial measures (depression, anxiety, and quality of life) were assessed before and after the MitraClip intervention in 24 HF patients and 23 healthy participants (comparison group). RESULTS: MitraClip intervention in HF patients was followed by improvements in figural long-term memory (p = .003) and executive function (planning ability, p < .001) relative to the comparison group. In addition, the intervention resulted in a significant improvement in depression (p = .002), anxiety (p = .003) and quality of life scores (physical p = .017, mental p = .013) as well as improved 6-minute walk test results over time (p = .002). CONCLUSIONS: The presented data provide evidence of a significant improvement in memory and executive function as well as in depression, anxiety, and quality of life scores in patients with chronic HF after MitraClip intervention. Further research is needed to shed light on the long-term development of cognitive function, psychosocial well-being, and clinical parameters after MitraClip intervention and how these factors depend on one another.

Long-Term Nephrotoxicity of 177Lu-PSMA Radioligand Therapy.

ß-emitting 177Lu targeting prostate-specific membrane antigen (PSMA) is an approved treatment option for metastatic castration-resistant prostate cancer. Data on its long-term nephrotoxicity are sparse. This study aimed to retrospectively evaluate post-177Lu-PSMA estimated glomerular filtration rate (eGFR) dynamics for at least 12 mo in a cohort of metastatic castration-resistant prostate cancer patients. Methods: The institutional databases of 3 German tertiary referral centers identified 106 patients who underwent at least 4 cycles of 177Lu-PSMA and had at least 12 mo of eGFR follow-up data. eGFR (by the Chronic Kidney Disease Epidemiology Collaboration formula) at 3, 6, and 12 mo after 177Lu-PSMA radioligand therapy was estimated using monoexponentially fitted curves through available eGFR data. eGFR changes were grouped (≥15%-<30%, moderate; ≥30%-<40%, severe; and ≥40%, very severe). Associations between eGFR changes (%) and nephrotoxic risk factors, prior treatment lines, and number of 177Lu-PSMA cycles were analyzed using multivariable linear regression. Results: At least moderate eGFR decreases were present in 45% (48/106) of patients; of those, nearly half (23/48) had a severe or very severe eGFR decrease. A higher number of risk factors at baseline (-4.51, P = 0.03) was associated with a greater eGFR decrease. Limitations of the study were the retrospective design, lack of a control group, and limited number of patients with a follow-up longer than 1 y. Conclusion: A considerable proportion of patients may experience moderate or severe decreases in eGFR 1 y from initiation of 177Lu-PSMA. A higher number of risk factors at baseline seems to aggravate loss of renal function. Further prospective trials are warranted to estimate the nephrotoxic potential of 177Lu-PSMA.

Development and evaluation of an internet- and mobile-based intervention for individualized return to work planning after inpatient rehabilitation - Study protocol for a randomized-controlled-trial.

Background: Following discharge, it is crucial for patients to transfer intentions and action plans from inpatient rehabilitation into everyday life. This ensures their reintegration into social and working life and prevents economic costs due to sick leave or reduced earning capacity pension. However, most established aftercare programs do not specifically address occupational problems or challenges during occupational measures such as graded return to work. The aim of this study is to evaluate the efficacy of the low-threshold online self-help intervention marena (Meine Arbeitsbezogene Reha-Nachsorge - My Work-related Rehabilitation Aftercare) to support return to work. Methods: A two-arm randomized-controlled-trial (RCT) will be conducted. A total of N = 400 rehabilitation inpatients across different indication areas (psychosomatic, orthopedic, or cardiologic) aged 18 to 65 years with a planned return to work after medical rehabilitation, have a heightened social-medical risk and private internet access and are insured with the German Pension insurance or statutory health insurance, will be recruited in four medical and psychosomatic clinics in Germany. Participants will be allocated to either the intervention (IG) or the control group (CG). In a stepped-care model, participants of the IG will receive access to the non-guided internet- and mobile-based intervention marena (IG subgroup 1) or marena in combination with GSA-Online plus (IG subgroup 2), a guided psychodynamic internet-based intervention that has proven effective in two trials regarding occupational and health objectives. Based on a priori defined indication criteria, clinic staff will recommend either IG subgroup 1 or IG subgroup 2. The CG will receive optimized treatment as usual with access to a survey feature within marena. The primary outcome will be work status after 6 months (T2) and 12 months (T4). The endpoint at 12 months (T4) after discharge from inpatient rehabilitation will be considered as secondary endpoint. Work status is defined as positive if the participant is working and has ≤ 6 weeks of sick leave at T2 and ≤ 12 weeks of sick leave at T4. Secondary outcomes include successful completion of graded return to work, successful application for benefits for participation in working life, current work ability, social-medical risk, subjective prognosis of future employment, quality of life, somatic symptoms, coping, social support, depression, anxiety, and psychosocial stress. Discussion: This study will contribute to the evidence concerning efficacy of online aftercare interventions. If proven efficacious, marena could provide an individualized and adaptable self-help approach to promote return to work following inpatient rehabilitation.

A multicenter, matched case-control analysis comparing burden of illness among patients with tuberous sclerosis complex related epilepsy, generalized idiopathic epilepsy, and focal epilepsy in Germany.

BACKGROUND: Depending on the underlying etiology and epilepsy type, the burden of disease for patients with seizures can vary significantly. This analysis aimed to compare direct and indirect costs and quality of life (QoL) among adults with tuberous sclerosis complex (TSC) related with epilepsy, idiopathic generalized epilepsy (IGE), and focal epilepsy (FE) in Germany. METHODS: Questionnaire responses from 92 patients with TSC and epilepsy were matched by age and gender, with responses from 92 patients with IGE and 92 patients with FE collected in independent studies. Comparisons were made across the main QoL components, direct costs (patient visits, medication usage, medical equipment, diagnostic procedures, ancillary treatments, and transport costs), indirect costs (employment, reduced working hours, missed days), and care level costs. RESULTS: Across all three cohorts, mean total direct costs (TSC: €7602 [median €2620]; IGE: €1919 [median €446], P < 0.001; FE: €2598 [median €892], P < 0.001) and mean total indirect costs due to lost productivity over 3 months (TSC: €7185 [median €11,925]; IGE: €3599 [median €0], P < 0.001; FE: €5082 [median €2981], P = 0.03) were highest among patients with TSC. The proportion of patients with TSC who were unemployed (60%) was significantly larger than the proportions of patients with IGE (23%, P < 0.001) or FE (34%, P = P < 0.001) who were unemployed. Index scores for the EuroQuol Scale with 5 dimensions and 3 levels were significantly lower for patients with TSC (time-trade-off [TTO]: 0.705, visual analog scale [VAS]: 0.577) than for patients with IGE (TTO: 0.897, VAS: 0.813; P < 0.001) or FE (TTO: 0.879, VAS: 0.769; P < 0.001). Revised Epilepsy Stigma Scale scores were also significantly higher for patients with TSC (3.97) than for patients with IGE (1.48, P < 0.001) or FE (2.45, P < 0.001). Overall Quality of Life in Epilepsy Inventory-31 items scores was significantly lower among patients with TSC (57.7) and FE (57.6) than among patients with IGE (66.6, P = 0.004 in both comparisons). Significant differences between patients with TSC and IGE were also determined for Neurological Disorder Depression Inventory for Epilepsy (TSC: 13.1; IGE: 11.2, P = 0.009) and Liverpool Adverse Events Profile scores (TSC: 42.7; IGE: 37.5, P = 0.017) with higher score and worse results for TSC patients in both questionnaires. CONCLUSIONS: This study is the first to compare patients with TSC, IGE, and FE in Germany and underlines the excessive QoL burden and both direct and indirect cost burdens experienced by patients with TSC.

Extensive 177Lu-PSMA Radioligand Therapy Can Lead to Radiation Nephropathy with a Renal Thrombotic Microangiopathy-like Picture.

Lutetium-177 prostate-specific membrane antigen (177Lu-PSMA) radioligand therapy is an option that is increasingly being used for treatment of metastatic castration-resistant prostate cancer. This delivers ß-radiation to cells expressing PSMA and high accumulation of the radiopharmaceutical occurs in the kidneys. Here we report three cases of radiation nephropathy with severe chronic kidney disease induced by renal thrombotic microangiopathy following extensive treatment with 177Lu-PSMA radioligand therapy.

Compartment-specific effects of muscle strength on bone microarchitecture in women at high risk of osteoporosis.

BACKGROUND: It is well known that skeletal integrity is influenced by the musculature. Poor muscle strength (i.e. sarcopenia) is considered a major predictor of fragility fractures. While this observation appears particularly relevant for older women with increased risk of osteoporosis, there has been no comprehensive investigation to determine the influence of muscle performance on compartment-specific bone microarchitecture in multiple body regions. METHODS: We retrospectively analysed data from different muscle performance and bone microarchitecture assessments in 230 women (aged 21 to 87 years) at high risk of osteoporosis. Muscle performance tests included grip strength and chair rising test (CRT) combined with mechanography. Balance was determined by Romberg posturography. Areal bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) at the hip and lumbar spine. Compartment-specific volumetric BMD, microarchitecture, and geometry were assessed by second-generation high-resolution peripheral quantitative computed tomography (HR-pQCT) at multiple skeletal sites (distal radius, tibia, and fibula). Regression models were applied to test for interactions between muscle and bone parameters. Subgroups were defined to compare women with osteoporosis and osteosarcopenia regarding BMD and microarchitecture. RESULTS: While osteoporosis was diagnosed in 115/230 (50.0%) women, sarcopenia was detected in 38/230 (16.5%). Positive associations of both grip strength and CRT maximum force with cortical geometric and microarchitectural parameters were detected at all measured sites, with the strongest effect applying to CRT maximum force and tibial parameters (e.g. tibial cortical area R2  = 0.36, P < 0.0001, and tibial cortical thickness R2  = 0.26, P < 0.0001). Balance parameters showed much weaker or no associations with HR-pQCT parameters. Major associations between muscle strength and trabecular parameters could not be confirmed. Age and body mass index were confirmed as negative and positive predictors for several microarchitectural parameters, respectively. An independent predictive value of grip strength on radial, tibial, and fibular (all P < 0.01) cortical area and of CRT maximum relative force on cortical thickness (all P < 0.05) was revealed. Women with osteosarcopenia showed significantly reduced cortical HR-pQCT parameters but no differences in DXA values compared with women with osteoporosis but no sarcopenia. Stratification by fracture and treatment status revealed that vertebral fractures and denosumab treatment altered the muscle-bone interaction. CONCLUSIONS: A systemic interaction between muscle strength and bone microarchitecture was demonstrated, and this interaction appears to be primarily with the cortical bone compartment. The value of muscle assessments in fracture risk evaluation may be partly mediated by their effects on bone microarchitecture.

Bone microarchitecture of the distal fibula assessed by HR-pQCT.

The distal fibula represents one of the most common fracture sites, and its epidemiology is characterized by a high incidence in both adolescence and the elderly. While fracture occurrence is influenced by trauma mechanism, a possible underlying skeletal microarchitectural deterioration in certain patient groups remains elusive. The purpose of this study was to determine the influence of age, sex, and overall skeletal status on fibular microarchitecture. We analyzed the microarchitecture of the distal fibula in 300 people by high-resolution peripheral quantitative computed tomography (HR-pQCT). Three areal bone mineral density (aBMD) groups (normal, osteopenia, osteoporosis; n = 100 per group) based on the concurrent assessment of aBMD by dual-energy X-ray absorptiometry (DXA) at the lumbar spine and total hip were established. Next to group comparisons, linear and non-linear regression analyses were carried out to assess the association between age, sex, BMI, tibial and fibular microarchitecture. While women had lower values for both trabecular bone volume fraction (BV/TVd, p < 0.001) and cortical thickness (Ct.Thd, p < 0.001) than men, osteoporosis by DXA negatively affected these parameters in both sexes. Remarkably, cortical but not trabecular microarchitecture declined with age, with a stronger decrease in females compared to males (Ct.Thd female -10.0 µm/year (95% CI: -12.2 to -7.7 µm/year), male -4.0 µm/year (95% CI: -6.3 to -1.7 µm/year)). Moderate positive associations between distal tibial and fibular microarchitecture were noted (e.g., BV/TVd R2 = 0.54, Ct.Thd R2 = 0.58). In summary, we here demonstrate the severe negative effects of age, female sex and osteoporosis on distal fibula bone mineralization and microarchitecture. The presented findings are likely to explain the higher susceptibility to distal fibula fractures in elderly women (independent of trauma mechanism). These alterations in fibular bone quality must be taken into account in the context of fracture prevention and treatment (e.g., osteosynthesis planning).

Quality of life and its predictors in adults with tuberous sclerosis complex (TSC): a multicentre cohort study from Germany.

BACKGROUND: Tuberous sclerosis complex (TSC) is a monogenetic, multisystemic disease characterised by the formation of benign tumours that can affect almost all organs, caused by pathogenic variations in TSC1 or TSC2. In this multicentre study from Germany, we investigated the influence of sociodemographic, clinical, and therapeutic factors on quality of life (QoL) among individuals with TSC. METHODS: We assessed sociodemographic and clinical characteristics and QoL among adults with TSC throughout Germany using a validated, three-month, retrospective questionnaire. We examined predictors of health-related QoL (HRQoL) using multiple linear regression analysis and compared the QoL among patients with TSC with QoL among patients with other chronic neurological disorders. RESULTS: We enrolled 121 adults with TSC (mean age: 31.0 ± 10.5 years; range: 18-61 years, 45.5% [n = 55] women). Unemployment, a higher grade of disability, a higher number of organ manifestations, the presence of neuropsychiatric manifestations or active epilepsy, and a higher burden of therapy-related adverse events were associated with worse QoL, as measured by two QoL instruments (EuroQoL-5 dimensions [EQ-5D] and Quality of Life in Epilepsy Patients [QOLIE-31]). Neuropsychiatric and structural nervous system manifestations, the number of affected organs, and therapy-related adverse events were also associated with higher depression, as measured by the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E). In multiple regression analysis, more severe therapy-related adverse events (large effect, p < 0.001), active epilepsy (large effect, p < 0.001), and neuropsychiatric manifestations (medium effect, p = 0.003) were independently associated with worse HRQoL, explaining 65% of the variance (p < 0.001). The HRQoL among patients with active TSC-associated epilepsy was worse than that among patients with drug-refractory mesial temporal lobe epilepsy (p < 0.001), and the generic QoL among patients with more than three TSC organ manifestations was similar to those of patients with severe migraine and uncontrolled asthma. CONCLUSIONS: Active epilepsy, neuropsychiatric manifestations (such as anxiety and depression), and therapy-related adverse events are important independent predictors of worse quality of life among adults with TSC. Generic quality of life in TSC with several manifestations is similar to uncontrolled severe chronic diseases and significantly negatively correlates with TSC severity. TRIAL REGISTRATION: DRKS, DRKS00016045 . Registered 01 March 2019.

Direct and indirect costs and cost-driving factors in adults with tuberous sclerosis complex: a multicenter cohort study and a review of the literature.

BACKGROUND: Tuberous sclerosis complex (TSC) is a monogenetic, multisystem disorder characterized by benign growths due to TSC1 or TSC2 mutations. This German multicenter study estimated the costs and related cost drivers associated with organ manifestations in adults with TSC. METHODS: A validated, three-month, retrospective questionnaire assessed the sociodemographic and clinical characteristics, organ manifestations, direct, indirect, out-of-pocket (OOP), and nursing care-level costs among adult individuals with TSC throughout Germany from a societal perspective (costing year: 2019). RESULTS: We enrolled 192 adults with TSC (mean age: 33.4 ± 12.7 years; range: 18-78 years, 51.6% [n = 99] women). Reported TSC disease manifestations included skin (94.8%) and kidney and urinary tract (74%) disorders, epilepsy (72.9%), structural brain defects (67.2%), psychiatric disorders (50.5%), heart and circulatory system disorders (50.5%), and lymphangioleiomyomatosis (11.5%). TSC1 and TSC2 mutations were reported in 16.7% and 25% of respondents, respectively. Mean direct health care costs totaled EUR 6452 (median EUR 1920; 95% confidence interval [CI] EUR 5533-7422) per patient over three months. Medication costs represented the major direct cost category (77% of total direct costs; mean EUR 4953), and mechanistic target of rapamycin (mTOR) inhibitors represented the largest share (68%, EUR 4358). Mean antiseizure drug (ASD) costs were only EUR 415 (6%). Inpatient costs (8%, EUR 518) and outpatient treatment costs (7%; EUR 467) were important further direct cost components. The mean care grade allowance as an approximator of informal nursing care costs was EUR 929 (median EUR 0; 95% CI EUR 780-1083) over three months. Mean indirect costs totaled EUR 3174 (median EUR 0; 95% CI EUR 2503-3840) among working-age individuals (< 67 years in Germany). Multiple regression analyses revealed mTOR inhibitor use and persistent seizures as independent cost-driving factors for total direct costs. Older age and disability were independent cost-driving factors for total indirect costs, whereas epilepsy, psychiatric disease, and disability were independent cost-driving factors for nursing care costs. CONCLUSIONS: This three-month study revealed substantial direct healthcare, indirect healthcare, and medication costs associated with TSC in Germany. This study highlights the spectrum of organ manifestations and their associated treatment needs in the German healthcare setting. TRIAL REGISTRATION: DRKS, DRKS00016045. Registered 01 March 2019, http://www.drks.de/DRKS00016045 .

Prescription patterns of antiseizure drugs in tuberous sclerosis complex (TSC)-associated epilepsy: a multicenter cohort study from Germany and review of the literature.

OBJECTIVE: Seizures are a primary and early disease manifestation of Tuberous Sclerosis Complex (TSC). We aimed to describe the age-stratified patterns of antiseizure drug (ASD) treatments among children, adolescents, and adults with TSC in Germany. Additionally, we reviewed real-world and clinical study evidence regarding ASD utilization in patients with TSC. METHODS: We evaluated the pattern of routine ASD use and everolimus prescriptions based on a 2019 multicenter survey of 268 individuals with TSC-associated epilepsy. We contextualized the results with a structured review of real-world and clinical study evidence. RESULTS: TSC-associated epilepsy treatment comprises a wide variety of ASDs. In this German sample, the majority of patients were treated with polytherapy, and lamotrigine (34.7%), valproate (32.8%), oxcarbazepine (28.7%), vigabatrin (19.0%), and levetiracetam (17.9%) were identified as the most-commonly used ASDs. In addition, everolimus was used by 32.5% of patients. In adherence to current TSC guidelines, the disease-modifying ASD vigabatrin was widely used in children (58% below the age of 5 years), whereas treatment in adults did not necessarily reflect guideline preference for (partial) GABAergic ASDs. CONCLUSIONS: The selection of ASDs for patients with TSC-associated epilepsy follows well-evaluated recommendations, including the guidelines regarding vigabatrin use in children. Several characteristics, such as the comparatively high frequency of valproate use and polytherapy, reflect the severity of TSC-associated epilepsy.

Efficacy, Retention and Tolerability of Everolimus in Patients with Tuberous Sclerosis Complex: A Survey-Based Study on Patients' Perspectives.

BACKGROUND: The approval of everolimus (EVE) for the treatment of angiomyolipoma (2013), subependymal giant cell astrocytoma (2013) and drug-refractory epilepsy (2017) in patients with tuberous sclerosis complex (TSC) represents the first disease-modifying treatment option available for this rare and complex genetic disorder. OBJECTIVE: The objective of this study was to analyse the use, efficacy, tolerability and treatment retention of EVE in patients with TSC in Germany from the patient's perspective. METHODS: A structured cross-age survey was conducted at 26 specialised TSC centres in Germany and by the German TSC patient advocacy group between February and July 2019, enrolling children, adolescents and adult patients with TSC. RESULTS: Of 365 participants, 36.7% (n = 134) reported the current or past intake of EVE, including 31.5% (n = 115) who were taking EVE at study entry. The mean EVE dosage was 6.1 ± 2.9 mg/m2 (median: 5.6 mg/m2, range 2.0-15.1 mg/m2) in children and adolescents and 4 ± 2.1 mg/m2 (median: 3.7 mg/m2, range 0.8-10.1 mg/m2) in adult patients. An early diagnosis of TSC, the presence of angiomyolipoma, drug-refractory epilepsy, neuropsychiatric manifestations, subependymal giant cell astrocytoma, cardiac rhabdomyoma and overall multi-organ involvement were associated with the use of EVE as a disease-modifying treatment. The reported efficacy was 64.0% for angiomyolipoma (75% in adult patients), 66.2% for drug-refractory epilepsy, and 54.4% for subependymal giant cell astrocytoma. The overall retention rate for EVE was 85.8%. The retention rates after 12 months of EVE therapy were higher among adults (93.7%) than among children and adolescents (88.7%; 90.5% vs 77.4% after 24 months; 87.3% vs 77.4% after 36 months). Tolerability was acceptable, with 70.9% of patients overall reporting adverse events, including stomatitis (47.0%), acne-like rash (7.7%), increased susceptibility to common infections and lymphoedema (each 6.0%), which were the most frequently reported symptoms. With a total score of 41.7 compared with 36.8 among patients not taking EVE, patients currently being treated with EVE showed an increased Liverpool Adverse Event Profile. Noticeable deviations in the sub-items 'tiredness', 'skin problems' and 'mouth/gum problems', which are likely related to EVE-typical adverse effects, were more frequently reported among patients taking EVE. CONCLUSIONS: From the patients' perspective, EVE is an effective and relatively well-tolerated disease-modifying treatment option for children, adolescents and adults with TSC, associated with a high long-term retention rate that can be individually considered for each patient. Everolimus therapy should ideally be supervised by a centre experienced in the use of mechanistic target of rapamycin inhibitors, and adverse effects should be monitored on a regular basis.

Pancreatic Islet Changes in Human Whole Organ Pancreas Explants: What Can Be Learned From Explanted Samples?

BACKGROUND: Whole pancreas transplantation (Tx) is a successful treatment for type 1 diabetes resulting in independence from antidiabetic therapies. Transplant-related factors contributing to pancreatic islet failure are largely unknown; both recurring insulitis and pancreatitis have been implicated. The aim was to determine if cellular changes in islets and exocrine tissue are evident early in Tx, which could contribute to eventual graft failure using well-preserved tissue of grafts explanted from largely normoglycemic recipients. METHODS: Histological specimens of explants (n = 31), Tx duration 1 day-8 years (median 29 d), cold ischemia time 7.2-17.3 hours (median 11.1 h), donor age 13-54 years (median 38 y) were examined; sections were labeled for inflammation, islet amyloidosis, and tissue fibrosis, and morphometry performed on immunolabeled insulin and glucagon positive islet cells. Data were related to clinical details of donor, recipient, and features of Tx. RESULTS: Islet inflammation consistent with recurrent insulitis was not seen in any sample. Insulin-labeled islet cell proportion decreased with donor age (P < 0.05) and cold ischemia (P < 0.01) in explants from 26 normoglycemic patients; glucagon-labeled area proportion increased with cold ischemia (P < 0.05). Clinical pancreatitis was the explant reason in 12 of 28 normoglycemic cases. Exocrine fibrotic area/pancreas was variable (0.7%-55%) and unrelated to clinical/pathological features. Islet amyloid was present in 3 normoglycemic cases (donor ages 58, 42, and 31 y; Tx duration 8 y, 31 and 33 d, respectively). In 1 patient receiving antidiabetic therapy, the insulin-labeled area was reduced but with no evidence of islet inflammation. CONCLUSIONS: Explant histological changes after short-term Tx are similar to those seen in type 2 diabetes and occur in the absence of immunologic rejection without causing hyperglycemia. This suggests that factors associated with Tx affect islet stability; persistent deterioration of islet integrity and exocrine tissue fibrosis could impact on sustainability of islet function.

Low Expression of Programmed Death 1 (PD-1), PD-1 Ligand 1 (PD-L1), and Low CD8+ T Lymphocyte Infiltration Identify a Subgroup of Patients With Gastric and Esophageal Adenocarcinoma With Severe Prognosis.

Prognosis of gastric and esophageal cancer is poor and treatment improvements are needed. Programmed cell death 1 receptor (PD-1) interaction with its ligand PD-L1 in tumor micro-environment promotes immune tolerance and blocking monoclonal antibodies have entered clinical practice. However, clinical significance of PD-1 and PD-L1 expression in gastric and esophageal adenocarcinomas, particularly in non-Asian patients, is still unclear. Three tissue microarrays including 190 clinically annotated esophageal (n = 31) and gastric (n = 159) adenocarcinomas and 58 paired mucosa specimens, were stained with PD-1, PD-L1, and CD8-specific reagents in indirect immunohistochemistry assays. PD-L1 expression was detectable in 23.2% of cancer specimens. High PD-1 expression was detectable in 37.3% of cases and high CD8+ infiltration in 76%. PD-L1 and high PD1 expression significantly correlated with each other (r s = 0.404, P < 0.0001) and both significantly correlated with CD8+ infiltration (r s = 0.435, P = 0.0003, and r s = 0.444; P = 0.0004, respectively). CD8+ lymphocyte infiltration correlated with improved survival in univariate (P = 0.009), but not multivariate analysis. Most interestingly, multivariate analysis and Kaplan-Meier curves indicate that combined low PD-1/PD-L1 expression and low CD8+ lymphocyte infiltration significantly correlate with poor prognosis. Our data document the clinical significance of a microenvironmental signature including PD-1/PD-L1 expression and CD8+ lymphocyte infiltration in gastric and esophageal adenocarcinomas and contribute to identify a patients' subset requiring more aggressive peri-operative treatments.

Case report of an intracaval leiomyomatosis 10 months after complete hysterectomy.

INTRODUCTION: Intravenous leiomyomatosis (IVL) is a rare smooth muscle tumor, usually found in women with tumors of the reproductive organs, such as uterus myomatosous. Surgically, this case belies the call for sternotomy and two-stage surgery in caval IVL extending to the right atrium: we suggest one-stage median laparotomy as a minimal procedure with maximal benefit. PRESENTATION OF CASE: We present the case of a 60-year-old postmenopausal woman with suspected intravenous leiomyomatosis of the right internal iliac vein. The patient had undergone hysterectomy and bilateral adnexectomy for uterus myomatosous in September 2015, where an IVL limited to the veins of the uterus and the right adnex had been diagnosed. No further medical treatment had been implemented. IVL of the inferior vena cava was diagnosed when a CT scan of the abdomen was performed due to an infected abdominal seroma in June 2016. Although histologically benign, we found this case of IVL to be clinically aggressive because of its expansion to the heart. This may lead to thromboembolic complications (e.g. pulmonary embolism) or signs of right sided cardiac failure. The patient was asymptomatic, but because of the extension of the intracaval thrombus to the heart, we decided to operate and performed thrombectomy via a median laparotomy. The patient left the hospital shortly after on newly started oral anticoagulation. DISCUSSION: For caval IVL without intracardiac attachment, the extraction via laparotomy without sternotomy is the treatment of choice. It calls for an interdisciplinary approach and careful surgical planning. CONCLUSION: There is no inherent need for sternotomy in IVL extending to the right atrium. A one-year follow-up with sonographic control is advised. Medium term oral anticoagulation should be considered. This work has been reported in line with the SCARE criteria Agha et al. (2016). The SCARE Statement: Consensus-based surgical case report guidelines. Agha RA, Fowler AJ, Saeta A, Barai I, Rajmohan S, Orgill DP; SCARE Group. Int J Surg. 2016 Oct;34:180-186 [1].