A genetically encoded protein tag for control and quantitative imaging of CAR T cell therapy.

Chimeric antigen receptor (CAR) T cell therapy has been successful for hematological malignancies. Still, a lack of efficacy and potential toxicities have slowed its application for other indications. Furthermore, CAR T cells undergo dynamic expansion and contraction in vivo that cannot be easily predicted or controlled. Therefore, the safety and utility of such therapies could be enhanced by engineered mechanisms that engender reversible control and quantitative monitoring. Here, we use a genetic tag based on the enzyme Escherichia coli dihydrofolate reductase (eDHFR), and derivatives of trimethoprim (TMP) to modulate and monitor CAR expression and T cell activity. We fused eDHFR to the CAR C terminus, allowing regulation with TMP-based proteolysis-targeting chimeric small molecules (PROTACs). Fusion of eDHFR to the CAR does not interfere with cell signaling or its cytotoxic function, and the addition of TMP-based PROTACs results in a reversible and dose-dependent inhibition of CAR activity via the proteosome. We show the regulation of CAR expression in vivo and demonstrate imaging of the cells with TMP radiotracers. In vitro immunogenicity assays using primary human immune cells and overlapping peptide fragments of eDHFR showed no memory immune repertoire for eDHFR. Overall, this translationally-orientied approach allows for temporal monitoring and image-guided control of cell-based therapies.

Association of Systemic Lupus Erythematosus Disease Activity With Choroidal Thickness.

OBJECTIVE: To determine the association between disease activity and choroidal thickness in patients with systemic lupus erythematosus (SLE). METHODS: We conducted a cohort study of 24 SLE patients and 13 healthy controls recruited at Washington University School of Medicine between June 2019 and November 2021. SLE disease activity was assessed using the SLE Disease Activity Index-2000 Responder Index-50 (S2K RI-50). Patients were divided into four groups: high disease activity/no lupus nephritis (HDA/no LN; S2K RI-50 > 4), HDA/active LN (HDA/active LN; S2K RI-50 > 4), low disease activity/inactive LN (LDA/inactive LN; S2K RI-50 ≤ 4), and LDA/no LN (LDA/no LN; S2K RI-50 ≤ 4). LDA/no LN patients were age-, sex-, and race-matched to healthy controls and patients in other SLE groups. Choroidal thickness of the right eye was measured blinded to disease activity on a horizontal section through the fovea on optical coherence tomography images taken within a week of disease assessment. RESULTS: Patients with HDA had choroidal thickening compared with matched patients with LDA. After controlling for multiplicity, choroidal thinning remained statistically significant at 1000 µm nasal to the fovea (308 ± 68 vs 228 ± 64 µm, p = 0.001). Choroidal thickness was not different between LDA/no LN and LDA/inactive LN or healthy controls. CONCLUSION: HDA in patient with SLE is associated with increased choroidal thickness whereas comorbid inactive LN did not affect choroidal thickness. Additional studies in a larger longitudinal cohort are needed to study whether choroidal thickness may be used as a noninvasive, adjunctive measure for disease activity in SLE.

The incidence and importance of the pseudogestational sac revisited.

BACKGROUND: In a pregnancy of unknown location, an intrauterine fluid collection may represent either the early gestational sac of an intrauterine pregnancy, or as reported in previous literature, the pseudogestational sac of an ectopic pregnancy. Various sonographic features have been used to distinguish these 2 entities, but the clinical relevance of the pseudogestational sac remains unclear. OBJECTIVE: To establish the incidence and relative rate of intrauterine fluid collection among ectopic and intrauterine pregnancies and to determine if the size of the collection differs between ectopic and intrauterine pregnancies STUDY DESIGN: We performed a retrospective cohort study of women with pregnancies of unknown location and pelvic or abdominal pain or bleeding. We calculated the incidences of intrauterine fluid collections among ectopic and intrauterine pregnancies, including both ongoing pregnancies and spontaneous abortions, given that that our focus was location and not viability. We calculated the relative risk of ectopic pregnancy if an intrauterine fluid collection was present, adjusting for age and vaginal bleeding. We compared the incidences of ectopic and intrauterine pregnancies among those with and without intrauterine fluid collections. Among those with collections, we compared the mean sac diameter between ectopic and intrauterine pregnancies in continuous and categorical fashions. RESULTS: We evaluated 1236 women presenting with a pregnancy of unknown location. The rates of ectopic and intrauterine pregnancies (including spontaneous abortions) were 13.1% and 63.9%, respectively, with the remainder lost to follow-up. On ultrasound, 452 women (36.6%) had an intrauterine fluid collection. Eight of 162 ectopic pregnancies (4.9%) had a collection, compared with 363 of 789 intrauterine pregnancies (46.0%) (P=.01). Of the ectopics with a fluid collection, 5 had an adnexal mass. The presence of intrauterine fluid collection decreased the risk of ectopic pregnancy (adjusted relative risk, 0.09; 95% confidence interval, 0.05-0.19) after adjusting for age and the presence of bleeding. Among those with an intrauterine fluid collection, the rate of ectopic pregnancy was 2.2%, and the rate of intrauterine pregnancy was 97.8%; among those without a collection, the rate of ectopic pregnancy was 26.7%, and the rate of intrauterine pregnancy was 73.3%. The mean sac diameter did not differ between ectopic and intrauterine pregnancies, whether analyzed continuously or categorically. CONCLUSION: In the presence of an intrauterine fluid collection, the rate of ectopic pregnancy is very low. The size of the intrauterine fluid collection in a woman with a pregnancy of unknown location cannot be used to distinguish between a gestational sac and a pseudogestational sac. Pseudogestational sacs are uncommon and of little clinical consequence. In assessing pregnancies of unknown location, clinicians should incorporate the entire clinical picture, including other sonographic findings, to avoid incorrect or delayed diagnoses.

Postpartum weight retention in women with polycystic ovary syndrome.

BACKGROUND: Compared with women without polycystic ovary syndrome, women with polycystic ovary syndrome have a higher prevalence of cardiometabolic risk factors. Postpartum weight retention has been shown to contribute to these risks in the general population, but little is known about postpartum weight retention among women with polycystic ovary syndrome. OBJECTIVE: This study aimed to compare postpartum weight retention and peripartum weight trends between women with polycystic ovary syndrome and controls. STUDY DESIGN: Data on live, full-term singleton deliveries from January 1, 2014, to January 1, 2019, in women with and without polycystic ovary syndrome were abstracted from the electronic medical record. Weights during the pregestational period, pregnancy, and up to 12 months postpartum were collected. The primary outcome was likelihood of high postpartum weight retention of ≥5 kg above pregestational weight at 12 months after delivery. Secondary outcomes included the prevalence of high weight retention at other postpartum time points (6 weeks, 3 months, 6 months), absolute postpartum weight retention, gestational weight gain, and excess weight gain above the Institute of Medicine guidelines for weight gain in pregnancy. RESULTS: A total of 6333 women had the requisite weight information (pregestational, peak pregnancy, and at least 1 postpartum weight), including 429 (6.8%) with polycystic ovary syndrome. After adjusting for age, pregestational body mass index, race, gestational diabetes mellitus, and parity, women with polycystic ovary syndrome were less likely to be high weight retainers at 6 weeks after delivery (adjusted odds ratio, 0.71; P=.02). There was no difference in postpartum weight retention between groups at 3, 6, and 12 months after delivery. Overall, the prevalence of high weight retainers at 12 months after delivery was high in both groups (22.7% in polycystic ovary syndrome vs 29.2% in controls; P=.13), and there was no difference in absolute weight retention (1.69 kg in polycystic ovary syndrome vs 2.05 kg in controls; P=.25). Although women with polycystic ovary syndrome had a higher pregestational body mass index, they had lower gestational weight gain (median, 12.7 kg) than controls (median, 13.5 kg) (P=.01). These findings were driven by the group with obesity. The percentage of women who surpassed the Institute of Medicine guidelines for gestational weight gain based on the body mass index category was similar between groups (43.4% in polycystic ovary syndrome vs 47.3% in controls; P=.12). Overall, 18.5% of women with polycystic ovary syndrome and 23.4% of controls had a higher body mass index category at 12 months after delivery than before pregnancy. CONCLUSION: Women with polycystic ovary syndrome had lower gestational weight gain and lower likelihood of high weight retention at 6 weeks after delivery but similar weight retention at 12 months after delivery compared with controls. Overall, the large proportion of women with high postpartum weight retention highlights the importance of the peripartum time period for weight management, particularly in this high-risk group predisposed to obesity and cardiometabolic disease.

Development and validation of lupus nephritis case definitions using United States veterans affairs electronic health records.

OBJECTIVE: International Classification of Diseases (ICD) codes are commonly used to identify patients with rare diseases in electronic health records (EHRs). However, misclassification is common, impacting the validity of study results. In this study, we compared the accuracies of several ICD-based case definitions of lupus nephritis (LN) in identifying United States veterans with LN. METHODS: Using the Department of Veterans Affairs (VA) EHR, we identified all veterans with ≥1 ICD-9 or 10 diagnostic codes for systemic lupus erythematosus (SLE) between October 1, 1999 and September 30, 2017. A cohort was randomly selected for diagnostic validation and 9 ICD-based LN case definitions were applied to this cohort. The diagnostic accuracy of each definition was assessed against gold standard criterion of biopsy-proven LN. RESULTS: 18,420 veterans had ≥1 ICD-9 or 10 diagnostic codes for SLE; 981 were randomly selected for diagnostic validation. 95 veterans (9.7%) had biopsy-proven LN. The case definitions had high specificity and NPV but variable sensitivity and PPV. The definition containing ≥2 ICD -9 codes for SLE and ≥2 nephritis indicators had the highest combination of sensitivity and specificity (87.4% and 94.6% respectively). ICD-10 code for LN had high specificity (99.8%) and PPV (93.9%). CONCLUSION: ICD-based case definitions of LN in the VA population have high specificity and NPV but variable sensitivity and PPV. Our results may help guide the design of future LN studies in VA cohorts. The choice of specific case definitions depends on the relative importance of different accuracy measures to individual studies.

Evaluation of a convolutional neural network for ovarian tumor differentiation based on magnetic resonance imaging.

OBJECTIVES: There currently lacks a noninvasive and accurate method to distinguish benign and malignant ovarian lesion prior to treatment. This study developed a deep learning algorithm that distinguishes benign from malignant ovarian lesion by applying a convolutional neural network on routine MR imaging. METHODS: Five hundred forty-five lesions (379 benign and 166 malignant) from 451 patients from a single institution were divided into training, validation, and testing set in a 7:2:1 ratio. Model performance was compared with four junior and three senior radiologists on the test set. RESULTS: Compared with junior radiologists averaged, the final ensemble model combining MR imaging and clinical variables had a higher test accuracy (0.87 vs 0.64, p < 0.001) and specificity (0.92 vs 0.64, p < 0.001) with comparable sensitivity (0.75 vs 0.63, p = 0.407). Against the senior radiologists averaged, the final ensemble model also had a higher test accuracy (0.87 vs 0.74, p = 0.033) and specificity (0.92 vs 0.70, p < 0.001) with comparable sensitivity (0.75 vs 0.83, p = 0.557). Assisted by the model's probabilities, the junior radiologists achieved a higher average test accuracy (0.77 vs 0.64, Δ = 0.13, p < 0.001) and specificity (0.81 vs 0.64, Δ = 0.17, p < 0.001) with unchanged sensitivity (0.69 vs 0.63, Δ = 0.06, p = 0.302). With the AI probabilities, the junior radiologists had higher specificity (0.81 vs 0.70, Δ = 0.11, p = 0.005) but similar accuracy (0.77 vs 0.74, Δ = 0.03, p = 0.409) and sensitivity (0.69 vs 0.83, Δ = -0.146, p = 0.097) when compared with the senior radiologists. CONCLUSIONS: These results demonstrate that artificial intelligence based on deep learning can assist radiologists in assessing the nature of ovarian lesions and improve their performance. KEY POINTS: • Artificial Intelligence based on deep learning can assess the nature of ovarian lesions on routine MRI with higher accuracy and specificity than radiologists. • Assisted by the deep learning model's probabilities, junior radiologists achieved better performance that matched those of senior radiologists.

Image Fusion-Augmented Angiography Improves Right Adrenal Vein Cannulation Success Rate in Adrenal Vein Sampling.

Image fusion-augmented angiography to guide cannulation during adrenal vein sampling (AVS) entails fusion between preprocedural CT images on which ring markers indicate adrenal vein ostia and live digital subtraction angiography fluoroscopic images. In patients who underwent adrenal vein sampling (18 without, 23 with image fusion-augmented angiography), image fusion-augmented angiography increased the success rate of right adrenal vein cannulation (55.6% to 87.0%; p = .04) and reduced fluoroscopy time (23.7 to 16.3 minutes; p = .03) and dose area product (532,195 to 91,403 mGy ∙ cm2; p = .006).

Update on ophthalmic manifestations of systemic lupus erythematosus: pathogenesis and precision medicine.

PURPOSE OF REVIEW: Systemic lupus erythematosus (SLE) is an autoimmune disease with manifestations in multiple organs including the eyes. Several ocular manifestations like dry eye, retinopathy, and choroidopathy have been linked with specific systemic manifestations like lupus nephritis or CNS disease. Furthermore, the presence of ocular manifesattions can correlated with the severity of SLE. Finally, some medications used in the treatment of uveitis can present with lupus-like disease. Therefore, communication between the ophthalmologist and rheumatologist is vital. RECENT FINDINGS: Ocular and systemic manifestations of SLE can be linked by common pathological processes including immune complex deposition, complement fixation, and vascular injury. Recent research correlating ophthalmic imaging with SLE disease has yielded heterogeneous results likely due to the clinical heterogeneity of SLE, but molecular technologies have and will continue to yield contributions to the emergence of new therapeutics for the treatment of SLE. SUMMARY: Ocular manifestations are prevalent in patients with SLE. The association with certain manifestations and other disease manifestations highlights the importance of collaboration between the ophthalmologist and rheumatologist. Additional research utilizing clinico-molecular techniques will likely continue to improve our knowledge in the treatment of SLE in the future.

Effects of a culturally adapted group based Montessori based activities on engagement and affect in Chinese older people with dementia: a randomized controlled trial.

BACKGROUND: The Montessori Method underpinned by the principle of person-centered care has been widely adopted to design activities for people with dementia. However, the methodological quality of the existing evidence is fair. The objectives of this study are to examine the feasibility and effects of a culturally adapted group-based Montessori Method for Dementia program in Chinese community on engagement and affect in community-dwelling people with dementia. METHODS: This was a two-arm randomized controlled trial. People who were aged 60 years or over and with mild to moderate dementia were recruited and randomly assigned to the intervention group to receive Montessori-based activities or the comparison group to receive conventional group activities over eight weeks. The attendance rates were recorded for evaluating the feasibility. The Menorah Park Engagement Scale and the Apparent Affect Rating Scale were used to assess the engagement and affect during the activities based on observations. Generalized Estimating Equation model was used to examine the intervention effect on the outcomes across the sessions. RESULTS: A total of 108 people with dementia were recruited. The average attendance rate of the intervention group (81.5%) was higher than that of the comparison group (76.3%). There was a significant time-by-group intervention effect on constructive engagement in the first 10 minutes of the sessions (Wald χ2 = 15.21-19.93, ps = 0.006-0.033), as well as on pleasure (Wald χ2 = 25.37-25.73, ps ≤ 0.001) and interest (Wald χ2 = 19.14-21.11, ps = 0.004-0.008) in the first and the middle 10 minutes of the sessions, adjusted for cognitive functioning. CONCLUSIONS: This study provide evidence that Montessori-based group activities adapted to the local cultural context could effectively engage community-dwelling Chinese older people with mild to moderate dementia in social interactions and meaningful activities and significantly increase their positive affect. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04352387. Registered 20 April 2020. Retrospectively registered.

An information-motivation-behavioural-based model and adherence to inhalation therapy and other health outcomes in patients with chronic obstructive pulmonary disease: A pilot randomized controlled trial.

AIMS: To explore the feasibility and effects of the programme based on information-motivation-behavioural skills (IMB) model (IMB programme) on adherence to inhalation therapy and other health outcomes in chronic obstructive pulmonary disease (COPD) patients. BACKGROUND: Poor adherence to inhalation therapy is common among COPD patients. The IMB model is supported by previous studies as useful in promoting adherence to health behaviours. METHODS: This pilot randomized controlled trial randomized 35 COPD patients to receive either the IMB-based programme or usual care. The 4-week IMB programme consisted of a face-to-face and two telephone sessions to empower patients with skills and knowledge on using inhalation therapy and support their goal attainment for treatment compliance. Outcome evaluation including adherence to inhalation therapy, inhalation techniques, disease impact, and quality of life was conducted at baseline and at 6 weeks after randomization. Feasibility of the IMB programme was evaluated by a satisfaction survey and implementation experience. RESULTS: Thirty patients completed the study, with an attrition rate of 14.3%. The intervention group (n = 15) had significant improvements in inhalation adherence, inhalation techniques, and quality of life than the control group over the evaluation period. Patient satisfaction survey results and observations on programme implementation suggested the feasibility of the IMB programme. CONCLUSION: A IMB model is a feasible and potentially effective intervention for improving COPD patients' adherence to inhalation therapy.

Development of a Rhinovirus Inoculum Using a Reverse Genetics Approach.

BACKGROUND: Experimental inoculation is an important tool for common cold and asthma research. Producing rhinovirus (RV) inocula from nasal secretions has required prolonged observation of the virus donor to exclude extraneous pathogens. We produced a RV-A16 inoculum using reverse genetics and determined the dose necessary to cause moderate colds in seronegative volunteers. METHODS: The consensus sequence of RV-A16 from a previous inoculum was cloned, and inoculum virus was produced using reverse genetics techniques. After safety testing, volunteers were inoculated with either RV-A16 (n = 26) or placebo (n = 10), Jackson cold scores were recorded, and nasal secretions were tested for shedding of RV-A16 ribonucleic acid. RESULTS: The reverse genetics process produced infectious virus that was neutralized by specific antisera and had a mutation rate similar to conventional virus growth techniques. The 1000 median tissue culture infectious dose (TCID50) dose produced moderate colds in most individuals with effects similar to that of a previously tested conventional RV-A16 inoculum. CONCLUSIONS: Reverse genetics techniques produced a RV-A16 inoculum that can cause clinical colds in seronegative volunteers, and they also serve as a stable source of virus for laboratory use. The recombinant production procedures eliminate the need to derive seed virus from nasal secretions, thus precluding introduction of extraneous pathogens through this route.

Measuring exercise self-efficacy in Hong Kong Chinese adults with cardiovascular risk: Validation of a Chinese version of the Cardiac Exercise Self-efficacy Instrument.

About one-third of adults are physically inactive and thus prone to cardiovascular diseases. While self-efficacy mediates health behavior, its influences on exercise behavior among Chinese is yet to be explored by a validated instrument. This study aimed to examine the psychometric properties of the Hong Kong Chinese version of the Cardiac Exercise Self-efficacy Instrument (CESEI-C), which had been translated previously by these authors. The psychometric properties of the CESEI-C were tested with 160 Hong Kong Chinese with cardiovascular risk. Participants were asked to complete the CESEI-C, a physical activity assessment tool, and perform the exercise stress test. Exploratory factor analysis identified a unidimensional structure of the CESEI-C. Good internal consistency (Cronbach's alpha = 0.91) and good content validity (content validity indices: 0.93-1.00) had been reported previously. The convergent validity of the CESEI-C was supported by the significant positive correlations between the CESEI-C score and the amount of moderate-to-vigorous exercise (r = 0.18, p = 0.03), and exercise capacity (r = 0.30, p < 0.01). A comparison of CESEI-C scores by exercise capacities indicated that those with moderate-to-high exercise capacity had significantly higher CESEI scores than those with low exercise capacity (t = 2.105, p = 0.04). Thus, the CESEI-C is a valid and reliable instrument to measure exercise self-efficacy among Hong Kong Chinese.

Increased odds of disordered eating in polycystic ovary syndrome: a systematic review and meta-analysis.

PURPOSE: We aimed to identify the risk of eating disorders (ED) in women with polycystic ovary syndrome (PCOS) compared to controls. METHODS: We performed a systematic review and meta-analysis of studies that included women with well-defined PCOS and controls and used validated ED screening/diagnostic tools to measure mean ED score, prevalence of abnormal ED scores, and/or prevalence of specific ED diagnoses such as bulimia nervosa and binge eating disorder. RESULTS: Eight studies, including 470 women with PCOS and 390 controls, met inclusion criteria for the systematic review. Meta-analysis of seven of those studies found that the odds of an abnormal ED score (OR 3.05; 95% CI 1.33, 6.99; four studies) and the odds of any ED diagnosis (OR 3.87; 95% CI 1.43, 10.49; four studies) were higher in women with PCOS compared to controls. CONCLUSIONS: Our study suggests that women with PCOS are at increased odds of having abnormal ED scores and specific ED diagnoses. Given the potential implications of an ED on weight management strategies, our findings support routine screening for ED in this population. LEVEL OF EVIDENCE: Level I, systematic review and meta-analysis.

Targeted inhibition of Axl receptor tyrosine kinase ameliorates anti-GBM-induced lupus-like nephritis.

Glomerulonephritis (GN) is a typical lesion in autoantibody and immune complex disorders, including SLE. Because the Gas6/Axl pathway has been implicated in the pathogenesis of many types of GN, targeting this pathway might ameliorate GN. Consequently, we have studied the efficacy and mechanism of R428, a potent selective Axl inhibitor, in the prevention of experimental anti-GBM nephritis. Axl upregulation was investigated with Sp1/3 siRNA in the SV40-transformed mesangial cells. For Axl inhibition, a daily dose of R428 (125 mg/kg) or vehicle was administered orally. GN was induced with anti-GBM sera. Renal disease development was followed by serial blood urine nitrogen (BUN) determinations and by evaluation of kidney histology at the time of sacrifice. Axl-associated signaling proteins were analyzed by Western blotting and inflammatory cytokine secretion was analyzed by Proteome array. SiRNA data revealed the transcription factor Sp1 to be an important regulator of mesangial Axl expression. Anti-GBM serum induced severe nephritis with azotemia, protein casts and necrotic cell death. R428 treatment diminished renal Axl expression and improved kidney function, with significantly decreased BUN and glomerular proliferation. R428 treatment inhibited Axl and significantly decreased Akt phosphorylation and renal inflammatory cytokine and chemokine expression; similar effects were observed in anti-GBM antiserum-treated Axl-KO mice. These studies support a role for Axl inhibition in glomerulonephritis.

Multicenter evaluation of the clinical utility of laparoscopy-assisted ERCP in patients with Roux-en-Y gastric bypass.

BACKGROUND AND AIMS: The obesity epidemic has led to increased use of Roux-en-Y gastric bypass (RYGB). These patients have an increased incidence of pancreaticobiliary diseases, yet standard ERCP is not possible because of surgically altered gastroduodenal anatomy. Laparoscopy-assisted ERCP (LA-ERCP) has been proposed as an option, but supporting data are derived from single-center small case series. Therefore, we conducted a large multicenter study to evaluate the feasibility, safety, and outcomes of LA-ERCP. METHODS: This is a retrospective cohort study of adult patients with RYGB who underwent LA-ERCP in 34 centers. Data on demographics, indications, procedure success, and adverse events were collected. Procedure success was defined when all the following were achieved: reaching the papilla, cannulating the desired duct, and providing endoscopic therapy as clinically indicated. RESULTS: A total of 579 patients (median age, 51; 84% women) were included. Indication for LA-ERCP was biliary in 89%, pancreatic in 8%, and both in 3%. Procedure success was achieved in 98%. Median total procedure time was 152 minutes (interquartile range [IQR], 109-210), with a median ERCP time of 40 minutes (IQR, 28-56). Median hospital stay was 2 days (IQR, 1-3). Adverse events were 18% (laparoscopy related, 10%; ERCP related, 7%; both, 1%) with the clear majority (92%) classified as mild/moderate, whereas 8% were severe and 1 death occurred. CONCLUSIONS: Our large multicenter study indicates that LA-ERCP in patients with RYGB is feasible with a high procedure success rate comparable with that of standard ERCP in patients with normal anatomy. The ERCP-related adverse events rate is comparable with conventional ERCP, but the overall adverse event rate was higher because of the added laparoscopy-related events.

What Is an Ectopic Pregnancy?

This JAMA Patient Page describes ectopic pregnancy and its risk factors, symptoms, diagnosis, and treatment.

High prevalence of moderate and severe depressive and anxiety symptoms in polycystic ovary syndrome: a systematic review and meta-analysis.

STUDY QUESTION: Do women with polycystic ovary syndrome (PCOS) have an increased prevalence of moderate and severe depressive and anxiety symptoms compared with control women, and do these symptoms correlate with age, BMI, testosterone, hirsutism or insulin resistance (IR)? SUMMARY ANSWER: Women with PCOS have significantly increased odds of moderate and severe depressive and anxiety symptoms, independent of obesity, and the symptoms are weakly associated with age, BMI, elevated testosterone, hirsutism and IR. WHAT IS KNOWN ALREADY: Previous studies have reported that women with PCOS have an increased prevalence of mild depressive and anxiety symptoms or an increase in mean depression and anxiety scores, although these scores are usually within the normal range. Thus, it is therefore not clear whether these findings are clinically significant. The prevalence of moderate and severe depressive and anxiety symptoms, which require follow-up and would benefit from treatment, is not known in this population. STUDY DESIGN, SIZE, DURATION: A comprehensive systematic review (SR) was performed up to January 2016 and included 30 cross-sectional studies, representing 3050 subjects with PCOS and 3858 controls, from 10 different countries. The meta-analysis (MA) on depressive symptoms included 18 studies and the MA on anxiety symptoms included 9 studies. A separate SR identified 15 studies for the meta-regression examining the associations with PCOS-related symptoms or comorbidities. PARTICIPANTS/MATERIALS, SETTING, METHODS: All studies included adult women with PCOS, defined by the National Institutes of Health or Rotterdam criteria, and a control group without PCOS. Ovid, Embase, PsychInfo and Cochrane were searched up to January 2016. Included studies used a validated screening tool to compare the prevalence or mean scores of depressive and/or anxiety symptoms. Random effects MA was used to estimate the pooled odds ratio (OR) of depressive and anxiety symptoms. Sensitivity analyses of methodological characteristics and a meta-regression of the pooled standardized mean difference (SMD) to evaluate PCOS-related clinical and laboratory associations were performed. MAIN RESULTS AND THE ROLE OF CHANCE: Women with PCOS had increased odds of any depressive symptoms (OR: 3.78; 95% CI: 3.03-4.72; 18 studies) and of moderate/severe depressive symptoms (OR: 4.18; 95% CI: 2.68-6.52; 11 studies). Women with PCOS had increased odds of any anxiety symptoms (OR: 5.62; 95% CI: 3.22-9.80, nine studies) and of moderate/severe anxiety symptoms (OR: 6.55; 95% CI: 2.87, 14.93; five studies). When subjects were matched on BMI, women with PCOS still had higher odds of both depressive (OR: 3.25; 95% CI 1.73-6.09; four studies) and anxiety symptoms (OR: 6.30, 95% CI: 1.88-21.09; three studies). There was no substantial heterogeneity among studies in the overall MA on depressive symptoms (I2 = 22.4%, P = 0.19), but there was significant heterogeneity among studies in the analysis on anxiety symptoms (I2 = 59.6%, P= 0.01). In the meta-regression evaluating pooled SMDs between groups, women with PCOS and concurrent depression had higher mean values of age, BMI, hirsutism score and IR, while women with PCOS and concurrent anxiety had higher mean values of BMI, hirsutism score and free testosterone (P < 0.05 for all comparisons). LIMITATIONS, REASON FOR CAUTION: All studies were cross-sectional, thus we can only hypothesize that the diagnosis of PCOS precedes the diagnosis of depression and anxiety. There were large variations in methodological characteristics especially in the studies screening for anxiety; however, they only partly explained effect size variation. WIDER IMPLICATIONS OF THE FINDINGS: This evidence-synthesis analysis shows that PCOS diagnosis is associated with an increased risk of moderate and severe depressive and anxiety symptoms and suggests that providers should consider screening women with PCOS for both depression and anxiety. Although age, obesity, hyperandrogenism and IR do not explain the entire association, well-designed studies are needed to assess the impact of treatment of these factors on depressive and anxiety symptoms in women with PCOS. STUDY FUNDING/COMPETING INTEREST(S): No funding was used for this study. There are no conflicts of interest. REGISTRATION NUMBER: N/A.

Diffusion Tensor Tractography of the Cerebellar Peduncles in Prematurely Born 7-Year-Old Children.

The objective of this study was to correlate neurodevelopmental outcome of preterm-born children and their perinatal clinical and imaging characteristics with diffusion magnetic resonance imaging (MRI) measures of the three cerebellar peduncles at age 7. Included in this prospective longitudinal study were 140 preterm-born children (<30 weeks gestation) who underwent neurodevelopmental assessment (IQ, motor, language, working memory) and diffusion-weighted imaging (DWI) at age 7 years. White matter tracts in the superior, middle, and inferior cerebellar peduncles were delineated using regions of interest drawn on T2-weighted images and fractional anisotropy (FA) maps. Diffusion measures (mean diffusivity (MD) and FA) and tract volumes were calculated. Linear regression was used to assess relationships with outcome. The severity of white matter injury in the neonatal period was associated with lower FA in the right superior cerebellar peduncle (SCP) and lower tract volumes of both SCPs and middle cerebellar peduncles (MCPs). In the MCP, higher IQ was associated with lower MD in the whole group and higher FA in right-handed children. In the SCP, lower motor scores were associated with higher MD and higher language scores were associated with higher FA. These associations remained significant in multivariable models. This study adds to the body of literature detailing the importance of cerebellar involvement in cognitive function related to reciprocal connections with supratentorial structures.

Effects of Lifestyle Intervention on Physiological Outcomes in Chinese Adults With, or at High Risk of, Metabolic Syndrome.

BACKGROUND: Metabolic syndrome (MS) increases the risk of cardiovascular events and the development of diabetes. This article reports the effects of lifestyle intervention on the physiological outcomes of people with or at high risk of MS in the community setting of Hong Kong. METHODS: Chinese adults with 2 or more MS components were recruited from 13 community centers, which were cluster-randomized to the intervention or control group. The intervention group received a low-intensity lifestyle intervention program for people with MS consisting of group sessions, individual counseling, and telephone follow-ups over 3 months. The control group received standard care plus an attention placebo. The primary outcomes were body weight and waist circumference, whereas the secondary outcomes included blood pressure, lipids, glucose, and number of MS components. Linear mixed-effects models were used to compare the effects of the program between the 2 groups. RESULTS: The final sample consisted of 183 adults (19.1% male) with a mean (SD) age of 54.0 (7.8) years. At 3 months, overall MS prevalence was reduced to 13.8%. Compared with the control group, subjects in the intervention group exhibited a reduced waist circumference (ß = -.146, P = .008) when the interaction effects of time and group were considered simultaneously. However, no significant differences were found for changes in the other measured outcomes. CONCLUSION: A low-intensity lifestyle intervention program for people with MS can reduce central obesity among people with or at high risk for MS. Further research is necessary to confirm the long-term physiological effects of the intervention.