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Abstract: Dyspareunia, or pain during sex, is a common and often debilitating symptom in individuals with endometriosis and/or interstitial cystitis/bladder pain syndrome (IC/BPS). Despite its significant impact on quality of life, it is frequently overlooked in research. This review evaluates how dyspareunia has been addressed in preclinical investigations of these conditions. A systematic search was conducted using Embase from 1998 to 2021, identifying original in vivo preclinical studies using female rodents to model (i) endometriosis and (ii) IC/BPS. The search aimed to identify studies that assessed dyspareunia. Study quality and risk of bias were evaluated using a modified CAMARADES checklist. Our analysis found 1,286 studies modelling endometriosis and 674 modelling IC/BPS, but only 18 and 1, respectively, measured dyspareunia. The most common method involved vaginal distention in rats, assessed by either behavioural escape responses or visceromotor reflexes of abdominal muscles. Despite the high prevalence of dyspareunia in these conditions, it is rarely measured in preclinical studies. We identify a significant gap in the literature and offer succinct recommendations for future translational research to address this important symptom., Lay Summary: Dyspareunia describes pain occurring before, during or after sexual intercourse. This poorly understood symptom is particularly common in people suffering from two chronic pain-related conditions: endometriosis and IC/BPS, severely impacting their quality of life. Therefore, effective treatments addressing painful sex in people with these conditions are needed. To see the benefits of medical research at the patient's bedside, it is important to build from basic science research to preclinical animal studies then to human studies. Our study aims to assess the work that has been done so far at the 'preclinical' stage. Developments have been made in the methodology used to investigate this symptom in animals, and a summary of all the key findings may help build a platform to design future studies. Given the urgent need to develop new therapeutic strategies, attention given to painful sex by scientific medical researchers and physicians needs to improve.

Cardiovascular disease (CVD) remains the leading cause of mortality in the U.S. accounting for 1 in 4 deaths each year. Environmental factors, such as neighborhood safety, may increase the risk of CVD. Therefore, the current study assessed perceived neighborhood safety and its association with CVD risk factors (i.e. dyslipidemia, hypertension, type II diabetes) among 663 adults (mean age: 49.97 years, 61.24% female, 78.28% White). Participants completed self-report measures as part of a larger study of environmental influences on cardiac health. Results indicated that individuals reporting low perceived neighborhood safety had greater odds of having at least one CVD risk factor (OR = 2.76, 95% CI: 1.46, 5.22) compared to those with high perceived safety. There was a significant interaction between gender and the presence of at least one CVD risk factor in relation to perceived neighborhood safety. Low perceived neighborhood safety was associated with greater odds of having at least one CVD risk factor among males (OR = 5.48, 95% C.I: 1.82, 16.52) but not females. These findings suggest that low perceived safety is associated with CVD risk factors, especially among males. Future work should seek to better understand the interaction by gender in the relationship between perceived safety and CVD risk factors.

Filsuvez ® (birch triterpenes) topical gel received approval in 2023 for the treatment of epidermolysis bullosa (EB) in pediatric patients (aged ≥6 months) and adults. It promotes wound healing by modulating inflammation, encouraging new tissue formation, and maintaining the skin barrier. In a randomized, double-blind, controlled, parallel-group, phase III trial (EASE, NCT03068780), 223 patients were randomly assigned to two groups: the first group received treatment with birch triterpenes topical gel (study gel, n = 109), and the second group received treatment with vehicle gel (n = 114). The study gel or vehicle gel was applied as a 1-mm layer to the affected wound surface once every 4 days for 90 days. The primary efficacy endpoint, defined as the first complete closure of the EB target wound by day 45, was achieved at a higher proportion in the study gel group (41.3% [45/109]), compared to the vehicle gel group (28.9% [33/114]). Application site reactions were reported in 7.3% (8/109) of patients in the study gel group and 6.1% (7/114) of patients in the vehicle gel group. It is recommended to apply as a 1-mm layer to the affected wound surface only.

Zelsuvmi TM (berdazimer) topical gel has been approved recently for the treatment of molluscum contagiosum (MC) in patients aged ≥1 year. In three phase 3, randomized, double-blind, vehicle-controlled trials of similar design, berdazimer was investigated for the treatment of MC. Berdazimer or vehicle was applied once daily on MC lesions until complete lesion clearance was observed or for up to 12 weeks. Berdazimer demonstrated higher efficacy in achieving the primary outcome at week 12 (Trial 1, berdazimer: 32.4% [144/444] and vehicle: 19.7% [88/447]; Trial 2, berdazimer: 30% [71/237] and vehicle: 20.3% [24/118]; and Trial 3, berdazimer: 26% [61/236] and vehicle: 22% [28/126]), compared to vehicle. Common adverse events were the mild to moderate reactions, including application site pain, dermatitis, exfoliation, erythema, pruritus, and lesions.

Introduction: Chronic pelvic pain affects up to 24% of women worldwide and for up to 55% of these there is no associated pathology. Despite this there are no established treatments in this cohort. This is a secondary analysis of a randomised-controlled trial (GaPP2) to explore if there are measures which enable us to predict treatment outcome., Methods: GaPP2 recruited women with chronic pelvic pain and no identified pathology and compared the response to gabapentin and placebo. This analysis used variables collected at baseline including validated questionnaires. Binary logistic regression was used to create models to explore whether baseline variables predicted treatment response. Treatment response was determined using 30% reduction in average pain intensity, 30% reduction in worst pain intensity and the Patient Global Impression of Change ('marked' or 'very marked' improvement) individually. We also explored whether baseline variables predicted the occurrence of side-effects (dizziness, visual disturbances and drowsiness)., Results: Using the Patient Global Impression of Change questionnaire, we found a significant binary logistic regression ( p = 0.029, explaining 31% of the variance), with those with lower worst pain intensity (odds ratio (OR) of 0.393, 95% CI [0.217, 0.712]), lower bladder symptom score (OR = 0.788, CI [0.628, 0.989]), and higher mental component quality of life score (OR = 0.911, CI [0.840, 0.988]), more likely to have 'marked' or 'very marked' improvement when treated with gabapentin. We could not identify predictors of experiencing side-effects to gabapentin. However, we did find predictors of these in the placebo group (binary logistic regression ( p = 0.009) and explained 33% of the variance). Worse mental health (OR = 1.247, CI [1.019, 1.525]) and lower baseline pain interference (OR = 0.687, CI [0.483, 0.978]) were associated with having side effects, whilst the use of hormones reduced the risk of experiencing side effects (OR = 0.239, CI [0.084, 0.676])., Discussion: Researchers and clinicians are increasingly aware of the importance of personalised medicine and treatment decisions being driven by knowledge of what treatments work for whom. Our data suggests an important role of the Patient Global Impression of Change in clinical trials as it may better reflect balance between symptoms reduction and side-effects and therefore be more useful in clinician-patients joint decision making., Competing Interests: KV, AH and SM are listed as co-inventors on a patent application (UK Patent App No. 2217921.2, International Patent App No. PCT/GB2023/053076) relating to the use of the NRG3 loci as a predictive test to determine efficacy of gabapentin for chronic pelvic pain treatment. AH’s institution has received honoraria for consultancy from Roche Diagnostics, Gesynta and Joii, and he has received lecture fees from Theramex. AH’s institution has received grant funding from Roche Diagnostics. KV’s institution has received honoraria for consultancy and lectures from Bayer Healthcare, Reckitt, AbbVie and Gedeon Richter., (Copyright © 2024 Coxon, Amer, Daniels, Doust, Mackenzie, Horne and Vincent.)

Objective: To quantify the variation, triggers and impact on quality of life of symptom flares in women with chronic pelvic pain (CPP)., Design: Cross-sectional questionnaire within the Translational Research in Pelvic Pain clinical cohort study., Setting: Women with CPP, with subgroups of women with endometriosis (EAP), interstitial cystitis/bladder pain syndrome (BPS), comorbid endometriosis and interstitial cystitis/bladder pain syndrome (EABP), and those with pelvic pain without endometriosis or interstitial cystitis/bladder pain syndrome (PP)., Population or Sample: A total of 100 participants., Methods: Descriptive and comparative analysis from flares questionnaire., Main Outcome Measures: The prevalence, characteristics and triggers of short, medium and long symptom flares in CPP., Results: We received 100 responses of 104 questionnaires sent. Seventy-six per cent of women with CPP have ever experienced symptom flares of at least one length (short, medium and/or long). Flares are associated with painful and non-painful symptoms. There is large variation for the frequency, duration, symptoms and triggers for flares. Over 60% of participants reported flares as stopping them from doing things they would usually do, >80% reported thinking about symptoms of flares and >80% reported flares being bothersome., Conclusions: Flares are prevalent and clinically very important in CPP. More research is needed to elucidate the mechanisms and characteristics underlying flares. Clinical practice should include an enquiry into flares with the aim of finding strategies to lessen their burden., (© 2024 The Author(s). BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Objective: To identify maternal and neonatal risk factors associated with progression to surgery or death after diagnosis of NEC., Study Design: Forty-seven demographic and clinical factors were evaluated across 216 validated cases of NEC occurring between 2010-2020. Nutrition at NEC onset was evaluated in 149 cases. The binary outcome of surgical NEC (progressing to surgery or death) vs. medical NEC (resolved with antibiotic/bowel rest) was compared across variables., Results: Elevated CRP, rapidly decreasing platelet counts, inotropic medication, intubation, and positive blood cultures within 24 h of diagnosis were associated with progression to surgery/death. Infants with surgical NEC had higher abdominal circumferences at birth. Maternal milk intake and receipt of human milk fortifiers were associated with medical NEC, and infants receiving fortified, maternal milk showed the lowest progression to surgery/death., Conclusion: The index of suspicion should be heightened for surgical NEC when these risk factors are present., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: This study was approved by the Institutional Review Board of the Medical University (Protocol 00104755) of South Carolina and consent was waived. The study was performed in accordance with the Declaration of Helsinki., (© 2024. The Author(s).)

Competing Interests: Competing interests: The authors declare no competing interests.

Efficient manufacturing of recombinant adenovirus-associated virus (AAV) vectors is critical to the successful development of genomic medicines. We attempted to optimize AAV vector production in a producer cell line platform. In this system, helper functions required for AAV replication and production are provided via infection with a replication-competent wild-type Adenovirus. To evaluate strategies for the reduction of replication and packaging of adenovirus and to understand the interplay of recombinant AAV and the helper virus during AAV vector production, wild-type adenovirus was compared to a mutant (Ad5ts149) containing a temperature-sensitive mutation in the DNA polymerase gene. Infection of a producer cell line with Ad5ts149 at the restrictive temperature reduced recombinant AAV titer and altered the pattern of AAV protein expression. Further investigation revealed that the adenoviral late L4-22K/33K gene products regulated both AAV rep/cap gene transcription and splicing of the rep/cap transcripts. Furthermore, the L4-33K gene products were found to impact AAV production in both the producer cell line and transient transfection platforms. Optimization of Adenovirus L4-22K/33K expression to facilitate efficient expression and splicing of AAV rep/cap transcripts therefore represents a unique opportunity to optimize AAV vector production., Competing Interests: All authors are employed by Sanofi US and may hold shares and/or stock options in the company. A provisional patent covering the findings from this study has been submitted., (© 2024 The Authors.)

Abstract: Endometriosis, a common cause for chronic pelvic pain, significantly affects quality of life, fertility, and overall productivity of those affected. Therapeutic options remain limited, and collating evidence on treatment efficacy is complicated. One reason could be the heterogeneity of assessed outcomes in nonsurgical clinical trials, impeding meaningful result comparisons. This systematic literature review examines outcome domains and patient-reported outcome measures (PROMs) used in clinical trials. Through comprehensive search of Embase, MEDLINE, and CENTRAL up until July 2022, we screened 1286 records, of which 191 were included in our analyses. Methodological quality (GRADE criteria), information about publication, patient population, and intervention were assessed, and domains as well as PROMs were extracted and analyzed. In accordance with IMMPACT domain framework, the domain pain was assessed in almost all studies (98.4%), followed by adverse events (73.8%). By contrast, assessment of physical functioning (29.8%), improvement and satisfaction (14.1%), and emotional functioning (6.8%) occurred less frequently. Studies of a better methodological quality tended to use more different domains. Nevertheless, combinations of more than 2 domains were rare, failing to comprehensively capture the bio-psycho-social aspects of endometriosis-associated pain. The PROMs used showed an even broader heterogeneity across all studies. Our findings underscore the large heterogeneity of assessed domains and PROMs in clinical pain-related endometriosis trials. This highlights the urgent need for a standardized approach to both, assessed domains and high-quality PROMs ideally realized through development and implementation of a core outcome set, encompassing the most pivotal domains and PROMs for both, stakeholders and patients., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Cabtreo TM (1.2% clindamycin phosphate, 0.15% adapalene, and 3.1% benzoyl peroxide) or IDP-126 topical gel was approved by the US Food and Drug Administration (FDA) in October 2023 for the treatment of moderate to severe acne vulgaris in patients aged ≥12 years. Its effectiveness and safety were evaluated in two phase 3 trials (Trial 1 and Trial 2). In both trials, subjects were randomized into two groups, one received IDP-126 gel and the other received vehicle gel. The primary efficacy end point was treatment success at week 12, defined as subjects achieving at least a 2-grade reduction from baseline in Evaluator's Global Severity Score (EGGS) and a final score ranging from 0 (clear) to 1 (almost clear) as well as reduced counts of inflammatory and non-inflammatory lesions. In Trial 1 (N = 183), treatment success was achieved in 49.6% (61/122) of subjects in the IDP-126 group versus 24.9% (15/61) of subjects in the vehicle group ( P < 0.01). In Trial 2 (N = 180), treatment success was achieved in 50.5% (61/120) of subjects in the IDP-126 group versus 20.5% (12/60) of subjects in the vehicle group ( P < 0.01). IDP-126 is therefore recommended to be applied as a thin layer to the affected area once daily.

BIMZELX ® (bimekizumab-bkzx) injection, for subcutaneous use, was approved in October 2023 for moderate to severe plaque psoriasis in patients aged ≥18 years. In three phase 3, randomized, double-blind, vehicle, and comparator-controlled studies (Be Vivid, Be Ready, and Be Sure), bimekizumab was investigated for the treatment of plaque psoriasis. The primary efficacy end point was psoriatic area and severity index (PASI) 90 (patients with 90% improvement in PASI from baseline) and investigator's global assessment (IGA) score of 0 (clear skin)-1 (almost clear skin) as well as ≥2-point improvement from baseline at week 16. In the Be Vivid study, patients were randomized into the bimekizumab, placebo, and ustekinumab groups. PASI 90 score was achieved by 85% (273/321) in the bimekizumab group, 5% (4/83) in the placebo group, and 50% (81/163) in the ustekinumab group. IGA 0/1 score was achieved by 84% (270/321) in the bimekizumab group, 5% (4/83) in the placebo group, and 53% (87/163) in the ustekinumab group. In the Be Ready study, patients were randomized into bimekizumab and placebo groups. PASI 90 score was achieved by 91% (317/349) in the bimekizumab group and 1% (1/86) in the placebo group. IGA 0/1 score was achieved by 93% (323/349) in the bimekizumab group and 1% (1/86) in the placebo group. In the Be Sure study, patients were randomized into two bimekizumab groups (receiving different bimekizumab regimens) and one adalimumab group. PASI 90 score was achieved by 86.2% (275/319) in combined bimekizumab groups and 47.2% (75/159) in the adalimumab group. IGA 0/1 score was achieved by 85.3% (272/319) in combined bimekizumab groups and 57.2% (91/159) in the adalimumab group. Bimekizumab was well tolerated with no unexpected safety findings.

Endometriosis-associated pain is burdensome to both the individual and wider society. However, current treatment leaves many with persisting pain. Here, we highlight how recent work considering endometriosis in the context of chronic pain has altered our understanding and how this has the potential to improve clinical care., Competing Interests: Declaration of interests K.V. declares fees paid to her institution for consultancy and lectures from Bayer Healthcare, Gedeon Richter, AbbVie, and Reckitts and grant funding from NIHR, NIH US, MRC, and EU IMI-2., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

In patients with dyssynchronous heart failure (DHF), cardiac conduction abnormalities cause the regional distribution of myocardial work to be non-homogeneous. Cardiac resynchronization therapy (CRT) using an implantable, programmed biventricular pacemaker/defibrillator, can improve the synchrony of contraction between the right and left ventricles in DHF, resulting in reduced morbidity and mortality and increased quality of life. Since regional work depends on wall stress, which cannot be measured in patients, we used computational methods to investigate regional work distributions and their changes after CRT. We used three-dimensional multi-scale patient-specific computational models parameterized by anatomic, functional, hemodynamic, and electrophysiological measurements in eight patients with heart failure and left bundle branch block (LBBB) who received CRT. To increase clinical translatability, we also explored whether streamlined computational methods provide accurate estimates of regional myocardial work. We found that CRT increased global myocardial work efficiency with significant improvements in non-responders. Reverse ventricular remodeling after CRT was greatest in patients with the highest heterogeneity of regional work at baseline, however the efficacy of CRT was not related to the decrease in overall work heterogeneity or to the reduction in late-activated regions of high myocardial work. Rather, decreases in early-activated regions of myocardium performing negative myocardial work following CRT best explained patient variations in reverse remodeling. These findings were also observed when regional myocardial work was estimated using ventricular pressure as a surrogate for myocardial stress and changes in endocardial surface area as a surrogate for strain. These new findings suggest that CRT promotes reverse ventricular remodeling in human dyssynchronous heart failure by increasing regional myocardial work in early-activated regions of the ventricles, where dyssynchrony is specifically associated with hypoperfusion, late systolic stretch, and altered metabolic activity and that measurement of these changes can be performed using streamlined approaches., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Patent applications related to the technology described here have been submitted in the United States (“Compositions and methods for patient-specific modeling to predict outcomes of cardiac resynchronization therapy,” serial no. P00015-268P01; “Patient-specific modeling of ventricular activation pattern using surface ECG-derived vectorcardiogram in bundle branch block,” serial no. PCT/US15/36788). A.D.M and J.H.O are co-founders and equity-holders in Insilicomed, Inc., a licensee of UC San Diego software used in this research. A.D.M, C.T.V, and D.E.K. are co-founders and equity holders of Vektor Medical Inc., which was not involved in this research. Vektor Medical and Insilicomed, Inc. had no involvement at all in design, performance, analysis or funding of the present study. Vektor Medical and Insilicomed are licensees of intellectual property arising from or used in this research. This relationship has been disclosed to, reviewed, and approved by the University of California San Diego in accordance with its conflict of interest policies., (Copyright: © 2024 Craine et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

DAXXIFY TM (daxibotulinumtoxinA-lanm) for intramuscular injection was recently approved for temporary improvement in the appearance of the moderate to severe glabellar lines (GLs) associated with corrugator and/or procerus muscle activity in adult patients. DaxibotulinumtoxinA for Injection (DAXI) includes a purified 150-kDA botulinum toxin Type A (BoNTA) formulated with a novel peptide excipient that is positively charged and helps to bind the neurotoxin to negatively charged neuronal membrane for a longer duration. The effectiveness of DAXI was evaluated in two phase 3 trials, SAKURA 1 and SAKURA 2, using a randomized, double-blind, placebo-controlled design. The primary endpoint (treatment success) was a composite clinical outcome (investigator and subjects) of ≥2-point improvement in severity of GLs at week 4. In SAKURA 1, the treatment success was 74% (148/201) in subjects treated with DAXI and 0% in subjects treated with placebo. In SAKURA 2, the treatment success was 74% (152/205) in subjects treated with DAXI and 0% in subjects treated with placebo. An open-label study, SAKURA 3, included 2,691 participants, who underwent three consecutive treatment cycles. These individuals were recruited from either SAKURA 1 or SAKURA 2 trials, or were new to the study and received DAXI. Treatment success proportions were 73.2%, 77.7%, and 79.6% across the three consecutive treatment cycles. The recommended dose is 40 units for the Glabellar-complex divided in traditional five intramuscular injections at five injection sites (medial and lateral corrugator bilaterally and one injection in the procerus muscle).

There is growing evidence that the uptake and use of telehealth is influenced by the distinct specialty area or type of healthcare service provided, with mental health services presenting particular challenges. However, little is known about how telehealth use differs between different mental health professions, and no qualitative research has explored variations in telehealth use and perspectives at the profession level within Australian mental health services. To address this gap, we analyzed transcripts from 19 semi-structured interviews conducted with mental healthcare professionals in a local health district within New South Wales, Australia. A secondary analysis of the data revealed the distinct ways in which different mental health professions perceive and engage with telehealth depending on their specific role and approach to practice. Application of a systems theory lens highlighted the challenges each profession faces at different levels of telehealth engagement, and the macro-systemic power dynamics and hierarchies that shape profession-specific differences in telehealth use., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Abstract: A cross-sectional multinational collaborative study on women with endometriosis from Latin America and Spain uncovered high levels of painful symptomatology and high pain catastrophizing scores. Associations between pain perception/catastrophizing and race/ethnicity have been documented. This study was conducted to uncover factors moderating pelvic pain severity, including socioeconomic variables, self-identified race, and pain catastrophizing in women with endometriosis from Latin America and Spain, a population encompassing diverse racial and sociocultural contexts. Self-reported data on demographics, clinical history, Ob-Gyn history, pelvic pain intensity, and pain catastrophizing were collected with the Spanish World Endometriosis Research Foundation (WERF) Endometriosis Phenome Project (EPhect) Clinical Questionnaire (ECQ). Multiple logistic regression was conducted to analyze effects of self-identified race, demographic clusters (defined as countries with similar racial population distribution), socioeconomic factors, and pain catastrophizing on reporting severe vs moderate-mild levels of dysmenorrhea, dyspareunia, and pelvic pain. Self-identified race did not affect the likelihood of reporting severe pelvic pain; however, there were significant differences in reporting severe dysmenorrhea at worst among demographic clusters. Older age was associated with severe dyspareunia at worst and recent pelvic pain. Pain catastrophizing score was highly predictive of reporting most types of severe pelvic pain, regardless of race and demographic cluster. These results negate a role of racial categories as moderator of pain in women from Latin America and Spain and support integration of pain catastrophizing assessments and psychological interventions into the pain management plan to enhance therapeutic outcomes and QoL for patients with endometriosis., (Copyright © 2024 International Association for the Study of Pain.)

This Perspectives article reflects on findings from our systematic review about adolescent dysmenorrhoea Q, drawing on sociology of diagnosis theory. We consider tensions and uncertainties between presentation with symptoms of dysmenorrhoea and processes of symptom categorisation and diagnosis in adolescents, tracing these through research and clinical guidance, considering possible implications for clinical practice. We argue that challenges in distinguishing between primary and secondary dysmenorrhoea in research translate into challenges in differentiation in clinical practice. We argue that framing this distinction as clear cut and straightforward belies the well-documented challenges in diagnosis of endometriosis, and that not recognising uncertainty and complexity inherent in this task may benefit neither clinicians nor patients., Competing Interests: KV has received research funding from Bayer Healthcare and honoraria for talks and consultancy fees paid to her institution from Bayer Healthcare, AbbVie, Reckitts, Gedeon Richter and Eli Lilly. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Dixon, Taghinejadi, Duddy, Holloway, Vincent and Ziebland.)

Spevigo ® (spesolimab-sbzo) injection was recently approved for the treatment of generalized pustular psoriasis (GPP) in adults aged 18- 75 years. Spesolimab, a monoclonal antibody, binds to the interleukin-36 (IL-36) receptor and prevents its activation by IL-36 cytokines, leading to reduced inflammation, skin lesions, and flares. In a randomized placebo-controlled, phase 2 study (Effisayil-1, NCT03782792), 53 patients were randomized to spesolimab (n = 35) and placebo (n = 18) to evaluate the effect of a one-time 900-mg dose of spesolimab versus placebo against GPP flares. The primary endpoint was Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 (no visible pustules) and the key secondary endpoint was the GPPGA total score of 0 or 1 (clear or almost clear skin) at the end of week 1. The primary endpoint was achieved by 54% (19/35) of patients in the spesolimab group and 6% (1/18) of patients in the placebo group. The key secondary endpoint was achieved by 43% (15/35) of patients in the spesolimab group and 11% (2/18) of patients in the placebo group. In the first week, adverse events (mild to severe) were reported in 66% (22/35) of patients in the spesolimab group and 56% (10/18) in the placebo group.

Libtayo ® (cemiplimab-rwlc) injection for intravenous use was recently approved by the US Food and Drug Administration (FDA) for locally advanced basal cell carcinoma (laBCC) and metastatic basal cell carcinoma (mBCC), both being the advanced stages of BCC. In the past, it was approved by the FDA for the treatment of metastatic cutaneous squamous cell carcinoma (mCSCC) and locally advanced cutaneous squamous cell carcinoma (laCSCC), both being the advanced stages of CSCC. Cemiplimab is a monoclonal antibody that works by blocking the programmed death-1 pathway. In two open-label, single-arm, phase 2 studies, cemiplimab was investigated for the treatment of advanced stages of BCC (study 1620, NCT03132636) and advanced stages of CSCC (study 1540, NCT02760498). The primary endpoint was objec-tive response rate (ORR) per independent central review. In the study 1620, both mBCC and laBCC received cemiplimab 350 mg every 3 weeks. ORR was 21% (6/28) and 31% (26/84) in the mBCC and laBCC groups, respectively. In the study 1520, mCSCC was divided into two groups: one receiving cemiplimab 350 mg every 3 weeks (Q3W) and another receiving 3-mg/kg cemiplimab every 2 weeks (Q2W); the third group, laCSCC, received cemiplimab 3 mg/kg every 2 weeks. ORR was 41% (23/56) in the Q3W group, 49% (29/59) in the Q2W group, and 44% (34/78) in the laCSCC group. An acceptable safety profile and antitumor activity was discovered in patients treated with cemiplimab. The recommended dosage for cemiplimab to treat advanced stages of BCC and CSCC is 350 mg every 3 weeks administered intravenously over 30 min.

Objective: The World Endometriosis Research Foundation established the Endometriosis Phenome and Biobanking Harmonisation Project (EPHect) to create standardized documentation tools (with common data elements) to facilitate the comparison and combination of data across different research sites and studies. In 2014, 4 data research standards were published: clinician-reported surgical data, patient-reported clinical data, and fluid and tissue biospecimen collection. Our current objective is to create an EPHect standard for the clinician-reported physical examination (EPHect-PE) for research studies., Design: An international consortium involving 26 clinical and academic experts and patient partners from 11 countries representing 25 institutions and organizations. Two virtual workshops, followed by the development of the physical examination standards underwent multiple rounds of iterations and revisions., Subjects: N/A MAIN OUTCOME MEASURE(S): N/A RESULT(S): The EPHect-PE tool provides standardized assessment of physical examination characteristics and pain phenotyping. Data elements involve examination of back and pelvic girdle; abdomen including allodynia and trigger points; vulva including provoked vestibulodynia; pelvic floor muscle tone and tenderness; tenderness on unidigital pelvic examination; presence of pelvic nodularity; uterine size and mobility; presence of adnexal masses; presence of incisional masses; speculum examination; tenderness and allodynia at an extra-pelvic site (e.g., forearm); and recording of anthropometrics., Conclusion(s): The EPHect-PE standards will facilitate the standardized documentation of the physical examination, including the assessment and documentation of examination phenotyping of endometriosis-associated pelvic pain., Competing Interests: Declaration of Interests T.L. has nothing to disclose. C.A. reports consultancy fees from AbbVie and Pfizer. S.A.-S reports consultancy fees from Myovant-Pfizer, Organon, and Bayer. P.S. has received royalties from UpToDate for a section about acute pelvic pain and from Frontiers in Reproductive Health as Specialty Editor for Gynecology, and participated in an AbbVie advisory board and is part of a team that received botulinum toxin and funds for monitoring a clinical trial that were provided by Allergan, Inc. through a Clinical Trials Agreement with the National Institutes of Health (NIH). K.V. has received research funding from Bayer AG and honoraria for consultancy from Bayer AG, Eli Lilly, AbbVie, and Reckitts. G.D.A. reports consultancy fees from Organon, Labcorp, and Cooper, and is the CEO of and has equity in ARC Fertility. L.A.-N. has nothing to disclose. D.B. is the owner of EPP Coaching and Consulting and has received travel expenses and speaking fees from Myovant and Guerbet. F.J., J.L and L.R., have nothing to disclose. J.S. is part of a team that received botulinum toxin and funds for monitoring a clinical trial that was provided by Allergan, Inc. through a Clinical Trials Agreement with the NIH. A.T. has nothing to disclose. L.H. is remunerated by WERF as the EPHect-PE project manager. S.A.M. reports consultancy and grant funding from AbbVie for population-based research unrelated to this project and from Frontiers in Reproductive Health as Field Chief Editor. P.J.Y. has nothing to disclose. The WERF EPHect Working Group (not listed in the author list): E.A. has nothing to disclose. J.C. is the IPPS vice-president and a consultant for SoLa Therapy, AbbVie, and Myovant; E.C. is an employee of Endometriosis UK; H.C.G has nothing to disclose. A.W.H.’s institution (University of Edinburgh) has received payment for consultancy and grant funding from Roche Diagnostics to assist in the early development of a possible blood diagnostic biomarker for endometriosis, consultancy fees from Gesynta and Joii, and grant funding from the UKRI, NIHR, CSO, and Wellbeing of Women for endometriosis research. A.W.H. has received payment for a lecture from Theramex, is president-elect of the World Endometriosis Society, co-editor in chief of Reproduction and Fertility, was a member of the NICE and ESHRE Endometriosis Guideline Groups, and is a trustee and medical advisor to Endometriosis UK; A.J. has nothing to disclose. G.L. is an employee of the US Veterans Health Administration, reports research funding from the NIH and Department of Defence, and has served as a consultant for Myovant, AbbVie, and Pelvic Sola Therapy. D.C.M. and O.C.N. have nothing to disclose. F.F.T. has royalties from Wolters Kluwer, has consulted for Bayer and Tremeau Pharmaceuticals, and received research support from Dot Laboratories., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Dysmenorrhoea affects many adolescents with significant impacts on education and well-being. In the UK, most of the adolescents who seek care (and many never do), will do so through general practice (primary care). Knowing how best to care for adolescents reporting menstrual pain is an area where UK general practitioners would like better guidance and resources., Methods: This mixed-methods narrative synthesis collates community and specialist evidence from 320 papers about adolescent dysmenorrhoea, with a UK general practice community health perspective., Results: We report a narrative summary of symptoms, cause, consequences and treatments for adolescent dysmenorrhoea. We highlight areas of tension or conflicted evidence relevant to primary care alongside areas of uncertainty and research gaps identified through this synthesis with input from lived experience advisers., Discussion: There is little evidence about primary care management of adolescent dysmenorrhoea or specific resources to support shared-decision making in general practice, although there are evidence-based treatments to offer. Primary care encounters also represent potential opportunities to consider whether the possibility of underlying or associated health conditions contributing to symptoms of dysmenorrhoea, but there is little epidemiological evidence about prevalence from within community health settings to inform this. The areas where there is little or uncertain evidence along the care journey for adolescent dysmenorrhoea, including at the interface between experience and expression of symptoms and potential underlying contributory causes warrant further exploration., Systematic Review Registration: https://www.crd.york.ac.uk/PROSPEROFILES/256458&#95;STRATEGY&#95;20210608.pdf, identifier (CRD42021256458)., Competing Interests: KV has received research funding from Bayer Healthcare and honoraria for talks and consultancy fees paid to her institution from Bayer Healthcare, AbbVie, Reckitts, Gedeon Richter and Eli Lilly. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Dixon, Hirst, Taghinejadi, Duddy, Vincent and Ziebland.)

Chronic pelvic pain (CPP) in women with no obvious pelvic pathology has few evidence-based treatment options. Our recent multicenter randomized controlled trial (GaPP2) in women with CPP and no obvious pelvic pathology showed that gabapentin did not relieve pain overall and was associated with more side effects than placebo. We conducted an exploratory genome-wide association study using eligible GaPP2 participants aiming to identify genetic variants associated with gabapentin response. One genome-wide significant association with gabapentin analgesic response was identified, rs4442490, an intron variant located in Neuregulin 3 ( NRG3 ) ( p  = 2·11×10 -8 ; OR = 18·82 (95% CI 4·86-72·83). Analysis of a large sample of UK Biobank participants demonstrated phenome-wide significant brain imaging features of rs4442490, particularly implicating the orbitofrontal cortex. NRG3 is expressed predominantly in central nervous system tissues and plays a critical role in nervous system development, maintenance, and repair, suggesting a neurobiologically plausible role in gabapentin efficacy and potential for personalized analgesic treatment., Competing Interests: SCM, NR, KV, KTZ, AWH, and LHRW are listed as co-inventors on a patent application (UK Patent App No. 2217921.2, International Patent App No. PCT/GB2023/053076) relating to the use of the NRG3 loci presented herein as a predictive test to determine the efficacy of gabapentin for chronic pelvic pain treatment. AWH’s institution has received honoraria for consultancy from Roche Diagnostics, Gesynta, and Joii, and he has received lecture fees from Theramex. AWH and LHRW’s institution has received grant funding from Roche Diagnostics. KV reports grant funding to the Institution from Bayer AG and honoraria for consultancy paid to the Institution from Bayer AG, Abbvie, Reckitts, and Gedeon Richter. KTZ reports grant funding to the Institution from Bayer AG, Roche Diagnostics, MDNA Life Sciences Ltd, and Exeltis Ltd, and royalty payments from scientific collaboration with Bayer AG. The other authors declare no competing interests., (Crown Copyright © 2024 Published by Elsevier Inc.)

Competing Interests: Financial Disclosure: Katy Vincent reports money was paid to her institution from Reckitts, Gedeon Richter, and UKRI. Research funding was paid to her institution from NIHR, NIH and the EU IMI2 scheme. Emma Evans did not report any potential conflicts of interest.

Background: Women who are black are less likely to be diagnosed with endometriosis than white women. There is no confirmed biological basis, so this likely represents structural barriers around health care. There is a lack of evidence exploring the interface between ethnicity and symptoms or experience of care and treatment., Aim: To map recording of sociodemographic diversity in the evidence informing an endometriosis guideline., Method: Inclusion of study setting, ethnicity, age, and socioeconomic status was documented within the evidence cited in National Institute for Health and Care Excellence (NICE) NG73 (2017) Endometriosis diagnosis and management . Included were 44 studies with 43 sample groups from the chapters: 'Signs and Symptoms', 'Information and Support', and 'Diagnosis'. Data were extracted independently by two researchers., Results: No studies were conducted in primary care. The evidence cited in 'Signs and Symptoms' and 'Diagnosis' was exclusively from tertiary care. 'Information and Support' included 9/16 studies from tertiary care, and 7/16 recruited through community and advocacy networks. For ethnicity, 4/44 studies formally reported participant ethnicity (three from 'Information and Support', one from 'Diagnosis'). In these, 93%, 90%, 60%, and 75% of participants were white/Caucasian (mean 79.5%). For age, 3/44 studies included adolescents. Many studies excluded women who were deemed outside reproductive age. For socioeconomic status, eight studies, all from 'Information and Support', reported socioeconomic status in some form. The majority of participants were tertiary educated., Conclusion: These results highlight the missing demographics within evidence cited in a national guideline for endometriosis. These align with documented inequities in diagnosis of endometriosis and warrant urgent attention., (© British Journal of General Practice 2024.)

Background: Dysmenorrhoea affects up to 94% of adolescents who menstruate; approximately one third miss school and activities. Dysmenorrhoea can occur without identified pelvic pathology (primary dysmenorrhoea) or in association with other conditions (secondary dysmenorrhoea). In adolescence, the commonest cause of secondary dysmenorrhoea is endometriosis. The incidence of symptoms in adolescence suggesting possible endometriosis has not been previously documented in GP records., Aim: To document incidence of adolescent endometriosis and symptoms associated with endometriosis in English GP records., Method: Data from the QResearch primary care database were used for adolescent females aged 10- 19 years between 1 January 2011 and 30 June 2021, reported using descriptive statistics., Results: The population cohort included 2 843 347 female adolescents; 98 887 participants had coded dysmenorrhoea (3.48%) and 1994 (0.07%) had documented endometriosis. The cumulative incidence for the cohort who turned 10 years old in 2011 was 7.2% for dysmenorrhoea and 0.12% for endometriosis. The period prevalence of coded symptoms during adolescence potentially associated with dysmenorrhoea and endometriosis includes: heavy menstrual bleeding (3.73%), irregular menstrual bleeding (2.21%), pelvic pain (0.63%), dyspareunia (0.40%), premenstrual syndrome (PMS)/premenstrual dysphoric disorder (PMDD) (0.22%), cystitis (8.45%), and irritable bowel syndrome (IBS) (1.00%). Disparities in coding were observed for these variables by ethnicity and socioeconomic status. Incidence of prescribed hormonal medication, with and without coded dysmenorrhoea, varied by ethnicity. This was less apparent for non-steroidal anti-inflammatory medications., Conclusion: Prevalence of coded dysmenorrhoea in GP records is significantly lower than community surveys suggest; however, adolescent menstrual symptoms are commonly encountered in primary care, and deserve specific guidance and resources. There are demographic patterns, likely structural, that warrant further exploration., (© British Journal of General Practice 2024.)

Objective: To examine the impact of a Patient and Public Involvement exercise on the development of British Congenital Cardiac Association Fetal Cardiology Standards 2021., Design: Open-ended, semi-structured interviews were undertaken to inform the design of a study to improve the quality of parents' experiences during antenatal and perinatal care of their child with CHD. This Patient and Public Involvement exercise was used to inform the final version of the drafted 'Standards'., Setting: One-on-one interviews with parents who responded to a request on the closed Facebook page of the user group "Little Hearts Matter": "Would you be interested in helping us to design a study about parents' experience on learning that their child had CHD"?, Patients: Parents of children with single ventricle CHD., Results: Twenty-one parents (18 mothers, 3 fathers) participated. Parents responses were reported to have variably reinforced, augmented, and added specificity in the later stages of drafting to six of the seven subsections of Section C Information and Support for Parents including: "At the time of the Scan"; "Counselling following the identification of an abnormality"; "Written information/resources"; "Parent support"; "Communication with other teams and ongoing care"; and "Bereavement support"., Conclusions: This Patient and Public Involvement exercise successfully informed the development of Standards after the initial drafting. It contributed to the establishment of face validity of the 'Standards', especially when consistent with what is reported in the literature. Further research is needed to explore approaches to involving and standardising Patient and Public Involvement in the development of clinical standards.

Epithelial ovarian cancer (EOC) has not significantly benefited from advances in immunotherapy, mainly because of the lack of well-defined actionable antigen targets. Using proteogenomic analyses of primary EOC tumors, we previously identified 91 aberrantly expressed tumor-specific antigens (TSAs) originating from unmutated genomic sequences. Most of these TSAs derive from non-exonic regions, and their expression results from cancer-specific epigenetic changes. The present study aimed to evaluate the immunogenicity of 48 TSAs selected according to two criteria: presentation by highly prevalent HLA allotypes and expression in a significant fraction of EOC tumors. Using targeted mass spectrometry analyses, we found that pulsing with synthetic TSA peptides leads to a high-level presentation on dendritic cells. TSA abundance correlated with the predicted binding affinity to the HLA allotype. We stimulated naïve CD8 T cells from healthy blood donors with TSA-pulsed dendritic cells and assessed their expansion with two assays: MHC-peptide tetramer staining and TCR Vβ CDR3 sequencing. We report that these TSAs can expand sizeable populations of CD8 T cells and, therefore, represent attractive targets for EOC immunotherapy.

In patients with dyssynchronous heart failure (DHF), cardiac conduction abnormalities cause the regional distribution of myocardial work to be non-homogeneous. Cardiac resynchronization therapy (CRT) using an implantable, programmed biventricular pacemaker/defibrillator, can improve the synchrony of contraction between the right and left ventricles in DHF, resulting in reduced morbidity and mortality and increased quality of life. Since regional work depends on wall stress, which cannot be measured in patients, we used computational methods to investigate regional work distributions and their changes after CRT. We used three-dimensional multi-scale patient-specific computational models parameterized by anatomic, functional, hemodynamic, and electrophysiological measurements in eight patients with heart failure and left bundle branch block (LBBB) who received CRT. To increase clinical translatability, we also explored whether streamlined computational methods provide accurate estimates of regional myocardial work. We found that CRT increased global myocardial work efficiency with significant improvements in non-responders. Reverse ventricular remodeling after CRT was greatest in patients with the highest heterogeneity of regional work at baseline, however the efficacy of CRT was not related to the decrease in overall work heterogeneity or to the reduction in late-activated regions of high myocardial work. Rather, decreases in early-activated regions of myocardium performing negative myocardial work following CRT best explained patient variations in reverse remodeling. These findings were also observed when regional myocardial work was estimated using ventricular pressure as a surrogate for myocardial stress and changes in endocardial surface area as a surrogate for strain. These new findings suggest that CRT promotes reverse ventricular remodeling in human dyssynchronous heart failure by increasing regional myocardial work in early-activated regions of the ventricles, where dyssynchrony is specifically associated with hypoperfusion, late systolic stretch, and altered metabolic activity and that measurement of these changes can be performed using streamlined approaches., Competing Interests: Competing Interests: Patent applications related to the technology described here have been submitted in the United States (“Compositions and methods for patient-specific modeling to predict outcomes of cardiac resynchronization therapy,” serial no. P00015–268P01; “Patient-specific modeling of ventricular activation pattern using surface ECG-derived vectorcardiogram in bundle branch block,” serial no. PCT/US15/36788). A.D.M and J.H.O are co-founders and equity-holders in Insilicomed, Inc., a licensee of UC San Diego software used in this research. A.D.M, C.T.V, and D.E.K. are co-founders and equity holders of Vektor Medical Inc., which was not involved in this research. Vektor Medical and Insilicomed, Inc. had no involvement at all in design, performance, analysis or funding of the present study. Vektor Medical and Insilicomed are licensees of intellectual property arising from or used in this research. This relationship has been disclosed to, reviewed, and approved by the University of California San Diego in accordance with its conflict of interest policies.

The hypomethylating agent 5-azacytidine (AZA) is the first-line treatment for AML patients unfit for intensive chemotherapy. The effect of AZA results in part from T-cell cytotoxic responses against MHC-I-associated peptides (MAPs) deriving from hypermethylated genomic regions such as cancer-testis antigens (CTAs), or endogenous retroelements (EREs). However, evidence supporting higher ERE MAPs presentation after AZA treatment is lacking. Therefore, using proteogenomics, we examined the impact of AZA on the repertoire of MAPs and their source transcripts. AZA-treated AML upregulated both CTA and ERE transcripts, but only CTA MAPs were presented at greater levels. Upregulated ERE transcripts triggered innate immune responses against double-stranded RNAs but were degraded by autophagy, and not processed into MAPs. Autophagy resulted from the formation of protein aggregates caused by AZA-dependent inhibition of DNMT2. Autophagy inhibition had an additive effect with AZA on AML cell proliferation and survival, increased ERE levels, increased pro-inflammatory responses, and generated immunogenic tumor-specific ERE-derived MAPs. Finally, autophagy was associated with a lower abundance of CD8 + T-cell markers in AML patients expressing high levels of EREs. This work demonstrates that AZA-induced EREs are degraded by autophagy and shows that inhibiting autophagy can improve the immune recognition of AML blasts in treated patients., (© 2024. The Author(s).)

The effectiveness of analgesics can be increased if synergistic behavioural, psychological, and pharmacological interventions are provided within a supportive environment., Competing Interests: W.L. is employed by the Reckitt group of companies, which owns and distributes the Nurofen and Biofreeze brands. This paper is based on the outputs of 3 virtual meetings which formed an advisory board on aspects of pain and analgesia which go beyond pharmacology. All authors were participants in the advisory board, which was funded by the Reckitt group of companies, which owns and distributes the Nurofen and Biofreeze brands.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

Transposable elements (TEs) are repetitive sequences representing ~45% of the human and mouse genomes and are highly expressed by medullary thymic epithelial cells (mTECs). In this study, we investigated the role of TEs on T-cell development in the thymus. We performed multiomic analyses of TEs in human and mouse thymic cells to elucidate their role in T-cell development. We report that TE expression in the human thymus is high and shows extensive age- and cell lineage-related variations. TE expression correlates with multiple transcription factors in all cell types of the human thymus. Two cell types express particularly broad TE repertoires: mTECs and plasmacytoid dendritic cells (pDCs). In mTECs, transcriptomic data suggest that TEs interact with transcription factors essential for mTEC development and function (e.g., PAX1 and REL), and immunopeptidomic data showed that TEs generate MHC-I-associated peptides implicated in thymocyte education. Notably, AIRE, FEZF2, and CHD4 regulate small yet non-redundant sets of TEs in murine mTECs. Human thymic pDCs homogenously express large numbers of TEs that likely form dsRNA, which can activate innate immune receptors, potentially explaining why thymic pDCs constitutively secrete IFN ɑ/β. This study highlights the diversity of interactions between TEs and the adaptive immune system. TEs are genetic parasites, and the two thymic cell types most affected by TEs (mTEcs and pDCs) are essential to establishing central T-cell tolerance. Therefore, we propose that orchestrating TE expression in thymic cells is critical to prevent autoimmunity in vertebrates., Competing Interests: JL, CL, AT, KV, LH, SB, CC, JH, ÉB, JL, CD, PG, JL, ER, SL, PT, CP No competing interests declared, (© 2023, Larouche et al.)

Xdemvy TM (lotilaner ophthalmic solution) 0.25% topical solution was recently approved for the treatment of Demodex blepharitis in adults aged ≥18 years. As an antiparasitic agent, lotilaner selectively inhibits gamma-aminobutyric acid chloride channels specific to the parasite and induces spastic paralysis, leading to death of Demodex blepharitis mites. In two randomized, double-masked, vehicle-controlled, multi-center, phase-3 clinical trials (Saturn-1 and Satuirn-2), lotilaner 0.25% topical solution was investigated for the treatment of Demodex blepharitis. Patients were assigned to receive either lotilaner 0.25% topical solution or vehicle (solution that did not contain lotilaner as an active ingredient) twice daily for 6 weeks. On day 43, lotilaner group demonstrated primary efficacy in achieving collarette cure ([collarette grade 0], Saturn-1: study group 44% [92/209], vehicle 7.4% [15/204]; Saturn-2: study group 56% [108/193], vehicle 12.5% [25/200]). Secondary efficacy was achieved by eradication of mite ([0 mite/lash], Saturn-1: study group 67.9% [142/209], vehicle 17.6% [36/304]; Saturn-2: study group 51.8% [99/193], vehicle 14.6% [29/200]), composite cure ([grade 0 collarette as well as grade 0 erythema], Saturn-1: study group 13.9% [29/209], vehicle 1.0% [2/204]; Saturn-2: study group 19.2% [37/193], vehicle 4% [8/200]), and erythema cure ([grade 0 erythema], study group 19.1% [40/209], vehicle 6.9% [14/204]; Saturn-2: study group 31.1% [60/193], vehicle 9.0% [18/199]). The adverse events were mild, with the most common being pain at instillation site. The recommended regimen for lotilaner 0.25% solution is one drop in each eye twice daily for 6 weeks.

Objective: Determine recurrent neonatal acute kidney injury (rAKI) incidence, risk factors, and associated outcomes., Study Design: Single-center retrospective cohort of neonates admitted to the NICU 1/1/20-6/30/21. Comparisons were made between those with no AKI, single AKI episode (sAKI), and rAKI. Multivariable linear and logistic regression models were used to assess associations between rAKI and length of mechanical ventilation (LMV), length of hospitalization stay (LOS), mortality, and hypertension (HTN) at discharge., Results: The incidence of AKI in the cohort of 869 infants was 19%: 705 (81%) no AKI, 100 (12%) sAKI, 64 (7%) rAKI. Both sAKI and rAKI were independently associated with longer LMV and LOS. sAKI was independently associated with almost 4x higher odds of mortality than rAKI., Conclusion: In this single center cohort of neonates, sAKI independently predicts mortality, however rAKI is independently associated with increased LMV and LOS suggesting rAKI is clinically important and warrants further study., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

This study provides an initial understanding of print awareness, a foundational literacy skill, in a group of 12 unhoused children at two shelters in a large urban setting. Children ranged in age from 4;1 to 8;0, representing grades associated with learning to read (i.e., pre-kindergarten to second grade). Findings indicate that the majority of children in this sample were significantly delayed in their acquisition of print awareness skills. Caregivers were surveyed regarding their beliefs about supporting literacy development and what would be beneficial for helping them in this area. Responses indicated that almost all caregivers believed that some literacy development should occur outside of the school setting and that it would be helpful if they (the caregivers) were taught both what skills to teach and how to teach them., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hoffmann, Little, Vincent, Lui and Pabalan.)

Importance: The incidence and associated outcomes of recurrent acute kidney injury (rAKI) in neonates remain largely unknown., Objective: To determine the incidence, risk factors, and clinical outcomes associated with rAKI in critically ill neonates., Design, Setting, and Participants: This cohort study was a secondary analysis of the multicenter, international Assessment of Worldwide Acute Kidney Injury Epidemiology in Neonates retrospective study. Comparisons were made among neonates with no AKI, a single AKI episode (sAKI), and rAKI. All neonates younger than 14 days who were admitted between January 1 and March 31, 2014, to 24 participating level II to IV neonatal intensive care units and received intravenous fluids for at least 48 hours were considered for inclusion. Neonates with congenital heart disease requiring surgery within the first week of life, lethal chromosomal anomalies, death within 48 hours of admission, or severe congenital kidney abnormalities were excluded. Data were analyzed from May 23, 2022, to December 8, 2023., Exposure: Recurrent AKI using the neonatal Kidney Disease: Improving Global Outcomes criteria. Determination of each rAKI required a complete return to the baseline serum creatinine level that defined the prior AKI episode., Main Outcomes and Measures: Incidence and risk factors of rAKI and associations of rAKI with length of stay (LOS; ie, birth to hospital discharge) and mortality., Results: The study cohort (n = 2162) included 1233 male neonates (57.0%). Gestational age distribution was less than 29 weeks for 276 neonates (12.8%), 29 to less than 36 weeks for 958 (44.3%), and 36 weeks or older for 928 (42.9%). Of 605 neonates with AKI, 133 (22.0%) developed rAKI with risk factors including younger gestational age, lower birthweight, and higher stage of initial AKI. Infants with rAKI experienced longer median LOS (no AKI, 17 [IQR, 8-34] days; sAKI, 18 [IQR, 9-45] days; rAKI, 60 [IQR, 25-109] days; P < .001). Time-varying Cox proportional hazards regression models suggest rAKI is independently associated with a lower hazard of discharge (adjusted hazard ratio, 0.7 [95% CI, 0.6-0.9]; P = .01) when compared with sAKI, but mortality did not differ between groups (adjusted hazard ratio, 1.4 [95% CI, 0.6-3.0]; P = .44)., Conclusions and Relevance: In this cohort study, neonatal rAKI was independently associated with longer LOS when compared with sAKI, suggesting that rAKI in neonates may be an important clinical distinction warranting further study and careful monitoring after an initial AKI episode.

Hormone receptor-positive breast cancer (HR+) is immunologically cold and has not benefited from advances in immunotherapy. In contrast, subsets of triple-negative breast cancer (TNBC) display high leukocytic infiltration and respond to checkpoint blockade. CD8+ T cells, the main effectors of anticancer responses, recognize MHC I-associated peptides (MAPs). Our work aimed to characterize the repertoire of MAPs presented by HR+ and TNBC tumors. Using mass spectrometry, we identified 57,094 unique MAPs in 26 primary breast cancer samples. MAP source genes highly overlapped between both subtypes. We identified 25 tumor-specific antigens (TSAs) mainly deriving from aberrantly expressed regions. TSAs were most frequently identified in TNBC samples and were more shared among The Cancer Genome Atlas (TCGA) database TNBC than HR+ samples. In the TNBC cohort, the predicted number of TSAs positively correlated with leukocytic infiltration and overall survival, supporting their immunogenicity in vivo. We detected 49 tumor-associated antigens (TAAs), some of which derived from cancer-associated fibroblasts. Functional expansion of specific T cell assays confirmed the in vitro immunogenicity of several TSAs and TAAs. Our study identified attractive targets for cancer immunotherapy in both breast cancer subtypes. The higher prevalence of TSAs in TNBC tumors provides a rationale for their responsiveness to checkpoint blockade.

Background: Women's health has historically lacked investment in research and development. Technologies that enhance women's health ('FemTech') could contribute to improving this. However, there has been little work to understand which priority unmet needs should be a focus for women's health technology development. The voices of clinicians and those who experience and utilise these technologies (including those used at home or encountered in clinical settings) are needed to ensure that device development aligns with need, without risking exacerbating or creating health inequities., Method: We undertook a priority setting partnership project exploring unmet needs in women's health and well-being where physical technologies or innovations could help. This comprised gathering feedback from: patients and clinicians using both qualitative surveys and discussions; collating and publishing these responses and asking for feedback; evidence checking unmet needs identified, and holding a partnership priority setting event to agree a top 10 and top 20 list of priorities., Results: We generated a 'longlist' of 54 suggestions for areas where better kit, devices or equipment could support women's health. For three, we found evidence of existing technologies which mitigated against that need. We took the remaining 51 suggestions to a partnership priority setting meeting which brought together clinicians and service users. Through discussion as this group, we generated a list of the top 10 areas identified as priorities for technological development and improvement. These included better devices to manage examination, diagnosis and treatment of pelvic pain (including endometriosis), prolapse care, continence (treatment and prevention, related to pregnancy and beyond), menstruation, vaginal pain and vaginismus, point of care tests for common infections, and nipple care when breastfeeding., Conclusion: The top priorities suggest far-reaching areas of unmet need across women's life course and across multiple domains of health and well-being, and opportunities where innovation in the devices that people use themselves or encounter in health settings could potentially enhance health and healthcare experiences., (© 2023. The Author(s).)

LITFULO TM (ritlecitinib) capsules were recently approved for the treatment of severe alopecia areata in adolescents and adults, aged ≥12 years. Ritlecitinib is the active ingredient and a dual inhibitor of Janus kinase 3 and the tyrosine kinase expressed in hepatocellular carcinoma kinase family. It prevents immune attack on the hair follicles that leads to hair loss. In a phase 2b-3 dose-dependant study, five doses of oral ritlecitinib and placebo administered once daily (QD) were investigated. Ritlecitinib demonstrated efficacy in achieving the primary outcome, Severity of Alopecia Tool (SALT) score of ≤20, at week 24 (31% [38/124] 200-mg ritlecitinib QD for 4 weeks, then 50 mg QD for 20 weeks; 22% [27/121] 200-mg ritlecitinib QD for 4 weeks, then 30 mg QD for 20 weeks; 23% [29/124] 50-mg ritlecitinib QD; 14% [17/119] 30-mg ritlecitinib QD; 2% [1/59] 10-mg ritlecitinib QD; and 2% [2/130] placebo). Mild to moderate common adverse effects were observed, which included headache, nasopharyngitis, and upper respiratory tract infection. The recommended regimen of ritlecitinib capsules is 50 mg QD with without food and swallowed whole.

Background: Pain is the leading cause of disability worldwide among adults and effective treatment options remain elusive. Data harmonization efforts, such as through core outcome sets (COS), could improve care by highlighting cross-cutting pain mechanisms and treatments. Existing pain-related COS often focus on specific conditions, which can hamper data harmonization across various pain states., Methods: Our objective was to develop four overarching COS of domains/subdomains (i.e., what to measure) that transcend pain conditions within different pain categories. We hosted a meeting to assess the need for these four COS in pain research and clinical practice. Potential COS domains/subdomains were identified via a systematic literature review (SLR), meeting attendees, and Delphi participants. We conducted an online, three step Delphi process to reach a consensus on domains to be included in the four final COS. Survey respondents were identified from the SLR and pain-related social networks, including multidisciplinary health care professionals, researchers, and people with lived experience (PWLE) of pain. Advisory boards consisting of COS experts and PWLE provided advice throughout the process., Findings: Domains in final COS were generally related to aspects of pain, quality of life, and physical function/activity limitations, with some differences among pain categories. This effort was the first to generate four separate, overarching COS to encourage international data harmonization within and across different pain categories., Interpretation: The adoption of the COS in research and clinical practice will facilitate comparisons and data integration around the world and across pain studies to optimize resources, expedite therapeutic discovery, and improve pain care., Funding: Innovative Medicines Initiative 2 Join Undertaking; European Union Horizon 2020 research innovation program, European Federation of Pharmaceutical Industries and Associations (EFPIA) provided funding for IMI-PainCare. RDT acknowledges grants from Esteve and TEVA., Competing Interests: Giulia Bova has nothing to disclose. Anthony Domenichiello has nothing to disclose. Janelle Letzen has nothing to disclose. Daniela C. Rosenberger has nothing to disclose. Andrew Siddons has nothing to disclose. Ulrike Kaiser is the principal investigator of VAPAIN. Adam Anicich has nothing to disclose. Ralf Baron reports grants from EU Projects: „Europain“ (115,007). DOLORisk (633,491). IMI Paincare (777,500). Ðerman Federal Ministry of Education and Research (BMBF): Verbundprojekt: Frühdetektion von Schmerzchronifizierung (NoChro) (13GW0338C). Ðerman Research Network on Neuropathic Pain (01EM0903). Ðfizer Pharma GmbH, Sanofi Genzyme GmbH, Grünenthal GmbH, Mundipharma Research GmbH und Co. KG., Alnylam Pharmaceuticals Inc., Zambon GmbH, Bayer AG, Sanofi Aventis GmbHÐ personal fees from Pfizer Pharma GmbH, Sanofi Genzyme GmbH, Grünenthal GmbH, Mundipharma, Lilly GmbH, Desitin Arzneimittel GmbH, Teva GmbH, Bayer AG, MSD GmbH, Seqirus Australia Pty. Ltd, Novartis Pharma GmbH, TAD Pharma GmbH, Grünenthal SA Portugal, Grünen¬thal Pharma AG Schweiz, Grünenthal B.V. Niederlande, Evapharma, Takeda Pharmaceuticals International AG Schweiz, Ology Medical Education Netherlands, Ever Pharma GmbH, Amicus Therapeutics GmbH, Novo Nordisk Pharma GmbH, Chiesi GmbH, Stada Mena DWC LLC Dubai, Hexal AG, Viatris, personal fees from Pfizer Pharma GmbH, Sanofi Genzyme GmbH, Grünenthal GmbH, Lilly, Novartis Pharma GmbH, Bristol-Myers Squibb, Biogenidec, AstraZeneca GmbH, Daiichi Sankyo, Glenmark Pharmaceuticals S.A., Seqirus Australia Pty. Ltd, Teva Pharmaceuticals Europe Niederlande, Teva GmbH, Genentech, Mundipharma International Ltd. UK, Galapagos NV, Kyowa Kirin GmbH, Vertex Pharmaceuticals Inc., Biotest AG, Celgene GmbH, Desitin Arzneimittel GmbH, Regeneron Pharmaceuticals Inc. USA, Theranexus DSV CEA Frankreich, Abbott Products Operations AG Schweiz, Bayer AG, Grünenthal Pharma AG Schweiz, Akcea Therapeutics Germany GmbH, Asahi Kasei Pharma Corporation, AbbVie Deutschland GmbH & Co. KG, Air Liquide Sante International Frankreich, Alnylam Germany GmbH, Lateral Pharma Pty Ltd, Hexal AG, Angelini, Janssen, SIMR Biotech Pty Ltd Australien, Confo Therapeutics N. V. Belgium, Merz Pharmaceuticals GmbH, Neumentum Inc., F. Hoffmann-La Roche Ltd. Switzerland, AlgoTherapeutix SAS France, Nanobiotix SA France, AmacaThera Inc. Canada, outside the submitted work. Judy Birch has nothing to disclose. Didier Bouhassira reports personal fees from Grunenthal, personal fees from Bayer, outside the submitted work. George Casey has nothing to disclose. Katie Golden has nothing to disclose. Smriti Iyengar has nothing to disclose. Barbara Karp has nothing to disclose. Hiltrud Liedgens has nothing to disclose. Winfried Meissner reports grants from European Commission, during the conduct of the study; personal fees from Grünenthal, grants from Mundipharma, grants from Pfizer, personal fees from Ethypharm, personal fees from Kyowa, personal fees from Spectrum Therapeutics, outside the submitted work. Kate Nicholson has no conflicts or disclosures. She is employed by the National Pain Advocacy Center, which takes no industry funding and advocates for the health and rights of people living with pain. She was a member on the patient Advisory Committee for this project and received an honorarium for attending early organizational strategic planning for the project. She also received support for attending the European Pain Federation (EFIC) conference to present on concepts from this project. Leah Pogorzala has nothing to disclose. Deidre Ryan has nothing to disclose. Rolf-Detlef Treede reports grants from Innovative Medicines Initiative EU and EFPIA, during the conduct of the study; grants from Deutsche Forschungsgemeinschaft, grants from Esteve, TEVA, personal fees from Bayer, Grünenthal, GSK, Merz, Saluda Medical, Sanofi, Cered, and Vertex outside the submitted work. Peter Tugwell has nothing to disclose. Dennis Turk has received in the past 5 years research grants and contracts from the US Food and Drug Administration and the US National Institutes of Health, U.S. Patient-Centered Outcome Research Institute, and US National Center for Occupational Health and Safety; received compensation for serving on advisory boards from Eli Lilly, GlaxoSmithKline, Novartis, and Pfizer. He received an honorarium from Wolters Kluwer in his role as editor-in-chief of The Clinical Journal of Pain. Katy Vincent reports grants from Innovative Medicines Initiative 2 Joint Undertaking (GA No. 777500) (Horizon 2020 and EFPIA), during the conduct of the study; grants and personal fees from Bayer Healthcare (paid to institution), and personal fees from Reckitts (paid to institution), outside the submitted work. She received payment from Gedeon Richter for consultancy and talks, paid to the institution. Jan Vollert reports personal fees from Vertex Pharmaceuticals, personal fees from Embody Orthopaedics, personal fees from Casquar, outside the submitted work. Paula Williamson chairs the COMET Initiative Management Group. Sarah Woller has nothing to disclose. Ruth Zaslansky has nothing to disclose. Laura Wandner has nothing to disclose. Esther Pogatzki-Zahn reports grants from the German Research Foundation (DFG), the Federal Ministry of Education and Research (BMBF), the Federal Joint Committee (G-BA) and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777500. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA. All money goes to the institutions (WWU/UKM) EPZ is working for. EPZ received personal fees (money went to her institution) from Gruenenthal, Medtronic and Novartis unrelated to the current work. She received an honorarium in her role as debuty-editor-in-chief of the European Journal of Anaesthesiology., (© 2023 Published by Elsevier Ltd.)

YCANTH TM (cantharidin) topical solution has been approved recently for the treatment of molluscum contagiosum (MC) in children (aged ≥2 years) and adults. It works by activating serine proteases that lead to blistering and inflammation, promoting shedding of infected cells and viral clearance. In two phase-3, randomized, double-blind, vehicle-controlled trials of similar design, VP-102 (a drug-device combination, containing cantharidin 0.7% w/v and inactive ingredients, such as gentian violet, acetone, and denatonium benzoate, administered with an applicator) was investigated for the treatment of MC. VP-102 and vehicle were applied topically once every 21 days until complete clearance of lesions was observed, or for up to four treatments. Cantharidin demonstrated efficacy in achieving the primary outcome, at day 84/visit 4 (Cantharidin Application in Molluscum Patients [CAMP-1], VP-102: 46% [73/160], vehicle: 18% [19/106]; and CAMP-2, VP-102: 54% [81/150], vehicle: 13% [15/112]). Common adverse events were mild to moderate, such as lesions at the site of application, pruritus, and pain. The recommended regimen of cantharidin topical solution is its application once every 21 days until complete clearance of lesions is observed, or up to four treatments.

ZORYVE TM (roflumilast) cream is a topical phosphodiesterase-4 (PDE-4) inhibitor that has been recently approved for the treatment of plaque psoriasis. It is also indicated for use in intertriginous areas. Roflumilast, the active ingredient, inhibits PDE-4, leading to the suppression of pro-inflammatory immune responses in psoriatic lesions. Two phase 3 clinical trials have demonstrated the efficacy of once daily application of roflumilast to treat plaque psoriasis in patients aged 12 years and older. At week 8, an investigator's global assessment score of 0 or 1 with a grade 2 improvement from baseline, the primary efficacy end point, was observed in 39.1% (225/576) of patients applying roflumilast, compared to 6.6% (20/305) of patients applying vehicle. Common adverse events reported were diarrhea, headache, insomnia, nausea, pain at application site, upper respiratory tract infection, and urinary tract infection.

Abstract: Chronic pelvic pain (CPP), despite its high prevalence, is still relatively poorly understood mechanistically. This study, as part of the Translational Research in Pelvic Pain (TRiPP) project, has used a full quantitative sensory testing (QST) paradigm to profile n = 85 women with and without CPP (endometriosis or bladder pain specifically). We used the foot as a control site and abdomen as the test site. Across 5 diagnostically determined subgroups, we found features which are common across different aetiologies, eg, gain of function in pressure pain threshold (PPT) when assessing responses from the lower abdomen or pelvis (referred pain site). However, disease-specific phenotypes were also identified, eg, greater mechanical allodynia in endometriosis, despite there being large heterogeneities within diagnostic groups. The most common QST sensory phenotype was mechanical hyperalgesia (>50% across all the groups). A "healthy' sensory phenotype was seen in <7% of CPP participants. Specific QST measures correlated with sensory symptoms assessed by the painDETECT questionnaire (pressure-evoked pain [painDETECT] and PPT [QST] [ r = 0.47, P < 0.001]; mechanical hyperalgesia (painDETECT) and mechanical pain sensitivity [MPS from QST] [ r = 0.38, P = 0.009]). The data suggest that participants with CPP are sensitive to both deep tissue and cutaneous inputs, suggesting that central mechanisms may be important in this cohort. We also see phenotypes such as thermal hyperalgesia, which may be the result of peripheral mechanisms, such as irritable nociceptors. This highlights the importance of stratifying patients into clinically meaningful phenotypes, which may have implications for the development of better therapeutic strategies for CPP., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

The splitting of hydrogen (H2) is an energy-yielding process, which is important for both biological systems and as a means of providing green energy. In biology, this reaction is mediated by enzymes called hydrogenases, which utilise complex nickel and iron cofactors to split H2 and transfer the resulting electrons to an electron-acceptor. These [NiFe]-hydrogenases have received considerable attention as catalysts in fuel cells, which utilise H2 to produce electrical current. [NiFe]-hydrogenases are a promising alternative to the platinum-based catalysts that currently predominate in fuel cells due to the abundance of nickel and iron, and the resistance of some family members to inhibition by gases, including carbon monoxide, which rapidly poison platinum-based catalysts. However, the majority of characterised [NiFe]-hydrogenases are inhibited by oxygen (O2), limiting their activity and stability. We recently reported the isolation and characterisation of the [NiFe]-hydrogenase Huc from Mycobacterium smegmatis, which is insensitive to inhibition by O2 and has an extremely high affinity, making it capable of oxidising H2 in air to below atmospheric concentrations. These properties make Huc a promising candidate for the development of enzyme-based fuel cells (EBFCs), which utilise H2 at low concentrations and in impure gas mixtures. In this review, we aim to provide context for the use of Huc for this purpose by discussing the advantages of [NiFe]-hydrogenases as catalysts and their deployment in fuel cells. We also address the challenges associated with using [NiFe]-hydrogenases for this purpose, and how these might be overcome to develop EBFCs that can be deployed at scale., (© 2023 The Author(s).)

Background: Artificial intelligence (AI) is predicted to be a solution for improving healthcare, increasing efficiency, and saving time and recourses. A lack of ethical principles for the use of AI in practice has been highlighted by several stakeholders due to the recent attention given to it. Research has shown an urgent need for more knowledge regarding the ethical implications of AI applications in healthcare. However, fundamental ethical principles may not be sufficient to describe ethical concerns associated with implementing AI applications., Objective: The aim of this study is twofold, (1) to use the implementation of AI applications to predict patient mortality in emergency departments as a setting to explore healthcare professionals' perspectives on ethical issues in relation to ethical principles and (2) to develop a model to guide ethical considerations in AI implementation in healthcare based on ethical theory., Methods: Semi-structured interviews were conducted with 18 participants. The abductive approach used to analyze the empirical data consisted of four steps alternating between inductive and deductive analyses., Results: Our findings provide an ethical model demonstrating the need to address six ethical principles (autonomy, beneficence, non-maleficence, justice, explicability, and professional governance) in relation to ethical theories defined as virtue, deontology, and consequentialism when AI applications are to be implemented in clinical practice., Conclusions: Ethical aspects of AI applications are broader than the prima facie principles of medical ethics and the principle of explicability. Ethical aspects thus need to be viewed from a broader perspective to cover different situations that healthcare professionals, in general, and physicians, in particular, may face when using AI applications in clinical practice., Competing Interests: The participants expressed that healthcare lacks suitable alliances within and across different parts of the organization, particularly between regional and municipal care and in relation to palliative patients. They mentioned lack of communication, followed by insufficient care plans, as the most significant problem within the healthcare system. This may be an ethical conflict if the information from AI applications shows that a patient should receive palliative care and if it is impossible to provide that due to the lack of resources within the care system. The participants also talked about problems related to legal regulations that could affect their decision-making process and make it more difficult to provide collaborative care across different departments and organizations since decisions are not linked or coordinated. They believed that AI could prevent and manage these challenges. The participants mentioned that transferring responsibility between different healthcare organizations would be an ethical challenge for healthcare professionals in relation to the use of AI applications for mortality prediction in the emergency department. There would likely be an increased transfer of responsibility toward home care in the municipalities. The participants questioned if there would be sufficient resources to manage an increased in-flow of patients.It also has a lot to do with the organization. It does not have much to do with the identification of [certain patients], but it has a lot to do with the structures that exist in the community and such. [Participant no. 3]The participants thought that AI applications could lead to a clash between the need to deal with new information and a lack of routines and care plans to do so with respect to the existing ethical principles. Adequate routines and systematic strategies were considered important to feel safe working with the AI applications.The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Introduction: Standardized handoffs reduce medical errors and prevent adverse events or near misses. This article describes a quality improvement initiative implementing a unique standardized handoff tool and process to transition from the operating room to the neonatal intensive care unit (NICU) at a level-four regional center with many inpatients requiring surgical intervention. Before this project, there was no standardized handoff tool or process for postsurgical transitions. The primary aim was to achieve 80% compliance with completing a structured postoperative OR to NICU handoff tool within 12 months of implementation., Methods: An interdisciplinary team developed and implemented a standardized NICU postoperative handoff tool and process that requires face-to-face communication, defines team members who should be present, and highlights communication with the family. In addition, the handoff tool compliance and process measures were monitored, evaluated, and audited., Results: Although not consistent, we achieved eighty percent compliance with the outcome measures using the handoff tool. We did not sustain 80% of appropriate providers present at handoff. In addition, insufficient data assess overall parental satisfaction with the surgical experience. Although improved, the process measure of immediate postoperative family updates did not reach the targeted goal. However, the balancing measure of staff experience and satisfaction did improve., Conclusion: Implementing a standardized handoff tool and process with an interdisciplinary and interdepartmental collaboration improves critical patient transitions from the operating room to the NICU., Competing Interests: The authors have no financial interest to declare in relation to the content of this article., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose of Review: This review looks to overview advances in endometriosis-associated pain, both in understanding the pain mechanisms involved and increasing treatment options with well designed clinical trials and meta-analyses., Recent Findings: Our understanding of endometriosis-associated pain has progressed from a purely nociceptive model to an awareness that both neuropathic and nociplastic mechanisms can be present for some people with endometriosis. Clinical trials and meta-analyses have demonstrated efficacy of surgical treatments and hormonal therapies. It is notable that currently, the basic science and clinical trials are not cross-fertilising., Summary: Following growth in other areas of chronic pain, there have been significant advances in our understanding of endometriosis-associated pain. However, there remains lots to explore and we are currently a long way from our goal of timely personalized holistic multidisciplinary treatment for all sufferers of endometriosis-associated pain., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Leiomyomas, the most common benign neoplasms of the female reproductive tract, currently have limited medical treatment options. Drugs targeting estrogen/progesterone signaling are used, but side effects and limited efficacy in many cases are major limitation of their clinical use. Previous studies from our laboratory and others demonstrated that 2-methoxyestradiol (2-ME) is promising treatment for uterine fibroids. However, its poor bioavailability and rapid degradation hinder its development for clinical use. The objective of this study is to evaluate the in vivo effect of biodegradable and biocompatible 2-ME-loaded polymeric nanoparticles in a patient-derived leiomyoma xenograft mouse model. PEGylated poly(lactide-co-glycolide) (PEG-PLGA) nanoparticles loaded with 2-ME were prepared by nanoprecipitation. Female 6-week age immunodeficient NOG (NOD/Shi-scid/IL-2Rγ null ) mice were used. Estrogen-progesterone pellets were implanted subcutaneously. Five days later, patient-derived human fibroid tumors were xenografted bilaterally subcutaneously. Engrafted mice were treated with 2-ME-loaded or blank (control) PEGylated nanoparticles. Nanoparticles were injected intraperitoneally and after 28 days of treatment, tumor volume was measured by caliper following hair removal, and tumors were removed and weighed. Up to 99.1% encapsulation efficiency was achieved, and the in vitro release profile showed minimal burst release, thus confirming the high encapsulation efficiency. In vivo administration of the 2-ME-loaded nanoparticles led to 51% growth inhibition of xenografted tumors compared to controls (P < 0.01). Thus, 2-ME-loaded nanoparticles may represent a novel approach for the treatment of uterine fibroids., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to report., (Copyright © 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)