Long-term results of PET-guided radiation in patients with advanced-stage diffuse large B-cell lymphoma treated with R-CHOP.

Consolidative radiation therapy (RT) for advanced-stage diffuse large B-cell lymphoma (DLBCL) remains controversial, with routine practice continuing to include RT in patients with initial bulky disease or residual masses. Positron emission tomography (PET)-computed tomography is a sensitive modality for detecting the presence of residual disease at the end of treatment (EOT). A PET-guided approach to selectively administering RT has been the policy in British Columbia since 2005. Patients with advanced-stage DLBCL diagnosed from 1 January 2005 to 1 March 2017 and treated with at least 6 cycles of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone plus rituximab), who underwent EOT PET, were included in this analysis. Those with complete metabolic response (PET-negative [PET-NEG]) were observed; those with PET-positive (PET-POS) scans were offered consolidative RT, when feasible. Of the patient records reviewed, 723 were identified, with median follow-up of 4.3 years: 517 (72%) were PET-NEG; 206 (28%) were PET-POS. Time to progression (TTP) and overall survival (OS) at 3 years were 83% vs 56% and 87% vs 64%, in patients with PET-NEG and PET-POS scans, respectively. PET-POS patients with nonprogressing disease treated with consolidative RT (109 and 206; 53%) had outcomes approaching those of PET-NEG patients, with 3-year estimates of 76% and 80% for TTP and OS. PET-NEG patients who had bulky disease (≥10 cm) at diagnosis had outcomes indistinguishable from those without bulk, despite the omission of RT. These data suggest that patients with advanced-stage DLBCL who are PET-NEG at EOT and receive no RT have excellent outcomes. 18F-fluorodeoxyglucose-PET can reliably guide selective administration of consolidative RT, even in patients with initially bulky disease.

Lysosomal acid lipase deficiency manifestations in children and adults: Baseline data from an international registry.

BACKGROUND AND AIMS: Lysosomal acid lipase deficiency (LAL-D) is a rare, autosomal recessive disease involving lysosomal accumulation of cholesteryl esters and triglycerides. The International Lysosomal Acid Lipase Deficiency Registry (NCT01633489), established in 2013 to understand LAL-D natural history and long-term outcomes, is accessible to centres caring for patients diagnosed by deficient LAL activity and/or biallelic pathogenic LIPA variants. We describe the registry population enrolled through 2 May 2022. METHODS: In this prospective observational study, we analysed demographic and baseline clinical characteristics of children (ages ≥6 months to <18 years) and adults diagnosed with LAL-D. RESULTS: Of 228 patients with confirmed disease, 61% were children; 202/220 (92%) with data on race were white. Median age was 5.5 years at sign/symptom onset and 10.5 years at diagnosis; median time from sign/symptom onset to diagnostic testing was 3.3 years. The most common manifestations raising suspicion of disease were elevated alanine (70%) and aspartate aminotransferase levels (67%) and hepatomegaly (63%). Among 157 with reported LIPA mutations, 70 were homozygous and 45 were compound heterozygous for the common exon 8 splice junction pathogenic variant (E8SJM-1). Seventy percent (159/228) of patients had dyslipidaemia. Among 118 with liver biopsies, 63% had microvesicular steatosis exclusively, 23% had mixed micro- and macrovesicular steatosis and 47% had lobular inflammation. Of 78 patients with fibrosis-stage data, 37% had bridging fibrosis and 14% had cirrhosis. CONCLUSIONS: Although LAL-D signs/symptoms occur early, diagnosis is often delayed. Abnormal transaminase levels associated with hepatomegaly and dyslipidaemia should raise suspicion and prompt earlier diagnosis of LAL-D. TRIAL REGISTRATION NUMBER: NCT01633489.

Intra-individual comparison of 18F-sodium fluoride PET-CT and 99mTc bone scintigraphy with SPECT in patients with prostate cancer or breast cancer at high risk for skeletal metastases (MITNEC-A1): a multicentre, phase 3 trial.

BACKGROUND: Detection of skeletal metastases in patients with prostate cancer or breast cancer remains a major clinical challenge. We aimed to compare the diagnostic performance of 99mTc-methylene diphosphonate (99mTc-MDP) single-photon emission CT (SPECT) and 18F-sodium fluoride (18F-NaF) PET-CT for the detection of osseous metastases in patients with high-risk prostate or breast cancer. METHODS: MITNEC-A1 was a prospective, multicentre, single-cohort, phase 3 trial conducted in ten hospitals across Canada. Patients aged 18 years or older with breast or prostate cancer with a WHO performance status of 0-2 and with high risk or clinical suspicion for bone metastasis, but without previously documented bone involvement, were eligible. 18F-NaF PET-CT and 99mTc-MDP SPECT were done within 14 days of each other for each participant. Two independent reviewers interpreted each modality without knowledge of other imaging findings. The primary endpoint was the overall accuracy of 99mTc-MDP SPECT and 18F-NaF PET-CT scans for the detection of bone metastases in the per-protocol population. A combination of histopathological, clinical, and imaging follow-up for up to 24 months was used as the reference standard to assess the imaging results. Safety was assessed in all enrolled participants. This study is registered with ClinicalTrials.gov, NCT01930812, and is complete. FINDINGS: Between July 11, 2014, and March 3, 2017, 290 patients were screened, 288 of whom were enrolled (64 participants with breast cancer and 224 with prostate cancer). 261 participants underwent both 18F-NaF PET-CT and 99mTc-MDP SPECT and completed the required follow-up for statistical analysis. Median follow-up was 735 days (IQR 727-750). Based on the reference methods used, 109 (42%) of 261 patients had bone metastases. In the patient-based analysis, 18F-NaF PET-CT was more accurate than 99mTc-MDP SPECT (84·3% [95% CI 79·9-88·7] vs 77·4% [72·3-82·5], difference 6·9% [95% CI 1·3-12·5]; p=0·016). No adverse events were reported for the 288 patients recruited. INTERPRETATION: 18F-NaF has the potential to displace 99mTc-MDP as the bone imaging radiopharmaceutical of choice in patients with high-risk prostate or breast cancer. FUNDING: Canadian Institutes of Health Research.

Old specimens for old branches: Assessing effects of sample age in resolving a rapid Neotropical radiation of squirrels.

Ultraconserved Elements (UCEs) have been useful to resolve challenging phylogenies of non-model clades, unpuzzling long-conflicted relationships in key branches of the Tree of Life at both deep and shallow levels. UCEs are often reliably recovered from historical samples, unlocking a vast number of preserved natural history specimens for analysis. However, the extent to which sample age and preservation method impact UCE recovery as well as downstream inferences remains unclear. Furthermore, there is an ongoing debate on how to curate, filter, and properly analyze UCE data when locus recovery is uneven across sample age and quality. In the present study we address these questions with an empirical dataset composed of over 3800 UCE loci from 219 historical and modern samples of Sciuridae, a globally distributed and ecologically important family of rodents. We provide a genome-scale phylogeny of two squirrel subfamilies (Sciurillinae and Sciurinae: Sciurini) and investigate their placement within Sciuridae. For historical specimens, recovery of UCE loci and mean length per locus were inversely related to sample age; deeper sequencing improved the number of UCE loci recovered but not locus length. Most of our phylogenetic inferences-performed on six datasets with alternative data-filtering strategies, and using three distinct optimality criteria-resulted in distinct topologies. Datasets containing more loci (40% and 50% taxa representativeness matrices) yielded more concordant topologies and higher support values than strictly filtered datasets (60% matrices) particularly with IQ-Tree and SVDquartets, while filtering based on information content provided better topological resolution for inferences with the coalescent gene-tree based approach in ASTRAL-III. We resolved deep relationships in Sciuridae (including among the five currently recognized subfamilies) and relationships among the deepest branches of Sciurini, but conflicting relationships remain at both genus- and species-levels for the rapid Neotropical tree squirrel radiation. Our results suggest that phylogenomic consensus can be difficult and heavily influenced by the age of available samples and the filtering steps used to optimize dataset properties.

Should pregnant women know their individual risk of future pelvic floor dysfunction? A qualitative study.

BACKGROUND: The study aimed to explore: • pregnant women's and healthcare professionals' perspectives on provision of individual risk scores for future Pelvic Floor Dysfunction (PFD), • the feasibility of providing this during routine maternity care, • actions women might take as a result of knowing their PFD risk. METHODS: Qualitative study. SETTING: UK NHS Health Board. PARTICIPANTS: Pregnant women (n = 14), obstetricians (n = 6), midwives (n = 8) and physiotherapists (n = 3). A purposive sample of pregnant women and obstetric healthcare professionals were introduced to the UR-CHOICE calculator, which estimates a woman's PFD risk, and were shown examples of low, medium and high-risk women. Data were collected in 2019 by semi-structured interview and focus group and analysed using the Framework Approach. RESULTS: Women's PFD knowledge was limited, meaning they were unlikely to raise PFD risk with healthcare professionals. Women believed it was important to know their individual PFD risk and that knowledge would motivate them to undertake preventative activities. Healthcare professionals believed it was important to discuss PFD risk, however limited time and concerns over increased caesarean section rates prevented this in all but high-risk women or those that expressed concerns. CONCLUSION: Women want to know their PFD risk. As part of an intervention based within a pregnant woman/ maternity healthcare professional consultation, the UR-CHOICE calculator could support discussion to consider preventative PFD activities and to enable women to be more prepared should PFD occur. A randomised controlled trial is needed to test the effectiveness of an intervention which includes the UR-CHOICE calculator in reducing PFD.

Prevention of Atherosclerotic Cardiovascular Disease in Children with Familial Hypercholesterolemia.

PURPOSE OF REVIEW: Familial hypercholesterolemia (FH), a common inherited disorder of LDL-C metabolism that predisposes to premature cardiovascular disease, is underdiagnosed. Despite recommendations for screening all children and initiation of lipid-lowering medication beginning at 8-10 years of age, adherence to guidelines is low. Most individuals with FH are inadequately treated, especially women and children. The purpose of this review is to discuss current literature and recommendations for the diagnosis and treatment of heterozygous FH (HeFH) in the pediatric population. RECENT FINDINGS: Twenty-year outcome data demonstrate lower rates of atherosclerotic cardiovascular disease (ASCVD) related events and death in individuals with FH who were treated with statins from childhood, compared to those who initiated statins in adulthood. While diagnosis rates of FH are slowly improving, most clinicians do not adhere to recommendations for cholesterol screening in youth. Identifying youth with FH offers the opportunity for early intervention to prevent ASCVD and identify affected relatives through reverse cascade screening.

Evaluation of 18F-EF5 for detection of hypoxia in localized adenocarcinoma of the prostate.

BACKGROUND: A common feature of solid tumours that are resistant to therapy is the presence of regions with low oxygen content (i.e., hypoxia). Oxygen electrode studies suggest that localized prostate adenocarcinoma is commonly hypoxic, although conflicting data have been reported between immunohistochemical detection of hypoxia-induced proteins in biopsy specimens and positron emission tomography (PET) imaging of 18F-labeled hypoxia reporters. Although the 2-nitroimidazole 18F-EF5 is well-established to label hypoxic tumour cells in pre-clinical tumour models and clinical trials of multiple primary tumour sites, it has yet to be tested in prostate cancer. The purpose of this study was to evaluate the feasibility of using 18F-EF5 to detect hypoxia in clinical prostate tumours. MATERIAL AND METHODS: Patients with localized adenocarcinoma of the prostate were recruited for pre-treatment 18F-EF5 PET scans. Immunohistochemistry was conducted on diagnostic biopsies to assess the expression of glucose transporter 1 (GLUT1), osteopontin (OPN), and carbonic anhydrase IX (CAIX). Immunoreactivity scores of staining intensity and frequency were used to indicate the presence of tumour hypoxia. RESULTS: We found low tumour-to-muscle ratios of 18F-EF5 uptake that were not consistent with tumour hypoxia, causing early termination of the study. However, we observed GLUT1 and OPN expression in all prostate tumour biopsies, indicating the presence of hypoxia in all tumours. CONCLUSION: Our data do not support the use of 18F-EF5 PET to detect hypoxia in prostate adenocarcinoma, and suggest the use of immunohistochemistry to quantify expression of the hypoxia-inducible proteins GLUT1 and OPN as indications of prostate tumour hypoxia.

Museomics of tree squirrels: a dense taxon sampling of mitogenomes reveals hidden diversity, phenotypic convergence, and the need of a taxonomic overhaul.

BACKGROUND: Tree squirrels (Sciuridae, Sciurini), in particular the highly diverse Neotropical lineages, are amongst the most rapidly diversifying branches of the mammal tree of life but also some of the least known. Negligence of this group by systematists is likely a product of the difficulties in assessing morphological informative traits and of the scarcity or unavailability of fresh tissue samples for DNA sequencing. The highly discrepant taxonomic arrangements are a consequence of the lack of phylogenies and the exclusive phenotypic-based classifications, which can be misleading in a group with conservative morphology. Here we used high-throughput sequencing and an unprecedented sampling of museum specimens to provide the first comprehensive phylogeny of tree squirrels, with a special emphasis on Neotropical taxa. RESULTS: We obtained complete or partial mitochondrial genomes from 232 historical and modern samples, representing 40 of the 43 currently recognized species of Sciurini. Our phylogenetic analyses-performed with datasets differing on levels of missing data and taxa under distinct analytical methods-strongly support the monophyly of Sciurini and consistently recovered 12 major clades within the tribe. We found evidence that the diversity of Neotropical tree squirrels is underestimated, with at least six lineages that represent taxa to be named or revalidated. Ancestral state reconstructions of number of upper premolars and number of mammae indicated that alternative conditions of both characters must have evolved multiple times throughout the evolutionary history of tree squirrels. CONCLUSIONS: Complete mitogenomes were obtained from museum specimens as old as 120 years, reinforcing the potential of historical samples for phylogenetic inferences of elusive lineages of the tree of life. None of the taxonomic arrangements ever proposed for tree squirrels fully corresponded to our phylogenetic reconstruction, with only a few of the currently recognized genera recovered as monophyletic. By investigating the evolution of two morphological traits widely employed in the taxonomy of the group, we revealed that their homoplastic nature can help explain the incongruence between phylogenetic results and the classification schemes presented so far. Based on our phylogenetic results we suggest a tentative supraspecific taxonomic arrangement for Sciurini, employing 13 generic names used in previous taxonomic classifications.

Initial assessment and ongoing monitoring of lysosomal acid lipase deficiency in children and adults: Consensus recommendations from an international collaborative working group.

BACKGROUND: Lysosomal acid lipase (LAL) deficiency is an ultra-rare, progressive, autosomal recessive disorder. Functional mutations in LIPA, the gene that encodes LAL, result in accumulation of cholesteryl esters and triglycerides in hepatocytes and in the macrophages of the intestines, vascular endothelial system, and numerous other organs. LAL deficiency has a broad clinical spectrum; children and adults can present with dyslipidemia, liver enzyme elevations, hepatosplenomegaly, hepatic steatosis, liver fibrosis and/or cirrhosis, and vascular disease, which may lead to significant morbidity and premature mortality in some patients. Given the systemic involvement and the wide range of healthcare specialists who manage patients with LAL deficiency, there is a need for guidelines to assess and monitor disease involvement. OBJECTIVES: To provide a set of recommendations for the initial assessment and ongoing monitoring of patients with LAL deficiency to help physicians in various disciplines effectively manage the disease based on the observed presentation and progression in each case. METHODS: A group of internationally recognized healthcare specialists with expertise in clinical genetics, pathology, hepatology, gastroenterology, cardiology, and lipidology convened to develop an evidence-based consensus of best practices for the initial assessment and ongoing monitoring of children and adults with LAL deficiency, regardless of treatment status; infants with LAL deficiency have been excluded from these guidelines because they require specialized care. RESULTS: The authors present guidance for the assessment and monitoring of patients with LAL deficiency based on age and disease manifestations that include the hepatic, cardiovascular, and gastrointestinal systems. A schedule for ongoing monitoring of disease progression is provided. In addition, the need to establish an interdisciplinary and integrated care team to optimize the approach to managing this systemic disease is highlighted. CONCLUSIONS: There is currently no published guidance on the assessment and monitoring of patients with LAL deficiency. These consensus recommendations for the initial assessment and ongoing monitoring of children and adults with LAL deficiency are intended to help improve the management of these patients.

The Utility of PET/CT in Guiding Radiotherapy Reduction for Children With Hodgkin Lymphoma Treated With ABVD.

ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) is standard upfront chemotherapy for adults diagnosed with Hodgkin lymphoma (HL), but positron emission tomography (PET)-based response data following ABVD is lacking for pediatrics. Among children who received ABVD for HL, we document interim and end of therapy PET-computed tomography (CT) response by Deauville criteria, and survival outcomes following a response-based reduction in involved field radiotherapy (IFRT). Children 18 years of age or below with HL treated with ABVD between 2006 and 2015 who had interim PET/CT scans after 2 cycles of chemotherapy were included. Interim and end of therapy PET/CT scans were retrospectively re-evaluated using Deauville criteria by 3 radiologists. Among 45 children, 32 (71%) met criteria for intermediate risk, 86% achieved rapid early response (RER) and only 4 (9%) received upfront IFRT. Patients achieving RER had superior 5-year event-free survival (EFS) 95%±4% versus 50%±18% (P≤0.001) and overall survival (OS) 100% versus 83%±15% (P=0.025). Patients with bulk who achieved RER and received no IFRT achieved 5-year EFS of 92%±6% and OS 100%. Low, intermediate, and high risk patients had 5-year EFS of 100%, 94%±4%, and 50%±18% (P=0.002) and 5-year OS of 100%, 100%, and 75%±15% (P=0.03). RER following 2 cycles of ABVD is predictive of survival outcomes in children and adolescents with HL and may identify a group who may omit IFRT.

Reverse Cascade Screening for Familial Hypercholesterolemia.

PROBLEM: Cardiovascular disease (CVD) is the leading cause of death in the U.S. and in most Western countries. Early identification and treatment of individuals with elevated levels of atherogenic cholesterol, a major contributor to CVD, have been shown to be effective and safe in reducing premature morbidity and mortality, especially in familial hypercholesterolemia (FH). Cholesterol screening of youth also provides a unique means of identifying affected family members through reverse cascade screening (RCS). ELIGIBILITY CRITERIA: A PubMed review of all relevant articles from 2000 to 2016 was conducted of familial hypercholesterolemia and cholesterol screening of youth. RESULTS: We provide an overview of cholesterol screening, outline the role of the pediatric nurse in the lipid clinic, and discuss effectiveness and potential barriers, including cost and confidentiality considerations of RCS. CONCLUSIONS: Early identification and effective intervention of youth with FH, including adoption of a heart-healthy lifestyle, has the potential of 1) markedly reducing or eliminating atherosclerotic cardiovascular disease and related events in future generations and 2) provides a unique means of identifying affected family members. IMPLICATIONS: Pediatric nurses play a vital role in the education and care coordination of children diagnosed with FH and screening of relatives. Identification of a child with FH with effective screening of relatives combines the benefits of universal and cascade screening, and has the potential of detecting all living cases of FH. While potentially providing significant benefit to those at risk for premature CVD, a RCS program needs to carefully consider ethical, psychological, and financial implications as well.

Pelvic floor muscle training for secondary prevention of pelvic organ prolapse (PREVPROL): a multicentre randomised controlled trial.

BACKGROUND: Pelvic floor muscle training can reduce prolapse severity and symptoms in women seeking treatment. We aimed to assess whether this intervention could also be effective in secondary prevention of prolapse and the need for future treatment. METHODS: We did this multicentre, parallel-group, randomised controlled trial at three centres in New Zealand and the UK. Women from a longitudinal study of pelvic floor function after childbirth were potentially eligible for inclusion. Women of any age who had stage 1-3 prolapse, but had not sought treatment, were randomly assigned (1:1), via remote computer allocation, to receive either one-to-one pelvic floor muscle training (five physiotherapy appointments over 16 weeks, and annual review) plus Pilates-based pelvic floor muscle training classes and a DVD for home use (intervention group), or a prolapse lifestyle advice leaflet (control group). Randomisation was minimised by centre, parity (three or less vs more than three deliveries), prolapse stage (above the hymen vs at or beyond the hymen), and delivery method (any vaginal vs all caesarean sections). Women and intervention physiotherapists could not be masked to group allocation, but allocation was masked from data entry researchers and from the trial statistician until after database lock. The primary outcome was self-reported prolapse symptoms (Pelvic Organ Prolapse Symptom Score [POP-SS]) at 2 years. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01171846. FINDINGS: Between Dec 21, 2008, and Feb 24, 2010, in New Zealand, and Oct 27, 2010, and Sept 5, 2011, in the UK, we randomly assigned 414 women to the intervention group (n=207) or the control group (n=207). One participant in each group was excluded after randomisation, leaving 412 women for analysis. At baseline, 399 (97%) women had prolapse above or at the level of the hymen. The mean POP-SS score at 2 years was 3·2 (SD 3·4) in the intervention group versus 4·2 (SD 4·4) in the control group (adjusted mean difference -1·01, 95% CI -1·70 to -0·33; p=0·004). The mean symptom score stayed similar across time points in the control group, but decreased in the intervention group. Three adverse events were reported, all of which were in the intervention group (one women had a fall, one woman had a pain in her tail bone, and one woman had chest pain and shortness of breath). INTERPRETATION: Our study shows that pelvic floor muscle training leads to a small, but probably important, reduction in prolapse symptoms. This finding will be important for women and caregivers considering preventive strategies. FUNDING: Wellbeing of Women charity, the New Zealand Continence Association, and the Dean's Bequest Fund of Dunedin School of Medicine.

Metformin Discontinuation prior to FDG PET/CT: A Randomized Controlled Study to Compare 24- and 48-hour Bowel Activity.

Purpose To investigate the relationship of 24- and 48-hour metformin discontinuation to bowel uptake of fluorine 18 fluorodeoxyglucose (FDG) on PET/CT scans. Materials and Methods Patients with diabetes who were treated with metformin and referred for FDG PET/CT were randomized to three equal groups based on duration of metformin discontinuation: 24 hours, 48 hours, and no discontinuation (control group). Two interpreters blinded to the study groups assessed FDG uptake in multiple segments of small and large bowel qualitatively and semiquantitatively by using maximum standardized uptake values (SUVsmax). Differences in age, sex, weight, dose of metformin, duration of metformin treatment, blood glucose levels, and FDG dose injected were assessed. Data were analyzed with analysis of variance when passing normality, and by nonparametric testing when not. Results Ninety study participants (62 male, 28 female; median age, 70 years) were enrolled from July 2010 through March 2012. There were no differences between study groups in weight, blood glucose levels 3 days prior to scanning, or normal organ uptake. Large bowel SUVmax was lower after 24 hours (4.10 ± 2.00 vs 5.42 ± 2.36; P = .020) and 48 hours (2.63 ± 0.88 vs 5.42 ± 2.36; P ˂ .001) of metformin discontinuation than for no discontinuation (control), and for 48 hours versus 24 hours of discontinuation (P = .0015). Small bowel SUVmax was lower after 24 hours (2.86 ± 0.67 vs 3.73 ± 1.08 [control]; P ˂ .001) and 48 hours (2.78 ± 0.73 vs 3.73 ± 1.08 [control]; P ˂ .001) of metformin discontinuation versus no metformin discontinuation, but not for 48 hours versus 24 hours of discontinuation (P = .57). Examination-day blood glucose levels increased after 48-hour withdrawal of metformin (8.41 mmol/L ± 2.86 vs 6.83 mmol/L ± 2.13 [control]; P = .002). Conclusion Metformin discontinuation for 48 hours prior to PET/CT was associated with lower accumulation of fluorodeoxyglucose in the bowel, compared to when there was no discontinuation (control group) or 24-hour discontinuation of metformin. © RSNA, 2018.

Predicting risk of pelvic floor disorders 12 and 20 years after delivery.

BACKGROUND: Little progress has been made in the prevention of pelvic floor disorders, despite their significant health and economic impact. The identification of women who are at risk remains a key element in targeting prevention and planning health resource allocation strategies. Although events around the time of childbirth are recognized clinically as important predictors, it is difficult to counsel women and to intervene around the time of childbirth because of an inability to convey a patient's risk accurately in the presence of multiple risk factors and the long time lapse, which is often decades, between obstetric events and the onset of pelvic floor disorders later in life. Prediction models and scoring systems have been used in other areas of medicine to identify patients who are at risk for chronic diseases. Models have been developed for use before delivery that predict short-term risk of pelvic floor disorders after childbirth, but no models that predict long-term risk exist. OBJECTIVE: The purpose of this study was to use variables that are known before and during childbirth to develop and validate prognostic models that will estimate the risks of these disorders 12 and 20 years after delivery. STUDY DESIGN: Obstetric variables were collected from 2 cohorts: (1) women who gave birth in the United Kingdom and New Zealand (n=3763) and (2) women from the Swedish Medical Birth Register (n=4991). Pelvic floor disorders were self-reported 12 years after childbirth in the United Kingdom/New Zealand cohort and 20 years after childbirth in the Swedish Register. The cohorts were split so that data during the first half of the cohort's time period were used to fit prediction models, and validation was performed from the second half (temporal validation). Because there is currently no consensus on how to best define pelvic floor disorders from a patient's perspective, we chose to fit the data for each model using multiple outcome definitions for prolapse, urinary incontinence, fecal incontinence, ≥1 pelvic floor disorder, and ≥2 pelvic floor disorders. Model accuracy was measured in the following manner: (1) by ranking an individual's risk among all subjects in the cohort (discrimination) with the use of a concordance index and (2) by observing whether the predicted probability was too high or low (calibration) at a range of predicted probabilities with the use of visual plots. RESULTS: Models were able to discriminate between women who experienced bothersome symptoms or received treatment at 12 and 20 years, respectively, for pelvic organ prolapse (concordance indices, 0.570, 0.627), urinary incontinence (concordance indices, 0.653, 0.689), fecal incontinence (concordance indices, 0.618, 0.676), ≥1 pelvic floor disorders (concordance indices, 0.639, 0.675), and ≥2 pelvic floor disorders (concordance indices, 0.635, 0.619). Route of delivery and family history of each pelvic floor disorder were strong predictors in most models. Urinary incontinence before and during the index pregnancy was a strong predictor for the development of all pelvic floor disorders in most models 12 years after delivery. The 12- and 20-year bothersome symptoms or treatment for prolapse models were accurate when predictions were provided for risk from 0% to approximately 15%. The 12- and 20-year primiparous model began to over predict when risk rates reached 20%. When we predicted bothersome symptoms or treatment for urinary incontinence, the 12-year models were accurate when predictions ranged from approximately 5-60%; the 20-year primiparous models were accurate from 5% and 80%. For bothersome symptoms or treatment for fecal incontinence, the 12- and 20-year models were accurate from 1-15% risk and began to over predict at rates at >15% and 20%, respectively. CONCLUSION: Models may provide an opportunity before birth to identify women who are at low risk of the development of pelvic floor disorders and may provide institute prevention strategies such as pelvic floor muscle training, weight control, or elective cesarean section for women who are at higher risk. Models are provided at http://riskcalc.org/UR_CHOICE/.

Diabetes management mediating effects between diabetes symptoms and health-related quality of life in adolescents and young adults with type 1 diabetes.

OBJECTIVES: The primary objective was to investigate the mediating effects of diabetes management in the relationship between diabetes symptoms and generic health-related quality of life (HRQOL) in adolescents and young adults (AYAs) with type 1 diabetes. The secondary objective explored patient health communication and perceived treatment adherence barriers as mediators in a serial multiple mediator model. METHODS: The PedsQL 3.2 Diabetes Module 15-item diabetes symptoms summary score, 18-item diabetes management summary score, and PedsQL 4.0 generic core scales were completed in a 10-site national field test study by 418 AYA aged 13 to 25 years with type 1 diabetes. Diabetes symptoms and diabetes management were tested for bivariate and multivariate linear associations with overall generic HRQOL. Mediational analyses were conducted to test the hypothesized mediating effects of diabetes management as an intervening variable between diabetes symptoms and generic HRQOL. RESULTS: The predictive effects of diabetes symptoms on HRQOL were mediated in part by diabetes management. In predictive analytics models utilizing multiple regression analyses, demographic and clinical covariates, diabetes symptoms, and diabetes management significantly accounted for 53% of the variance in generic HRQOL (P < 0.001), demonstrating a large effect size. Patient health communication and perceived treatment adherence barriers were significant mediators in an exploratory serial multiple mediator model. CONCLUSIONS: Diabetes management explains in part the effects of diabetes symptoms on HRQOL in AYA with type 1 diabetes. Patient health communication to healthcare providers and perceived treatment adherence barriers further explain the mechanism in the relationship between diabetes symptoms and overall HRQOL.

Experiences of gender incongruence and the relationship between social exclusion, psychological distress, and dysfunction among South African transgender adults: A field-study for ICD-11.

BACKGROUND: The classification of sexuality-related conditions and conditions relating to transgender identity has generated controversy. Growing evidence suggests that the distress and dysfunction reported by transgender individuals is more likely associated with social exclusion, stigmatization, and violence than as a result of gender incongruence per se. Our study aimed to explore the experiences of South African transgender individuals through: 1) their self-reported accounts of gender incongruence, and 2) associations between their experiences of social exclusion and violence, and their reports of psychological distress and dysfunction during adolescence. METHODS: Our sample of 57 South African transgender adults completed a structured interview, in English, including questions related to experiences of gender incongruence duration, distress, dysfunction, social exclusion, and violence. RESULTS: Many transgender individuals reported having experienced an intense desire to be a different gender, with all noting discomfort with several aspects of their bodies. Importantly, psychological distress and dysfunction were significantly associated with social exclusion (most commonly perpetuated by family and friends) and not with gender incongruence per se. CONCLUSIONS: This study adds to the growing evidence that experiences of social exclusion play a significant role in the psychological distress and dysfunction reported by transgender persons.

Diabetes symptoms predictors of health-related quality of life in adolescents and young adults with type 1 or type 2 diabetes.

OBJECTIVES: The objective was to investigate the patient-reported diabetes symptoms predictors of generic health-related quality of life (HRQOL) in adolescents and young adults (AYA) with type 1 or type 2 diabetes. METHODS: The 15-item PedsQL™ 3.2 Diabetes Module Diabetes Symptoms Summary Score and PedsQL™ 4.0 Generic Core Scales were completed in a 10-site national field test study by 513 AYA ages 13-25 years with type 1 (n = 424) or type 2 (n = 89) diabetes. Diabetes symptoms were tested for bivariate and multivariate linear associations with generic HRQOL. RESULTS: Diabetes symptoms were associated with decreased HRQOL in bivariate analyses. In predictive analytics models utilizing hierarchical multiple regression analyses controlling for relevant demographic and clinical covariates, diabetes symptoms accounted for 38 and 39% of the variance in patient-reported generic HRQOL for type 1 and type 2 diabetes, respectively, reflecting large effect sizes. The diabetes symptoms facets hyperglycemia symptoms, hypoglycemia symptoms, and nonspecific diabetes symptoms individually accounted for a significant percentage of the variance in separate exploratory predictive analytics models after controlling for demographic and clinical covariates, with small-to-large effect sizes. CONCLUSIONS: Diabetes symptoms are potentially modifiable predictors of generic HRQOL in AYA with diabetes. Identifying specific diabetes symptoms or symptoms facets that are the most important predictors from the patient perspective facilitates a patient-centered approach in clinical research, clinical trials, and practice designed to enhance overall generic HRQOL in AYA with diabetes.

Distinct intrinsic functional brain network abnormalities in methamphetamine-dependent patients with and without a history of psychosis.

Chronic methamphetamine use is associated with executive functioning deficits that suggest dysfunctional cognitive control networks (CCNs) in the brain. Likewise, abnormal connectivity between intrinsic CCNs and default mode networks (DMNs) has also been associated with poor cognitive function in clinical populations. Accordingly, we tested the extent to which methamphetamine use predicts abnormal connectivity between these networks, and whether, as predicted, these abnormalities are compounded in patients with a history of methamphetamine-associated psychosis (MAP). Resting-state fMRI data were acquired from 46 methamphetamine-dependent patients [19 with MAP, 27 without (MD)], as well as 26 healthy controls (CTRL). Multivariate network modelling and whole-brain voxel-wise connectivity analyses were conducted to identify group differences in intrinsic connectivity across four cognitive control and three DMN networks identified using an independent components analysis approach (meta-ICA). The relationship of network connectivity and psychotic symptom severity, as well as antipsychotic treatment and methamphetamine use variables, was also investigated. Robust evidence of hyper-connectivity was observed between the right frontoparietal and anterior DMN networks in MAP patients, and 'normalized' with increased duration of treatment with antipsychotics. Attenuation of anticorrelated anterior DMN-dorsal attention network activity was also restricted to this group. Elevated coupling detected in MD participants between anterior and posterior DMN networks became less apparent with increasing duration of abstinence from methamphetamine. In summary, we observed both alterations of RSN connectivity between DMN networks with chronic methamphetamine exposure, as well as DMN-CCN coupling abnormalities consistent with possible MAP-specific frontoparietal deficits in the biasing of task-appropriate network activity.

Social cognition and aggression in methamphetamine dependence with and without a history of psychosis.

In substance use and psychotic disorders, socially problematic behaviours, such as high aggression may, in part, be explained by deficits in social cognition skills, like the detection of emotions or intentions in others. The aim of this study was to assess the magnitude of social cognition impairment and its association with aggression in individuals with methamphetamine (MA) dependence, methamphetamine-associated psychosis (MAP), and healthy controls (CTRL). A total of 20 MAP participants, 21 MA-dependent participants without psychosis, and 21 CTRL participants performed a facial morphing emotion recognition task (ERT) across four basic emotions (anger, fear, happiness and sadness) and the reading the mind in the eyes task (RMET), and completed the aggression questionnaire. Both MA-dependent groups showed impairment in social cognition in terms of lower RMET scores relative to CTRL participants (MA; p = .047; MAP: p < .001). Additionally, performance decrements were significantly greater in MAP (p = .040), compared to MA-dependent participants. While deficits in recognising emotional expressions were restricted to anger in the MA group (p = .020), a generalized impairment across all four emotions was observed in MAP (all p ≤ .001). Additionally, both patient groups demonstrated higher levels of aggression than CTRLs, yet no association was found with social cognition. This study supported the notion of deficits in recognising facial emotional expressions and inferring mental states of others in MA dependence, with additional impairments in MAP. Failure to detect an association between social cognitive impairment and aggressive behaviour may implicate independent disturbances of the two phenomena in MA dependence.