CD19 CAR T cells for B cell malignancies: a systematic review and meta-analysis focused on clinical impacts of CAR structural domains, manufacturing conditions, cellular product, doses, patient's age, and tumor types.

CD19-targeted chimeric antigen receptors (CAR) T cells are one of the most remarkable cellular therapies for managing B cell malignancies. However, long-term disease-free survival is still a challenge to overcome. Here, we evaluated the influence of different hinge, transmembrane (TM), and costimulatory CAR domains, as well as manufacturing conditions, cellular product type, doses, patient's age, and tumor types on the clinical outcomes of patients with B cell cancers treated with CD19 CAR T cells. The primary outcome was defined as the best complete response (BCR), and the secondary outcomes were the best objective response (BOR) and 12-month overall survival (OS). The covariates considered were the type of hinge, TM, and costimulatory domains in the CAR, CAR T cell manufacturing conditions, cell population transduced with the CAR, the number of CAR T cell infusions, amount of CAR T cells injected/Kg, CD19 CAR type (name), tumor type, and age. Fifty-six studies (3493 patients) were included in the systematic review and 46 (3421 patients) in the meta-analysis. The overall BCR rate was 56%, with 60% OS and 75% BOR. Younger patients displayed remarkably higher BCR prevalence without differences in OS. The presence of CD28 in the CAR's hinge, TM, and costimulatory domains improved all outcomes evaluated. Doses from one to 4.9 million cells/kg resulted in better clinical outcomes. Our data also suggest that regardless of whether patients have had high objective responses, they might have survival benefits from CD19 CAR T therapy. This meta-analysis is a critical hypothesis-generating instrument, capturing effects in the CD19 CAR T cells literature lacking randomized clinical trials and large observational studies.

Endometriosis in infertile women: an observational and comparative study of quality of life, anxiety, and depression.

BACKGROUND: A women's chances of getting pregnant decreases in cases of infertility, which may have several clinical etiologies. The prevalence of infertility is estimated as 10-15% worldwide. One of the causes of infertility is endometriosis, defined as the presence of an endometrial gland and/or stroma outside the uterus, inducing a chronic inflammatory reaction. Thus, infertility and endometriosis are diagnoses that significantly affect women's mental health. This study accessed and compared the levels of depression, anxiety, and quality of life in infertile women with and without endometriosis. METHODS: was an observational and cross-sectional study which included 201 infertile women, 81 of whom were also diagnosed with endometriosis. The STROBE Guidelines was used. The data were collected using validated scales: Hamilton D Questionnaire, Beck Depression Inventory, and Fertility Quality of Life Questionnaire; The data were collected at the Ideia Fertil Institute (Santo Andre, Brazil), between February 28 and June 8, 2019. RESULTS: the infertile women with endometriosis reported higher presence of depressive symptoms and a lower quality of life compared to women with infertility only. Similar presence of anxiety symptoms was observed regardless of being diagnosed with endometriosis. Women with infertility and endometriosis presented lower levels in quality-of-life domains when compared to women with infertility only - Mind and Body (58.33 × 79.17, p < 0.001), Relational (75 × 81.25, p = 0.009), Social (66.67 × 77.08, p = 0.001), Emotional (50.62 × 67.43, p < 0.001). CONCLUSION: the findings indicate the need for increased psychosocial support care for women suffering from infertility and endometriosis to assist them in maintaining and managing their own mental health and achieving their reproductive goals.

Implementing high-value, cost-conscious care: experiences of Irish doctors and the role of education in facilitating this approach.

BACKGROUND: Adopting high-value, cost-conscious care (HVCCC) principles into medical education is growing in importance due to soaring global healthcare costs and the recognition that efficient care can enhance patient outcomes and control costs. Understanding the current opportunities and challenges doctors face concerning HVCCC in healthcare systems is crucial to tailor education to doctors' needs. Hence, this study aimed to explore medical students, junior doctors, and senior doctors' experiences with HVCCC, and to seek senior doctors' viewpoints on how education can foster HVCCC in clinical environments. METHODS: Using a mixed-methods design, our study involved a cross-sectional survey using the Maastricht HVCCC-Attitude Questionnaire (MHAQ), with a subset of consultants engaging in semi-structured interviews. Descriptive analysis provided insights into both categorical and non-categorical variables, with differences examined across roles (students, interns, junior doctors, senior doctors) via Kruskal-Wallis tests, supplemented by two-group analyses using Mann-Whitney U testing. We correlated experience with MHAQ scores using Spearman's rho, tested MHAQ's internal consistency with Cronbach's alpha, and employed thematic analysis for the qualitative data. RESULTS: We received 416 responses to the survey, and 12 senior doctors participated in the semi-structured interviews. Overall, all groups demonstrated moderately positive attitudes towards HVCCC, with more experienced doctors exhibiting more favourable views, especially about integrating costs into daily practice. In the interviews, participants agreed on the importance of instilling HVCCC values during undergraduate teaching and supplementing it with a formal curriculum in postgraduate training. This, coupled with practical knowledge gained on-the-job, was seen as a beneficial strategy for training doctors. CONCLUSIONS: This sample of medical students and hospital-based doctors display generally positive attitudes towards HVCCC, high-value care provision, and the integration of healthcare costs, suggesting receptiveness to future HVCCC training among students and doctors. Experience is a key factor in HVCCC, so early exposure to these concepts can potentially enhance practice within existing healthcare budgets.

Oral health-related quality of life in patients aged 8 to 19 years with cleft lip and palate: a systematic review and meta-analysis.

BACKGROUND: Cleft lip and palate (CLP) is the most common facial birth defect worldwide and causes morphological, aesthetic, and functional problems with psychosocial implications for an individual's life and well-being. The present systematic review and meta-analysis assessed whether the treatment of CLP impacts the oral health-related quality of life (OHRQoL) in children and adolescents in comparison to healthy controls. METHODS: We searched MEDLINE/PubMed, EMBASE, and PsycINFO databases using terms related to CLP, and included articles until August 2023. Observational comparison studies that assessed OHRQoL in non-syndromic CLP patients aged 8-19 years with validated scales designed to such aim or scales capable to identify aspects related to oral health compared to healthy controls were included. We used the ROBINS-I tool for risk of bias assessment. A meta-analysis of continuous variables was performed using inverse variance for pooling estimates, Standardized Mean Difference (SMD) as a summary measure, with random effects model. Heterogeneity was estimated by the I2 statistics. Sensitivity analyses included subgrouping based on the scale, risk of bias and scale domains. Meta-regression was performed under a mixed-effects model considering the variables type of scale, scale domains and risk of bias. RESULTS: Fourteen studies were included comprising 1,185 patients with CLP and 1,558 healthy controls. The direction of the effect of OHRQoL favoured the healthy group (-0.92; 95% CI:-1,55;-0,10) and I2 = 95%. After removing three studies, I2 dropped to 80%. Meta-regression showed no influence on risk of bias (p = 0.2240) but influence of scale type (p = 0.0375) and scale domains (p < 0.001). The subgroup analysis indicated that the CPQ and COHIP scales presented very discrepant SMD values, despite pointing to the same effect direction. In contrast, the OHIP scale showed a non-significant difference between cases and controls, with estimates much lower than the other two scales. Results also suggest that OHRQoL associated with oral functionality and social well-being is more influential on outcomes than emotional well-being. CONCLUSION: The global OHRQoL is slightly worst in the CLP patients than control group. The difference between OHRQoL was mainly detected through OHIP. The most affected domains are functional, emotional and social. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022336956.

Knowledge, attitudes, and practices of active surveillance in prostate cancer among urologists: a real-life survey from Brazil.

BACKGROUND: Active surveillance (AS) is the preferred treatment for patients with very low-and low-risk prostate cancer (PCa), but it is underperformed worldwide. This study aimed to report knowledge, attitudes, and practices (KAP) of AS for PCa among urologists in Brazil. METHODS: This cross-sectional study used a questionnaire with 50 questions divided into participant characteristics, knowledge regarding inclusion criteria for AS, follow-up, intervention triggers, acceptance, and practice for an index patient. Data analysis comprises absolute and relative frequencies of the variables. After that, a logistic regression was performed in order to verify possible patterns of answers provided by the respondents in the index patient questionnaire. RESULTS: Questionnaires were sent through the SurveyMonkey® platform to 5,015 urologists using email addresses and through social media. A total of 600 (12%) questionnaires returned and 413 (8.2%) were completed and included in the analysis. Only 53% of urologists adopt AS for low- and very-low-risk PCa. Inclusion criteria were patients with age > 50 years (32.2%), prostate specific antigen (PSA) < 10 ng/mL (87.2%), T1 clinical stage (80.4%), Biopsy Gleason score ≤ 6, positive cores ≤ 2 (44.3%), positive core involvement < 50% (45.3%), and magnetic resonance imaging findings (38.7%). The PSA doubling time was still used by 60.3%. Confirmatory biopsy (55.9%), PSA level (36.6%), and digital rectal examination (34.4%) were considered by most urologists for follow-ups. Patient preference (85.7%), upgrade of Gleason score (73.4%), and increased number of positive cores (66.8%) were associated with conversion to definitive treatment. In an index patient, non-acceptance and active treatment request were the most cited reasons for not performing AS. CONCLUSION: There is significant variability in the KAP of AS in Brazil, which indicates the need to reinforce AS, its inclusion and follow-up criteria, and the benefits for physicians and the general population. TRIAL REGISTRATION: Not applicable.

Development and validation of The Breaking Bad News Attitudes Scale.

BACKGROUND: Communication of bad news plays a critical role in the physician-patient relationship, and a variety of consensus guidelines have been developed to this purpose, including the SPIKES protocol. However, little is known about physicians' attitudes towards breaking bad news and to be trained to deliver it. This study aimed to develop and validate a self-report questionnaire to assess physicians' attitudes towards principles of the SPIKES protocol and training on them. METHODS: The Breaking Bad News Attitudes Scale (BBNAS) was administered to 484 pediatricians and 79 medical students, recruited at two scientific conferences and two medical schools in Brazil. The questionnaire structural validity, reliability, and associations with other variables were tested. RESULTS: The BBNAS showed adequate validity and good reliability, with two factors measuring attitudes towards the SPIKES strategy for braking bad news (α = 0.81) and the possibility to be trained on it (α = 0.77), respectively. CONCLUSION: The novel questionnaire is a psychometrically sound measure that provides information on physicians' agreement with the SPIKES protocol. The BBNAS can provide useful information for planning training and continuing education programs for clinicians on communication of bad news using the SPIKES as a framework.

Paraoxonase single nucleotide variants show associations with polycystic ovary syndrome: a meta-analysis.

BACKGROUND: Etiology of polycystic ovary syndrome (PCOS) is attributed to genetic and environmental factors. One environmental factor is oxidative stress. Paraoxonase 1 (PON1) is an antioxidant high-density lipoprotein-associated enzyme encoded by the PON1 gene. The PON1 gene has been implicated in the risk for PCOS, the influence of which appears to come from single nucleotide variants (SNVs) at multiple genetic loci. However, association study reports have been inconsistent which compels a meta-analysis to obtain more precise estimates. METHODS: From 12 publications, extracted genotype data were used in two genetic procedures. First, linkage disequilibrium (LD) was used to group eight PON SNVs into three: LD1, LD2 and LD3. Second, frequencies of the variant (var), wild-type (wt) and heterozygous (het) genotypes were used for genetic modeling (allele-genotype for LD1 and standard for LD2 and LD3). Risk associations were expressed in terms of pooled odds ratios (ORs), 95% confidence intervals (CIs) and Pa-values. Evidence was considered strong when significance was high (Pa < 0.0001) and heterogeneity absent (I2 = 0%). Pooled effects were subjected to modifier (power), subgroup (Asian/Caucasian), outlier, sensitivity and publication bias treatments. Multiple comparisons were Bonferroni-corrected. RESULTS: This meta-analysis generated 11 significant outcomes, five in LD1, six in LD2 and none in LD3. All six LD2 outcomes did not survive the Bonferroni-correction but two of the five in LD1 did. These two core LD1 findings conferred greater odds of PCOS to the var allele in the highly significant (Pa < 0.0001) overall (OR 1.44, 95% CI 1.24-1.67) and Asian (OR 1.41, 95% CI 1.20-1.65) outcomes. Of these two core outcomes, the Asian effect was homogeneous (I2 = 0%) but not the overall (I2 = 29%). CONCLUSIONS: Of the eight PON SNVs examined, two (rs854560 and rs662) were associated with PCOS risk. These 1.4-fold increased risk effects rendered Asians susceptible to PCOS. High statistical power, high significance, zero to low-level heterogeneity, robustness and lack of bias in the core outcomes underpinned the strong evidence for association.

The role of Kisspeptin levels in polycystic ovary syndrome: a systematic review and meta-analysis.

PURPOSE: Polycystic ovarian syndrome (PCOS) is a complex and not fully elucidated pathology. This prevalent endocrinopathy affects patients in reproductive age, impacts on estrogen-dependent diseases, as well as in infertility. In this context, Kisspeptin (KP) may be considered a potential biomarker for PCOS diagnosis and follow-up. Here, we aimed to verify the levels of KP in obese and non-obese patients with PCOS, their relationship with other hormones, in comparison to healthy controls. METHODS: A systematic review and meta-analysis were performed according to the PRISMA guidelines. We searched MEDLINE, EMBASE, PsycINFO, Global Health, The Cochrane Library, Health Technology Assessment Database, and Web of Science for eligible studies. A random effects model meta-analysis of standardized mean difference (SMD) was conducted and the I2 was used to assess heterogeneity. Meta-regression was conducted through mixed-effects model. RESULTS: A total of 12 studies were included, comprising 660 PCOS patients and 600 controls. The KP levels were lower in the control group (0.76: 0.17-1.35; 95% CI). In the subgroup analyses, patients were divided in non-overweight/obese (BMI < 25) and overweight/obese (BMI ≥ 25) groups. The meta-regression revealed a difference between the obese and non-obese groups (z = 2.81; p = 0.0050). CONCLUSIONS: PCOS patients showed higher KP levels than control, and obese non-PCOS patients also showed altered KP levels. All studies had poor descriptions of sample collection, pre-analytical and analytical procedures, which is critical considering structural characteristics of the KP molecule.

Kisspeptin/GPR54 System: What Do We Know About Its Role in Human Reproduction?

Kisspeptin is involved in the control of human reproduction bridging the gap between the sex steroid levels and feedback mechanisms that control the gonadotropin releasing hormone (GnRH) secretion; however, studies considering this peptide and infertility are limited. We conducted a review and critical assessment of available evidence considering kisspeptin structure, physiology, function in puberty and reproduction, its role in assisted reproduction treatments, kisspeptin dosage and the impact on KISS1 and GPR54 genes. Literature searches were conducted in PubMed using keywords related to: (i) kisspeptin or receptors, kisspeptin-1 (ii) reproduction or infertility or fertility (iii) gene and (iv) dosage or measurement or quantification or serum level, in human. Kisspeptin is a product of KISS1 gene that binds to a G-protein-coupled receptor (GPR54/KISS1R) stimulating the release of GnRH by hypothalamic neurons, leading to secretion of pituitary gonadotropins (LH and FSH) and sexual steroids, which in turn will act in the gonads to produce the gametes. Kisspeptin is being recognized as a crucial regulator of the onset of puberty, the regulation of sex hormone mediated secretion of gonadotropins, and the control of fertility. Inactivating and activating mutations in both KISS1 or GPR54 genes were associated with hypogonadotropic hypogonadism and precocious puberty. Despite this, studies considering kisspeptin and infertility are scarce. The understanding of the role of kisspeptin may lead to its use as a biomarker in infertility treatments and use in controlled ovarian hyperstimulation.

Ultrasound-Guided Vascular Access Simulator for Medical Training: Proposal of a Simple, Economic and Effective Model.

OBJECTIVE: To present a simple and affordable model able to properly simulate an ultrasound-guided venous access. DESIGN: The simulation was made using a latex balloon tube filled with water and dye solution implanted in a thawed chicken breast with bones. RESULTS: The presented model allows the simulation of all implant stages of a central catheter. The obtained echogenicity is similar to that observed in human tissue, and the ultrasound identification of the tissues, balloon, needle, wire guide and catheter is feasible and reproducible. CONCLUSION: The proposed model is simple, economical, easy to manufacture and capable of realistically and effectively simulating an ultrasound-guided venous access.

Associations of Polymorphisms in Anti-Müllerian Hormone (AMH Ile49Ser) and its Type II Receptor (AMHRII -482 A>G) on Reproductive Outcomes and Polycystic Ovary Syndrome: a Systematic Review and Meta-Analysis.

BACKGROUND/AIMS: Reported associations of reproductive outcomes (RO) and polycystic ovary syndrome (PCOS) with genotypes of the Ile49Ser and -482A>G polymorphisms in the Anti-Müllerian hormone (AMH) gene and its type II receptor (AMHRII), respectively, have conflicting results. METHODS: PubMed, Google Scholar and Science Direct databases were searched for studies that investigated Ile49Ser and -482A>G in RO and PCOS. Using the metaanalytic approach, we estimated risk (odds ratio [OR] with 95% confidence intervals) using standard genetic models. RESULTS: All calculated summary effects were non-significant. Overall associations of Ile49Ser and -482A>G with RO were absent (OR 0.95-0.99, P = 0.76-0.96) but implied increased risk in PCOS (OR 1.07-1.17, P = 0.49-0.55). Where heterogeneity of the pooled ORs were present, its sources were explored using the Galbraith plot. Detection and omission of the outlying studies in both polymorphisms not only erased heterogeneity of the recalculated pooled outcomes but also changed direction of association, where null effects turned to increased risk (Ile49Ser in RO) and increased risk became reduced risk (-482A>G in PCOS). Implications of the Ile49Ser and -482A>G, effects pointed to protection for Caucasians (OR 0.64-0.89, P = 0.36-0.73) in RO and increased risk in PCOS (OR 1.19-1.45, P = 0.28-0.65). Asian effects in RO and PCOS were variable (OR 0.97-1.24, P = 0.58-0.91). CONCLUSIONS: In summary, we found no evidence of significant associations of Ile49Ser and -482A>G with RO and PCOS, although contrasting Ile49Ser effects were implied among Caucasians between RO (up to 0.36% reduced risk) and PCOS (up to 1.5-fold increased risk).

Previous Use of Combined Oral Contraception in High Complexity Assisted Reproduction Treatments in Protocol with Oral Progestin - Previous use of COC and ART.

OBJECTIVE: To evaluate the impact of prior use of combined oral contraceptives in assisted reproduction techniques with ovulation blockade by oral progestin. METHODS: Retrospective cohort study with a single-center convenience sample of patients treated between 2018 and 2021. Two groups were compared: with and without a history of combined oral contraceptives (comparator). The clinical variables were age, body mass index, type of infertility and smoking. Regarding treatment, antral follicle count; follicles >14 mm; oocytes in metaphase I and II; number of embryos; days of treatment; total dose of medication, chemical and clinical pregnancy rate and delivery after 1st embryo transfer. Absolute and relative frequencies were used for the qualitative variables; means, medians and t-test for the quantitative ones. Association between qualitative variables used the Chi-square test and, for quantitative variables, the Mann-Whitney test (p<0.05). The statistical program used was Stata 16.0. RESULTS: Among 407 medical records, 351 were included (combined oral contraceptive=243 and comparator=108). The combined oral contraceptive and the comparator groups had, respectively, mean (SD±) age 38.2 (4.5) and 38.2 (4.5) years; chemical pregnancy rates of 30.5% and 29.6% (p=0.281); clinical pregnancy rates of 24.8% and 24.1% (p=0.313) and abortion, 5% and 4.6% (p=0.544). The median time on combined oral contraceptives was 6 years. CONCLUSIONS: Previous use of combined oral contraceptives did not impact reproductive results in relation to the comparator group in patients undergoing assisted reproduction techniques in protocols with oral progestin.

Efficacy of letrozole for the treatment of tubal ectopic pregnancy: A meta-analysis.

BACKGROUND: Tubal ectopic pregnancy (EP) is a life-threatening condition, especially if undiagnosed or misdiagnosed, tipically in low income countries and/or where women have limited access to health care. The current management protocol of tubal EP consists of either surgical management, or medical management with methotrexate. Recent studies, while few, have suggested that letrozole, an aromatase inhibitor, may play a role in the medical treatment of tubal EP. OBJECTIVES: To evaluate the effectiveness of letrozole alone in the medical treatment of tubal EP. SEARCH STRATEGY: Electronic databases were searched until 31 December 2023. SELECTION CRITERIA: Retrospective or prospective studies reporting the treatment of tubal EP with letrozole alone were considered eligible for inclusion. DATA COLLECTION AND ANALYSIS: Pooled results were expressed as OR with 95 %CI. Heterogeneity was assessed using Higgins I2. Subgroup analysis was performed to compare outcomes according to time after intervention. Subgroup differences were checked through χ2 test. RESULTS: A total of 152 patients were included. Seventy-nine patients (51.97 %) were treated with letrozole, 39 patients (16.54 %) with methotrexate, and 34 patients (31.49 %) underwent surgical treatment. Pooled data analysis supports the consistency of the effect of letrozole in reducing ß-hCG over time at a comparable rate among studies, and that treatment with letrozole is superior to surgery and has the same efficacy as methotrexate. However, all the included studies were judged at high risk of bias in terms of study design, sample representativeness, and sampling technique. Furthermore, short and long term side effects were not reported in any of the included studies. CONCLUSIONS: Letrozole is a promising alternative to methotrexate and surgical therapy in the treatment of tubal EP. Although this meta-analysis suggests efficacy and low hazard of the drug and encourages its application, the data available today remain extremely sparse, which weakens any claims that can be made, and is not sufficient to assert that letrozole is safe and effective in the treatment of EPs. There is an absolute need for randomized studies with accurate patient selection, fixed doses, large sample sizes, and reporting of short- and long-term side effects to refute or confirm this assumption.

Salvage local treatment for recurrent prostate cancer after focal therapy: A systematic review and meta-analysis.

OBJECTIVES: To evaluate the role of salvage local treatment in managing recurrent PCa following FT, focusing on oncological and functional outcomes. METHODS: A systematic review and meta-analysis were performed following the PRISMA framework. A comprehensive literature search using the PubMed/MEDLINE and EMBASE databases was performed until July 2023. Eligible studies included patients with clinically localised PCa initially treated with FT, who experienced relapse during surveillance and subsequently underwent salvage radical prostatectomy (sRP), salvage external beam radiation therapy (sEBRT) or salvage focal therapy (sFT). The primary endpoint was the biochemical recurrence rate post-salvage treatment. The secondary endpoints were functional outcomes, including urinary incontinence and erectile dysfunction rates. RESULTS: In 26 retrospective studies including 990 patients, the overall pooled biochemical recurrence rate postsalvage treatment was 26%. The subgroup analysis revealed a biochemical recurrence rate of 20%, 22%, and 42% after sRP, sEBRT, and sFT, respectively. The overall pooled rate of urinary incontinence was 20%. Salvage FT had the lowest prevalence of urinary incontinence, followed by sRP and sEBRT. The overall pooled rate of erectile dysfunction was 43%. Salvage RP had the highest prevalence of erectile dysfunction, followed by sFT and sEBRT. Substantial heterogeneity was observed among the studies, primarily due to different sample sizes. Meta-regression analysis revealed no to low contributions of salvage treatment modalities, extent of ablation, age, prostatic specific antigen level before salvage treatment, proportion of patients with Gleason score ≥7 at recurrence, and time between the primary and salvage therapies to heterogeneity. CONCLUSION: Salvage local treatment for recurrent PCa after FT is feasible, and it provides acceptable oncological and functional outcomes. Among all treatment modalities, sRP and sEBRT appeared to have the lowest biochemical recurrence rates, whereas sFT was associated with improved functional outcomes.

Low and High-Normal FMR1 Triplet Cytosine, Guanine Guanine Repeats Affect Ovarian Reserve and Fertility in Women Who Underwent In Vitro Fertilization Treatment? Results from a Cross-Sectional Study.

Dynamic mutations in the 5' untranslated region of FMR1 are associated with infertility. Premutation alleles interfere with prenatal development and increase infertility risks. The number of CGG repeats that causes the highest decrease in ovarian reserves remains unclear. We evaluated the effect of FMR1 CGG repeat lengths on ovarian reserves and in vitro fertilization (IVF) treatment outcomes in 272 women with alleles within the normal range. FMR1 CGG repeat length was investigated via PCR and capillary electrophoresis. Alleles were classified as low-normal, normal, and high-normal. Serum levels of follicle-stimulating hormone and anti-Mullerian hormone (AMH) in the follicular phase of the menstrual cycle were measured, and antral follicles (AFC) were counted. IVF outcomes were collected from medical records. Regarding FMR1 CGG repeat length alleles, 63.2% of women presented at least one low-normal allele. Those carrying low-normal alleles had significantly lower AMH levels than women carrying normal or high-normal alleles. Low-normal/low-normal genotype was the most frequent, followed by low-normal/normal and normal/normal. A comparison of ovarian reserve markers and reproductive outcomes of the three most frequent genotypes revealed that AFC in the low-normal/normal genotype was significantly lower than the low-normal/low-normal genotype. The low number of FMR1 CGG repeats affected AMH levels and AFC but not IVF outcomes per cycle of treatment.

General Health Questionnaire (GHQ12): new evidence of construct validity.

This study aimed to gather evidence on the adequacy of the General Health Questionnaire (GHQ-12) in Brazil, considering a random sample of Brazilian physicians. Specifically aimed: (1) to test the GHQ-12 bifactor structure compared to alternative models, (2) to check its factorial invariance regarding to gender and the diagnosis of mental and behavioral disorders, and (3) to know the association of this measure with indicators of poor health (e.g., suicidal thoughts, decreased libido, medication use). The study included 1,085 physicians with a mean age of 45.7 (SD = 10.6), mostly male (61.5%), married (72.6%) and Catholic (59.2%). They answered the GHQ-12, the Positive and Negative Suicidal Ideation Inventory, and demographic questions. The best fit model was the bifactor structure composed of anxiety and depression, in addition to a general dimension, which presented Cronbach's alpha, McDonald's ω and composite reliability higher than 0.70 just for a general fact. Psychological distress scores correlated with suicidal ideation and indicators of health and sexual satisfaction. This is a psychometrically suitable instrument that can be used in terms of its total, but its specific factors need to be used with caution.

Effect of thyroid function on assisted reproduction outcomes in euthyroid infertile women: A single center retrospective data analysis and a systematic review and meta-analysis.

Background: The influence of thyroid-stimulating hormone (TSH) on gestational outcomes have been studied and checked whether differing TSH levels are relevant on human reproduction outcomes. International guidelines recommend TSH values <2.5 mIU/L in women trying to conceive, since values above this level are related to a higher frequency of adverse reproductive outcomes. This study aimed to evaluate whether TSH values correlate with different gestational outcomes in euthyroid infertile women without autoimmune thyroid disease. Methods: A retrospective cohort study was conducted involving 256 women who underwent in vitro fertilization (IVF) treatment. The participants were divided into two groups: TSH 0.5-2.49 mIU/L (n=211) and TSH 2.5-4.5 mIU/L (n=45). The clinical data, hormonal profiles and reproductive outcomes were compared between groups. Additionally, a systematic review with meta-analysis following the PRISMA protocol was carried out in PubMed/MEDLINE, EMBASE, and SciELO, with no time or language restrictions, for articles comparing TSH groups named "low TSH" (<2,5 mIU/L) and "high TSH" (≥2.5 mIU/L). A meta-analysis of proportions was performed with pooled estimates expressed as relative risk (RR) of events and a random effects model. Results: Age, BMI, free thyroxine levels (FT4) hormonal profile and IVF outcomes were not different between groups, neither gestational outcomes (p=0.982). Also, no difference was observed when the TSH and FT4 levels were compared between patients with positive or negative gestational outcomes (p=0.27 and p=0.376). Regarding the systematic review with meta-analysis, 17 studies from 2006 to 2022 were included, and added by this original retrospective research comprising 13.247 women undergoing IVF. When comparing the proportions of clinical pregnancy between the TSH groups, no significant difference was found (RR 0.93, 95% CI 0.80-1.08), with high between studies heterogeneity (I²: 87%; τ2: 0.0544; p<0.01). The number of deliveries was not significantly different between groups, despite a trend towards higher frequency in the high-TSH group (RR 0.96, 95% CI 0.90-1.02). Conclusion: Variation in TSH levels within the normal range was not associated with pregnancy and delivery rates in women, without autoimmune thyroid disease, who underwent IVF treatment. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD 42022306967.

The Infertility-Related Stress Scale: Validation of a Brazilian-Portuguese Version and Measurement Invariance Across Brazil and Italy.

Infertility constitutes an essential source of stress in the individual and couple's life. The Infertility-Related Stress Scale (IRSS) is of clinical interest for exploring infertility-related stress affecting the intrapersonal and interpersonal domains of infertile individuals' lives. In the present study, the IRSS was translated into Brazilian-Portuguese, and its factor structure, reliability, and relations to sociodemographic and infertility-related characteristics and depression were examined. A sample of 553 Brazilian infertile individuals (54.2% female, mean aged 36 ± 6 years) completed the Brazilian-Portuguese IRSS (IRSS-BP), and a subsample of 222 participants also completed the BDI-II. A sample of 526 Italian infertile individuals (54.2% female, mean aged 38 ± 6 years) was used to test for the IRSS measurement invariance across Brazil and Italy. Results of exploratory structural equation modeling (ESEM) indicated that a bifactor solution best represented the structure underlying the IRSS-BP. Both the general and the two specific intrapersonal and interpersonal IRSS-BP factors showed satisfactory levels of composite reliability. The bifactor ESEM solution replicated well across countries. As evidence of relations to other variables, female gender, a longer duration of infertility, and higher depression were associated with higher scores in global and domain-specific infertility-related stress. The findings offer initial evidence of validity and reliability of the IRSS-BP, which could be used by fertility clinic staff to rapidly identify patients who need support to deal with the stressful impact of infertility in the intrapersonal and interpersonal life domains, as recommended by international guidelines for routine psychosocial care in infertility settings.

Effects of FSHR and FSHB Variants on Hormonal Profile and Reproductive Outcomes of Infertile Women With Endometriosis.

Background: Single nucleotide variants (SNVs) FSHB:c.-211G>T, FSHR:c.919G>A, and FSHR:c.2039G>A were reported to be associated with the variability in FSH and LH levels, and in vitro fertilization (IVF) outcomes. In this study, we aimed to evaluate the effects of FSHB:c.-211G>T, FSHR:c.919G>A, and FSHR:c.2039G>A variants, alone and combined, on the hormonal profile and reproduction outcomes of women with endometriosis. Methods: A cross-sectional study was performed comprising 213 infertile Brazilian women with endometriosis who underwent IVF treatment. Genotyping was performed using TaqMan real-time PCR. Variables were compared according to the genotypes of each variant and genetic models, and the combined effects of the SNVs were evaluated using the multifactorial dimensionality reduction method. Results: FSHB:c.-211G>T affected LH levels in women with overall endometriosis and minimal/mild disease. FSHR:c.919G>A affected FSH levels in women with overall endometriosis and the number of oocytes retrieved in those with moderate/severe endometriosis. Moreover, the FSHR:c.2039G>A affected FSH levels in women with overall endometriosis, LH levels and total amount of rFSH in those with minimal/mild disease, and number of follicles and number of oocytes retrieved in those with moderate/severe endometriosis. No effect on hormone profile or reproductive outcomes was observed when the genotypes were combined. Conclusions: Variants of the FSHB and FSHR genes separately interfered with the hormonal profiles and IVF outcomes of women with endometriosis.

Transition to clinical practice during the COVID-19 pandemic: a qualitative study of young doctors' experiences in Brazil and Ireland.

OBJECTIVES: To explore and compare the perspectives of junior doctors in Brazil and Ireland regarding transition and professional socialisation during the COVID-19 pandemic, with the purpose of identifying better ways to support doctors as they assume their new professional role. DESIGN: 27 semistructured interviews. Transcripts were analysed using qualitative thematic analysis. Cruess' framework of professional socialisation in medicine supported the interpretation of these data. SETTING: Public health hospitals across four Brazilian states (Santa Catarina, São Paulo, Ceará, Paraíba) and County Cork in the South of Ireland. PARTICIPANTS: Twenty-seven male and female medical junior doctors who had graduated between November 2019 and April 2020. RESULTS: Fourteen Brazilian and 13 Irish junior doctors were interviewed for this study. Entry to clinical practice during the pandemic had a significant impact on factors influencing the professional socialisation of junior doctors. This impact was reflected across the following six thematic areas: lack of preparedness; disrupted trajectory of role adaptation; fewer opportunities for experiential learning; solidarity and isolation; altered interactions with patients; challenges to health and well-being. CONCLUSIONS: Transition to clinical practice is an important stage in junior doctors' professional socialisation and identity formation. The COVID-19 pandemic created the opportunity for medical graduates to enter the workforce earlier than usual. Entering the workforce during this period created a lack of confidence among junior doctors concerning the boundaries of their new role and responsibilities, while simultaneously disrupting their social integration. Priorities to mitigate the impact of COVID-19 and future pandemics on this transition are presented.