Combined expansion and STED microscopy reveals altered fingerprints of postsynaptic nanostructure across brain regions in ASD-related SHANK3-deficiency.

Synaptic dysfunction is a key feature of SHANK-associated disorders such as autism spectrum disorder, schizophrenia, and Phelan-McDermid syndrome. Since detailed knowledge of their effect on synaptic nanostructure remains limited, we aimed to investigate such alterations in ex11|SH3 SHANK3-KO mice combining expansion and STED microscopy. This enabled high-resolution imaging of mosaic-like arrangements formed by synaptic proteins in both human and murine brain tissue. We found distinct shape-profiles as fingerprints of the murine postsynaptic scaffold across brain regions and genotypes, as well as alterations in the spatial and molecular organization of subsynaptic domains under SHANK3-deficient conditions. These results provide insights into synaptic nanostructure in situ and advance our understanding of molecular mechanisms underlying synaptic dysfunction in neuropsychiatric disorders.

Exploring the Relationship between Adherence to Therapy, Treatment Acceptability, and Clinical Outcomes in Adults with Attention-Deficit/Hyperactivity Disorder: Results from the COMPAS Multicenter Randomized Controlled Trial.

INTRODUCTION: Cognitive behavioral therapy and dialectical behavior therapy (DBT) can be effective in treating adults with ADHD, and patients generally consider these interventions useful. While adherence, as measured by attendance at sessions, is mostly sufficient, adherence to therapy skills has not been assessed. Furthermore, the relationship between patient evaluation of therapy effectiveness, treatment adherence, and clinical outcomes is understudied. OBJECTIVE: This study aimed to examine treatment acceptability and adherence in relation to treatment outcomes in a large randomized controlled trial comparing a DBT-based intervention with a nonspecific active comparison, combined with methylphenidate or placebo. METHOD: A total of 433 adult patients with ADHD were randomized. Participants reported how effective they found the therapy, and adherence was measured by attendance at therapy sessions and by self-reports. Descriptive, between-groups, and linear mixed model analyses were conducted. RESULTS: Participants rated psychotherapy as moderately effective, attended 78.40-94.37% of sessions, and used skills regularly. The best-accepted skills were sports and mindfulness. Groups receiving placebo and/or nonspecific clinical management rated their health condition and the medication effectiveness significantly worse than the psychotherapy and methylphenidate groups. Improvements in clinical outcomes were significantly associated with treatment acceptability. Subjective (self-reported) adherence to psychotherapy was significantly associated with improvements in ADHD symptoms, clinical global efficacy and response to treatment. DISCUSSION: These results further support the acceptability of DBT for adult ADHD and suggest the need to address adherence to treatment to maximize clinical improvements. Results may be limited by the retrospective assessment of treatment acceptability and adherence using an ad hoc instrument.

Burden of sequelae and healthcare resource utilization in the first year of life in infants born with congenital cytomegalovirus (cCMV) infection in Germany: A retrospective statutory health insurance claims database analysis.

BACKGROUND: Congenital cytomegalovirus (cCMV) infection can have a broad range of manifestations. This study aimed to assess cCMV-associated sequelae and healthcare resource utilization (HCRU) in infants during the first year of life in Germany. METHODS: A retrospective, controlled cohort study using German claims data from the Institute for Applied Health Research Berlin (InGef) database was conducted. cCMV-associated sequelae and HCRU during the first year of life were assessed by matching (1:60) infants with at least one inpatient/outpatient cCMV diagnosis (ICD-10-GM: P35.1) ≤90 days after birth (cCMV90 cohort) and infants with at least one inpatient cCMV diagnosis plus specific sequelae ≤21 days after birth (cCMV21-S) to infants without cCMV or CMV (ICD-10-GM: B25) diagnosis (control group), respectively. Outcomes were analyzed during the first 365 days of life. RESULTS: Between 2014-2018, we identified 54 newborns for cCMV90 and 24 newborns for cCMV21-S cohort. Compared to the 3,240 and 1,440 controls, respectively, more cCMV90 infants (83.3% vs. 41.9%, p<0.01) presented with at least one sequela during the first year of life, including intrauterine growth retardation (42.6% vs. 5.3%, p<0.01), sensorineural hearing loss (SNHL) to deafness (38.9% vs. 2.2%, p<0.01), and motor development disorders (33.3% vs. 10.9%, p<0.01). Further, 13.0% of cCMV90 infants (vs. 2.3%, p<0.01) suffered from visual impairment. In cCMV21-S cohort, intrauterine growth retardation (79.2% vs. 6.0%, p<0.01), prematurity (54.2% vs. 7.3%, p<0.01), and motor development disorders (50.0% vs. 11.0%, p<0.01) were the most frequent sequelae. Infants in the cCMV90 and cCMV21-S cohort had, on average, 7.3 times and 9.5 times more hospitalizations and 2.0 times and 2.1 times more outpatient physician visits than their respective controls (p<0.01). Hospitalized infants with cCMV stayed, on average, significantly longer in hospital compared to their controls (cCMV90 cohort: 30.3 days vs. 9.0 days, p<0.01; cCMV21-S cohort: 46.5 days vs. 9.3 days, p<0.01). CONCLUSIONS: cCMV-infection shows a considerable disease and healthcare burden during the first year of life. More than 80% of the identified newborns with cCMV suffered from at least one associated sequela during the first year of life, including long-term sequelae such as SNHL (40%) and visual impairment (13%). Additional steps for prevention of cCMV infection and associated sequelae as well as a comprehensive monitoring of disease burden are needed.

Exploring the efficacy of dialectical behaviour therapy and methylphenidate on emotional comorbid symptoms in adults with attention Deficit/Hyperactivity disorder: Results of the COMPAS multicentre randomised controlled trial.

This study evaluated the efficacy of dialectical behaviour group therapy (GPT) vs. individual clinical management (CM) and methylphenidate (MPH) vs. placebo (PLB) on emotional symptoms in adults with ADHD. This longitudinal multicentre RCT compared four groups (GPT+MPH, GPT+PLB, CM+MPH, and CM+PLB) over five assessment periods, from baseline to week 130. Emotional symptomatology was assessed using SCL-90-R subscales. Of the 433 randomised participants, 371 remained for final analysis. At week 13, the GPT+MPH group showed smaller reductions in anxiety symptoms than the CM groups, but the differences disappeared at subsequent assessments. Improvements in emotional symptom were significantly predicted by reductions in core ADHD symptoms in all groups except the GPT+MPH group. The unexpected lack of between-group differences may be explained by a "floor effect", different intervention settings (group vs. individual), and psychotherapy type. Multiple regression analyses suggest a more specific effect of combined interventions (GPT+MPH). Implications for clinical practice are discussed. Clinical trial registration: ISRCTN54096201 (Current Controlled Trials).

Circulating cell-free HPV DNA is a strong marker for disease severity in cervical cancer.

For cervical cancer (CC), circulating cell-free HPV DNA (ccfHPV) may establish disease severity. Furthermore, HPV integration has been correlated to viral load and survival. In this study, pre-treatment plasma from 139 CC cases (50 primary surgery patients, 22 primary surgery + adjuvant oncological therapy patients, and 67 primary oncological therapy patients) was collected (2018-2020). Furthermore, plasma from 25 cervical intraepithelial neoplasia grade 3 patients and 15 healthy women (negative controls) were collected. Two next-generation sequencing (NGS) panels were used to establish ccfHPV presence and human papillomavirus type 16 (HPV16) integration status. ccfHPV was detected in four primary surgery (8.0%), eight primary surgery + adjuvant oncology (36.4%), and 54 primary oncology (80.6%) patients. For primary oncology patients with HPV16-related cancer (n = 37), more ccfHPVneg than ccfHPVpos patients had HPV16 integration (P = 0.04), and in patients with HPV16 integration (n = 13), ccfHPVpos patients had higher disease stages than ccfHPVneg patients (P = 0.05). In summary, ccfHPV presence is related to disease severity and may add to the debated Sedlis criteria used for identifying patients for adjuvant oncological therapy. However, ccfHPV detection is influenced by HPV integration status and disease stage, and these factors need to be considered in ccfHPVneg patients.

Health status and comorbidities of adult patients with late-diagnosed phenylketonuria (PKU) born before the newborn screening in France - A nationwide study of health insurance claims data.

BACKGROUND: Phenylketonuria (PKU) is an inborn error of metabolism. When diagnosed late, it causes developmental delay or severe irreversible intellectual disability. This study aimed at evaluating the health status and healthcare consumption of late-diagnosed PKU patients in France. METHODS: This retrospective observational study used health insurance claims data from the French SNDS (Système National des Données de Santé) database, which contains data from over 66 million French inhabitants. Patients with PKU were identified between 2006 and 2018 by ICD-10 diagnosis codes E70.0 / E70.1 documented as a chronic condition (affection de longue durée - ALD) or in the inpatient setting. Patients with PKU were matched to controls by age, sex, and region. Patients with late-diagnosed PKU were defined as patients born before the nationwide implementation of newborn screening in France in 1972. Outcomes were analyzed for the year 2018. RESULTS: In total, 3549 patients with PKU were identified in the database on January 1st, 2018. Of those, 3469 patients could be matched to 17,170 controls without PKU. Of these, 2175 patients were at least 16 years old of whom 647 patients were categorized as late-diagnosed. The late-diagnosed PKU patients suffered significantly more often from hypertension (60.9% vs. 50.4%, p < 0.0001), hypercholesterolemia (41.7% vs. 26.9%, p < 0.0001), diabetes (24.4% vs. 14.1%, p < 0.0001), depression (20.6% vs. 13.8%, p < 0.0001), ischemic heart disease (16.1% vs. 6.6%, p < 0.0001), obesity (7.9% vs. 2.5%, inpatient diagnoses only, p < 0.0001), and chronic kidney disease (5.2% vs. 1.3%, inpatient diagnoses only, p < 0.0001) compared with their non-PKU controls. Consequently, significantly more patients with late-diagnosed PKU received medication to treat comorbidities associated with the nervous (82.6% vs 77.0%; p = 0.0021) and cardiovascular system (69.5% vs 58.0%; p < 0.0001). Overall, only 3.4% of patients with late-diagnosed PKU received dietary amino-acid supplements and 0.7% received sapropterin. CONCLUSION: The results indicate that PKU is associated with a significantly higher risk of comorbidities along with increased pharmaceutical prescriptions in patients with late-diagnosed PKU, compared with non-PKU controls. The increased risk of comorbidities was more pronounced than in patients with early-diagnosed PKU, as shown in previous research, but these patients are older than those with early-diagnosed PKU. Only few late-diagnosed patients were treated specifically for PKU. Patients with late-diagnosed PKU should be referred to specialized centers to prevent and manage comordities and introduce PKU-specific treatment when it is possible.

Clinical outcomes using a 3D printed tandem-needle-template and the EMBRACE-II planning aims for image guided adaptive brachytherapy in locally advanced cervical cancer.

BACKGROUND: Extensive local disease or narrow vagina may compromise brachytherapy (BT) in patients with cervical cancer. This is the first study to analyze long-term outcomes of using 3D printed vaginal tandem-needle templates (3DP TNT) for transvaginal insertion of needles in parallel (P) or parallel and oblique (P&O) direction to the tandem. MATERIAL AND METHODS: All patients treated with BT using 3DP TNT from 2015-2020 were included. Decision to use a 3DP TNT and preplanning were made after 4-5 weeks of external beam radiotherapy, based on gynecological examination and MRI with a tandem-ring applicator in situ. The TNT was 3D-printed in house consisting of a circular template with P&O holes for guidance of plastic needles and a shaft fitting the uterine tandem. Thus, the radioactive source was never in direct contact with the 3DP TNT. The TNT was 3D printed in a standard or personalized configuration. Planning aims were based on the Embrace II protocol. RESULTS: 101 patients (median age of 63 years) were included: 49 with P needles only and 52 with P&O needles. Personalized TNT was used in 19 patients in the P&O group. Performance status (WHO) was > 0 in 48%. FIGO2018 stage III-IV was present in 77%. T-score at diagnosis and BT was 9.1 and 6.3 respectively, with a significantly higher T-score in the P&O compared to P group. The mean high-risk CTV D90 was 93 Gy with no significant difference between the two groups. Three-year local control rates were 85%, 95%, 75% for the overall, P- and P&O group respectively and 68%, 80% and 56% for cancer specific survival. Grade ≥3 treatment related complications were observed in 10 (10%) patients. CONCLUSIONS: 3DP TNT for BT in cervical cancer provides successful management of very extensive local disease and/or unfavorable anatomy with the possibility for treatment individualization.

Did the change of the vaccination schedule effect pneumococcal conjugate vaccination compliance and adherence of premature and mature born infants in Germany? Answers from a claims database analysis.

BACKGROUND: In August 2015, the German Standing Committee on Vaccination (STIKO) changed the pneumococcal conjugate vaccination (PCV) schedule for mature infants from a 3+1 to a 2+1scheme. For premature infants, the 3+1schedule remained unchanged. Aim was to assess vaccination rates, completeness, and timeliness for PCV stratified by premature and mature infants before and after the recommendation change based on real-world data. METHODS: Retrospective claims data analyses were conducted using a comprehensive research database. The study population consisted of all mature and premature infants born in 2013, 2016, or 2018 with an individual follow-up of 24 months using ICD-10-GM codes P07.2 and P07.3 for premature infants. Hexavalent (HEXA) combination vaccination with a consistent 3+1recommendation for premature and mature infants was analyzed as a reference. RESULTS: After follow-up of 24 months, rates of premature and mature infants receiving ≥1PCV and HEXA vaccination steadily increased since the change of STIKO's recommendation. However, in 2018 (2016/2013), only 47 % (41 %/65 %) of premature but 74 % (72 %/68 %) of mature infants obtained the recommended 3+1 respectively 2+1 PCV doses. At the same age, a consistent increase in complete HEXA vaccination with 3+1 doses was observed over time in premature (2013/2016/2018: 66 %/68 %/70 %) and mature (2013/2016/2018: 69 %/72 %/73 %) infants. Timeliness of PCV and HEXA booster administration remained stable with âˆ¼50 % of all premature and mature infants receiving the booster according to recommended timelines. CONCLUSION: There is no proven evidence that the reduced PCV schedule for mature infants induced a higher acceptance of vaccination. The rate of unvaccinated infants remained at a considerable level and vaccinations were often delayed. Although the STIKO still recommends a 3+1 PCV schedule for premature infants in Germany, less than half of children showed a completed vaccination series. To protect these vulnerable groups, efforts are needed to increase adherence to the STIKO recommendation especially for premature infants.

Health status and comorbidities of adult patients with phenylketonuria (PKU) in France with a focus on early-diagnosed patients - A nationwide study of health insurance claims data.

BACKGROUND: This study aimed at evaluating the health status and healthcare consumption of ≥16-year-old patients with phenylketonuria (PKU), with a focus on early-diagnosed patients. METHODS: This retrospective observational study used health insurance claims data from the French SNDS (Système National des Données de Santé) database. Patients with PKU were identified between 2006 and 2018 by ICD-10 diagnosis codes E70.0 (classic PKU) or E70.1 (other causes of hyperphenylalaninemia). They were matched to controls by age, sex, and region. Patients with early-diagnosed PKU were defined as patients born after implementation of nationwide newborn screening in France in 1972. Outcomes were analyzed for the year 2018. RESULTS: Overall, 3549 patients with PKU were identified on January 1st, 2018. Of those, 3469 patients could be matched to 17,170 controls without PKU. Of these patients, 2175 were at least 16 years old and suffered significantly more than controls from specific comorbidities of interest - osteoporosis (28.7% vs 19.8%, p < 0.0001), hypertension (20.9% vs 17.0%, p < 0.0001), hypercholesterolemia (12.8% vs 8.3%, p < 0.0001), diabetes (7.8% vs 4.7%, p < 0.0001), obesity (4.2% vs 1.3%, p < 0.0001), ischemic heart diseases (4.8% vs 2.0%, p < 0.0001), and depression (10.3% vs 8.2%, p = 0.0011). Prescriptions for many medications were also more frequent in patients with PKU than controls. Among ≥16-year-old patients, 1528 were categorized as early-diagnosed. Osteoporosis (0.3% vs 0.01%, p = 0.0035), chronic renal failure (0.6% vs 0.1%, p = 0.0020), hypertension (4.0% vs 2.7%, p = 0.0063), and obesity (2.5% vs 0.8%, p < 0.0001) were significantly more prevalent in early-diagnosed adult patients compared with matched controls. In total, 28.6% of ≥16-year-old patients with PKU and 40.4% of early-diagnosed patients with PKU received dietary amino-acid supplements. Sapropterin was prescribed to 5.0% and 7.0% patients, respectively. CONCLUSION: The results indicate that PKU is associated with a significantly higher comorbidity risk along with increased pharmaceutical prescriptions in adulthood. The comorbidity burden is less distinct in early-diagnosed patients but still present. Few patients are treated specifically for PKU in adulthood. Healthcare of patients with PKU should include prevention and management of comorbidities and especially target PKU-specific treatment adherence and consistent care in specialized medical centers in adulthood.

Real-world treatment patterns and healthcare resource utilization among migraine patients: a German claims database analysis.

AIMS: Despite migraine being one of the most common neurological diseases, affected patients are often not effectively treated. This analysis describes the burden of migraine in Germany and assesses real-world treatment patterns and healthcare resource utilization (HCRU) of preventive-treated migraine patients from the perspective of Statutory Health Insurance. METHODS: A retrospective analysis was conducted using InGef Research Database claims data from 2018-2019. Migraine patients were stratified into cohorts by acute and preventive treatment status. Patients on preventive treatment were further stratified according to the type of prophylaxis received. Disease burden in preventively treated migraine patients was reported via treatment patterns, pathways, and comorbidities. HCRU was assessed through outpatient provider visits, hospitalizations, and sick leave. RESULTS: 160,164 adult migraine patients were identified, of which 55,378 (34.6%) were prescribed preventive treatment with conventional (n = 25,984, 46.9%), calcitonin gene-related peptide monoclonal antibody (CGRP mAb) (n = 613, 1.1%), or off-label therapies (n = 28,781, 52.0%). 936 (1.7%) patients received Botulinum Neurotoxin Type A (BoNTA). CGRP mAb-treated patients had a high rate of triptan prescriptions (2018: 95.5%; 2019: 88.9%), migraine-related hospitalizations (2018: 33.0%; 2019: 21.0%), and sick leave (2018: 26.8%; 2019: 22.5%). A high proportion of CGRP mAb- and BoNTA-treated patients was diagnosed with abdominal and pelvic pain (34.3% and 36.2%) and low back pain (34.1% and 35.3%). These patients also showed a high prevalence of depressive episodes (49.1% and 50.1%) and chronic pain disorders (37.5% and 32.9%). LIMITATIONS: This study focused on descriptive analyses which do not allow for assessment of causality when comparing treatment groups. CONCLUSIONS: Disease burden was high in patients receiving CGRP mAbs suggesting that patients treated preventively with CGRP mAbs shortly after product launch in Germany were severely affected, chronic migraine patients. The same may be true for patients receiving BoNTA who also showed an increased disease burden.

Early versus late reversal of diverting loop ileostomy in rectal cancer surgery: a multicentre randomized controlled trial.

Diverting loop ileostomy has become routine in low anterior resection (LAR) for rectal cancer. The optimal time for stoma reversal is controversial. The aim of the present study was to compare the results after planned early (within 8-12 days) versus late (> 3 months) stoma reversal. The primary outcomes were morbidity and mortality, as measured by the Comprehensive Complication Index (CCI) within 30 days after stoma reversal, and the secondary outcomes were morbidity and mortality within 90 days after LAR. This was a multicentre trial including all patients scheduled for anterior low resection for rectal cancer with curative intent. Inclusion period was from April 2011 to December 2018. All patients were randomized 1:1 prior to surgery. Among 257 consecutive and eligible patients, a total of 214 patients were randomized: 107 patients to early stoma reversal and 107 to late reversal. A total of 68 patients were excluded for various reasons, and 146 patients completed the study, with 77 in the early reversal group and 69 in the late reversal group. The patients were asked to complete the Gastrointestinal Quality of Life Index before surgery (baseline) and at 6 and 12 months after LAR. Ostomy-related complications were evaluated by dedicated ostomy staff using the validated DET score. ClinicalTrials Identifier: NCT01865071. Fifty-three patients (69%) in the early reversal group and 60 patients (87%) in the late reversal group received the intended treatment. There were no significant differences in CCI within 90 days after index surgery with the LAR and within 30 days after stoma reversal between the two groups. There were no differences in patient-reported quality of life but significantly more stoma-related complications in the late reversal group. A total of 5 patients experienced anastomotic leakage (AL) after stoma reversal, 4 in the early reversal group and one in the late reversal group. Early and late stoma reversal showed similar outcomes in terms of overall complications and quality of life. The risk of developing anastomotic leakage after early ostomy reversal is a concern.

Healthcare costs of congenital cytomegalovirus (cCMV) disease in infants during the first two years of life: a retrospective German claims database analysis.

BACKGROUND: Congenital cytomegalovirus (cCMV) infection can cause severe neurological damage, growth retardation, hearing loss, and microcephaly in infants. We aimed at assessing healthcare costs of infants with recorded cCMV diagnosis in an administrative claims database in the first 2 years of life. METHODS: We conducted a retrospective, controlled cohort study using German claims data from the Institute for Applied Health Research Berlin (InGef) database. Incremental healthcare costs during the first and second year of life were assessed by matching (1:60) infants with cCMV diagnoses ≤ 90 days after birth (cCMV90 cohort) to infants without cCMV diagnosis ("representative" controls) and infants with cCMV diagnoses ≤ 21 days after birth plus specific symptoms (cCMV21-S) to infants without cCMV and any ICD-10-GM records (besides Z00-Z99) until 4th preventive health check-up ("healthy" controls). Due to missing data, mean imputation was applied for aids and remedies costs. RESULTS: We identified 54 and 24 infants born 2014-2018 for the cCMV90 and cCMV21-S cohorts, respectively. During the first year, mean (median) healthcare costs were significantly higher in cCMV90 cases vs. "representative" controls (€22,737 (€9759) vs. €3091 (€863), p < 0.001), with 87.2% inpatient costs. Healthcare costs for cCMV21-S cases compared to "healthy" controls were €34,498 (€20,924) vs. €680 (€569), p < 0.001. Differences decreased for both comparisons in the second year but remained statistically significant. CONCLUSIONS: cCMV comprises a considerable economic burden for the German healthcare system (€19,646 to €33,818 higher mean costs for infants with recorded cCMV diagnosis in the first year of life). Attempts should be made to reduce this burden.

Overall Severe Morbidity After Chemo-Radiation Therapy and Magnetic Resonance Imaging-Guided Adaptive Brachytherapy in Locally Advanced Cervical Cancer: Results From the EMBRACE-I Study.

PURPOSE: To evaluate overall severe late morbidity (grade ≥3) in patients with locally advanced cervical cancer treated with chemo-radiation therapy and magnetic resonance image guided adaptive brachytherapy within the prospective EMBRACE-I study, and to compare the results with published literature after standard radiograph based brachytherapy (BT). METHODS AND MATERIALS: From 2008 to 2015 the EMBRACE-I study enrolled 1416 patients. Morbidity was assessed (Common Terminology Criteria for Adverse Events version 3.0) every 3 months the 1st year, every 6 months the second and third year, and yearly thereafter and 1251 patients had available follow-up on late morbidity. Morbidity events (grade 3-5) were summarized as the maximum grade during follow-up (crude incidence rates) and actuarial estimates at 3 and 5 years. To compare with the published literature on standard radiograph based BT, Common Terminology Criteria for Adverse Events scores from the EMBRACE-I study were retrospectively converted into a corresponding score in the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer system. RESULTS: In total, 534 severe events occurred in 270 patients; 429 events were grade 3 and 105 were grade 4 events. Actuarial estimates for grade ≥3 gastrointestinal (GI), genitourinary (GU), vaginal and fistula events at 5 years were 8.5% (95% confidence interval [CI], 6.9%-10.6%), 6.8% (95% CI, 5.4%-8.6%), 5.7% (95% CI, 4.3%-7.6%), and 3.2% (95% CI, 2.2%-4.5%), respectively. The 5-year actuarial estimate for organ-related events (GI, GU, vaginal, or fistula) was 18.4% (95% CI, 16.0%-21.2%). The 5-year actuarial estimate when aggregating all G≥3 endpoints (GI, GU, vaginal, fistulas, and non-GI/GU/vaginal) was 26.6% (95% CI, 23.8%-29.6%). Thirteen patients had a treatment-related death, 8 of which were associated with GI morbidity. CONCLUSIONS: This report assesses severe morbidity from the largest prospective study on chemo-radiation therapy and image guided adaptive brachytherapy for locally advanced cervical cancer to date. Severe late morbidity was limited per endpoint and organ category, but considerable when aggregated across organs and all endpoints. The late morbidity results in the EMBRACE-I study compare favorably with published literature on standard radiograph based BT for GI morbidity, vaginal morbidity, and fistulas.

National Strategies to Reduce the Use of Coercive Measures in Psychiatry in Denmark - A Review of Two Decades of Initiatives.

Coercive measures are a major infringement of the autonomy of psychiatric patients and no medical justification exists for applying mechanical restraint (MR) to these patients currently. Knowledge regarding how preventive strategies affect the use of MR is limited. This paper aimed to understand the link between the initiatives taken by national authorities and the practical implications to MR reduction. Policy texts and the number of coercive measures used in two decades were reviewed. Trends were discussed with five experts with real-life experience and suggestions were obtained regarding how to end the use of mechanical restraint in mental health care settings.

Healthcare resource utilization and costs of cardiovascular events in patients with atherosclerotic cardiovascular disease in Germany - results of a claims database study.

OBJECTIVES: We assessed healthcare resource utilization (HCRU) and costs of cardiovascular (CV) events in patients with a history of atherosclerotic cardiovascular disease (ASCVD) in Germany. METHODS: We conducted a retrospective matched case-control study based on German claims data from 1 January 2012 to 31 December 2017 using the "Institute for Applied Health Research Berlin" (InGef) Research Database. Cases who had a myocardial infarction (MI), stroke and angina pectoris identified by ICD-10-GM codes between 1 January 2014 and 31 December 2016 were matched to event-free controls by an exact matching approach without replacement at a ratio of 1:2. Costs and HCRU were assessed in individual 1-year follow-up periods after the index event for the overall cohort and subgroups of MI cases and stroke cases. RESULTS: The overall cohort consisted of a total of 14,169 cases with a CV index event matched to 28,338 controls. The mean age of the overall cohort was 73.3 years, 34.1% of the patients were female, 3,717 (26.2%) had an MI, and 3,752 (26.5%) had stroke. Following the index events, 12.2% of cases in the overall cohort, 12.6% of MI cases, and 8.7% of stroke cases experienced a recurrent CV event. CV cases had on average 1.7 more all-cause hospitalizations (p <0.001) and 6.1 more outpatient visits (p <0.001) during the 1-year follow-up period than did controls. In the MI and stroke subgroups, cases had on average 1.8 and 1.6 more all-cause hospitalizations and 7.0 and 4.0 more outpatient visits, respectively (differences were statistically significant). Compared to controls, cases incurred on average higher total healthcare costs: by €11,898 for overall cases, by €16,349 for MI, and by €14,360 in stroke cases (overall: p <0.001; MI: p <0.001; stroke: p <0.001). CONCLUSION: CV events in ASCVD patients pose a considerable clinical burden on patients and cause significant costs for the German statutory healthcare system.

Healthcare resource utilization and costs in 23-25-year-old women with human papillomavirus (HPV) associated anogenital diseases in Germany - a retrospective analysis of statutory health insurance claims data.

BACKGROUND: Human papilloma virus (HPV) causes multiple anogenital diseases including cervical cancer and is the most common sexually transmitted infection. Healthcare resource utilization (HRU) associated with HPV-related anogenital diseases includes diagnostic and disease specific treatment regimens. A recent study showed disease burden of young women aged 23-25 years, who were the first populations eligible to receive HPV vaccination after its introduction in Germany. Cost for the German statutory health insurance (SHI) due to HPV­related anogenital diseases in this population are unknown. This study aimed at assessing HRU and costs related to HPV-associated anogenital diseases for the Germany SHI. METHODS: We used a retrospective, matched cohort design to leverage the prior identified cohort of 23-25-year-old women born between 1989-1992 diagnosed with HPV-related anogenital disease from the Institute for Applied Health Research Berlin (InGef) Research Database. German SHI claims data from 2012-2017 were analyzed. The prior identified cases were matched (direct, without replacement) to women without anogenital diseases (1:10 ratio). HRU and costs for inpatient care, outpatient care, and pharmaceutical during a 3-year observation period were determined for both cases and controls and increments between the groups were assessed. RESULTS: 2,972 women diagnosed with anogenital diseases (cases) who were matched to 29,720 women without anogenital diseases (controls). Cases had more outpatient visits (52.4 visits vs. 39.2 visits) and more cases (45.2% vs. 31.7%) were hospitalized at least once in the 3­year observation period. Most common outpatient procedures performed in cases were conization of the cervix uteri (4.4% cases; n < 5 controls), followed by other excision and destruction of diseased tissue of the cervix uteri (3.1% in cases; 0.0% in controls). Median difference in total healthcare costs of €684 (mean difference: €1,089, 95%CI: €752-1,426) suggest that HPV-related anogenital diseases were responsible for approximately €3.2 Million more healthcare costs for the identified cases in the four birth cohorts within the 3­year observation period in the InGef Research Database. Costs were mainly driven by outpatient care (41.6% of total costs). CONCLUSION: In Germany, HPV-related anogenital diseases among young women are associated with considerable HRU and financial expenditures, mostly driven by outpatient care.

The Diagnostic Value of Circulating Cell-Free HPV DNA in Plasma from Cervical Cancer Patients.

Circulating cell-free HPV DNA (ccfHPV DNA) may serve as a marker for cervical cancer. In this study, we used digital droplet PCR (ddPCR) to detect and quantify ccfHPV DNA in plasma from patients with HPV16- or HPV18-associated cervical cancer. Blood samples from 60 patients diagnosed with cervical cancer (FIGO IA1-IVA) at Aarhus or Odense University Hospital (June 2018 to March 2020) were collected prior to treatment, and patients were subdivided into an early stage (n = 30) and a late-stage subgroup (n = 30) according to disease stage. Furthermore, blood samples from eight women with HPV16- or 18-associated premalignant conditions (CIN3), and 15 healthy controls were collected. ddPCR was used to analyze plasma from all participants. ccfHPV DNA was detected in 19 late-stage patients (63.33%), 3 early stage patients (10.00%), and none of the CIN3 patients or controls. Quantitative evaluation showed significant correlations between ccfHPV DNA level and stage, tumor score, and tumor size. Thus, our results indicate that ccfHPV DNA may not be a useful marker for early detection of cervical cancer. However, for patients with advanced stage cervical cancer, ccfHPV DNA level represents a promising tool to establish tumor burden, making it useful for establishing treatment response and monitoring the disease.

Multimodal treatment efficacy differs in dependence of core symptom profiles in adult Attention-Deficit/Hyperactivity Disorder: An analysis of the randomized controlled COMPAS trial.

There is broad consensus that to improve the treatment of adult Attention-Deficit/Hyperactivity Disorder (ADHD), the various therapy options need to be tailored more precisely to the individual patient's needs and specific symptoms. This post-hoc analysis evaluates the multimodal effects of first-line medication (methylphenidate [MPH] vs placebo [PLB]) and psychotherapeutic (group psychotherapy [GPT] vs clinical management [CM]) treatments on the ADHD core symptoms inattention, hyperactivity and impulsivity. For the two-by-two factorial, observer-blinded, multicenter, randomized controlled Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS; ISRCTN54096201), 419 outpatients with ADHD were considered for analysis. ADHD symptoms were assessed by blind observer-rated and patient-rated Conners Adult ADHD Rating Scales before treatment (T1), 13 weeks (T2) and 26 weeks (T3) after T1, at treatment completion after 52 weeks (T4), and at follow-up (130 weeks, T5). MPH was superior to PLB in improving symptoms of inattention at almost all endpoints (observer-rated T2, T3, T4, T5; patient-rated T2, T3, T4), while a significant decrease in hyperactivity and impulsivity was at first found after 6 months of treatment. CM compared to GPT decreased inattention and impulsivity in the early treatment phase only (observer-rated T2, patient-rated T2, T3). In conclusion, while MPH seems to have a direct and sustained effect on inattention, premature medication discontinuation should particularly be avoided in patients with hyperactive-impulsive symptoms. Also, especially in high inattention and/or impulsivity presentations, initial individual patient management might be beneficial. Consequently, considering individual core symptom profiles may enhance the efficacy of treatments in adult ADHD.

Burden of CIN2+ diagnoses and conizations in women aged 18-45 years-a retrospective secondary data analysis of German statutory health insurance claims data.

PURPOSE: High grade cervical intraepithelial neoplasia (CIN2+) may progress to cervical cancer. They may be detected by screening and are usually treated by conization. This study aimed at assessing annual proportions of screening, prevalent and incident CIN2+ diagnoses, as well as proportions of (re-)conizations during 24 months follow-up after conization in Germany. METHODS: A descriptive retrospective claims data analysis of the years 2013-2018 was conducted using the InGef Research Database. Women aged 18-45 years with CIN2+ diagnoses were identified by ICD-10-GM codes (N87.1, N87.2, D06.-, and C53.-). Cervical conizations were identified by OPS codes (5-671.0* or 5-671.1*). Screening participation was identified by EBM codes (01730, 01733, 32819 or 32820). Annual proportions were calculated as women with the respective documented codes divided by all women in the respective age group per calendar year. RESULTS: Overall annual proportions of screened women spanned from 60.01 to 61.33% between 2013 and 2018. The overall annual prevalence of CIN2+ diagnoses (regardless of screening participation) ranged from 0.72 to 0.84% between 2013 and 2018, with highest proportions observed in women aged 27-45 years. Also, CIN2+ incidence was highest in women 27-45 years. Annual proportion of women undergoing conization was 0.24% in 2013 and 0.21% in 2018. During a 24-month follow-up period after conization, 2.91% of women underwent a re-conization 3 months or later after the initial conization. CONCLUSION: This analysis demonstrates a considerable burden of CIN2+, conizations and re-conizations in Germany, especially in women aged 27-45 years. This highlights the need for intensified prevention efforts such as expanding human papillomavirus (HPV) vaccination.

Prognostic Implications of Uterine Cervical Cancer Regression During Chemoradiation Evaluated by the T-Score in the Multicenter EMBRACE I Study.

PURPOSE: A simple scoring system (T-score, TS) for integrating findings from clinical examination and magnetic resonance imaging (MRI) of the primary tumor at diagnosis has shown strong prognostic capability for predicting local control and survival in locally advanced cervical cancer treated with chemoradiation and MRI-guided brachytherapy (BT). The aim was to validate the performance of TS using the multicenter EMBRACE I study and to evaluate the prognostic implications of TS regression obtained during initial chemoradiation. METHODS AND MATERIALS: EMBRACE I recruited 1416 patients, of whom 1318 were available for TS. Patients were treated with chemoradiation followed by MRI-guided BT. A ranked ordinal scale of 0 to 3 points was used to assess 8 anatomic locations typical for local invasion of cervical cancer. TS was calculated separately at diagnosis (TSD) and at BT (TSBT) by the sum of points obtained from the 8 locations at the 2 occasions. RESULTS: Median TSD and TSBT was 5 and 4, respectively. TS regression was observed in 71% and was an explanatory variable for BT technique (intracavitary vs intracavitary/interstitial) and major dose-volume histogram parameters for BT, such as high-risk clinical target (CTVHR), CTVHR D90 (minimal dose to 90% of the target volume), D2cm3 bladder (minimal dose to the most exposed 2 cm3 of the bladder), and D2cm3 rectum. TS regression (TSBT≤5) was associated with improved local control and survival and with less morbidity compared with patients with TSBT remaining high (>5) despite initial chemoradiation. TS regression was significant in multivariate analysis for both local control and survival when analyzed in consort with already established prognostic parameters related to the patient, disease, and treatment. CONCLUSIONS: TS was validated in a multicenter setting and proven to be a strong multidisciplinary platform for integration of clinical findings and imaging with the ability to quantitate local tumor regression and its prognostic implications regarding BT technique, dose-volume histogram parameters, local control, survival, and morbidity.