Homozygous novel truncating variant of CLPP associated with severe Perrault syndrome.

A female proband and her affected niece are homozygous for a novel frameshift variant of CLPP. The proband was diagnosed with severe Perrault syndrome encompassing hearing loss, primary ovarian insufficiency, abnormal brain white matter and developmental delay.

World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project: V. physical examination standards in endometriosis research.

OBJECTIVE: The World Endometriosis Research Foundation (WERF) 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, four 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 that underwent multiple rounds of iterations and revisions. SUBJECTS: N/A MAIN OUTCOME MEASURE(S): N/A RESULT(S): The EPHect physical examination (EPHect-PE) tool provides standardised assessment of physical examination characteristics and pain phenotyping. Data elements involve examination of a) back and pelvic girdle; b) abdomen including allodynia and trigger points; c) vulva including provoked vestibulodynia; d) pelvic floor muscle tone and tenderness; e) tenderness on unidigital pelvic exam; f) presence of pelvic nodularity; g) uterine size and mobility; h) presence of adnexal masses; i) presence of incisional masses; j) speculum examination; k) tenderness and allodynia at an extra-pelvic site (e.g. forearm); and l) recording of anthropometrics. CONCLUSION(S): The EPHect physical examination standards (EPHect-PE) will facilitate the standardised documentation of the physical examination, including the assessment and documentation of examination phenotyping of endometriosis-associated pelvic pain.

Developing a set of patient-centered outcomes for routine use in endometriosis: An international Delphi study.

INTRODUCTION: There is large variation in individual patient care for endometriosis. A uniform approach to measure outcomes could be incorporated into routine clinical practice to personalize and monitor treatments and potentially improve the quality of care. The aim of this study is to identify a group of patient-centered outcomes for use in routine endometriosis care which are relevant to all patient profiles. MATERIAL AND METHODS: By means of a modified two-round Delphi study with international representation including healthcare professionals, researchers and patient representatives (51 participants, 16 countries) we developed a set of patient-centered measurements. The participants evaluated 47 Patient Reported Outcome Measures (PROMs) and 30 Clinician Reported Outcome Measures (CROMs) regarding their feasibility and relevance for their use in routine endometriosis care. After the two rounds of quotation, meetings of the experts were convened to participate in a final discussion to finalize the consensus of the final set of included measures. RESULTS: The final set of patient-centered outcomes includes six PROMs (measuring symptomatic impact, pain, work productivity and quality of life) and 10 CROMs (measuring clinical, imaging and surgical indicators). A supplementary list of outcomes was added to include important dimensions that were considered essential by the expert panel but are not relevant to all patients. In addition the need for development of specific tools (PROMs) measuring the psychological impact and the impact in sexual activity of endometriosis was highlighted. CONCLUSIONS: We have developed a set of patient-centered outcomes measures in endometriosis care. The selected outcomes comprise the common features for all patients suffering from endometriosis. adapted for use in routine practice. The list of outcomes has been adapted for use in routine practice from which clinicians can chose, depending on their needs.

A phase III randomized crossover trial of plerixafor versus G-CSF for treatment of WHIM syndrome.

BACKGROUNDWarts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a primary immunodeficiency disorder caused by heterozygous gain-of-function CXCR4 mutations. Myelokathexis is a kind of neutropenia caused by neutrophil retention in bone marrow and in WHIM syndrome is associated with lymphopenia and monocytopenia. The CXCR4 antagonist plerixafor mobilizes leukocytes to the blood; however, its safety and efficacy in WHIM syndrome are undefined.METHODSIn this investigator-initiated, single-center, quadruple-masked phase III crossover trial, we compared the total infection severity score (TISS) as the primary endpoint in an intent-to-treat manner in 19 patients with WHIM who each received 12 months treatment with plerixafor and 12 months treatment with granulocyte CSF (G-CSF, the standard of care for severe congenital neutropenia). The treatment order was randomized for each patient.RESULTSPlerixafor was nonsuperior to G-CSF for TISS (P = 0.54). In exploratory endpoints, plerixafor was noninferior to G-CSF for maintaining neutrophil counts of more than 500 cells/µL (P = 0.023) and was superior to G-CSF for maintaining lymphocyte counts above 1,000 cells/µL (P < 0.0001). Complete regression of a subset of large wart areas occurred on plerixafor in 5 of 7 patients with major wart burdens at baseline. Transient rash occurred on plerixafor, and bone pain was more common on G-CSF. There were no significant differences in drug preference or quality of life or the incidence of drug failure or serious adverse events.CONCLUSIONPlerixafor was not superior to G-CSF in patients with WHIM for TISS, the primary endpoint. Together with wart regression and hematologic improvement, the infection severity results support continued study of plerixafor as a potential treatment for WHIM syndrome.TRIAL REGISTRATIONClinicaltrials.gov NCT02231879.FUNDINGThis study was funded by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases.

Applications of botulinum toxin to the female pelvic floor: Botulinum toxin for genito-pelvic pain penetration disorder and chronic pelvic pain in women.

Chronic pain conditions like genito-pelvic pain penetration disorder and chronic pelvic pain cause significant morbidity in women worldwide and yet are underdiagnosed and undertreated. While the use of botulinum toxin for pain conditions has expanded, there are few randomized controlled studies of botulinum toxin for pelvic pain conditions in women. This paper provides an update on the current status and context for considering botulinum toxin treatment for these conditions to complement and expand currently available approaches. High quality clinical trials to evaluate safety and efficacy and to determine optimal doses and approaches to injection are urgently needed.

Endometriosis-associated chronic pelvic pain.

Endometriosis is a heterogeneous disease where neurogenic sensitization can lead to chronic pain within and beyond the pelvis. Coincident pain and comorbidities merit specific attention. We discuss the causes, comorbidities, and management of endometriosis-associated chronic pelvic pain, advocating for a multidisciplinary approach to develop more effective treatments.

Clinical trials and pregnancy.

Traditionally, there has been a reluctance to involve pregnant people in clinical trials due to complex ethical issues surrounding the risk to unborn babies. However it is crucial that new interventions are safe and effective for all patients and ensuring this can be difficult to achieve in the absence of clinical trials.

Perspectives From Advancing National Institutes of Health Research to Inform and Improve the Health of Women: A Conference Summary.

The health of women remains understudied. In response to a request from Congress, the Office of Research on Women's Health of the National Institutes of Health (NIH) evaluated research on the health of women currently underway related to 1) rising rates of maternal morbidity and mortality, 2) rising rates of chronic debilitating conditions in women, and 3) stagnant cervical cancer survival rates. Input on the three priority areas was obtained from experts in women's health, members of the public, and federal stakeholders. The NIH research portfolios on these three topics were reviewed. On October 20, 2021, a conference on advancing NIH research on women's health was held to present, discuss, and delineate gaps and opportunities in the current portfolio. Across the life course, significant gaps in evidence regarding conditions, disorders, and diseases that occur in women were illustrated. Fundamental basic and translational knowledge gaps in many female-specific conditions and diseases with sex-specific presentations, symptoms, or responses to treatments have hampered the generation of robust scientific data needed to provide high-quality, evidence-based care to women. Key opportunities identified to improve the health of women include enhanced implementation of existing best practices and interventions to reduce disparities. Undertaking intentional clinical research on the health of women will produce significant returns on investment and has the potential to greatly improve human health.

Efficacy of Cochleated Amphotericin B in Mouse and Human Mucocutaneous Candidiasis.

Candida albicans causes debilitating, often azole-resistant, infections in patients with chronic mucocutaneous candidiasis (CMC). Amphotericin B (AMB) resistance is rare, but AMB use is limited by parenteral administration and nephrotoxicity. In this study, we evaluated cochleated AMB (CAMB), a new oral AMB formulation, in mouse models of oropharyngeal candidiasis (OPC) and vulvovaginal candidiasis (VVC) and in patients with azole-resistant CMC. OPC and VVC were modeled in Act1-/- mice, and mucosal tissue fungal burden was assessed after once-daily treatment with CAMB, vehicle, or AMB-deoxycholate (AMB-d). Four patients with azole-resistant CMC enrolled in a phase 2 CAMB dose-escalation study. The primary endpoint was clinical improvement at 2 weeks followed by optional extension for long-term CMC suppression to assess safety and efficacy. CAMB-treated mice had significantly reduced tongue and vaginal fungal burdens compared to vehicle-treated mice and exhibited comparable fungal burden reduction relative to AMB-d-treated mice. All CAMB-treated patients reached clinical efficacy by 2 weeks, three at 400 mg twice daily and one at 200 mg twice-daily dosing. All patients continued to the extension phase, with three having sustained clinical improvement of OPC and esophageal candidiasis (EC) for up to 60 months. One patient had a relapse of esophageal symptoms at week 24 and was withdrawn from further study. Clinical responses were not seen for onychomycosis or VVC. CAMB was safe and well-tolerated, without any evidence of nephrotoxicity. In summary, oral CAMB reduced tongue and vaginal fungal burdens during murine candidiasis. A proof-of-concept clinical trial in human CMC showed efficacy with good tolerability and safety. This study has been registered at ClinicalTrials.gov under identifier NCT02629419.

Hematopoietic Cell Transplantation and Outcomes Related to Human Papillomavirus Disease in GATA2 Deficiency.

GATA2 deficiency is a bone marrow failure syndrome effectively treated with hematopoietic cell transplantation (HCT), which also addresses the predisposition to many infections (prominently mycobacterial). However, many GATA2-deficient persons who come to HCT also have prevalent and refractory human papilloma virus disease (HPVD), which can be a precursor to cancer. We analyzed 75 HCT recipients for the presence of HPVD to identify patient characteristics and transplantation results that influence HPVD outcomes. We assessed the impact of cellular recovery and iatrogenic post-transplantation immunosuppression, as per protocol (PP) or intensified/prolonged (IP) graft-versus-host disease (GVHD) prophylaxis or treatment, on the persistence or resolution of HPVD. Our experience with 75 HCT recipients showed a prevalence of 49% with anogenital HPVD, which was either a contributing or primary factor in the decision to proceed to HCT. Of 24 recipients with sufficient follow-up, 13 had resolution of HPVD, including 8 with IP and 5 with PP. Eleven recipients had persistent HPVD, including 5 with IP and 6 with PP immunosuppression. No plausible cellular recovery group (natural killer cells or T cells) showed a significant difference in HPV outcomes. One recipient died of metastatic squamous cell carcinoma, presumably of anogenital origin, at 33 months post-transplantation after prolonged immunosuppression for chronic GVHD. Individual cases demonstrate the need for continued aggressive monitoring, especially in the context of disease prevalent at transplantation or prior malignancy. HCT proved curative in many cases in which HPVD was refractory and recurrent prior to transplantation, supporting a recommendation that HPVD should be considered an indication rather than contraindication to HCT, but post-transplantation monitoring should be prolonged with a high level of vigilance for new or recurrent HPVD.

Gynaecological and reproductive health of women with telomere biology disorders.

Reproductive health may be adversely impacted in women with dyskeratosis congenita (DC) and related telomere biology disorders (TBD). We evaluated gynaecological problems, fertility, and pregnancy outcomes in 39 females aged 10-81 years who were followed longitudinally in our DC/TBD cohort. Twenty-six had bone marrow failure and 12 underwent haematopoietic cell transplantation. All attained menarche at a normal age. Thirteen women reported menorrhagia; ten used hormonal contraception to reduce bleeding. Nine experienced natural normal-aged menopause. Gynaecological problems (endometriosis = 3, pelvic varicosities = 1, cervical intraepithelial neoplasia = 1, and uterine prolapse = 2) resulted in surgical menopause in seven. Twenty-five of 26 women attempting fertility carried 80 pregnancies with 49 (61%) resulting in livebirths. Ten (38%) women experienced 28 (35%) miscarriages, notably recurrent pregnancy loss in five (19%). Preeclampsia (n = 6, 24%) and progressive cytopenias (n = 10, 40%) resulted in maternal-fetal compromise, including preterm (n = 5) and caesarean deliveries (n = 18, 37%). Gynaecological/reproductive problems were noted mainly in women with autosomal-dominant inheritance; others were still young or died early. Although women with TBDs had normal menarche, fertility, and menopause, gynaecological problems and pregnancy complications leading to caesarean section, preterm delivery, or transfusion support were frequent. Women with TBDs will benefit from multidisciplinary, coordinated care by haematology, gynaecology and maternal-fetal medicine.

Pregnant in the United States in the COVID-19 pandemic: A collision of crises we cannot ignore.

NO abstract intended, Introduction is listed here The COVID-19 pandemic and call for social justice is occurring when the United States, unlike its peer countries, has already experienced a steady 20-year rise in maternal morbidity and mortality with pregnant women today facing a 50 percent higher risk of mortality than their mothers. 1 Most vulnerable are women of color, black and American Indian/Alaska Native women, who have experienced longstanding disparities in access to and quality of healthcare and may begin pregnancy with hypertension, diabetes, and obesity, complications known to be more common in women enduring segregation. 2-4 Initially, the race-related health disparities and resultant disproportionately higher rates of COVID-19 cases and mortality in indigenous communities and black, latinx, or other communities of color were mistakenly considered innate racial differences. More recently, these higher rates have been attributed to underlying social, structural, and environmental determinants of health including resource inequities, inadequate housing, and occupational and environmental hazards that result in greater exposure to and less protection from COVID-19. 5,6 Augmented by the added physiologic stress of pregnancy, these comorbidities and disparities compound the risk of pregnancy-associated cardiomyopathy, thromboembolism, and hemorrhage, often resulting in lasting physical and mental health consequences.

Widespread myofascial dysfunction and sensitisation in women with endometriosis-associated chronic pelvic pain: A cross-sectional study.

BACKGROUND: Chronic pelvic pain persists in some women with endometriosis even after lesion removal and optimized hormonal treatment. OBJECTIVE: Characterize the presence and distribution of pain, myofascial dysfunction and sensitisation beyond the pelvis in women with endometriosis-associated chronic pelvic pain. METHODS: Cross-sectional study of 30 women prior to participation in a clinical trial. Evaluation included pain-focused abdominopelvic gynaecologic examination with the identification of pelvic floor muscle spasm. Neuro-musculoskeletal examination assessed paraspinal allodynia and hyperalgesia bilaterally and myofascial trigger points in 13 paired muscles. Pressure-pain thresholds were measured over interspinous ligaments and trigger points. Women completed the body territories element of the Body Pain Index. RESULTS: All women had a pelvic floor muscle spasm that they self-identified as a major focus of pain. Twenty of 30 women described their pelvic pain as focal. However, all demonstrated widespread myofascial dysfunction with low pressure-pain thresholds and trigger points in over two-thirds of 26 assessed regions. Widespread spinal segmental sensitisation was present in 17/30, thoracic in 21/30 and lumbosacral/pelvic in 18/30. Cervical sensitisation manifested as low pressure-pain thresholds with 23/30 also reporting recurrent, severe headaches and 21/30 experiencing orofacial pain. Those reporting diffuse pelvic pain were more likely to have widespread (p = .024) and lumbosacral/pelvic (p = .036) sensitisation and report over 10 painful body areas (p = .009). CONCLUSIONS: Women with endometriosis-associated chronic pelvic pain often have myofascial dysfunction and sensitisation beyond the pelvic region that may be initiated or maintained by on-going pelvic floor spasm. These myofascial and nervous system manifestations warrant consideration when managing pain in this population. Clinicaltrials.gov identifier: NCT01553201. SIGNIFICANCE: Women with endometriosis often have pelvic pain persisting after surgery despite hormonal therapies and these women have regional pelvic sensitisation and myofascial dysfunction. Pelvic floor muscle spasm is a major pain focus in this population. Sensitisation and myofascial dysfunction are widespread, beyond the pelvic region. On-going pelvic floor spasm may initiate or maintain sensitisation. Myofascial/sensitisation manifestations warrant consideration when managing pain in this population.

Hypothalamic-Pituitary-Adrenal Axis Responses in Women with Endometriosis-Related Chronic Pelvic Pain.

Some chronic pain conditions and comorbidities suppress the hypothalamic-pituitary-adrenal (HPA) axis and response to dynamic testing. We measured HPA axis responses to corticotropin-releasing hormone (CRH) administration in relation to chronic pelvic pain and endometriosis. In a cross-sectional study of women (n = 54) with endometriosis-associated chronic pelvic pain (n = 22), chronic pelvic pain alone (n = 12), or healthy volunteers (n = 20), adrenocorticotropic-releasing hormone (ACTH) and cortisol levels were measured at 0, 15, 30, and 45 min after intravenous ovine CRH administration. ACTH and cortisol delta (peak-baseline) and area under the curve (AUC) were compared by study group and assessed for association with race and menstrual and non-menstrual pain severity. HPA axis responses did not differ among the racially diverse groups or in those with pain compared with healthy volunteers. However, when stratified by race, ACTH delta (129.9 ± 130.7 vs. 52.5 ± 66.0 pg/mL; p = 0.003), ACTH AUC (4813 ± 4707 vs. 2290 ± 2900 min*pg/mL; p = 0.013), and cortisol delta (26.3 ± 21.5 vs. 13.2 ± 9.7 µg/mL; p = 0.005) were significantly higher in black (n = 10) than predominately white (non-black) subjects (n = 44; 39/44 white). In analyses among primarily white (non-black) women, greater menstrual pain severity was associated with blunted ACTH delta (p = 0.015) and cortisol delta (p = 0.023), and greater non-menstrual pain severity with blunted cortisol delta (p = 0.017). Neuroendocrine abnormalities in women with chronic pelvic pain may differ by pain manifestations and may vary by race. The higher HPA axis response in black women merits investigation in pelvic pain studies stratified by race. In white (non-black) women experiencing pain, a blunted response was related to pain severity suggesting pain affects women independently of endometriosis lesions.

Immune Response Following Quadrivalent Human Papillomavirus Vaccination in Women After Hematopoietic Allogeneic Stem Cell Transplant: A Nonrandomized Clinical Trial.

Importance: Human papillomavirus (HPV) infection is found in about 40% of women who survive allogeneic hematopoietic stem cell transplant and can induce subsequent neoplasms. Objective: To determine the safety and immunogenicity of the quadrivalent HPV vaccine (HPV-6, -11, -16, and -18) in clinically stable women post-allogeneic transplant compared with female healthy volunteers. Interventions: Participants received the quadrivalent HPV vaccine in intramuscular injections on days 1 and 2 and then 6 months later. Design, Setting, and Participants: This prospective, open-label phase-1 study was conducted in a government clinical research hospital and included clinically stable women posttransplant who were or were not receiving immunosuppressive therapy compared with healthy female volunteers age 18 to 50 years who were followed up or a year after first receiving quadrivalent HPV vaccination. The study was conducted from June 2, 2010, until July 19, 2016. After all of the results of the study assays were completed and available in early 2018, the analysis took place from February 2018 to May 2019. Main Outcomes and Measures: Anti-HPV-6, -11, -16, and -18-specific antibody responses using L1 virus-like particle enzyme-linked immunosorbent assay were measured in serum before (day 1) and at months 7 and 12 postvaccination. Anti-HPV-16 and -18 neutralization titers were determined using a pseudovirion-based neutralization assay. Results: Of 64 vaccinated women, 23 (35.9%) were receiving immunosuppressive therapy (median age, 34 years [range, 18-48 years]; median 1.2 years posttransplant), 21 (32.8%) were not receiving immunosuppression (median age, 32 years [range, 18-49 years]; median 2.5 years posttransplant), and 20 (31.3%) were healthy volunteers (median age, 32 years [range, 23-45 years]). After vaccine series completion, 18 of 23 patients receiving immunosuppression (78.3%), 20 of 21 not receiving immunosuppression (95.2%), and all 20 volunteers developed antibody responses to all quadrivalent HPV vaccine types (P = .04, comparing the 3 groups). Geometric mean antibody levels for each HPV type were higher at months 7 and 12 than at baseline in each group (all geometric mean ratios >1; P < .001) but not significantly different across groups. Antibody and neutralization titers for anti-HPV-16 and anti-HPV-18 correlated at month 7 (Spearman ρ = 0.92; P < .001 for both). Adverse events were mild and not different across groups. Conclusions and Relevance: Treatment with the HPV vaccination was followed by strong, functionally active antibody responses against vaccine-related HPV types and no serious adverse events. These findings suggest that HPV vaccination may be safely administered to women posttransplant to potentially reduce HPV infection and related neoplasia. Trial Registration: ClinicalTrials.gov Identifier: NCT01092195.