Oocyte cryopreservation for women with GATA2 deficiency.

PURPOSE: To describe controlled ovarian stimulation (COS) in a population of women with GATA2 deficiency, a genetic bone marrow failure syndrome, prior to allogeneic hematopoietic stem cell transplant METHODS: This is a retrospective case series of nine women with GATA2 deficiency who underwent oocyte preservation at a research institution. Main outcomes measured include baseline fertility characteristics ((antimullerian hormone (AMH) and day 3 follicle-stimulating hormone (FSH) and estradiol (E2)) and total doses of FSH and human menopausal gonadotropins (HMG), E2 on day of trigger, and total number of metaphase II oocytes retrieved. RESULTS: The mean age was 24 years [16-32], mean AMH was 5.2 ng/mL [0.7-10], and day 3 mean FSH was 5.1 U/L [0.7-8.1], and E2 was 31.5 pg/mL [< 5-45]. The mean dose of FSH was 1774 IU [675-4035], and HMG was 1412 IU [375-2925] with a mean E2 of 2267 pg/mL [60.7-4030] on day of trigger. The mean total of metaphase II oocytes was 7.7 [0-15]. One patient was diagnosed with a deep vein thrombosis (DVT) with pulmonary embolism (PE) during COS. CONCLUSION: This study is the first to analyze the outcomes of COS in women with GATA2 deficiency. The response to ovarian stimulation suggests that oocyte cryopreservation should be considered prior to gonadotoxic therapy. However, due to the risk of potentially life-threatening complications, it is prudent that patients are properly counseled of the risks and are evaluated by a multi-disciplinary medical team prior to COS.

Endometrial stem cell transplantation in MPTP- exposed primates: an alternative cell source for treatment of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease caused by the loss of dopaminergic neurons in the substantia nigra. Cell-replacement therapies have emerged as a promising strategy to slow down or replace neuronal loss. Compared to other stem cell types, endometrium-derived stem cells (EDSCs) are an attractive source of stem cells for cellular therapies because of their ease of collection and vast differentiation potential. Here we demonstrate that endometrium-derived stem cells may be transplanted into an MPTP exposed monkey model of PD. After injection into the striatum, endometrium-derived stem cells engrafted, exhibited neuron-like morphology, expressed tyrosine hydroxylase (TH) and increased the numbers of TH positive cells on the transplanted side and dopamine metabolite concentrations in vivo. Our results suggest that endometrium-derived stem cells may provide a therapeutic benefit in the primate model of PD and may be used in stem cell based therapies.

LGBTQIA+ Cultural Competence in Physical Therapy: An Exploratory Qualitative Study From the Clinician's Perspective.

OBJECTIVE: The purpose of this study was to understand the lesbian, gay, bisexual, transgender, queer, intersex, agender, and other gender and sexually diverse identities (LGBTQIA+) health care experience and associated cultural competence from the physical therapist perspective (physical therapist and physical therapist assistant). METHODS: An exploratory qualitative approach implementing semi-structured focus groups and private interviews was utilized. To further anonymity, researchers allowed subjects to keep their camera off on Zoom. An interview protocol included questions guided by Campinha-Bacote domains of cultural competence (cultural awareness, skill, knowledge, encounter, and desire) to collect individual experiences, stories, discussions, thoughts, and opinions. Physical therapist clinicians were recruited from the clinical education affiliation lists of Regis University and Thomas Jefferson University. Seventy-one practicing physical therapists from the USA agreed to be part of the study. RESULTS: Themes were organized using the Social Ecological Model Framework. Themes are in parentheses following each level of the Social Ecological Model and include intrapersonal level (psychological stress and implicit and explicit biases), interpersonal (acceptance and competency), organizational (experience), community (advocacy), and society and policy (explicit biases and policy). CONCLUSION: Cultural competence in physical therapy is influenced by intrapersonal, interpersonal, organizational, community, and social and policy factors. Themes of psychological stress, limited awareness, decreased acceptance, and competency as well as limited exposure and experience, and a lack of advocacy and broader societal and policy issues prevent adequate LGBTQIA+ cultural competency of physical therapist providers. Further research in the physical therapist profession is needed to elaborate on the student, educator, and patient perspectives and how this information informs the LGBTQIA+ cultural competence of clinicians. IMPACT: This project may have a significant impact on suggestions for the delivery of content for health profession education to best impact health equity goals and save lives. Implementation of this content may have a direct impact on health disparities in LGBTQIA+ populations by reducing stigma and discrimination from health care providers, thus improving quality of health care and decreasing rates of patient mortality for LGBTQIA+ individuals.

X-chromosome inactivation in monkey embryos and pluripotent stem cells.

Inactivation of one X chromosome in female mammals (XX) compensates for the reduced dosage of X-linked gene expression in males (XY). However, the inner cell mass (ICM) of mouse preimplantation blastocysts and their in vitro counterparts, pluripotent embryonic stem cells (ESCs), initially maintain two active X chromosomes (XaXa). Random X chromosome inactivation (XCI) takes place in the ICM lineage after implantation or upon differentiation of ESCs, resulting in mosaic tissues composed of two cell types carrying either maternal or paternal active X chromosomes. While the status of XCI in human embryos and ICMs remains unknown, majority of human female ESCs show non-random XCI. We demonstrate here that rhesus monkey ESCs also display monoallelic expression and methylation of X-linked genes in agreement with non-random XCI. However, XIST and other X-linked genes were expressed from both chromosomes in isolated female monkey ICMs indicating that ex vivo pluripotent cells retain XaXa. Intriguingly, the trophectoderm (TE) in preimplantation monkey blastocysts also expressed X-linked genes from both alleles suggesting that, unlike the mouse, primate TE lineage does not support imprinted paternal XCI. Our results provide insights into the species-specific nature of XCI in the primate system and reveal fundamental epigenetic differences between in vitro and ex vivo primate pluripotent cells.

Derivation of insulin producing cells from human endometrial stromal stem cells and use in the treatment of murine diabetes.

Pancreatic islet cell transplantation is an effective approach to treat type 1 diabetes, however the shortage of cadaveric donors and limitations due to rejection require alternative solutions. Multipotent cells derived from the uterine endometrium have the ability to differentiate into mesodermal and ectodermal cellular lineages, suggesting the existence of mesenchymal stem cells in this tissue. We differentiated human endometrial stromal stem cells (ESSC) into insulin secreting cells using a simple and nontransfection protocol. An in vitro protocol was developed and evaluated by assessing the expression of pan ß-cell markers, followed by confirmation of insulin secretion. PAX4, PDX1, GLUT2, and insulin, were all increased in differentiated cells compared to controls. Differentiated cells secreted insulin in a glucose responsive manner. In a murine model, differentiated cells were injected into the kidney capsules of diabetic mice and human insulin identified in serum. Within 5 weeks blood glucose levels were stabilized in animals transplanted with differentiated cells, however those treated with undifferentiated cells developed progressive hyperglycemia. Mice transplanted with control cells lost weight and developed cataracts while those receiving insulin producing cells did not. Endometrium provides an easily accessible, renewable, and immunologically identical source of stem cells with potential therapeutic applications in diabetes.

Activated partial thromboplastin time is a better trending tool in pediatric extracorporeal membrane oxygenation.

OBJECTIVES: To determine whether activated partial thromboplastin times are a better heparin management tool than activated clotting times in pediatric extracorporeal membrane oxygenation. DESIGN: A single-center retrospective analysis of perfusion and patient records. SETTING: Academic pediatric tertiary care center. PATIENTS: Pediatric patients (<21 yrs old) requiring extracorporeal membrane oxygenation support initiated at Children's Hospital of Pittsburgh. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Point-of-care activated clotting time and activated partial thromboplastin time values, clinical laboratory activated partial thromboplastin time values, weight-normalized heparin administration (units/kg/hr), and reported outcomes were collected for pediatric patients treated for cardiac and/or respiratory failure with extracorporeal membrane oxygenation. Spearman's ranked correlations were performed for each coagulation test compared to heparin dosage. The Bland-Altman test was used to determine the validity of the point-of-care activated partial thromboplastin time. Hazard analysis was conducted for outcomes and complications for patients whose heparin management was based on the clinical laboratory activated partial thromboplastin time or the activated clotting time. Only the clinical laboratory activated partial thromboplastin time showed a correlation (ρ = 0.40 vs. ρ = -0.04 for activated clotting time) with the heparin administration (units/kg/hr). Point-of-care activated partial thromboplastin time and activated partial thromboplastin time values correlated well (ρ = 0.76), with <5% of samples showing a difference outside 2 SDs, but differences in their absolute values (Δactivated partial thromboplastin time = 100 secs) preclude them from being interchangeable measures. Furthermore, despite no effective change in the mean activated clotting time, cardiac patients showed a significantly improved correlation to heparin dose for all coagulation tests (e.g., point-of-care activated partial thromboplastin time ρ = 0.60). Management of patients with the clinical laboratory activated partial thromboplastin time did not significantly affect patient survival rates but did significantly reduce bleeding complications and significantly increased clotting in the extracorporeal membrane oxygenation circuit. A hazard analysis demonstrated that bleeding complications were associated with an increased risk of mortality, whereas clotting complications in the extracorporeal membrane oxygenation circuit were not. CONCLUSIONS: The activated clotting time is not an accurate monitoring tool for heparin management in pediatricextracorporeal membrane oxygenation. The point-of-care activated partial thromboplastin time correlates well with the clinical laboratory activated partial thromboplastin time but cannot be substituted for the clinical laboratory activated partial thromboplastin time values. Management of pediatric extracorporeal membrane oxygenation patients with the clinical laboratory activated partial thromboplastin time reduced bleeding complications which are associated with increases in mortality.

Endometrial stem cell transplantation restores dopamine production in a Parkinson's disease model.

Parkinson's disease (PD) is a neurodegenerative disorder caused by the loss of dopaminergic neurons. Adult human endometrial derived stem cells (HEDSC), a readily obtainable type of mesenchymal stem-like cell, were used to generate dopaminergic cells and for transplantation. Cells expressing CD90, platelet derived growth factor (PDGF)-Rß and CD146 but not CD45 or CD31 were differentiated in vitro into dopaminergic neurons that exhibited axon projections, pyramidal cell bodies and dendritic projections that recapitulate synapse formation; these cells also expressed the neural marker nestin and tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. Whole cell patch clamp recording identified G-protein coupled inwardly rectifying potassium current 2 channels characteristic of central neurons. A 1-methyl 4-phenyl 1,2,3,6-tetrahydro pyridine induced animal model of PD was used to demonstrate the ability of labelled HEDSC to engraft, migrate to the site of lesion, differentiate in vivo and significantly increase striatal dopamine and dopamine metabolite concentrations. HEDSC are a highly inducible source of allogenic stem cells that rescue dopamine concentrations in an immunocompetent PD mouse model.

Creating an Artificial 3-Dimensional Ovarian Follicle Culture System Using a Microfluidic System.

We hypothesized that the creation of a 3-dimensional ovarian follicle, with embedded granulosa and theca cells, would better mimic the environment necessary to support early oocytes, both structurally and hormonally. Using a microfluidic system with controlled flow rates, 3-dimensional two-layer (core and shell) capsules were created. The core consists of murine granulosa cells in 0.8 mg/mL collagen + 0.05% alginate, while the shell is composed of murine theca cells suspended in 2% alginate. Somatic cell viability tests and hormonal assessments (estradiol, progesterone, and androstenedione) were performed on days 1, 6, 13, 20, and 27. Confocal microscopy confirmed appropriate compartmentalization of fluorescently-labeled murine granulosa cells to the inner capsule and theca cells to the outer shell. Greater than 78% of cells present in capsules were alive up to 27 days after collection. Artificially constructed ovarian follicles exhibited intact endocrine function as evidenced by the production of estradiol, progesterone, and androstenedione. Oocytes from primary and early secondary follicles were successfully encapsulated, which maintained size and cellular compartmentalization. This novel microfluidic system successfully encapsulated oocytes from primary and secondary follicles, recapitulating the two-compartment system necessary for the development of the mammalian oocyte. Importantly, this microfluidic system can be easily adapted for sterile, high throughput applications.

Rapamycin Corrects T Regulatory Cell Depletion and Improves Embryo Implantation and Live Birth Rates in a Murine Model.

There are few treatments for patients with recurrent pregnancy loss (RPL) or recurrent implantation failure (RIF). Women with RPL and unexplained infertility have lower T regulatory cell (Treg) expression when compared to fertile controls. A murine model has been developed with depletion of regulatory T cells (DEREG) after administration of diphtheria toxin (DT), resulting in smaller litter sizes, secondary to embryo implantation failure. Numerous murine studies have shown that adoptive transfer of CD4+CD25+FoxP3+ Tregs from donors improves litter sizes in DEREG mice with depleted Tregs. Our hypothesis is that DEREG mice treated with a single dose of DT will deplete Tregs and subsequently decrease litter sizes and that treatment with rapamycin (sirolimus; Pfizer) during the time of embryo implantation will increase Tregs and restore litter sizes nearly back to normal levels. Syngeneic mating of DEREG mice after depletion of Tregs resulted in smaller litter sizes and this defect was reversed when these DEREG mice were treated with rapamycin at the time of embryo implantation. The importance of Tregs at the time of embryo implantation has been well established and immunotherapy treatments, such as rapamycin (mammalian target of rapamycin inhibitor), may prove to be an effective treatment for patients with RPL, RIF, or unexplained infertility with low Treg.

Evidence-informed management of chronic low back pain with nonsteroidal anti-inflammatory drugs, muscle relaxants, and simple analgesics.

The management of chronic low back pain (CLBP) has proven to be very challenging in North America, as evidenced by its mounting socioeconomic burden. Choosing amongst available nonsurgical therapies can be overwhelming for many stakeholders, including patients, health providers, policy makers, and third-party payers. Although all parties share a common goal and wish to use limited health-care resources to support interventions most likely to result in clinically meaningful improvements, there is often uncertainty about the most appropriate intervention for a particular patient. To help understand and evaluate the various commonly used nonsurgical approaches to CLBP, the North American Spine Society has sponsored this special focus issue of The Spine Journal, titled Evidence-Informed Management of Chronic Low Back Pain Without Surgery. Articles in this special focus issue were contributed by leading spine practitioners and researchers, who were invited to summarize the best available evidence for a particular intervention and encouraged to make this information accessible to nonexperts. Each of the articles contains five sections (description, theory, evidence of efficacy, harms, and summary) with common subheadings to facilitate comparison across the 24 different interventions profiled in this special focus issue, blending narrative and systematic review methodology as deemed appropriate by the authors. It is hoped that articles in this special focus issue will be informative and aid in decision making for the many stakeholders evaluating nonsurgical interventions for CLBP.

Evidence-informed management of chronic low back pain with trigger point injections.

The management of chronic low back pain (CLBP) has proven very challenging in North America, as evidenced by its mounting socioeconomic burden. Choosing amongst available nonsurgical therapies can be overwhelming for many stakeholders, including patients, health providers, policy makers, and third-party payers. Although all parties share a common goal and wish to use limited health-care resources to support interventions most likely to result in clinically meaningful improvements, there is often uncertainty about the most appropriate intervention for a particular patient. To help understand and evaluate the various commonly used nonsurgical approaches to CLBP, the North American Spine Society has sponsored this special focus issue of The Spine Journal, titled Evidence-Informed Management of Chronic Low Back Pain Without Surgery. Articles in this special focus issue were contributed by leading spine practitioners and researchers, who were invited to summarize the best available evidence for a particular intervention and encouraged to make this information accessible to nonexperts. Each of the articles contains five sections (description, theory, evidence of efficacy, harms, and summary) with common subheadings to facilitate comparison across the 24 different interventions profiled in this special focus issue, blending narrative and systematic review methodology as deemed appropriate by the authors. It is hoped that articles in this special focus issue will be informative and aid in decision making for the many stakeholders evaluating nonsurgical interventions for CLBP.

Two Unique Cases of Ciprofloxacin-Associated Avulsion of Ligament and Tendon.

Ciprofloxacin is recognized to have a deleterious relationship with tendons, particularly Achilles tendinopathy, which makes up most case reports. Tendinopathy seems to occur because of induction of collagen-degrading enzymes causing damage and ischemia of the poorly vascularized regions preventing repair. The focus on the relationship of ciprofloxacin and the Achilles tendon leaves patients on fluoroquinolones with non-Achilles tendinopathy symptoms at risk of misdiagnosis. There have not been any documented instances of ligament damage with ciprofloxacin administration in the literature, although ligament and tendon compositions are similar and should have similar susceptibility. This report includes two cases, one presenting with right lateral thumb pain and a medical history of gastroenteritis treated with ciprofloxacin. Physical examination showed swelling of the right metacarpophalangeal joint and ultrasound confirmed disruption of the radial collateral ligament at insertion on first metacarpal; the second case is of a woman presenting with right hip pain in setting of chronic recurrent diverticulitis treated with ciprofloxacin. She received work-up for lumbar disc disease and spondylosis. After standard therapy with pharmacotherapy and physical therapy for radiculopathy failed, magnetic resonance imaging was performed showing near complete avulsion of the right hamstring tendons from the ischial tuberosity.

Maternal T Regulatory Cell Depletion Impairs Embryo Implantation Which Can Be Corrected With Adoptive T Regulatory Cell Transfer.

Maternal immune tolerance of fetal engraftment is critical for the establishment and maintenance of pregnancy, but the exact mechanisms permitting this semi-allograft in the maternal host are not completely understood. Further, failure of the embryo to implant in the uterus accounts for at least 30% of the best prognosis in vitro fertilization cycles when a perfect embryo is transferred to a normal uterus. We hypothesized that T regulatory cells (Tregs), defined by CD4+CD25hi surface expression and the FoxP3+ transcription factor, play an important role in the initiation of the earliest stages of pregnancy, specifically implantation of the embryo. In this study, we evaluated the role of Tregs in the establishment of pregnancy using a conditional depletion of Treg transgenic mouse model. We found that embryo implantation in the syngeneic mating was defective as evidenced by smaller litter sizes after Treg depletion and that embryo implantation could be restored by adoptively transferring Tregs into the mating mice. In allogeneic mating, litter sizes were not different but breeding efficiency was significantly decreased. These data reveal that Tregs are important for the establishment of the earliest stages of pregnancy and may be a potential cause of infertility due to recurrent implantation failure, which may be amenable to cellular or pharmacologic therapy to improve maternal immune tolerance of embryo implantation.

Longitudinal changes in menopausal symptoms comparing women randomized to low-dose oral conjugated estrogens or transdermal estradiol plus micronized progesterone versus placebo: the Kronos Early Estrogen Prevention Study.

OBJECTIVE: The objective of the present study was to compare the efficacy of two forms of menopausal hormone therapy in alleviating vasomotor symptoms, insomnia, and irritability in early postmenopausal women during 4 years. METHODS: A total of 727 women, aged 42 to 58, within 3 years of their final menstrual period, were randomized to receive oral conjugated estrogens (o-CEE) 0.45 mg (n = 230) or transdermal estradiol (t-E2) 50 µg (n = 225; both with micronized progesterone 200 mg for 12 d each mo), or placebos (PBOs; n = 275). Menopausal symptoms were recorded at screening and at 6, 12, 24, 36, and 48 months postrandomization. Differences in proportions of women with symptoms at baseline and at each follow-up time point were compared by treatment arm using exact χ tests in an intent-to-treat analysis. Differences in treatment effect by race/ethnicity and body mass index were tested using generalized linear mixed effects modeling. RESULTS: Moderate to severe hot flashes (from 44% at baseline to 28.3% for PBO, 7.4% for t-E2, and 4.2% for o-CEE) and night sweats (from 35% at baseline to 19% for PBO, 5.3% for t-E2, and 4.7% for o-CEE) were reduced significantly by 6 months in women randomized to either active hormone compared with PBO (P < 0.001 for both symptoms), with no significant differences between the active treatment arms. Insomnia and irritability decreased from baseline to 6 months postrandomization in all groups. There was an intermittent reduction in insomnia in both active treatment arms versus PBO, with o-CEE being more effective than PBO at 36 and 48 months (P = 0.002 and 0.05) and t-E2 being more effective than PBO at 48 months (P = 0.004). Neither hormone treatment significantly affected irritability compared with PBO. Symptom relief for active treatment versus PBO was not significantly modified by body mass index or race/ethnicity. CONCLUSIONS: Recently postmenopausal women had similar and substantial reductions in hot flashes and night sweats with lower-than-conventional doses of oral or transdermal estrogen. These reductions were sustained during 4 years. Insomnia was intermittently reduced compared with PBO for both hormone regimens.

Are intracytoplasmic sperm injection and high serum estradiol compounding risk factors for adverse obstetric outcomes in assisted reproductive technology?

OBJECTIVE: To evaluate whether intracytoplasmic sperm injection (ICSI) use and E2 on the final day of assisted reproductive technology (ART) stimulation are associated with adverse obstetric complications related to placentation. DESIGN: Retrospective cohort study. SETTING: Large private ART practice. PATIENT(S): A total of 383 women who underwent ART resulting in a singleton live birth. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Adverse placental outcomes composed of placenta accreta, placental abruption, placenta previa, intrauterine growth restriction, preeclampsia, gestational hypertension, and small for gestational age infants. RESULT(S): Patients with adverse placental outcomes had higher peak serum E2 levels and were three times more likely to have used ICSI. Adverse placental outcomes were associated with increasing E2 (odds ratio 1.36, 95% confidence interval 1.13-1.65) and ICSI (odds ratio 3.86, 95% confidence interval 1.61-9.27). Adverse outcomes increased when E2 was >3,000 pg/mL and continued to increase in a linear fashion until E2 was >5,000 pg/mL. The association of ICSI with adverse outcomes was independent of male factor infertility. Interaction testing suggested the adverse effect of E2 was primarily seen in ICSI cycles, but not in conventional IVF cycles. Estradiol >5,000 pg/mL was associated with adverse placental events in 36% of all ART cycles and 52% of ICSI cycles. CONCLUSION(S): ICSI and elevated E2 on the day of hCG trigger were associated with adverse obstetric outcomes related to placentation. The finding of a potential interaction of E2 and ICSI with adverse placental events is novel and warrants further investigation.

Effects of hormones on skin wrinkles and rigidity vary by race/ethnicity: four-year follow-up from the ancillary skin study of the Kronos Early Estrogen Prevention Study.

OBJECTIVE: To measure skin wrinkles and rigidity in menopausal women of varying race/ethnicity with or without hormone therapy (HT) for up to four years. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Academic medical centers. PATIENT(S): Women (42-58 years of age) within 36 months of last menstrual period and enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). INTERVENTION(S): Treatment with 0.45 mg oral conjugated equine estrogens (CEE), transdermal E2 (50 µg/d) with micronized P (200 mg daily), or placebo for 4 years. MAIN OUTCOME MEASURE(S): Skin wrinkles were assessed at 11 locations on the face and neck, and skin rigidity was assessed at the forehead and cheek at baseline and yearly for 4 years. RESULT(S): Neither total wrinkle score nor total rigidity score was significantly different at baseline or over the 4-year follow-up among patients randomized to CEE, E2, or placebo. Skin wrinkle and rigidity scores were primarily affected by race/ethnicity, with scores being significantly different between races for almost all of the wrinkle parameters and for all of the rigidity measures. There was no association between race and response to HT for total wrinkle or rigidity scores. Black women had the lowest wrinkle scores compared with white women across all 4 years. In general, skin rigidity decreased in all groups over time, but black women had significantly reduced total facial rigidity compared with white women after 4 years. CONCLUSION(S): Race is the strongest predictor of the advancement of skin aging in the 4 years following menopause. HT does not appear to affect skin wrinkles or rigidity at most facial locations. CLINICAL TRIAL REGISTRATION NUMBER: NCT00154180.

Oral prenylation inhibition with lonafarnib in chronic hepatitis D infection: a proof-of-concept randomised, double-blind, placebo-controlled phase 2A trial.

BACKGROUND: Therapies for chronic hepatitis delta virus (HDV) infection are unsatisfactory. Prenylation is essential for HDV and inhibition abrogates HDV production in experimental models. In a proof-of-concept study, we aimed to assess the effect on HDV RNA levels, safety, and tolerability of the prenylation inhibitor lonafarnib in patients with chronic delta hepatitis. METHODS: In this phase 2A double-blind, randomised, placebo-controlled study, patients aged 18 years or older with chronic HDV infection were randomly assigned (3:1 in group 1 and 2:1 in group 2) to receive lonafarnib 100 mg (group 1) or lonafarnib 200 mg (group 2) twice daily for 28 days with 6 months' follow-up. Participants were randomised by random-number tables blocked in groups of four without stratification. Both groups enrolled six treatment participants and two placebo participants. Group 1 placebo patients received open-label lonafarnib as group 2 participants. The primary therapeutic endpoint was a decrease in HDV RNA viral titre in serum and the primary safety endpoint was the ability to tolerate the drug at the prescribed dose for the full 4-week duration, defined as drug discontinuation due to intolerance or grade 3/4 adverse events. This trial is registered with ClinicalTrials.gov, number NCT01495585. FINDINGS: Between Jan 19, 2012, and April 28, 2014, 14 patients were enrolled, of whom eight were assigned to group 1 and six were assigned to group 2. At day 28, compared with placebo, mean log HDV RNA declines from baseline were -0·73 log IU/mL in group 1 (95% CI 0·17-1·31; p=0·03) and -1·54 log IU/mL in group 2 (1·21-1·93; p<0·0001). Lonafarnib serum concentrations correlated with HDV RNA change (r(2)=0·78, p<0·0001). Model fits show that hepatitis B surface antigen (HBsAg) remained stable after a short pharmacological delay (0·75 days [SE 0·24]), lonafarnib effectiveness in blocking HDV production was greater in group 2 than in group 1 (0·952 [SE 0·06] vs 0·739 [0·05], p<0·001), and the HDV half-life was 1·62 days (0·07). There was no evidence of virological resistance. Adverse events were mainly mild to moderate with group 1 patients experiencing diarrhoea in three patients (50%) and nausea in two patients (33%) and in group 2 with all patients (100%) experiencing nausea, diarrhoea, abdominal bloating, and weight loss greater than 2 kg (mean of 4 kg). No treatment discontinuations occurred in any treatment groups. INTERPRETATION: Treatment of chronic HDV with lonafarnib significantly reduces virus levels. The decline in virus levels significantly correlated with serum drug levels, providing further evidence for the efficacy of prenylation inhibition in chronic HDV. FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute, National Institutes of Health, and Eiger Biopharmaceuticals Inc.

Value of the day 3 follicle-stimulating hormone measurement.

Although elevated day 3 FSH is associated with diminished ovarian reserve, the predictive value is low in young women. Its use in this population as an exclusion criterion is unjustified.

Assessment of neuromuscular conditions using ultrasound.

Upper extremity pain in persons with spinal cord injury is a common cause of morbidity. Ultrasound of nerve, muscle, and tendon has the potential to become a valuable modality in assessing this population, and has the advantage of reduced health care costs, portability, and use in populations that cannot tolerate MRI. It has the potential to detect issues before the onset of significant morbidity, and preserve patient independence. Upper extremity ultrasound already has many studies showing its utility in diagnosis, and newer techniques have the potential to enhance its use in the diagnosis and management of musculoskeletal conditions.