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Abstract Introduction Sex‐dependent risk factors may underlie sex differences in Alzheimer's disease (AD). Methods Using sex‐stratified genome‐wide association studies (GWAS) of AD, we evaluated associations of 12 traits with AD through polygenic risk scores (PRS) and Mendelian randomization (MR), and explored joint genetic architecture among significant traits by genomic structural equation modeling and network analysis. Results AD was associated with lower PRS for premorbid cognitive performance, intelligence, and educational attainment. MR showed a causal role for the cognition‐related traits in AD, particularly among females. Their joint genetic components encompassed RNA processing, neuron projection development, and cell cycle pathways that overlap with cellular senescence. Cholesterol and C‐reactive protein showed pleiotropy but no causality with AD. Discussion Lower cognitive reserve is causally related to AD. The stronger causal link between cognitive performance and AD in females, despite similar PRS between sexes, suggest these differences may result from gene–environmental interactions accumulated over the lifespan.

Objectives: To determine the endometrial response in postmenopausal women treated with a sequential hormone replacement therapy (HRT) of estradiol and, either chlormadinone acetate (CA) or micronized progesterone (MP).Methods: Three hundred and thirty-six postmenopausal women with a normal endometrium were randomized in the double-blind study. All patients received percutaneous estradiol 1.5 mg/day from day 1 to day 24 and either CA 10 mg/day or oral MP 200 mg/day from day 10 to day 24. The total duration of treatment was 18 months. Endometrial biopsies were performed before treatment and between day 18 and day 24 of the 18th month of HRT.Results: Of the 336 patients selected, 317 had a biopsy at inclusion. Of them, 244 patients (124 in the CA group and 120 in the P group) were suitable for evaluation for analysis at the 18th month. Insufficient sampling occurred in 33.9% in the CA group and 60% in the MP group (probably atrophic). No case of hyperplasia could be reported in both groups. The endometrium was atrophic in 19.5 versus 27.1%, proliferative in 3.7 versus 8.3% and secretory in 76.8 versus 62.5% in CA and MP groups, respectively. It was possible to see histological differences induced by the two progestins. The CA endometria showed fewer glands lined by a cubo-cylindrical epithelium, with an edematous stroma, compared to the MP endometria which had more glands lined by a cylindrical epithelium, stroma being poorly edematous. These figures varied in intensity due to the length of progestative impregnation, predecidualization occurring later in the CA group, with distended capillaries.Conclusions: These results show that CA 10 mg/day is a powerful progestin compared to MP 200 mg/day, on weakly estradiol-primed endometria, giving a molecule-specific histological aspect with a good endometrial safety. [ABSTRACT FROM AUTHOR]

There is an emerging focus on the role of robotic surgery in ovarian cancer. To date, the operational and cost implications of the procedure remain unknown. The objective of the current study was to evaluate the impact of integrating minimally invasive robotic surgery on patient flow, resource utilization, and hospital costs associated with the treatment of ovarian cancer during the in-hospital and post-discharge processes. 261 patients operated for the primary treatment of ovarian cancer between January 2006 and November 2014 at a university-affiliated tertiary hospital were included in this study. Outcomes were compared by surgical approach (robotic vs. open surgery) as well as pre- and post-implementation of the robotics platform for use in ovarian cancer. The in-hospital patient flow and number of emergency room visits within 3 months of surgery were evaluated using multi-state Markov models and generalized linear regression models, respectively. Robotic surgery cases were associated with lower rates of postoperative complications, resulted in a more expedited postoperative patient flow (e.g., shorter time in the recovery room, ICU, and inpatient ward), and were between $10,376 and $7,421 less expensive than the average laparotomy, depending on whether or not depreciation and amortization of the robotic platform were included. After discharge, patients who underwent robotic surgery were less likely to return to the ER (IRR 0.42, p = 0.02, and IRR 0.47, p = 0.055, in the univariate and multivariable models, respectively). With appropriate use of the technology, the addition of robotics to the medical armamentarium for the management of ovarian cancer, when clinically feasible, can bring about operational efficiencies and entails cost savings., (© 2022. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Introduction: With the rapid uptake of robotic surgery in surgical oncology, its use in the treatment of epithelial ovarian cancers is being evaluated. Complete cytoreduction represents the goal of surgery either at primary cytoreduction or after neoadjuvant chemotherapy in the setting of interval cytoreduction. In selected patients, the extent of disease would enable minimally invasive surgery. The objective of this study was to evaluate the impact of introducing robotic surgery for interval cytoreduction of selected patients with stage III-IV ovarian cancer., Methods: All patients who underwent surgery from November 2008 to 2014 (concurrent time period when robotic and open surgery were used simultaneously) after receiving neoadjuvant chemotherapy for advanced ovarian cancer (stage III-IV) were compared with all consecutive patients who underwent cytoreductive surgery by laparotomy after neoadjuvant chemotherapy between January 2006 and November 2008. Inclusion criteria included an interval cytoreductive surgery by laparotomy or robotic assistance for stage III-IV non-mucinous epithelial ovarian, fallopian tube, or primary peritoneal cancer. Exclusion criteria included patients treated concurrently for a non-gynecologic cancer, as well as secondary cytoreductive surgeries and diagnostic surgeries without an attempt at tumor reduction. Overall survival, progression-free survival, and peri-operative outcomes were compared for the entire patient cohort with those with advanced ovarian cancer who received neoadjuvant chemotherapy immediately before and after the introduction of robotic surgery., Results: A total of 91 patients were selected to undergo interval cytoreduction either via robotic surgery (n=57) or laparotomy (n=34) after the administration of neoadjuvant chemotherapy. The median age of the cohort was 65 years (range 24-88), 78% had stage III disease, and the median follow-up time was 37 months (5.6-91.4 months). The median survival was 42.8±3.1 months in the period where both robotic surgery and laparotomy were offered compared with 37.9±9.8 months in the time period preceding when only laparotomy was performed (p=0.6). All patients selected to undergo interval robotic cytoreduction following neoadjuvant chemotherapy had a reduction of cancer antigen 125 by at least 80%, resolution of ascites, and CT findings suggesting the potential to achieve optimal interval cytoreduction. All these patients achieved optimal cytoreduction with <1 cm residual disease, including 82% with no residual disease. The median blood loss was 100 mL (mean 135 mL, range 10-1250 mL), and the median hospital stay was 1 day., Conclusion: Robotic interval cytoreductive surgery is feasible in well-selected patients. Future studies should aim to define ideal patients for minimally invasive cytoreductive surgery., Competing Interests: Competing interests: WG and SL obtained partial travel support for proctoring robotic surgery., (© IGCS and ESGO 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: To evaluate the anatomical location of sentinel lymph nodes (SLN) following intra-operative cervical injection in endometrial cancer., Methods: All consecutive patients with endometrial cancer undergoing sentinel lymph node mapping were included in this prospective study following intra-operative cervical injection of tracers. Areas of SLN detection distribution were mapped., Results: Among 436 patients undergoing SLN mapping, there were 1095 SLNs removed, and 7.9% of these SLNs found in 13.1% of patients, were detected in areas not routinely harvested during a standard lymph node dissection. These included the internal iliac vein, parametrial, and pre-sacral areas. The SLN was the only positive node in 46.1% (15/36) of cases with successful mapping and completion lymphadenectomy, including 3 cases where the sentinel node in the atypical location was the only node with metastatic disease., Conclusion: SLN mapping using intra-operative cervical injection is capable to map out areas not typically included in a standard lymphadenectomy. The sentinel node is the most relevant lymph node to analyze and may enable to discover metastatic disease in unusual areas., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Sentinel lymph node (SLN) mapping has emerged as a promising solution to the ongoing debate regarding lymphadenectomy in the initial surgical management of endometrial cancer. Currently, little is known about its possible impact on location of disease recurrence compared to systematic lymphadenectomy., Methods: In this retrospective study, 472 consecutive patients with endometrial cancer who underwent either SLN mapping (SLN cohort, n=275) or systematic lymphadenectomy (LND cohort, n=197) from sequential, non-overlapping historical time points were compared. Clinical characteristics were extracted from a prospectively gathered electronic database. Both overall and pelvic sidewall recurrence free survival (RFS) were evaluated at 48-month post-operative follow-up., Results: No significant difference in overall RFS could be identified between the cohorts at 48months (HR 0.74, 95% CI 0.43-1.28, p=0.29). However, the SLN cohort had improved pelvic sidewall RFS compared to the LND cohort (HR 0.32, 95% CI 0.14-0.74, p=0.007). The pelvic sidewall recurrences accounted for 30% of recurrences in the SLN cohort (8 out of 26 recurrences) compared to 71.4% in the LND cohort (20 out of 28 recurrences)., Conclusions: SLN mapping may enable more efficient detection of the LNs at greatest risk of metastasis and help to guide adjuvant therapy, which in turn seems to decrease the risk of pelvic sidewall recurrences., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The objective of this randomized, controlled trial was to assess whether voluntary participation in a proctored, proficiency-based, virtual reality robotic suturing curriculum using the da Vinci(®) Skills Simulator™ improves robotic suturing performance. Residents and attending surgeons were randomized to participation or non-participation during a 5 week training curriculum. Robotic suturing skills were evaluated before and after training using an inanimate vaginal cuff model, which participants sutured for 10 min using the da Vinci(®) Surgical System. Performances were videotaped, anonymized, and subsequently graded independently by three robotic surgeons. 27 participants were randomized. 23 of the 27 completed both the pre- and post-test, 13 in the training group and 10 in the control group. Mean training time in the intervention group was 238 ± 136 min (SD) over the 5 weeks. The primary outcome (improvement in GOALS+ score) and the secondary outcomes (improvement in GEARS, total knots, satisfactory knots, and the virtual reality suture sponge 1 task) were significantly greater in the training group than the control group in unadjusted analysis. After adjusting for lower baseline scores in the training group, improvement in the suture sponge 1 task remained significantly greater in the training group and a trend was demonstrated to greater improvement in the training group for the GOALS+ score, GEARS score, total knots, and satisfactory knots.

Introduction: Vaginal vault dehiscence following robotic-assisted hysterectomy for gynecologic cancer may be attributed to surgical techniques and postoperative therapeutic interventions. We searched for risk factors in patients with gynecologic cancers and complemented this with a literature review., Methods: Evaluation of prospectively gathered information on all consecutive robotic surgeries for gynecologic cancers was performed in a tertiary academic cancer center between December 2007 and March 2012. The literature was reviewed for articles relevant to "gynecologic oncology" and "robotics" with "vaginal cuff dehiscence" in the English and French languages. Respective authors were contacted to complete relevant information., Results: Seven dehiscences were identified of 441 cases with established gynecologic cancers. The closures in these 7 were performed using interrupted 1-Vicryl (Ethicon Inc) (3/167; 1.8%), combination of interrupted 1-Vicryl and 1-Biosyn (Covidien Inc) (3/156, 1.9%), and V-Loc (Covidien Inc) (1/118, 0.8%) sutures. Associated risk factors included adjuvant chemotherapy and/or brachytherapy, early resumption of sexual activity, and low body mass index (mean, 23 ± 3.23 kg/m²). Dehiscences occurred regardless of suturing by staff or trainees. Review of operative videos did not reveal a detectable etiologic factor, such as excessive cautery damage to the vaginal cuff or shallow tissue sutured. All 7 colporrhexis repairs were performed through a vaginal approach without the need of laparoscopy or laparotomy., Conclusions: Postoperative chemotherapy, brachytherapy, and early resumption of sexual activities are risk factors for vaginal vault dehiscence. Surgical technique, particularly the use of delayed absorbable sutures, deserves further evaluation.

Objective: The objective of this study is to evaluate the detection rate and diagnostic accuracy of sentinel lymph node (SLN) mapping using intra-operative cervical injection of filtered 99mTc-sulfur colloid (99mTc-SC) and patent blue in patients with endometrial cancer., Methods: Prospective evaluation of the first 100 endometrial cancer patients undergoing SLN mapping using cervical injection of patent blue combined with filtered 99mTc-SC in the operating room was done. Patients underwent robotic-assisted lymphatic mapping with frozen section, hysterectomy, BSO, and completion bilateral lymphadenectomy (including para-aortic nodes in grade 2 and 3 tumors)., Results: At least one SLN was detected in 92% of patients; in 66 of these (72%) bilateral SLN were detected, and in 15 cases the SLN was in the para-aortic area. Eleven percent of all patients had lymph node metastases, and 4 of which had pre-operative grade 1 tumor. The SLN was the only positive node in 44% of the cases with positive nodes. Sensitivity was 89% with 1 false negative result, yielding a negative predictive value of 99% (95% CI 93-100). Specificity was 100% (95% CI 94-100), and positive predictive value was 100% (95% CI 60-100). No complications or anaphylactic reactions were noted., Conclusions: Intra-operative SLN biopsy, using cervical injection of patent blue and filtered 99mTc-SC in endometrial cancer patients is feasible and yields adequate detection rates., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: This is a prospective evaluation of the outcome of minimal invasive surgery using robotics in function of the body mass index (BMI) of patients., Methods: This is a prospective cohort study of consecutive women undergoing surgery for endometrial cancer at a tertiary care facility since the initiation of a robotic program in December 2007. Surgical and personal outcome variables as well as quality of life and postoperative recovery were assessed using a combination of objective and subjective/self-report questionnaires. Women were divided into 3 groups based on their BMI. Comparative analyses among nonobese (n = 52), obese (n = 33) and morbidly obese (n = 23) women were performed on the outcome measures after surgery., Results: The mean BMI and the range in each of the BMI categories was 25 kg/m² (18.7-29.4 kg/m²), 34 kg/m² (30.1-38.4 kg/m²), and 46 kg/m² (40.0-58.8 kg/m²). Women with higher BMI tended to be more frequently affected with comorbidities such as diabetes (15.4%, 26.0%, and 27.3%, respectively; P = 0.32) and hypertension (55.8%, 69.6%, and 69.7%, respectively; P = 0.19). Despite these differences, surgical console time (P = 0.20), major postoperative complications (P = 0.52), overall wound complications (P = 0.18), and median length of hospitalization in days (P = 0.17) were not statistically different among the 3 groups. Only 5.6% of women needed a mini laparotomy all of which were performed for the removal of their enlarged uterus, which could not be delivered safely via the vagina, at the end of the surgical procedure. There was no increased conversion to laparotomy due to increased BMI. Women in all 3 groups reported rapid resumption of hygiene regimens and chores, little need for narcotic analgesia, and high satisfaction with the procedure., Conclusions: Obese and morbidly obese patients with endometrial cancer are also good candidates for robotic surgery. These women benefit considerably from minimal invasive surgery and have little perioperative complications.

To investigate the development of new technical approaches for improving the implementation of robotics in gynaecologic surgery, we conducted a prospective evaluation of five technical modifications developed during the implementation of a robotics program that included 171 robotic endometrial staging procedures from December 2007 until May 2010. Modification of the use of a Hohl uterine manipulator by applying only the intravaginal component minimizes the theoretical risk of spillage of endometrial cancer cells, without losing the capability of delineating the vaginal fornices. Entry to the peritoneal cavity under visual control using a left upper quadrant approach and a 5-mm endoscope through a 5-mm Endopath(®) trocar is quick and decreases the risk of bowel or vessel injury. Use of 12-mm Endopath(®) trocars with blunt tips without closure of the fascia was not associated with post-operative hernias. Positioning the Da Vinci(®) Surgical System at a 30° angle at the side of the patient allows easy access to the vagina for removal of large surgical specimens and does not interfere with proper movements of the robotic arms. Use of a tissue specimen bag introduced via the vagina at completion of surgery allows removal of large uteri vaginally to avoid (mini-)laparotomy and its morbidities. Finally, suturing of the vault using interrupted delayed absorbable monofilament sutures was not associated with vaginal cuff dehiscence. Early evaluation of evolving minor technical and surgical approaches was associated with low morbidity, and appears to benefit patients undergoing robotic surgery for gynaecologic cancers.

Objective: Mass-media campaigns have been known to modify the outcome of low back pain (LBP). We assessed the impact on outcome of standardized written information on LBP given to patients with acute LBP., Design: A 3-month pragmatic, multicenter controlled trial with geographic stratification., Setting: Primary care practice in France., Participants: 2752 patients with acute LBP., Intervention: An advice book on LBP (the "back book")., Main Outcome Measures: The main outcome measure was persistence of LBP three months after baseline evaluation., Results: 2337 (85%) patients were assessed at follow-up and 12.4% of participants reported persistent LBP. The absolute risk reduction of reporting persistent back pain in the intervention group was 3.6% lower than in the control group (10.5% vs. 14.1%; 95% confidence interval [-6.3% ; -1.0%]; p value adjusted for cluster effect = 0.01). Patients in the intervention group were more satisfied than those in the control group with the information they received about physical activities, when to consult their physician, and how to prevent a new episode of LBP. However, the number of patients who had taken sick leave was similar, as was the mean sick-leave duration, in both arms, and, among patients with persistent pain at follow-up, the intervention and control groups did not differ in disability or fear-avoidance beliefs., Conclusions: The level of improvement of an information booklet is modest, but the cost and complexity of the intervention is minimal. Therefore, the implications and generalizability of this intervention are substantial., Trial Registration: ClinicalTrials.gov NCT00343057.

The objectives of this cross-sectional study conducted in primary care practice in France were to describe general practitioners' (GPs) fear-avoidance beliefs about low back pain (LBP), investigate the impact of these beliefs on their following guidelines for bed rest, physical activities, and sick leave, and uncover factors associated with GPs' fear-avoidance beliefs. A total of 864 GPs completed a 5-part self-administered questionnaire. Parts 1, 2, and 3 concerned demographic, professional data, and personal history of back pain, respectively. Part 4 dealt with GPs' education about LBP and practice for LBP. Part 5 assessed GPs' fear-avoidance beliefs on the Fear-Avoidance Beliefs Questionnaire (FABQ). GPs' mean age was 48.2+/-7.0 years, 80% were male, 88% had been practicing for more than 10 years, and 52% reported a previous personal episode of acute LBP. Forty-six percent had participated in an educational session on LBP during the last 3 years. Mean scores for the FABQ Phys and Work were 9.6+/-4.8 and 17.5+/-6.7, respectively. Sixteen percent of participants had high rating on the FABQ Phys (FABQ Phys score>14). FABQ Phys score was associated with recommendation of bed rest or rest during sick leave (p<0.0001) for acute LBP and less advice to maintain maximum bearable physical activities (p<0.001) for chronic LBP. FABQ Work score was associated with prescribing sick leave during painful periods (p<0.005) for acute LBP and less advice to maintain maximum bearable physical activities (p<0.001) for chronic LBP. GPs' fear-avoidance beliefs about LBP negatively influence their following guidelines concerning physical and occupational activities for patients with LBP.

Introduction: Being an easy-to-use (eight items) quality of life questionnaire specific to GERD, the Reflux-Qual Short form (RQS) was developed for use in everyday practice. The purpose of this study was to assess the psychometric properties of the RQS., Methods and Materials: The reliability of the RQS was measured by the Cronbach's alpha coefficient and its clinical validity by comparing the RQS score for increasing clinical severity groups. The RQS discriminative power was compared with that of the SF12. Sensitivity to change over time was measured by calculating effect-sizes., Results: The reliability and validity of the questionnaire were assessed on a sample of 1195 patients. Its psychometric properties were very satisfactory: Cronbach alpha = 0.84; RQS score significantly reduced for the worst-affected patients; the discriminative power was up to 5 times higher when compared with the SF-12. Sensitivity to change over time, evaluated with 362 patients, showed highly significant differences between groups with different levels of clinical progression (P = 0.0001)., Conclusion: The RQS is a quality of life measurement instrument specific to GERD which is short, reliable, valid, and sensitive to within and between-subject differences.

Objective: The RELIEF investigation was a 48-week, multicenter, international study comprising 2 phases. Results from the first phase, a 24-week open-label cohort study that evaluated the safety and efficacy of leflunomide, as well as predisposing factors to treatment response, are reported here., Methods: Patients received leflunomide 100 mg once daily for 3 days, followed by 20 mg once daily thereafter. All adverse events were documented. Efficacy variables were the European League Against Rheumatism (EULAR) response criteria using the Disease Activity Score (DAS 28) responder rate and the response rate according to American College of Rheumatology (ACR) criteria. At Week 24, baseline data were analyzed to determine predictive factors for treatment response., Results: A total of 969 patients were entered in the trial. No adverse events that have not previously been seen with leflunomide were reported. Among 968 evaluable patients, 673 (69.6%) completed 24 weeks of treatment and were responders according to DAS 28 response rate, and 587 (60.6%) completed 24 weeks of treatment and were responders according to ACR 20%. Thus, there was a high correlation between the EULAR and ACR criteria in determining treatment response. In addition, 240 (24.8%) patients had a low DAS 28 (< or = 3.2) and 123 (12.7%) patients fulfilled the disease remission criteria (DAS 28 < 2.6) at the end of the study., Conclusion: This study demonstrates that leflunomide is well tolerated, with a safety profile similar to that seen previously in Phase III studies, and confirms the efficacy of leflunomide across a range of patient categories.

Objective: The efficacy and safety of chlormadinone acetate (CA) versus micronized progesterone (P) were assessed in non-hysterectomized postmenopausal women., Materials and Methods: This was a multicenter, randomized, parallel group study with a 6-month double-blind period followed by a 12-month open period. Patients were randomized to receive every month during 18 months percutaneous 17 beta-estradiol (E(2)) 1.5 mg/day from Day 1 to 24 of treatment cycle, combined from Day 11 to 24 to either CA 10 mg/day (n=167) or P 200 mg/day (n=169). Endometrial biopsy (EB, main analysis criterion) was performed at baseline, and at Day 18-24 of the 6th and 18th cycles., Results: At Month 6, EB did not evidence any hyperplasia. EB were inadequate for assessment in 24.5% and 47.5% of patients in the CA and MP groups, respectively. CA was found to be as protective as P (96.3% and 92.0% of success). However, the hormonal status of the endometrium differed (P<0.001): a secretory endometrium was found in 81.5% of the CA patients, compared to 50.7% in the P group. These transformations resulted in predictable, cyclic bleeding in 94.5% of the CA patients, compared to only 62.3% of the P patients (P=0.0001). Unscheduled bleeding, spotting and/or metrorrhagia, were more frequent under P than under CA (17.9% and 13.7%, respectively). The beneficial effects on hot flushes were more important in the CA group than in the P (P<0.001). At Month 18, the biopsy and clinical results were similar to those obtained at Month 6. The safety profile, particularly the lipid one, was similar in both groups, except for drowsiness and dizziness, which were significantly more frequent under P than under CA., Conclusion: The progestative effects of CA on the endometrium and on menopause-related symptoms were at least as good as those of P. Moreover, CA resulted more often than P in secretory effects, and in satisfying bleeding patterns.

Blastogenic responses in vitro to phytohemagglutinin and pokeweed mitogen were examined in microcultures of peripheral blood lymphocytes from a group of 12 healthy, long-term marihuana smokers and a group of matched control subjects. With either mitogen, no significant difference in cellular incorporation of (3H)thymidine was noted between the groups. These results were interpreted to indicate that the functional status of blood lymphocytes was not altered by long-term smoking of marihuana.