Low-energy Auger and conversion electron spectroscopy of 99Mo ß--decay.

The preparation of nanometer-thick molybdenum-99 (99Mo) sources using the droplet deposition method was investigated. The quality of these prepared sources was analyzed using scanning electron microscopy (SEM), electron Rutherford backscattering (ERBS) techniques, and Geant4 simulations. The emitted electrons resulting from the ß--decay of the prepared 99Mo sources, with energies below 2.2 keV, were measured and compared with existing literature data as well as the results obtained from our in-house Monte-Carlo model, BrIccEmis.

Barriers and facilitators for healthy lifestyle and recommendations for counseling in endometrial cancer follow-up care: a qualitative study.

OBJECTIVES: Lifestyle promotion during follow-up consultations may improve long-term health and quality of life in endometrial cancer patients. This study aimed to identify barriers and facilitators to improve and sustain a healthy lifestyle that can be translated to behavioral methods and strategies for lifestyle counseling. METHODS: Endometrial cancer patients from three hospitals were recruited to participate in a semi-structured interview. The data were transcribed and coded. Thematic analysis was applied to identify themes and the behavior change wheel was used as a theoretical framework. Data saturation was confirmed after 18 interviews. RESULTS: Barriers included knowledge gaps as well as lack of motivation and environmental opportunities to engage in health-promoting behavior. Facilitators included applying incremental lifestyle changes, social support, positive reinforcements, and the ability to overcome setbacks. CONCLUSIONS: We propose the following intervention functions: education, persuasion, training, environmental restructuring, and enablement. Suitable behavior change techniques to deliver the intervention functions include information about the consequences of certain behavior, feedback on behavior, credible source, graded tasks, habit formation, restructuring of the environment, prompts/cues, goal setting, action planning, and social support. Including these recommendations in lifestyle counseling could aid lasting lifestyle change since it suits the needs and preferences of patients.

Reproductive outcomes in women opting for fertility preservation after fertility-sparing surgery for borderline ovarian tumors.

PURPOSE: What are the reproductive outcomes of women who had fertility preservation (FP) using either oocyte or embryo vitrification after fertility-sparing surgery (FSS) for a borderline ovarian tumor (BOT)? METHODS: A retrospective, single-center cohort study was conducted between January 2013 and December 2021. Patients with BOT who resorted to FP by vitrifying oocytes or embryos were included. Both clinical and reproductive parameters were reviewed. The primary outcome was live birth. RESULTS: In total, thirteen patients who performed 31 FP cycles were included. Of those, six patients achieved eight live births after a mean follow-up period of 79 months. Three further pregnancies are still ongoing. All pregnancies/live births were obtained without using their cryopreserved oocytes or embryos. CONCLUSION: Women who had FSS for BOT have favorable prospects of live offspring, even without the need to use their cryopreserved material. Fertility preservation in patients with BOT has to be considered as a tool to mitigate the risk of infertility that may arise in case of BOT recurrence requiring castrating surgery.

A search strategy for detecting duodenoscope-associated infections: a retrospective observational study.

BACKGROUND: Duodenoscope-associated infections (DAIs) are exogenous infections resulting from the use of contaminated duodenoscopes. Though numerous outbreaks of DAI have involved multidrug-resistant micro-organisms (MDROs), outbreaks involving non-MDROs are also likely to occur. Detection challenges arise as these infections often resolve before culture or because causative strains are not retained for comparison with duodenoscope strains. AIM: To identify and analyse DAIs spanning a seven-year period in a tertiary care medical centre. METHODS: This was a retrospective observational study. Duodenoscope cultures positive for gastrointestinal flora between March 2015 and September 2022 were paired with duodenoscope usage data to identify patients exposed to contaminated duodenoscopes. Analysis encompassed patients treated after a positive duodenoscope culture and those treated within the interval from a negative to a positive culture. Patient identification numbers were cross-referenced with a clinical culture database to identify patients developing infections with matching micro-organisms within one year of their procedure. A 'pair' was established upon a species-level match between duodenoscope and patient cultures. Pairs were further analysed via antibiogram comparison, and by whole-genome sequencing (WGS) to determine genetic relatedness. FINDINGS: Sixty-eight pairs were identified; of these, 21 exhibited matching antibiograms which underwent WGS, uncovering two genetically closely related pairs categorized as DAIs. Infection onset occurred up to two months post procedure. Both causative agents were non-MDROs. CONCLUSION: This study provides crucial insights into DAIs caused by non-MDROs and it highlights the challenge of DAI recognition in daily practice. Importantly, the delayed manifestation of the described DAIs suggests a current underestimation of DAI risk.

Progestin primed ovarian stimulation using dydrogesterone from day 7 of the cycle onwards in oocyte donation cycles: a longitudinal study.

RESEARCH QUESTION: Does a progestin-primed ovarian stimulation (PPOS) protocol with dydrogesterone from cycle day 7 yield similar outcomes compared with a gonadotrophin-releasing hormone (GnRH) antagonist protocol in the same oocyte donors? DESIGN: This retrospective longitudinal study included 128 cycles from 64 oocyte donors. All oocyte donors had the same type of gonadotrophin and daily dose in both stimulation cycles. The primary outcome was the number of cumulus-oocyte complexes (COC) retrieved. RESULTS: The number of COC retrieved (mean ± SD 19.7 ± 10.8 versus 19.2 ± 8.3; P = 0.5) and the number of metaphase II oocytes (15.5 ± 8.4 versus 16.2 ± 7.0; P = 0.19) were similar for the PPOS and GnRH antagonist protocols, respectively. The duration of stimulation (10.5 ± 1.5 days versus 10.8 ± 1.5 days; P = 0.14) and consumption of gonadotrophins (2271.9 ± 429.7 IU versus 2321.5 ± 403.4 IU; P = 0.2) were also comparable, without any cases of premature ovulation. Nevertheless, there was a significant difference in the total cost of medication per cycle: €898.3 ± 169.9 for the PPOS protocol versus €1196.4 ± 207.5 (P < 0.001) for the GnRH antagonist protocol. CONCLUSION: The number of oocytes retrieved and number of metaphase II oocytes were comparable in both stimulation protocols, with the advantage of significant cost reduction in favour of the PPOS protocol compared with the GnRH antagonist protocol. No cases of premature ovulation were observed, even when progestin was started later in the stimulation.

Phenotype-guided targeted therapy based on functional signal transduction pathway activity in recurrent ovarian cancer patients: The STAPOVER study protocol.

Objective: Ovarian cancer is the fifth cause of cancer-related death among women. The benefit of targeted therapy for ovarian cancer patients is limited even if treatment is stratified by molecular signature. There remains a high unmet need for alternative diagnostics that better predict targeted therapy, as current diagnostics are generally inaccurate predictors. Quantitative assessment of functional signal transduction pathway (STP) activity from mRNA measurements of target genes is an alternative approach. Therefore, we aim to identify aberrantly activated STPs in tumour tissue of patients with recurrent ovarian cancer and start phenotype-guided targeted therapy to improve survival without compromising quality of life. Study design: Patients with recurrent ovarian cancer and either 1) have platinum-resistant disease, 2) refrain from standard therapy or 3) are asymptomatic and not yet eligible for standard therapy will be included in this multi-centre prospective cohort study with multiple stepwise executed treatment arms. Targeted therapy will be available for patients with aberrantly high functional activity of the oestrogen receptor, androgen receptor, phosphoinositide 3-kinase or Hedgehog STP. The primary endpoint of this study is the progression-free survival (PFS) ratio (PFS2/PFS1 ratio) according to RECIST 1.1 determined by the PFS on matched targeted therapy (PFS2) compared to PFS on prior therapy (PFS1). Secondary endpoints include among others best overall response, overall survival, side effects, health-related quality of life and cost-effectiveness. Conclusion: The results of this study will show the clinical applicability of STP activity in selecting recurrent ovarian cancer patients for effective therapies.

Clinical outcomes from ART in predicted hyperresponders: in vitro maturation of oocytes versus conventional ovarian stimulation for IVF/ICSI.

STUDY QUESTION: Do ongoing pregnancy rates (OPRs) differ in predicted hyperresponders undergoing ART after IVM of oocytes compared with conventional ovarian stimulation (OS) for IVF/ICSI? SUMMARY ANSWER: One cycle of IVM is non-inferior to one cycle of OS in women with serum anti-Müllerian hormone (AMH) levels ≥10 ng/ml. WHAT IS KNOWN ALREADY: Women with high antral follicle count and elevated serum AMH levels, indicating an increased functional ovarian reserve, are prone to hyperresponse during ART treatment. To avoid iatrogenic complications of OS, IVM has been proposed as a mild-approach alternative treatment in predicted hyperresponders, including women with polycystic ovary syndrome (PCOS) who are eligible for ART. To date, inferior pregnancy rates from IVM compared to OS have hampered the uptake of IVM by ART clinics. However, it is unclear whether the efficiency gap between IVM and OS may differ depending on the extent of AMH elevation. STUDY DESIGN, SIZE, DURATION: This study is a retrospective cohort analysis of clinical and laboratory data from the first completed highly purified hMG (HP-hMG) primed, non-hCG-triggered IVM or OS (FSH or HP-hMG stimulation in a GnRH antagonist protocol) cycle with ICSI in predicted hyperresponders ≤36 years of age at a tertiary referral university hospital. A total of 1707 cycles were included between January 2016 and June 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Predicted hyperresponse was defined as a serum AMH level ≥3.25 ng/ml (Elecsys® AMH, Roche Diagnostics). The primary outcome was cumulative ongoing pregnancy rate assessed 10-11 weeks after embryo transfer (ET). The predefined non-inferiority limit was -10.0%. The analysis was adjusted for AMH strata. Time-to-pregnancy, defined as the number of ET cycles until ongoing pregnancy was achieved, was a secondary outcome. Statistical analysis was performed using a multivariable regression model controlling for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: Data from 463 IVM cycles were compared with those from 1244 OS cycles. Women in the IVM group more often had a diagnosis of Rotterdam PCOS (434/463, 93.7%) compared to those undergoing OS (522/1193, 43.8%), were significantly younger (29.5 years versus 30.5 years, P ≤ 0.001), had a higher BMI (25.7 kg/m2 versus 25.1 kg/m2, P ≤ 0.01) and higher AMH (11.6 ng/ml versus 5.3 ng/ml, P ≤ 0.001). Although IVM cycles yielded more cumulus-oocyte complexes (COCs) (24.5 versus 15.0 COC, P ≤ 0.001), both groups had similar numbers of mature oocytes (metaphase II (MII)) (11.9 MII versus 10.6 MII, P = 0.9). In the entire cohort, non-adjusted cumulative OPR from IVM was significantly lower (198/463, 42.8%) compared to OS (794/1244, 63.8%), P ≤ 0.001. When analysing OPR across different serum AMH strata, cumulative OPR in both groups converged with increasing serum AMH, and OPR from IVM was non-inferior compared to OS from serum AMH levels >10 ng/ml onwards (113/221, 51.1% (IVM); 29/48, 60.4% (OS)). The number of ETs needed to reach an ongoing pregnancy was comparable in both the IVM and the OS group (1.6 versus 1.5 ET's, P = 0.44). Multivariable regression analysis adjusting for ART type, age, BMI, oocyte number, and PCOS phenotype showed that the number of COCs was the only parameter associated with OPR in predicted hyperresponders with a serum AMH >10 ng/ml. LIMITATIONS, REASONS FOR CAUTION: These data should be interpreted with caution as the retrospective nature of the study holds the possibility of unmeasured confounding factors. WIDER IMPLICATIONS OF THE FINDINGS: Among subfertile women who are eligible for ART, IVM, and OS resulted in comparable reproductive outcomes in a subset of women with a serum AMH ≥10 ng/ml. These findings should be corroborated by a randomised controlled trial (RCT) comparing both treatments in selected patients with elevated AMH. STUDY FUNDING/COMPETING INTEREST(S): There was no external funding for this study. P.D. has been consultant to Merck Healthcare KGaA (Darmstadt, Germany) from April 2021 till June 2023 and is a Merck employee (Medical Director, Global Medical Affairs Fertility) with Merck Healthcare KGAaA (Darmstadt, Germany) since July 2023. He declares honoraria for lecturing from Merck KGaA, MSD, Organon, and Ferring. The remaining authors declared no conflict of interest pertaining to this study. TRIAL REGISTRATION NUMBER: N/A.

Does dual oocyte retrieval with continuous FSH administration increase the number of mature oocytes in low responders? An open-label randomized controlled trial.

STUDY QUESTION: Is there an increase in the total number of metaphase II (MII) oocytes between a conventional ovarian stimulation (OS) and a double uninterrupted stimulation? SUMMARY ANSWER: There is no increase in the total number of MII oocytes when comparing one conventional OS to a continuous stimulation with double oocyte aspiration. WHAT IS KNOWN ALREADY: Based on the concept of multiple follicular waves, the combination of two stimulations in the same ovarian cycle has gained interest in patients with a low ovarian reserve. This so-called dual stimulation approach is usually characterized by a discontinuation of FSH administration for ∼5 days and appears to have a favourable impact on the number of retrieved oocytes without affecting the embryo quality or ploidy status. The outcomes of dual uninterrupted OS have not yet been studied. STUDY DESIGN, SIZE, DURATION: This was an open-label randomized controlled trial (RCT) with superiority design, performed in a single tertiary centre. Subjects were randomized with a 1:1 allocation into two groups between October 2019 and September 2021. All patients underwent a conventional stimulation with recombinant FSH. When two or more follicles of 17 mm were present, the final inclusion criterion was assessed; randomization occurred only in the presence of ≤9 follicles of ≥11 mm. In Group A, ovulation was triggered with hCG, and oocyte retrieval (OR) was performed 34-36 h later, followed by a fresh single or double embryo transfer (SET or DET) on Day 3/5. In Group B, ovulation was triggered with GnRH agonist, followed by another OS, without discontinuation of the FSH administration. In the presence of one or more follicles of ≥17 mm, the second stimulation was completed with hCG. A freeze-all strategy (Day 3/5) was applied for both retrievals, followed by transfer of one or two embryos in an artificially prepared frozen-thawed cycle. In the absence of one or more follicles of ≥17 mm after 13 additional days of stimulation, the second cycle was cancelled. All ORs were executed by a senior fertility specialist who was blinded for the first treatment, and all follicles >10 mm were aspirated, according to routine clinical practice. The primary outcome was the total number of MII oocytes. Patients were followed up until all embryos were transferred, or until live birth was achieved. Other secondary outcomes included the number of cumulus-oocyte complexes (COCs), the number of good quality embryos (Day 3/5), the ongoing pregnancy rate, and gonadotropin consumption. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients between 25 and 40 years old, with an anti-Müllerian hormone level of ≤1.5 ng/ml, antral follicle count of ≤6, or ≤5 oocytes after a previous stimulation, were included. At the start, 70 patients were eligible for participation in the trial, of whom 48 patients fulfilled the final inclusion criterium and were randomized. After drop-out of two patients, 23 patients were randomized to a single round of OS (Group A), and 23 patients were randomized to two uninterrupted rounds of OS (Group B). MAIN RESULTS AND THE ROLE OF CHANCE: Baseline characteristics were similar between both groups. The cumulative number of COCs and MII oocytes after completion of the second OR was similar in Group A and Group B [5.3 ± 2.7 versus 5.3 ± 3.0 (P = 0.95); 4.1 ± 2.4 versus 4.3 ± 2.7 (P = 0.77)]. Likewise, a comparable number of excellent and good quality embryos was available on Day 3 (3.0 ± 2.0 versus 2.7 ± 2.0; P = 0.63). In Group B, the cancellation rate due to insufficient response to the second round of stimulation was 39.1% (9/23). When focusing on the first stimulation in both groups, there were no significant differences regarding basal FSH, gonadotropin consumption, and the number of preovulatory follicles. After the first OR, the mean number of COC and MII oocytes was significantly higher in Group A (who had hCG triggering), compared to Group B (who had GnRH agonist triggering) [5.3 ± 2.7 versus 3.3 ± 2.2; difference 95% CI (0.54 to 3.45), P = 0.004 and 4.1 ± 2.4 versus 3.0 ± 2.2; difference 95% CI (-0.15 to 2.6), P = 0.05, respectively]. Likewise, the number of excellent and good quality embryos on Day 3 was significantly higher (3.0 ± 2.0 versus 1.9 ± 1.7; P = 0.02) in Group A. LIMITATIONS, REASONS FOR CAUTION: This study was powered to demonstrate superiority for the number of MII oocytes after dual stimulation. Investigating the impact of dual stimulation on pregnancy rates would have required a larger sample size. Furthermore, the heterogeneity in embryo vitrification and transfer policies precluded a correct comparison of embryologic outcomes between both groups. WIDER IMPLICATIONS OF THE FINDINGS: This is the first RCT investigating the role of continuous stimulation with double aspiration in low responders. Our results show no statistically significant differences in the cumulative number of MII oocytes between one conventional stimulation with fresh ET and two consecutive stimulations with a freeze-only approach. Furthermore, the observed suboptimal oocyte yield after agonist ovulation triggering in low responders in the dual uninterrupted OS group is a reason for concern and further scrutiny, given that previous RCTs have shown similar outcomes in normal and high responders after hCG and GnRH agonist triggers. STUDY FUNDING/COMPETING INTEREST(S): This work was supported in part by a research grant from Organon. H.T. received honoraria for lectures and presentations from Abbott, Cooper Surgical, Gedeon-Richter, Cook, Goodlife, and Ferring. L.B. received fees for lectures from Merck & Organon and support for attending ESHRE 2023. M.D.V. reports fees for lectures from Ferring, Merck, Organon, IBSA, Gedeon Richter, and Cooper Surgical and support for attending ASRM 2023. S.M. received honoraria for lectures and presentations from Abbott, Cooper Surgical, Gedeon-Richter, IBSA, and Merck. C.B. was on the Advisory board and received consulting fees from Theramex and received honoraria for lectures and presentations from Abbott, Ferring, Gedeon-Richter, IBSA, and Merck. TRIAL REGISTRATION NUMBER: NCT03846544. TRIAL REGISTRATION DATE: 19 February 2019. DATE OF FIRST PATIENT'S ENROLMENT: 28 October 2019.

Pharmacy compounded pilocarpine: An adequate solution to overcome shortage of pilogel® discs for sweat testing in patients with cystic fibrosis.

To respond to shortage of pilocarpine discs due to CE-licensing problems a pharmacy compounded pilocarpine HCL solution was developed and validated for use in CF diagnosis. The aim of this study was to compare the results from a pharmacy compounded pilocarpine HCL solution versus Pilogel® discs for the measurements of sweat chloride concentrations. Ten pediatric and adult patients with CF underwent a sweat test using both Pilogel® discs and pilocarpine HCL solution. The average difference between both methods was -3.25 mmol/L (95% Limits of Agreement: -7.19 [95% CI: -9.19;-5.19] and 0.69 [95% CI: -1.31;2.69] mmol/L. Passing-Bablok regression showed that zero was enclosed with the 95% CI of the calculated intercept (0.15 [95% CI: -1.70;1.42] mmol/L). These data show a good agreement in chloride concentrations obtained using the two pilocarpine products. Therefore, the pharmacy compounded pilocarpine HCL solution can be used as an alternative for Pilogel® discs during times of shortage.

A 10-year follow-up of reproductive outcomes in women attempting motherhood after elective oocyte cryopreservation.

STUDY QUESTION: Which reproductive treatment outcomes are observed in women who underwent elective oocyte cryopreservation (EOC) and who returned to the clinic with a desire for a child? SUMMARY ANSWER: Whether to warm oocytes or to first use fresh own oocytes for ART depends on age upon returning, but both strategies result in favorable reproductive outcomes. WHAT IS KNOWN ALREADY: Most affluent countries have observed a trend toward postponement of childbearing, and EOC is increasingly used based on the assumption that oocytes cryopreserved at a younger age may extend a woman's reproductive lifespan and mitigate her age-related fertility decline. Although most follow-up studies after EOC have focused on women who requested oocyte warming, a substantial proportion of women who do not conceive naturally will embark on fertility treatment without using their cryopreserved oocytes. Reports on reproductive outcomes in past EOC users are scarce, and the lack of reproductive treatment algorithms in this group of women hampers counseling toward the most efficient clinical strategy. STUDY DESIGN, SIZE, DURATION: This retrospective observational single-center study encompasses 843 women who had elective oocyte vitrification between 2009 and 2019 at our fertility clinic. Women who underwent fertility preservation for medical or oncological reasons were excluded. This study describes the outcomes of the diverse reproductive treatment strategies performed until May 2022 in women returning to our clinic to attempt motherhood. PARTICIPANTS/MATERIALS, SETTING, METHODS: Using descriptive statistics, patient characteristics and data of ovarian stimulation (OS) of EOC cycles were analyzed, as well as data related to OS and laboratory data of ART in women who pursued fertility treatment with and/or without using their cryopreserved oocytes. The primary outcome was live birth rate (LBR) per patient after oocyte warming and after ART using fresh oocytes. Secondary outcomes were return rate, utilization rate of the cryopreserved oocytes, laboratory outcomes upon return, and LBR per embryo transfer. A multivariable regression model was developed to identify factors associated with the decision to thaw oocytes as the primary strategy and factors associated with ongoing pregnancy upon return to the clinic. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 1353 EOC cycles (mean ± SD, 1.6 ± 0.9 per patient) were performed. At the time of EOC, the mean age was 36.5 ± 2.8 years, mean anti-Müllerian hormone (AMH) was 2.3 ± 2.0 ng/ml, and 174 (20.6%) women had a partner. On average, 13.9 ± 9.2 mature oocytes were cryopreserved. Two hundred thirty-one (27.4%) women returned to the clinic, an average of 39.9 ± 23.4 months after EOC. Upon returning, their mean age was 40.4 ± 3.1 years, mean AMH was 1.5 ± 1.5 ng/ml, and 158/231 (68.3%) patients had a partner. As a primary approach, 110/231 (47.6%) past EOC users embarked on oocyte warming, 50/231 (21.6%) had intrauterine insemination, and 71/231 (30.7%) had ART using fresh own oocytes. Cumulative LBR (CLBR) was 45.9% (106/231) notwithstanding a miscarriage rate (MR) of 30.7% (51/166) in the entire cohort. In total, 141 women performed oocyte warming at some stage in their treatment trajectory. A subset of 90/231 (39.0%) patients exclusively had oocyte warming (41.6 ± 3.0 years, with 10.0 ± 5.2 oocytes warmed per patient). 52/231 (22.5%) patients exclusively had ART using fresh own oocytes (mean age of 39.0 ± 2.8 years, with 9.9 ± 7.4 mature oocytes retrieved per patient). CLBR was 37/90 (41.1%) in the oocyte warming-only group and 25/52 (48.1%) in the OS-only group. MR/transfer was 25.0% and 29.3% in the oocyte warming-only group and the OS-only group, respectively. LIMITATIONS, REASONS FOR CAUTION: Both sample size and the retrospective design are limitations of this study. The decision to embark on a specific reproductive treatment strategy was based on patient preference, after counseling on their treatment options. This precludes direct comparison of the efficiency of reproductive treatment options in past EOC users in this study. WIDER IMPLICATIONS OF THE FINDINGS: Reporting on clinical outcomes of women who underwent EOC and returned to the clinic to embark on divergent reproductive treatment strategies is mandatory to establish guidelines for best clinical practice in this growing patient population. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A.

To Test or Not? Xpert MTB/RIF as an Alternative to Smear Microscopy to Guide Line Probe Assay Testing for Drug-Resistant Tuberculosis.

Xpert MTB/RIF (Xpert) revolutionized tuberculosis (TB) diagnosis. Laboratory decision making on whether widely-used reflex drug susceptibility assays (MTBDRplus, first-line resistance; MTBDRsl, second-line) are conducted is based on smear status, with smear-negative specimens often excluded. We performed receiver operator characteristic (ROC) curve analyses using bacterial load information (smear microscopy grade, Xpert-generated semi-quantitation categories and minimum cycle threshold [CTmin] values) from Xpert rifampicin-resistant sputum for the prediction of downstream line probe assay results as "likely non-actionable" (no resistance or susceptible results generated). We evaluated actionable-to-non-actionable result ratios and pay-offs with missed resistance versus LPAs done universally. Smear-negatives were more likely than smear-positive specimens to generate a non-actionable MTBDRplus (23% [133/559] versus 4% [15/381]) or MTBDRsl (39% [220/559] versus 12% [47/381]) result. However, excluding smear-negatives would result in missed rapid diagnoses (e.g., only 49% [264/537] of LPA-diagnosable isoniazid resistance would be detected if smear-negatives were omitted). Testing smear-negatives with a semi-quantitation category ≥ "medium" had a high ratio of actionable-to-non-actionable results (12.8 or a 4-fold improvement versus testing all using MTBDRplus, 4.5 or 3-fold improvement for MTBDRsl), which would still capture 64% (168/264) and 77% (34/44) of LPA-detectable smear-negative resistance, respectively. Use of CTmins permitted optimization of this ratio with higher specificity for non-actionable results but decreased resistance detected. Xpert quantitative information permits identification of a smear-negative subset in whom the payoffs of the ratio of actionable-to-non-actionable LPA results with missed resistance may prove acceptable to laboratories, depending on context. Our findings permit the rational expansion of direct DST to certain smear-negative sputum specimens.

Exploring the expression and potential function of follicle stimulating hormone receptor in extragonadal cells related to abdominal aortic aneurysm.

INTRODUCTION: Follicle stimulating hormone (FSH) is identified to play a role in postmenopausal disease and hypothesized to affect abdominal aortic aneurysm (AAA) onset/progression in postmenopausal women. We aimed to detect FSHR gene expression in AAA tissue and cell types involved in AAA formation. METHODS: FSH stimulation of human umbilical cord endothelial cells (HUVECs), smooth muscle cells (HUCs) and PMA-differentiated macrophages to assess gene expression of FSHR and various markers. Human macrophages activated with various stimuli were assessed for FSHR gene expression. AAA dataset, AAA tissue samples and AAA-derived smooth muscle cells (SMC) obtained from elderly female donors were assessed for FSHR gene expression. AAA-SMCs were stimulated with FSH to assess its effect on gene expression. Lastly, oxidized low-density-lipoprotein (ox-LDL) uptake and abundance of cell surface protein markers were assessed by flow cytometry after FSH stimulation of human monocytes. RESULTS: FSH stimulation showed similar levels of gene expression in HUVECs and HUCs. Only ACTA2 was downregulated in HUCs. In PMA-differentiated macrophages, gene expression of inflammation markers was unchanged after FSH stimulation. FSHR gene expression was found to be low in the AAA datasets. Female AAA-SMCs show occasional FSHR gene expression at a very low level, yet stimulation with FSH did not affect gene expression of SMC- or inflammation markers. FSH stimulation did not impact ox-LDL uptake or alter cell surface protein expression in monocytes. While FSHR gene expression was detected in human testis tissue, it was below quantification level in all other investigated cell types, even upon activation of macrophages with various stimuli. CONCLUSION: Despite previous reports, we did not detect FSHR gene expression in various extragonadal cell types, except in occasional female AAA-SMCs. No clear effect on cell activation was observed upon FSH stimulation in any cell type. Our data suggest that a direct effect of FSH in AAA-related extragonadal cells is unlikely to influence AAA.

Validity of self-reported compliance and behavioural determinants of observed compliance: an application of the COM-B hand hygiene questionnaire in nine Dutch hospitals.

BACKGROUND: Hand hygiene compliance (HHC) can be influenced by behavioural determinants, but knowledge on this remains scarce. The Capability, Opportunity, Motivation-Behaviour (COM-B) hand hygiene questionnaire was developed by Lydon et al. to gain insight into self-reported behavioural determinants and self-reported HHC. AIMS: To determine the validity of self-reported HHC using the COM-B questionnaire; and investigate the influence of self-reported behavioural determinants on observed HHC, taking environmental determinants into account. METHODS: This was a cross-sectional study, from September to November 2019, in nine hospitals in the Netherlands. Healthcare workers (HCWs) completed the COM-B questionnaire, and direct hand hygiene observations were performed. In addition, information on environmental determinants (workload, ward category, hospital type and ward infrastructure) was collected. Validity of self-reported HHC was determined using the intraclass correlation coefficient (ICC). Univariable and multi-variable regression analyses were performed to investigate the relationship between behavioural and environmental determinants and observed HHC. FINDINGS: The ICC showed no association between self-reported HHC and observed HHC [0.04, 95% CI -0.14 to 0.21]. In univariable regression analyses, ward category and the opportunity and motivation subscales were significantly associated with observed HHC. In multi-variable regression analysis, only ward category and the motivation subscale remained significant. CONCLUSION: Self-reported HHC is not a valid substitute for direct hand hygiene observations. Motivation (behavioural determinant) was significantly associated with HCC, while almost none of the environmental determinants had an effect on observed HHC. In further development of hand hygiene interventions, increasing the intrinsic motivation of HCWs should receive extra attention.

Study protocol for a randomized, controlled trial using a novel, family-centered diet treatment to prevent nonalcoholic fatty liver disease in Hispanic children.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the leading liver disorder among U.S. children and is most prevalent among Hispanic children with obesity. Previous research has shown that reducing the consumption of free sugars (added sugars + naturally occurring sugars in fruit juice) can reverse liver steatosis in adolescents with NAFLD. This study aims to determine if a low-free sugar diet (LFSD) can prevent liver fat accumulation and NAFLD in high-risk children. METHODS: In this randomized controlled trial, we will enroll 140 Hispanic children aged 6 to 9 years who are ≥50th percentile BMI and without a previous diagnosis of NAFLD. Participants will be randomly assigned to either an experimental (LFSD) or a control (usual diet + educational materials) group. The one-year intervention includes removal of foods high in free sugars from the home at baseline, provision of LFSD household groceries for the entire family (weeks 1-4, 12, 24, and 36), dietitian-guided family grocery shopping sessions (weeks 12, 24, and 36), and ongoing education and motivational interviewing to promote LFSD. Both groups complete assessment measures at baseline, 6, 12, 18, and 24 months. Primary study outcomes are percent hepatic fat at 12 months and incidence of clinically significant hepatic steatosis (>5%) + elevated liver enzymes at 24 months. Secondary outcomes include metabolic markers potentially mediating or moderating NAFLD pathogenesis. DISCUSSION: This protocol describes the rationale, eligibility criteria, recruitment strategies, analysis plan as well as a novel dietary intervention design. Study results will inform future dietary guidelines for pediatric NAFLD prevention. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05292352.

Functional estrogen receptor signal transduction pathway activity and antihormonal therapy response in low-grade ovarian carcinoma.

BACKGROUND: Advanced low-grade ovarian carcinoma (LGOC) is difficult to treat. In several studies, high estrogen receptor (ER) protein expression was observed in patients with LGOC, which suggests that antihormonal therapy (AHT) is a treatment option. However, only a subgroup of patients respond to AHT, and this response cannot be adequately predicted by currently used immunohistochemistry (IHC). A possible explanation is that IHC only takes the ligand, but not the activity, of the whole signal transduction pathway (STP) into account. Therefore, in this study, the authors assessed whether functional STP activity can be an alternative tool to predict response to AHT in LGOC. METHODS: Tumor tissue samples were obtained from patients with primary or recurrent LGOC who subsequently received AHT. Histoscores of ER and progesterone receptor (PR) were determined. In addition, STP activity of the ER STP and of six other STPs known to play a role in ovarian cancer was assessed and compared with the STP activity of healthy postmenopausal fallopian tube epithelium. RESULTS: Patients who had normal ER STP activity had a progression-free survival (PFS) of 16.1 months. This was significantly shorter in patients who had low and very high ER STP activity, with a median PFS of 6.0 and 2.1 months, respectively (p < .001). Unlike ER histoscores, PR histoscores were strongly correlated to the ER STP activity and thus to PFS. CONCLUSIONS: Aberrant low and very high functional ER STP activity and low PR histoscores in patients with LGOC indicate decreased response to AHT. ER IHC is not representative of functional ER STP activity and is not related to PFS.

SAFESTEREO: phase II randomized trial to compare stereotactic radiosurgery with fractionated stereotactic radiosurgery for brain metastases.

BACKGROUND: Stereotactic radiosurgery (SRS) is a frequently chosen treatment for patients with brain metastases and the number of long-term survivors is increasing. Brain necrosis (e.g. radionecrosis) is the most important long-term side effect of the treatment. Retrospective studies show a lower risk of radionecrosis and local tumor recurrence after fractionated stereotactic radiosurgery (fSRS, e.g. five fractions) compared with stereotactic radiosurgery in one or three fractions. This is especially true for patients with large brain metastases. As such, the 2022 ASTRO guideline of radiotherapy for brain metastases recommends more research to fSRS to reduce the risk of radionecrosis. This multicenter prospective randomized study aims to determine whether the incidence of adverse local events (either local failure or radionecrosis) can be reduced using fSRS versus SRS in one or three fractions in patients with brain metastases. METHODS: Patients are eligible with one or more brain metastases from a solid primary tumor, age of 18 years or older, and a Karnofsky Performance Status ≥ 70. Exclusion criteria include patients with small cell lung cancer, germinoma or lymphoma, leptomeningeal metastases, a contraindication for MRI, prior inclusion in this study, prior surgery for brain metastases, prior radiotherapy for the same brain metastases (in-field re-irradiation). Participants will be randomized between SRS with a dose of 15-24 Gy in 1 or 3 fractions (standard arm) or fSRS 35 Gy in five fractions (experimental arm). The primary endpoint is the incidence of a local adverse event (local tumor failure or radionecrosis identified on MRI scans) at two years after treatment. Secondary endpoints are salvage treatment and the use of corticosteroids, bevacizumab, or antiepileptic drugs, survival, distant brain recurrences, toxicity, and quality of life. DISCUSSION: Currently, limiting the risk of adverse events such as radionecrosis is a major challenge in the treatment of brain metastases. fSRS potentially reduces this risk of radionecrosis and local tumor failure. TRIAL REGISTRATION: ClincalTrials.gov, trial registration number: NCT05346367 , trial registration date: 26 April 2022.

Temporal evolution of new T1-weighted hypo-intense lesions and central brain atrophy in patients with a first clinical demyelinating event treated with subcutaneous interferon ß-1a.

OBJECTIVE: Evaluate the effect of subcutaneous interferon ß-1a (sc IFN ß-1a) versus placebo on the evolution of T1-weighted MRI lesions and central brain atrophy in in patients with a first clinical demyelinating event (FCDE). METHODS: Post hoc analysis of baseline-to-24 month MRI data from patients with an FCDE who received sc IFN ß-1a 44 µg once- (qw) or three-times-weekly (tiw), or placebo, in REFLEX. Patients were grouped according to treatment regimen or conversion to clinically definite MS (CDMS) status. The intensity of new lesions on unenhanced T1-weighted images was classified as T1 iso- or hypo-intense (black holes) and percentage ventricular volume change (PVVC) was assessed throughout the study. RESULTS: In patients not converting to CDMS, sc IFN ß-1a tiw or qw, versus placebo, reduced the overall number of new lesions (P < 0.001 and P = 0.005) and new T1 iso-intense lesions (P < 0.001 and P = 0.002) after 24 months; only sc IFN ß-1a tiw was associated with fewer T1 hypo-intense lesions versus placebo (P < 0.001). PVVC findings in patients treated with sc IFN ß-1a suggested pseudo-atrophy that was ~ fivefold greater versus placebo in the first year of treatment (placebo 1.11%; qw 4.28%; tiw 6.76%; P < 001); similar findings were apparent for non-converting patients. CONCLUSIONS: In patients with an FCDE, treatment with sc IFN ß-1a tiw for 24 months reduced the number of new lesions evolving into black holes.

Update to the study protocol Face Your Fears: Virtual reality-based cognitive behavioral therapy (VR-CBT) versus standard CBT for paranoid ideations in patients with schizophrenia spectrum disorders: a randomized clinical trial.

We unfortunately need to make an update to our published study protocol that describes a significant change in the design of the study. The Committee on Health Research Ethics of the Capital Region Denmark recently rejected the approval of changing the primary outcome in the trial, on the invariable grounds that the trial has already commenced. It is therefore necessary to retain the Green Paranoid Thought Scale (GPTS) part B, ideas of persecution, as our primary outcome, and GPTS part A, ideas of social reference, as a secondary outcome, which is described opposite in our published study protocol. The exchange of outcomes has not affected participation in our trial or the informed consent. Intervention in both groups and assessments are unchanged. The two outcomes together constitute GPTS and the unifying concept we attempt to treat, namely paranoid ideations. As this is a blinded, methodologically rigorous trial, we did not have-and still do not have-access to preliminary data, and therefore, we have no knowledge of the distribution of our two intervention groups nor the potential effect of the intervention. The power calculation remains unchanged irrespective of the selection of the primary outcome. We have been fully transparent with the changes in primary and secondary outcomes on ClinicalTrials.gov throughout the trial. Due to the considerations mentioned above, we assumed that there would not be any ethical implications of the change of primary outcome. We sincerely apologize for the irregularity caused because of this assumption.Trial registrationClinicalTrials.gov NCT04902066 . Initial release April 19th, 2021.

Patient characteristics and factors contributing to recurrence of bacterial vaginosis presented in primary care.

BACKGROUND: Bacterial vaginosis (BV) is a common problem in primary care. BV symptoms often have a negative impact on patients' quality of life and may predispose to gynaecological problems. Some patients experience recurring episodes of BV. This study's objective is to identify possible factors that may be associated with BV recurrence and describe the characteristics of these patients and interventions performed by general practitioners. METHODS: In this retrospective cohort study, we used data from a primary care registration network in the Netherlands in the period 2015-2020. We analysed differences between patients with recurrent BV and patients with a single episode of BV in terms of characteristics and interventions performed by general practitioners. RESULTS: We found that patients with recently prescribed antibiotics, and a medical history of sexually transmitted infections and/or Candidiasis significantly more often presented with recurrent BV. Patients with recurrent BV had more remote consultations and less in-person consultations than single-episode patients. The reason for encounter was more often a request for medication. Regarding GPs' diagnostic and therapeutic interventions, microbiological tests were more frequently performed in recurrent BV patients. Moreover, most patients in both groups were prescribed oral metronidazole most frequently. CONCLUSIONS: Our findings might help GPs to better recognise patients at risk of recurrence. GPs could re-evaluate their approach to the diagnosis and treatment of recurrent BV, opting for in-person consultation and using standardised diagnostic criteria and microbiological testing in patients with recurrent complaints. Antibiotic use for other conditions in these patients may lead to new BV episodes.