Epidemiology of Medically Attended Respiratory Syncytial Virus Lower Respiratory Tract Infection in Japanese Children, 2011-2017.

BACKGROUND: The objective was to report critical respiratory syncytial virus (RSV)-related epidemiological and healthcare resource utilization measures among Japanese children stratified by gestational and chronological age groups. METHODS: The JMDC (formerly the Japan Medical Data Center) was used to retrospectively identify infants with or without RSV infection (beginning between 1 February 2011 and 31 January 2016, with follow-up through 31 December 2017). The incidence of RSV medically attended lower respiratory tract infection (MALRI) was captured by flagging hospitalizations, outpatient, and emergency department/urgent care visits with an RSV diagnosis code during the season. RESULTS: Of 113 529 infants and children identified, 17 022 (15%) had an RSV MALRI (14 590 during the season). The RSV MALRI and hospitalization rates in the first 5 months were 14.3/100 child-years (CY) and 6.0/100 CY, respectively (13.4/100 and 5.8/100 CY for full-term infants and 20/100 and 6.8/100 CY for late preterm infants, respectively). Among those with ≥1 type of MALRI event during the RSV season, >80% of children had it by 24 months of chronological age, although this observation differed by prematurity status. Sixty percent of healthcare resource utilization measures started in the outpatient setting. CONCLUSIONS: This study emphasizes the RSV burden in young children and critically highlights the data needed to make decisions about new preventive strategies.

Power to the People: Why person-generated health data is important for pharmacoepidemiology.

Person-generated health data (PGHD) are valuable to study outcomes relevant to everyday living, to obtain information not otherwise available, for long-term follow-up and in situations where decisions cannot wait for traditional clinical research to be completed. While there is no dispute that these data are subject to bias, insights gained may be better than an information void, provided the biases are understood and acknowledged. People will share information known uniquely to them about exposures that may affect drug tolerance, safety and effectiveness, e.g., using non-prescription and complementary medications, alcohol, tobacco, illicit drugs, exercise, etc. Patients may be the best source of safety information when long-term follow-up is needed, e.g., the 5-15-year follow-up required for some gene therapies. Validation studies must be performed to evaluate what people can accurately report and when supplementary confirmation information is needed. But PGHD has already proven valuable in quantifying and contrasting COVID-19 vaccine benefits and risks, and for evaluating disease transmission and the accuracy of COVID-19 testing. Going forward, PGHD will be used for patient-measured and patient-relevant outcomes, including regulatory purposes, and will be linked to broader health data networks using tokenization, becoming a mainstay for signals about risks and benefits for diverse populations.

Treatment and follow-up of children with chronic myeloid leukaemia in chronic phase (CML-CP) in the tyrosine kinase inhibitor (TKI) era-Two decades of experience from the Tata Memorial Hospital paediatric CML (pCML) cohort.

Tyrosine kinase inhibitors (TKIs) have drastically improved the outcomes of pCML (paediatric CML) but data on long-term off-target toxicities of TKIs in children are scarce. In this single-centre, retrospective cum prospective study of pCML in chronic phase, we report our experience of treating 173 children with imatinib and following them for long-term toxicities. Mean (SD) time to attain CHR, CCyR and MMR were 3.05 (2.1), 10.6 (8.4) and 43.4 (31.8) months respectively. DMR was not attained in 59 (34%) patients at last follow-up. Ten patients were switched to second-generation TKIs (2G-TKIs; nilotinib = 1/dasatinib = 9) due to poor/loss in response, of which seven had kinase domain mutations. Three patients progressed to the blastic phase. At a median follow-up of 84 (3-261) months, the 5-year EFS and OS for the entire cohort were 96.9% (95% CI: 93.4-100) and 98.7% (95% CI: 96.9-100) respectively. Screening for long-term toxicities revealed low bone density and hypovitaminosis D in 70% and 80% respectively. Other late effects included short stature (27%), delayed puberty (15%), poor sperm quality (43%) and miscellaneous endocrinopathies (8%). Children younger than 5 years at diagnosis were more susceptible to growth and endocrine toxicities (p = 0.009). Regular monitoring for long-term toxicities, timely intervention and trial of discontinuation whenever feasible are likely to improve the long-term outlook of pCML.

Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

Early monitoring of anti-infliximab antibodies by drug-tolerant assay predicts later immunogenicity and drug survival in rheumatic diseases.

OBJECTIVES: To investigate the appearance of anti-drug antibodies (ADA) against infliximab (IFX) determined by drug-sensitive and drug-tolerant assays and their relationship with drug levels and drug survival. METHODS: This longitudinal observational study included 45 patients with rheumatoid arthritis (RA) and 61 with spondyloarthritis (SpA). Serum samples were obtained at weeks 2, 6, 12, 24, and 52. Serum IFX levels were measured by a capture enzyme-linked immunosorbent assay (ELISA) and ADA by an in-house drug-sensitive two-site (bridging) enzyme-linked immunosorbent assay (bELISA) and a commercially available drug-tolerant ELISA (IDK, Immundiagnostik, Germany). RESULTS: Anti-drug antibodies were detected earlier by IDK than by bELISA. Once ADA appeared, positivity persisted throughout the study period. Patients who were bELISA ADA+ had higher IDK ADA levels (than bELISA ADA- patients). Circulating IFX levels were detected in all patients except those found to be bELISA ADA+. Serum IFX levels were lower in IDK ADA+ than in IDK ADA-patients.Most patients (64%) discontinued due to inefficacy. The early onset of immunogenicity was related to IFX survival. Both in RA and SpA, the median survival (years) was shorter in patients with earlier development of ADA (IDK+ before or at week 24) than those who became IDK+ later (after week 24) or never developed ADA. CONCLUSION: A drug-tolerant assay detects ADA during IFX therapy earlier and more frequently than a drug-sensitive assay. The onset of immunogenicity detected by drug-tolerant assays is related to the subsequent detection of ADA by drug-sensitive assays and drug survival.

Long-term clinical outcomes in early rheumatoid arthritis that was treated-to-target in the BeSt and IMPROVED studies.

OBJECTIVES: To assess disease outcomes after 20 and 12 years of patients with rheumatoid (RA) or undifferentiated arthritis (UA), treated-to-target in the BeSt and IMPROVED trials. METHODS: In BeSt (inclusion 2000-2002, duration 10 years), 508 patients with early RA were randomized to: 1. sequential monotherapy, 2. step-up combination therapy, 3. initial csDMARD combination therapy, 4. initial bDMARD/csDMARD combination therapy. The treatment target was low disease activity (DAS ≤ 2.4).In IMPROVED (inclusion 2007-2010, duration 5 years), 610 patients with early RA/UA started MTX with prednisone bridging. The treatment target was remission (DAS < 1.6). Patients not in early remission were randomized to 1. csDMARD combination therapy or 2. bDMARD/csDMARD combination therapy.Between 2019-2022, these patients were invited for long-term follow-up. RESULTS: One-hundred-fifty-three ex-Best and 282 ex-IMPROVED patients participated in the follow-up study after median 12 and 20 years since study start.In ex-BeSt and ex-IMPROVED patients the rate of low disease activity was 91%, and 68% were in DAS remission. Median SHS was 14.0 in ex-BeSt (IQR 6.0-32.5; progression since end BeSt 6.0, IQR 2.0-12.5) and 8 in ex-IMPROVED participants (IQR 3-16; progression since end IMPROVED 4, IQR 2-9). Mean HAQ was 0.8 ± 0.6 in ex-BeSt (change since end BeSt: 0.3 ± 0.5) and 0.6 ± 0.6 in ex-IMPROVED participants (change since end IMPROVED: 0.06 ± 0.5). CONCLUSION: At 12/20 years after treatment start, the majority of RA and UA patients who had been treated to target low DAS or DAS remission were in DAS remission and had limited functional disability. Radiographic damage progression was mild although not completely suppressed.

Health-related risk behaviors among U.S. childhood cancer survivors: a nationwide estimate.

BACKGROUND: Childhood cancer survivors (CCS) are subject to a substantial burden of treatment-related morbidity. Engaging in health protective behaviors and eliminating risk behaviors are critical to preventing chronic diseases and premature deaths. This study is aimed to provide updated information on currently smoking, physical inactivity, binge drinking patterns and associated factors among CCS using a nationwide dataset. METHODS: We constructed a sample of CCS (cancer diagnosis at ages < 21y) and healthy controls (matched on age, sex, residency, race/ethnicity) using 2020 Behavioral Risk Factor Surveillance System. We used Chi-square tests and Wilcoxon rank-sum test to examine differences in sociodemographics and clinical characteristics between two groups. Logistic, ordinal regression and multivariable models (conditional models for matching) were used to determine factors associated with risk behaviors. RESULTS: The final sample (18-80y) included 372 CCS and 1107 controls. Compared to controls, CCS had a similar proportion of binge drinking (~ 18%) but higher prevalence of currently smoking (26.6% vs. 14.4%, p < 0.001), physical inactivity (23.7% vs. 17.7%, p = 0.012), and of having 2-or-3 risk behaviors (17.2% vs. 8.1%, p < 0.001). Younger age, lower educational attainment, and having multiple chronic health conditions were associated with engaging in more risk behaviors among CCS. Females, compared to male counterparts, had lower odds of binge drinking (adjusted odds ratio (aOR) = 0.30, 95% confidence interval (CI): 0.16-0.57) among CCS but not in all sample. Having multiple chronic health conditions increased odds of both currently smoking (aOR = 3.52 95%CI: 1.76-7.02) and binge drinking (aOR = 2.13 95%CI: 1.11-4.08) among CCS while it only increased odds of currently smoking in all sample. DISCUSSION: Our study provided risk behavior information for wide age-range CCS, which is currently lacking. Every one in four CCS was currently smoking. Interventions targeting risk behavior reduction should focus on CCS with multiple chronic health conditions.

The association of adverse childhood experiences with long-term outcomes of psychosis: a 21-year prospective cohort study after a first episode of psychosis.

BACKGROUND: Evidence suggests a possible relationship between exposure to childhood adversity (CA) and functional impairment in psychosis. However, the impact of CA on long-term outcomes of psychotic disorders remains poorly understood. METHODS: Two hundred and forty-three patients were assessed at their first episode of psychosis for CA and re-assessed after a mean of 21 years of follow-up for several outcome domains, including symptoms, functioning, quality of life, cognitive performance, neurological dysfunction, and comorbidity. The unique predictive ability of CA exposure for outcomes was examined using linear regression analysis controlling for relevant confounders, including socioeconomic status, family risk of schizophrenia, and obstetric complications. RESULTS: There were 54% of the patients with a documented history of CA at mild or higher levels. CA experiences were more prevalent and severe in schizophrenia than in other psychotic disorders (p < 0.001). Large to very large effect sizes were observed for CA predicting most role functioning variables and negative symptoms (ΔR2 between 0.105 and 0.181). Moderate effect sizes were observed for positive symptoms, personal functioning, impaired social cognition, impaired immediate verbal learning, poor global cognition, internalized stigma, poor personal recovery, and drug abuse severity (ΔR2 between 0.040 and 0.066). A dose-response relationship was observed between levels of CA and severity of outcome domains. CONCLUSION: Our results suggest a strong and widespread link between early adversity exposure and outcomes of psychotic disorders. Awareness of the serious long-term consequences of CA should encourage better identification of those at risk and the development of effective interventions.

20-year neurocognitive development following a schizophrenia spectrum disorder and associations with symptom severity and functional outcomes.

BACKGROUND: Cognitive deficits are a core feature of schizophrenia and are closely associated with poor functional outcomes. It remains unclear if cognitive deficits progress over time or remain stable. Determining patients at increased risk of progressive worsening might help targeted neurocognitive remediation approaches. METHODS: This 20-year follow-up study examined neurocognitive outcomes of 156 participants from the OPUS I trial. Neurocognition was assessed using the brief assessment of cognition in schizophrenia at the 10- and 20-year follow-up, allowing us to examine changes in neurocognition over ten years. RESULTS: We found that 30.5% of patients had a declining course of neurocognition, 49.2% had a stable course of neurocognition and 20.3% experienced improvements in neurocognition. Good cognitive functioning at the 20-year follow-up was significantly associated with higher levels of social functioning (B 6.86, CI 4.71-9.02, p < 0.001) while increasing experiential negative symptoms were significantly correlated to cognitive worsening (PC-0.231, p = 0.029). Younger age at inclusion (B: 0.23 per 10-years, CI 0.00-0.045, p = 0.047) and low level of education (below ten years) (mean difference: -0.346, CI -0.616 to -0.076, p = 0.012) predicted declining neurocognition. CONCLUSION: Our findings support the notion of different schizophrenia subtypes with varying trajectories. Neurocognitive impairment at the 20-year follow-up was associated with other poor outcomes, highlighting the importance of treatments aimed at improving neurocognition in patients with schizophrenia spectrum disorders.

Outcome improvement over time in reduced intensity conditioning hematopoietic transplantation: a 20-year experience.

The current study includes all consecutive patients (N = 484) who received a reduced-intensity conditioning regimen (RIC) allogeneic hematopoietic stem cell transplantation in our center from 1999 to 2020. Conditioning regimens were based on fludarabine with melphalan or busulfan, with low-dose thiotepa and pharmacological GVHD prophylaxis consisted of cyclosporine A (CsA)-methotrexate (MTX)/mofetil (MMF) (n = 271), tacrolimus-sirolimus (n = 145), and post-transplantation cyclophosphamide (PTCy)-tacrolimus (n = 68). The median time of overall follow-up in survivors was 8 years (1-22 years) and was at least 3 years in all three GVHD prophylaxis groups. Thirty-three percent had a high or very high disease risk index, 56% ≥ 4 European bone marrow transplantation risk, and 65% ≥ 3 hematopoietic stem cell transplantation comorbidity index score-age score. Neutrophil and platelet engraftment was longer for PTCy-tacro (p 0.0001). Cumulative incidence of grade III-IV aGVHD was 17% at 200 days, and that of moderate-severe cGvHD was 36% at 8 years. GVHD prophylaxis was the only prognostic factor in the multivariable analyses for the development of aGVHD and moderate-severe cGVHD (p 0.0001). NRM and relapse incidences were 29% and 30% at 8 years, while OS and PFS rates were 43% and 39% at 8 years. At 3 years, OS was highest in the PTCy-tacro group (68%) than in the tacro-siro (61%) and CsA-MTX/MMF (49%) cohorts (p < 0.01). In the three groups, respectively, the 200-day incidence of grade III-IV aGvHD (6% vs. 12% vs. 23%) and 3-year moderate-severe cGVHD (8% vs. 40% vs. 38%) were lower in the PTCy cohort. These better outcomes were confirmed in multivariable analyses. Based on our recent results, the PTCy could be considered as a real GvHD prophylaxis in the RIC setting due to improve best 3-year GvHD and survival outcomes.

Final 5-year report of BIONYX comparing the thin-composite wire-strut zotarolimus-eluting stent versus ultrathin-strut sirolimus-eluting stent.

BACKGROUND: The BIONYX randomized trial is the first study to evaluate the Resolute Onyx durable polymer-coated zotarolimus-eluting stent (ZES) in all-comers. Furthermore, it is the first trial to assess safety and efficacy of this stent versus the Orsiro biodegradable-polymer sirolimus-eluting stent (SES) in all-comers, paying particular attention to patients with diabetes. It has previously shown promising results until 3 years of follow-up. AIMS: We aimed to assess long-term clinical outcome after percutaneous coronary intervention (PCI) with Onyx ZES versus Orsiro SES at 5-year follow-up. METHODS: The main composite endpoint was target vessel failure (TVF): cardiac death, target vessel myocardial infarction, or target vessel revascularization. Time to primary and secondary endpoints was assessed using Kaplan-Meier methods, applying the log-rank test for between-group comparison. RESULTS: Follow-up was available in 2414/2488 (97.0%) patients. After 5 years, TVF showed no significant difference between Onyx ZES and Orsiro SES (12.7% vs. 13.7%, hazard ratio [HR] 0.94, 95% confidence interval [CI] [0.75-1.17], plog-rank = 0.55). Landmark analysis between 3- and 5-year follow-up found a lower target lesion revascularization rate for Onyx ZES (1.1% vs. 2.4%, HR 0.47, 95% CI [0.24-0.93], plog-rank = 0.026). A prespecified subgroup analysis showed no significant between-stent difference in clinical outcome among patients with diabetes. After treatment with Onyx ZES, patients aged ≥75 years had significantly lower rates of TVF (13.8% vs. 21.9%, HR 0.60, 95% CI [0.39-0.93], plog-rank = 0.023). CONCLUSIONS: The final 5-year analysis of the randomized BIONYX trial showed favorable and similar long-term outcomes of safety and efficacy for Onyx ZES and Orsiro SES in both all-comers and patients with diabetes.

Long term clinical outcome of sirolimus drug coated balloons in large coronary vessels.

BACKGROUND: Studies evaluating the safety and efficacy of drug coating balloons (DCB) for the treatment of lesions in large coronary vessel are limited. AIMS: Our study aimed to evaluate the performance of a sirolimus DCB in large coronary arteries. METHODS: We analyzed all the procedures included in the EASTBOURNE Registry (NCT03085823) enrolling patients with a clinical indication to percutaneous coronary intervention performed by a sirolimus DCB according to investigator judgment. In the present analysis, a cut-off of 2.75 mm was used to define large coronary arteries. Primary endpoint of the study was clinically driven target lesion revascularization (TLR) at 24 months whereas secondary endpoint included procedural success, myocardial infarction (MI), cardiac death and total mortality. RESULTS: Among the 2123 patients and 2440 lesions enrolled in the EASTBOURNE study between 2016 and 2020, 757 patients/810 lesions fulfilled the criteria for the present analysis. Mean reference vessel diameter was 3.2 ± 0.3 mm with mean lesion length of 22 ± 7 mm. Procedural success was high (96%) and at 2-year follow up the device showed a good efficacy with a TLR rate of 9%. There were 34 deaths (4.5%), 30 MIs (4%) and 8 BARC type 3-5 bleedings (1.1%). In-stent restenosis (629 lesions) and de novo lesions (181) were associated with 11% and 4% rates of TLR at 2 years, respectively (p = 0.003). CONCLUSIONS: Clinical performance of a sirolimus DCB in large coronary artery vessels shows promising signals at 2-year follow up, both in de novo and in-stent restenosis lesions.

Long-term clinical and ultrasound follow-up after transient perivascular inflammation of the carotid artery (TIPIC) syndrome: a multicenter study.

BACKGROUND: The present study aimed to describe the clinical and ultrasound (US) long-term follow-up of patients with transient perivascular inflammation of the carotid artery (TIPIC) syndrome and the risk of recurrence. METHODS: We enrolled patients with a definitive diagnosis of TIPIC syndrome who were included in a retrospective multicenter study. These patients were recontacted at least six months after the first TIPIC episode for a clinical and imaging follow-up. Each patient underwent a clinical evaluation through a tailored questionnaire as well as US imaging. RESULTS: Twenty-eight patients were enrolled with a median follow-up of 58.7 months (interquartile range = 8-121). Nineteen out of the 28 patients (67.8%) had residual pain, eight (28.6%) had experienced a clinical recurrence and 12 (42.9%) had a thickening of the carotid wall on US. No patients had neurological complication or other associated diseases. CONCLUSIONS: Patients with TIPIC syndrome have often residual pain and recurrence in about one quarter of cases but the long-term follow-up is in favor a benign self-limited pathology.Trial registration: ClinicalTrials.gov (identifier NCT03804112).

Ureteroscopic management in cystinuric patients: long-term results from a tertiary care referral center.

OBJECTIVE: To evaluate long-term surgical and functional outcomes of cystinuric patients exclusively treated with Ureteroscopy (URS). METHODS: Data from patients treated for cystine stones at a single academic center were retrospectively analyzed. The management protocol consisted of (i) treating symptomatic or > 7 mm stones, (ii) multi-staged URS for voluminous stones, (iii) referring patients to a dedicated nephrological clinic. The eGFR was calculated according to the MDRD formula. CKD category was assessed according to the NKF classification. Relevant CKD was defined as CKD category ≥ 3a. Descriptive statistics were used to analyze the cohort data. RESULTS: Data from 46 cystinuric patients treated with 332 URS were available. Median age at diagnosis and at first URS in our center were 18 and 32 years, respectively. Median follow-up was 101 months. Median number of URS and recurrences per patient were 6 and 2, respectively. The median interval between the first and the last available creatinine level was 64 months. Median first and last eGFR were 72 and 74 mL/min, respectively. Overall, 83% of patients had stable or improved renal function within the study period. Ureteral stricture occurred in 3 (6.5%) patients. CONCLUSIONS: Cystinuria requires intensive endoscopic management. Most patients treated with URS have stable or improved renal function within a long-term follow-up. CKD is a not neglectable event that potentially occurs at an early stage of life. Current findings should be considered for the surgical management of cystinuric patients.

Follow-up of vascular-targeted photodynamic therapy in a real-world setting.

PURPOSE: Vascular-targeted photodynamic therapy (VTP) is an approved treatment option for unilateral low-risk prostate cancer (PCa). METHODS: Patients with unilateral low- or intermediate-risk PCa undergoing hemiablation by VTP were evaluated in a real-world setting. Oncological outcome after VTP was measured by MRI-based re-biopsy at 12 and 24 months. Functional outcome after 1 year was investigated by IIEF-5 and IPSS questionnaires. Progression was defined as the evidence3 of ISUP ≥ 2 PCa. RESULTS: At any control biopsy (n = 46) after VTP, only 37% of patients showed no evidence of PCa. Recurrence-free survival was 20 months (95% CI 4.9-45.5) and progression-free survival was 38.5 months (95% CI 33.5-43.6 months). In-field and out-field recurrent PCa occurs in 37% (55% ISUP ≥ 2 PCa) and 35% (56% ISUP ≥ 2 PCa). Seventy-nine percent of patients preserved erectile function, respectively. Ten percent of patients presented long-term bladder outlet obstruction. None of the patients presented incontinence. CONCLUSION: Due to the high-recurrence in- and out-field recurrence rate in a mainly low-risk prostate cancer cohort, VTP has to be regarded critically as a therapy option in these patients. Pre-interventional diagnostic evaluation is the main issue before focal therapy to reduce the risk of tumor recurrence and progression.

The continuously evolving phenotype of succinic semialdehyde dehydrogenase deficiency.

The objective of the study is to evaluate the evolving phenotype and genetic spectrum of patients with succinic semialdehyde dehydrogenase deficiency (SSADHD) in long-term follow-up. Longitudinal clinical and biochemical data of 22 pediatric and 9 adult individuals with SSADHD from the patient registry of the International Working Group on Neurotransmitter related Disorders (iNTD) were studied with in silico analyses, pathogenicity scores and molecular modeling of ALDH5A1 variants. Leading initial symptoms, with onset in infancy, were developmental delay and hypotonia. Year of birth and specific initial symptoms influenced the diagnostic delay. Clinical phenotype of 26 individuals (median 12 years, range 1.8-33.4 years) showed a diversifying course in follow-up: 77% behavioral problems, 76% coordination problems, 73% speech disorders, 58% epileptic seizures and 40% movement disorders. After ataxia, dystonia (19%), chorea (11%) and hypokinesia (15%) were the most frequent movement disorders. Involvement of the dentate nucleus in brain imaging was observed together with movement disorders or coordination problems. Short attention span (78.6%) and distractibility (71.4%) were the most frequently behavior traits mentioned by parents while impulsiveness, problems communicating wishes or needs and compulsive behavior were addressed as strongly interfering with family life. Treatment was mainly aimed to control epileptic seizures and psychiatric symptoms. Four new pathogenic variants were identified. In silico scoring system, protein activity and pathogenicity score revealed a high correlation. A genotype/phenotype correlation was not observed, even in siblings. This study presents the diversifying characteristics of disease phenotype during the disease course, highlighting movement disorders, widens the knowledge on the genotypic spectrum of SSADHD and emphasizes a reliable application of in silico approaches.

Long-Term Effectiveness of Cognitive Behavioral Therapy in Routine Outpatient Care for Youth with Anxiety Disorders.

INTRODUCTION: This study examined the long-term effectiveness of cognitive behavioral therapy (CBT) (≥ 2 years after the end of therapy) in the routine care of youth (mean 11.95 years; SD = 3.04 years) with primary anxiety disorder (AD). METHODS: Two hundred and ten children with any AD as a primary diagnosis and with any comorbidity were included in the "Kids Beating Anxiety (KibA)" clinical trial and received evidence-based CBT. Diagnoses, severity of diagnoses, and further dimensional outcome variables of symptoms and functioning were assessed before (baseline), after the last treatment session (POST), and at two follow-up (FU) assessments in the child and caregiver report: 6 months (6MONTHS-FU) and >2 years (mean 4.31; SD = 1.07 years) after the last treatment session (long-term FU). RESULTS: At POST, 61.38% showed total remission of all and any ADs. At long-term FU, the remission rate was 63.64%. Compared to baseline, ratings of severity, anxiety, impairment/burden, and life quality improved significantly after CBT in child and caregiver report. All pre-post/FU improvements and global success ratings were stable in child (Pre-Post: Hedges' g = 3.57; Pre-6MONTHS-FU: Hedges' g = 3.43; Pre-LT-FU: Hedges' g = 2.34) and caregiver report (Pre-Post: Hedges' g = 2.00; Pre-6MONTHS-FU: Hedges' g = 2.31; Pre-LT-FU: Hedges' g = 2.31) across all POST- and FU-assessment points. Some outcomes showed further significant improvement, and no deterioration was found over the course of time. Effect sizes calculated in the present study correspond to, or even exceed, effect sizes reported in previous meta-analysis. CONCLUSIONS: Stable long-term effects of "KibA" CBT for youth with ADs, comparable to those results from efficacy studies, were achieved in a routine practice setting by applying treatment manuals tested in randomized controlled trials. These findings are remarkable, as the patient group studied here consisted of an age group within the main risk phase of developing further mental disorders, and therefore an increase in new-onset anxiety and further mental disorders would be expected over the long time span studied here.

Long-term follow-up of patients with intermediate-risk neuroblastoma treated with response- and biology-based therapy: A report from the Children's Oncology Group study ANBL0531.

BACKGROUND: We previously reported excellent three-year overall survival (OS) for patients with newly diagnosed intermediate-risk neuroblastoma treated with a biology- and response-based algorithm on the Children's Oncology Group study ANBL0531. We now present the long-term follow-up results. METHODS: All patients who met the age, stage, and tumor biology criteria for intermediate-risk neuroblastoma were eligible. Treatment was based on prognostic biomarkers and overall response. Event-free survival (EFS) and OS were estimated by the Kaplan-Meier method. RESULTS: The 10-year EFS and OS for the entire study cohort (n = 404) were 82.0% (95% confidence interval (CI), 77.2%-86.9%) and 94.7% (95% CI, 91.8%-97.5%), respectively. International Neuroblastoma Staging System stage 4 patients (n = 133) had inferior OS compared with non-stage 4 patients (n = 271; 10-year OS: 90.8% [95% CI, 84.5%-97.0%] vs 96.6% [95% CI, 93.9%-99.4%], p = .02). Infants with stage 4 tumors with ≥1 unfavorable biological feature (n = 47) had inferior EFS compared with those with favorable biology (n = 61; 10-year EFS: 66.8% [95% CI, 50.4%-83.3%] vs 86.9% [95% CI, 76.0%-97.8%], p = .02); OS did not differ (10-year OS: 84.4% [95% CI, 71.8%-97.0%] vs 95.0% [95% CI, 87.7%-100.0%], p = .08). Inferior EFS but not OS was observed among patients with tumors with (n = 26) versus without (n = 314) 11q loss of heterozygosity (10-year EFS: 68.4% [95% CI, 44.5%-92.2%] vs 83.9% [95% CI, 78.7%-89.2%], p = .03; 10-year OS: 88.0% [95% CI, 72.0%-100.0%] vs 95.7% [95% CI, 92.8%-98.6%], p = .09). CONCLUSIONS: The ANBL0531 trial treatment algorithm resulted in excellent long-term survival. More effective treatments are needed for subsets of patients with unfavorable biology tumors.

Systematic Review of Long Term Sinonasal Outcomes in CRSwNP after Endoscopic Sinus Surgery: A call for Unified and Standardized Criteria and Terms.

PURPOSE OF REVIEW: To present current evidence in long-term (> 5 years) results after endoscopic sinus surgery (ESS) focusing on Patients Reported Outcome Measures (PROMs) and other sinonasal outcomes while assessing the role of ESS in the treatment of CRSwNP, and identifying outcomes which affect the results of ESS and defining recommendations for future studies. RECENT FINDINGS: Long-term results of ESS in CRSwNP can be branched in PROMs and other objective measurements. Despite the heterogeneity of reported outcomes make it difficult to perform comparisons and meta-analysis, ESS improves PROMs, including symptoms, QOL and olfaction. Objectives outcomes such as NPS, LMS, type of surgery, or recurrence and revision surgery don't have a clear role in long-term results. Clustering patients suggest asthma, N-ERD, allergy, eosinophil count and IL-5 could have a role in predicting recurrence and severe disease. Long-term studies of CRSwNP treated with ESS are scarce. There is a significant need to standardize the report of results. The use of tools as SNOT-22, NPS, validated smell tests, defined criteria for disease recurrence and control and ESS extension in a unified systematic way could allow better comparisons between treatments in the new era of biologics.

Association of Valve Size and Hemodynamic Performance With Clinical Outcomes in Aortic Valve Replacement　- A Long-Term Follow-up in an Asian Population.

BACKGROUND: Studies of the influence of smaller body type on the severity of prosthesis-patient mismatch (PPM) after small-sized surgical aortic valve replacement (SAVR) are few, but the issue is particularly relevant for Asian patients.Methods and Results: 695 patients who underwent SAVR with bioprosthetic valves had their hemodynamic valve performance analyzed at 3 months, 1 year, 3 years, and 5 years after operation, and clinical outcomes were assessed. The patients were stratified into 3 valve size groups: 19/21, 23, and 25/27 mm. A smaller valve was associated with higher mean pressure gradients at the 4 time points after operation (P trend <0.05). However, the 3 valve size groups demonstrated no significant differences in the risk of clinical events. At none of the time points did patients with projected PPM show increased mean pressure gradients (P>0.05), whereas patients with measured PPM did (P<0.05). Compared with patients with projected PPM, those with measured PPM demonstrated higher rates of infective endocarditis readmission (adjusted hazard ratio [aHR] 3.31, 95% confidence interval [CI] 1.06-10.39) and a higher risk of composite outcomes (aHR 1.45, 95% CI 0.95-2.22, P=0.087). CONCLUSIONS: Relative to those receiving larger valves, patients receiving small bioprosthetic valves had poorer hemodynamic performance but did not demonstrate differences in clinical events in long-term follow-up.