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Abstract Background Genetic testing can offer early diagnosis and subsequent treatment of rare neuromuscular diseases. Options for these tests could be improved by understanding the preferences of patients for the features of different genetic tests, especially features that increase information available to patients. Methods We developed an online discrete-choice experiment using key attributes of currently available tests for Pompe disease with six test attributes: number of rare muscle diseases tested for with corresponding probability of diagnosis, treatment availability, time from testing to results, inclusion of secondary findings, necessity of a muscle biopsy, and average time until final diagnosis if the first test is negative. Respondents were presented a choice between two tests with different costs, with respondents randomly assigned to one of two costs. Data were analyzed using random-parameters logit. Results A total of 600 online respondents, aged 18 to 50 years, were recruited from the U.S. general population and included in the final analysis. Tests that targeted more diseases, required less time from testing to results, included information about unrelated health risks, and were linked to shorter time to the final diagnosis were preferred and associated with diseases with available treatment. Men placed relatively more importance than women on tests for diseases with available treatments. Most of the respondents would be more willing to get a genetic test that might return unrelated health information, with women exhibiting a statistically significant preference. While respondents were sensitive to cost, 30% of the sample assigned to the highest cost was willing to pay $500 for a test that could offer a diagnosis almost 2 years earlier. Conclusion The results highlight the value people place on the information genetic tests can provide about their health, including faster diagnosis of rare, unexplained muscle weakness, but also the value of tests for multiple diseases, diseases without treatments, and incidental findings. An earlier time to diagnosis can provide faster access to treatment and an end to the diagnostic journey, which patients highly prefer.

Abstract Background Clinical trials for rare diseases often include multiple endpoints that capture the effects of treatment on different disease domains. In many rare diseases, the primary endpoint is not standardized across trials. The win ratio approach was designed to analyze multiple endpoints of interest in clinical trials and has mostly been applied in cardiovascular trials. Here, we applied the win ratio approach to data from COMET, a phase 3 trial in late-onset Pompe disease, to illustrate how this approach can be used to analyze multiple endpoints in the orphan drug context. Methods All possible participant pairings from both arms of COMET were compared sequentially on changes at week 49 in upright forced vital capacity (FVC) % predicted and six-minute walk test (6MWT). Each participant’s response for the two endpoints was first classified as a meaningful improvement, no meaningful change, or a meaningful decline using thresholds based on published minimal clinically important differences (FVC ± 4% predicted, 6MWT ± 39 m). Each comparison assessed whether the outcome with avalglucosidase alfa (AVA) was better than (win), worse than (loss), or equivalent to (tie) the outcome with alglucosidase alfa (ALG). If tied on FVC, 6MWT was compared. In this approach, the treatment effect is the ratio of wins to losses (“win ratio”), with ties excluded. Results In the 2499 possible pairings (51 receiving AVA × 49 receiving ALG), the win ratio was 2.37 (95% confidence interval [CI], 1.30–4.29, p = 0.005) when FVC was compared before 6MWT. When the order was reversed, the win ratio was 2.02 (95% CI, 1.13–3.62, p = 0.018). Conclusion The win ratio approach can be used in clinical trials of rare diseases to provide meaningful insight on treatment benefits from multiple endpoints and across disease domains.

Abstract Background Methotrexate (MTX) is a common chemotherapeutic drug that inhibits DNA synthesis and induces apoptosis. Treatment with MTX increased CD73 expression, which leads to higher levels of extracellular adenosine. Adenosine levels are also high in the tumor microenvironment through Cancer cells metabolism. That promotes the survival of cancer cells and contributes to tumor immune evasion through the Adenosine 2a Receptor. A2A receptor antagonists are an emerging class of agents that treat cancers by enhancing immunotherapy, both as monotherapy and in combination with other therapeutic agents. Caffeine is an adenosine receptor antagonist. Herein, we demonstrate the ability of a novel well prepared and characterized nano formula CAF-FA-CS-NPs (D4) for A2aR blockade when combination with MTX to improve its antitumor efficacy by enhancing the immune system and eliminating immune suppression. Methods CAF-FA-CS-NPs (D4) were prepared and characterized for particle size, loading efficiency, and release profile. Molecular docking was used to validate the binding affinity of caffeine and folic acid to A2A receptor. The effects of the nano formula were evaluated on human liver cancer cells (HepG2), breast cancer cells (MCF-7), and MDA-MB-231, as well as normal human cells (WI-38). Different combination ratios of MTX and D4 were studied to identify the optimal combination for further genetic studies. Results Molecular docking results validated that caffeine and folic acid have binding affinity to A2A receptor. The CS-NPs were successfully prepared using ionic gelation method, with caffeine and folic acid being loaded and conjugated to the nanoparticles through electrostatic interactions. The CAF loading capacity in D4 was 77.9 ± 4.37% with an encapsulation efficiency of 98.5 ± 0.37. The particle size was optimized through ratio variations. The resulting nanoparticles were fully characterized. The results showed that (D4) had antioxidant activity and cytotoxicity against different cancer cells. The combination of D4 with MTX (IC50 D4 + 0.5 IC50 MTX) resulted in the downregulation of Bcl-2, FOXP3, CD39, and CD73 gene expression levels and upregulation of Bax and A2AR gene expression levels in HepG2 cells. Conclusions This study suggests that CAF-FA-CS-NPs (D4) in combination with MTX may be a promising candidate for cancer immunotherapy, by inhibiting A2aR signaling and leading to improved immune activation and anti-tumor activity of MTX.

Abstract Background Globally, the increased use of cesarean sections has become prevalent in high-income and low and middle-income countries. In Palestine, the rate had risen from 20.3% in 2014 to 25.1% in 2018. We have rates as high as 35.8% in some governmental hospitals and some as low as 15%. This study aimed to understand better why there is a variation in cesarean rates in governmental hospitals that use the same guidelines. Methods A qualitative and quantitative research approach was used. In-depth interviews were conducted with 27 specialists, obstetrics and gynecologists, and midwives in five government hospitals. The hospitals were selected based on the 2017 Annual Health Report reported cesarean section rates. The interview guide was created with the support of specialists and researchers and was piloted. Questions focused mainly on adherence to the obstetric guidelines and barriers to the use, sources of information, training for healthcare providers, the hospital system, and the factors that affect decision-making. Each hospital's delivery records for one month were analyzed to determine the reason for each cesarean section. Results The results indicated that each governmental hospital at the system level had a different policy on cesarean sections. The National Guidelines were found to be interpreted differently among hospitals. One obstetrician-gynecologist decided on a cesarean section at high-rate hospitals, while low-rate hospitals used collective decision-making with empowered midwives. At the professional level, all hospitals urged the importance of a continuous training program to refresh the medical team knowledge, in-house training of new members joining the hospital, and discussion of cases subjective to obstetrician-gynecologists interpretations. Conclusion Several institutional factors were identified to strengthen the implementation of the national obstetric guidelines. For example, encouraging collective decision-making between obstetrician-gynecologists and midwives, promoting the use of a second opinion, and mandatory training.

Sixteen fuberidazole derivatives as potential new anticancer bioreductive prodrugs were prepared and characterized. The in vitro anticancer potential was examined to explore their cytotoxic properties by employing apoptosis, DNA damage, and proliferation tests on chosen hypoxic cancer cells. Eight substances (Compound 5a, 5c, 5d, 5e, 5g, 5h, 5i, and 5m) showed promising cytotoxicity values compared to the standard control. The potential of compounds was also examined through in silico studies (against human serum albumin), including chem-informatics, to understand the structure-activity relationship (SAR), pharmacochemical strength, and the mode of interactions responsible for their action. The DFT calculations revealed that only the 5b compound showed the lowest ΔET (2.29 eV) while 5i showed relatively highest βtot (69.89 x 10-31 esu), highest αave (3.18 x 10-23 esu), and dipole moment (6.49 Debye). This study presents a novel class of fuberidazole derivatives with selectivity toward hypoxic cancer cells.

Kaposi’s sarcoma associated herpesvirus (KSHV) is causative agent of Kaposi’s sarcoma, Multicentric Castleman Disease and Pleural effusion lymphoma. KSHV-encoded ORF17 encodes a protease which cleaves -Ala-Ala-, -Ala-Ser- or -Ala-Thr-bonds. The protease plays an important role in assembly and maturation of new infective virions. In the present study, we investigated expression pattern of KSHV-encoded protease during physiologically allowed as well as chemically induced reactivation condition. The results showed a direct and proportionate relationship between ORF17 expression with reactivation time. We employed virtual screening on a large database of natural products to identify an inhibitor of ORF17 for its plausible targeting and restricting Kaposi’s sarcoma associated herpesvirus assembly/maturation. A library of 307,814 compounds of biological origin (A total 481,799 structures) has been used as a screen library. 1-oleoyl-2-hydroxy-sn-glycero-3-phospho-(1′-myo-inositol) was highly effective against ORF17 in in-vitro experiments. The screened compound was tested for the cytotoxic effect and potential for inhibiting Kaposi’s sarcoma associated herpesvirus production upon induced reactivation by hypoxia, TPA and butyric acid. Treatment of reactivated KSHV-positive cells with 1-oleoyl-2-hydroxy-sn-glycero-3-phospho-(1′-myo-inositol) resulted in significant reduction in the production of Kaposi’s sarcoma associated herpesvirus. The study identified a lysophosphatidic acid molecule for alternate strategy to inhibit KSHV-encoded protease and target Kaposi’s sarcoma associated herpesvirus associated malignancies.

Background: T-box family members are transcription factors characterized by highly conserved residues corresponding to the DNA-binding domain known as the T-box. TBX2 has been implicated in several developmental processes, such as coordinating cell fate, patterning, and morphogenesis of a wide range of tissues and organs, including lungs, limbs, heart, kidneys, craniofacial structures, and mammary glands.Methods: In the present study, we have clinically and genetically characterized a proband showing a severe form of chondrodysplasia with developmental delay. Whole-exome sequencing (WES), Sanger sequencing, and 3D protein modeling were performed in the present investigation.Results: Whole-exome sequencing revealed a novel nonsense variant (c.529A>T; p.Lys177*; NM_005994.4) in TBX2. 3D-TBX2 protein modeling revealed a substantial reduction of the mutated protein, which might lead to a loss of function (LOF) or nonsense-mediated decay (NMD).Conclusion: This study has not only expanded the mutation spectrum in the gene TBX2 but also facilitated the diagnosis and genetic counseling of related features in affected families.

Abstract Background Late-onset Pompe Disease (LOPD) is a rare, heterogeneous disease manifested by a range of symptoms varying in severity. Research establishing the frequency of these symptoms and their impact on patients’ daily lives is limited. The objective of this study was to develop a conceptual model that captures the most relevant symptoms and functional limitations experienced by patients with LOPD, to inform the development of new patient-reported outcome (PRO) tools. Methods A preliminary conceptual model was constructed following a literature review and revised through interviews with expert clinicians to identify important and relevant concepts regarding symptoms and impacts of LOPD. This preliminary model informed the development of a qualitative patient interview guide, which was used to gather the patient perspective on symptoms and impacts relating to LOPD or its treatment (including symptom/impact frequency and levels of disturbance). Patient interviews aided further refinement of the conceptual model. The findings from the patient interviews were triangulated with the literature review and clinician interviews to identify the most relevant and significant effects of LOPD from the patient perspective. Results Muscle weakness, fatigue, pain, and breathing difficulties (especially while lying down) were the most common and highly disturbing symptoms experienced by patients. Limitations associated with mobility (e.g., difficulty rising from a sitting position, getting up after bending) and activities of daily living, (e.g., reduced ability to participate in social/family activities or work/study) were the most frequently reported impacts with the highest levels of disturbance on the patient’s daily life. These identified symptoms and impacts were included in the new conceptual model of disease. Conclusions This qualitative patient interview study, also informed by a literature review and clinician interviews, identified the most frequent and relevant symptoms and the functional impact of LOPD on patients. The study interviews also captured the patient-preferred language to describe symptoms and impacts of LOPD. The results from this study can be used to develop future PRO instruments that are tailored to the specific symptoms and impacts experienced by patients with LOPD.

Human noroviruses (NV) are the most prevalent cause of sporadic and pandemic acute gastroenteritis. NV infections cause substantial morbidity and death globally, especially amongst the aged, immunocompromised individuals, and children. There are presently no authorized NV vaccines, small-molecule therapies, or prophylactics for humans. NV 3 C L protease (3CLP) has been identified as a promising therapeutic target for anti-NV drug development. Herein, we employed a structure-based virtual screening method to screen a library of 700 antiviral compounds against the active site residues of 3CLP. We report three compounds, Sorafenib, YM201636, and LDC4297, that were revealed to have a higher binding energy (BE) value with 3CLP than the control (Dipeptidyl inhibitor 7) following a sequential screening, in-depth molecular docking and visualization, physicochemical and pharmacological property analysis, and molecular dynamics (MD) study. Sorafenib, YM201636, and LDC4297 had BEs of -11.67, -10.34, and -9.78 kcal/mol with 3CLP, respectively, while control had a BE of -6.38 kcal/mol. Furthermore, MD simulations of the two best compounds and control were used to further optimize the interactions, and a 100 ns MD simulation revealed that they form stable complexes with 3CLP. The estimated physicochemical, drug-like, and ADMET properties of these hits suggest that they might be employed as 3CLP inhibitors in the management of gastroenteritis. However, wet lab tests are a prerequisite to optimize them as NV 3CLP inhibitors.

Abstract Background The systematic collection of disease-specific symptoms and impacts on the lives of patients with Fabry Disease (FD) can offer unique insights into the patient experience, yet no disease-specific tool to measure FD symptoms exists. This study describes the development of the Fabry Disease Patient-Reported Outcome (FD-PRO). Methods A targeted literature search, interviews with key opinion leaders (KOLs), and concept elicitation (CE) interviews with patients identified the most frequent signs and symptoms associated with FD and their impact on daily life. Cognitive interviews evaluated patients’ ability to understand the FD-PRO instructions and respond to the items on the draft FD-PRO instrument. Results The targeted literature search identified key signs and symptoms in domains that were confirmed in KOL interviews. In CE interviews with 37 treated and treatment-naïve patients, neuropathic pain symptoms (95% treated, 82% treatment-naïve), temperature intolerance (95% treated, 88% treatment-naïve), energy difficulties (95% treated, 94% treatment-naïve), hearing/vision impairment (95% treated, 71% treatment-naïve), and gastrointestinal symptoms (80% treated, 59% treatment-naïve) were most frequently mentioned. Results were similar for men and women in both treated and treatment-naïve groups. While treatment-naïve patients in general expressed fewer and milder symptoms compared to treated patients, the overall sets of symptoms expressed by the two groups were similar. The most severe symptoms were neuropathic pain, stomach pain, burning pain, and fatigue. The most bothersome symptoms were stomach pain, breathing difficulty, fatigue, neuropathic pain, and constipation. The most frequent impacts were in the work/school limitations domain for both treated and treatment-naïve patients. The impacts with the highest difficulty ratings were stress, limited outdoor activity, and guilt. Cognitive interviews with 14 treated and treatment-naïve patients resulted in the refinement of FD-PRO items and language. Conclusions The FD-PRO is a novel, disease-specific instrument that measures the patient experience in Fabry disease. Such tools are valuable in capturing the burden of disease in patients with FD and demonstrating the value of treatment in clinical trials.

Brain-derived neurotrophic factor (BDNF) involving tropomyosin kinase B and low affinity p75 neurotropin receptors is the most abundant and researched neurotropins in mammal’s brain. It is one of the potential targets for therapeutics in Alzheimer’s disease (AD) owing to its key role in synaptic plasticity. Low levels of BDNF are implicated in the pathophysiology of neurological diseases including AD. However, a healthy lifestyle, exercise, and dietary modifications are shown to positively influence insulin regulation in the brain, reduce inflammation, and up-regulate the levels of BDNF, and are thus expected to have roles in AD. In this review, the relationship between BDNF, mental health, and AD is discussed. Insights into the interrelationships between nutrition, lifestyle, and environment with BDNF and possible roles in AD are also provided in the review. The review sheds light on the possible new therapeutic targets in neurodegenerative diseases.

Intellectual disability (ID) has become very common and is an extremely heterogeneous disorder, where the patients face many challenges with deficits in intellectual functioning and adaptive behaviors. A single affected family revealed severe disease phenotypes such as ID, developmental delay, dysmorphic facial features, postaxial polydactyly type B, and speech impairment. DNA of a single affected individual was directly subjected to whole exome sequencing (WES), followed by Sanger sequencing. Data analysis revealed a novel biallelic missense variant (c.1511G>C; p.(Trp504Ser)) in the ALKBH8 gene, which plays a significant role in tRNA modifications. Our finding adds another variant to the growing list of ALKBH8-associated tRNA modifications causing ID and additional phenotypic manifestations. The present study depicts the key role of the genes associated with tRNA modifications, such as ALKBH8, in the development and pathophysiology of the human brain.

BackgroundSchistosomiasis (SCH) and soil-transmitted helminthiasis (STH) are known to be endemic in Yemen. However, the distribution of both diseases had not previously been assessed by a well-structured national mapping study covering all governorates. The main aim of this study was, therefore, to map the prevalence of SCH and STH in Yemen in order to better inform implementation of effective national control and elimination interventions. The assessment of the distribution of anaemia was also included as a well-known consequence of infection with both SCH and STH. Secondarily, the study aimed to provide a broad indication of the impact of large-scale treatment on the distribution of infection.Methodology and principal findingsTo achive these aims, 80,432 children (10-14 years old) from 2,664 schools in 332 of Yemen's 333 districts were included, in 2014, into this national cross-sectional survey. Countrywide, 63.3% (210/332) and 75.6% (251/332) of districts were found to be endemic for SCH and STH respectively. More districts were affected by intestinal than urogenital SCH (54.2% and 31.6% respectively). SCH infection was mostly mild and moderate, with no districts reporting high infection. One quarter (24.4%) of Yemeni districts had high or moderate levels of Ascaris lumbricoides infection. Infection with Trichuris trichiura was the second most common STH (44.9% of districts infected) after A. lumbricoides (68.1%). Hookworm was the least prevalent STH (9.0%). Anaemia was prevalent in 96.4% of districts; it represented a severe public health problem (prevalence ≥ 40%) in 26.5% of districts, and a mild to moderate problem in two thirds of the districts (33.7% and 36.1% respectively).ConclusionThis study provided the first comprehensive mapping of SCH, STH, and anaemia across the country. This formed the basis for evaluating and continuing the national control and elimination programme for these neglected tropical diseases in Yemen.

Background: Nausea and vomiting affects up to 80% of the pregnant women population and are the third leading causes of maternal hospitalization during pregnancy. Many pregnant females, and even some healthcare professionals, dread using antiemetic drugs due to a false beliefof their teratogenicrisk. Aim of the work:This study aimed to evaluate ondansetron to a combination of doxylamine and pyridoxine in controlling pregnancy-related nausea and vomiting. Patients and Methods:This randomized controlled trial included 156 pregnant women, at 16 weeks of gestation, with mild-to-moderate nausea and vomiting. Meanwhile, women with severe symptoms indicating admission, those already on anti-emetics, and those who wouldn’t be able to show up for follow-up visits were excluded. Seventy-eight patients received intravenous injection of ondansetron [Zofran] at a dose of 8 mg once daily for 5 days, whereas the other 78 patients received oral pyridoxine at a dose of 25 mg plus doxylamine at a dose of 12.5 mg [Diclegis] twice daily for 5 days. Each patient was subjected to full history taking, complete clinical examination and investigations. Results: Women on Ondansetron reported better alleviation of nausea compared to those receiving pyridoxine and doxylamine [96.2% vs. 52.6%, P

Abstract Background The GM2 gangliosidoses (GM2), Tay-Sachs and Sandhoff diseases, are rare, autosomal recessive genetic disorders caused by mutations in the lysosomal enzyme β-hexosaminidase A (HEXA) or β-hexosaminidase B (HEXB) genes, respectively. A minority of patients have a late-onset form of disease that presents from late-childhood to adulthood and has a slowly progressive course with prolonged survival. Little research has been published documenting patient experiences with late-onset Tay-Sachs and Sandhoff diseases and how the disease impacts their daily lives and functioning. This study explored the most frequent symptoms and functional impacts experienced by patients with late-onset GM2 gangliosidosis through interviews with patients and caregivers. Methods A qualitative research study design was employed, using three focus groups and 18 one-on-one interviews with patients who were recruited at the National Tay-Sachs and Allied Diseases Annual Family Conference. Transcripts were generated from the discussions, and patient quotes were analyzed using a content analysis approach. Concepts were aggregated into symptom and functional impacts, and the frequency of mention in the focus groups and individual interviews was calculated. Key findings Many of the frequently described symptoms [muscle weakness (n = 19, 95%), “clumsy” gait (n = 12, 60%), fatigue (n = 10, 50%)] and impacts [difficulty walking (n = 19, 95%), falling (n = 17, 85%), and climbing stairs (n = 16, 80%)] disclosed by patients and caregivers were similar to those previously reported in the literature. However, less frequently described symptoms such as gastrointestinal issues (n = 4, 20%) and coughing fits (n = 5, 25%) have been expanded upon. This study evaluated the immediate impact of these symptoms on the patients’ lives to highlight the burden of these symptoms and the functional limitations on daily living activities, independence, and emotional well-being. The findings were used to develop a conceptual disease model that could serve as a foundation for patient-centered outcomes in clinical trials and provide insights to the medical community that may benefit patient care. Conclusions This study contributes to the current understanding of symptoms associated with late-onset GM2 gangliosidosis, and further identifies the many consequences and impacts of the disease. These symptoms and impacts could be measured in clinical trials to examine the effects of novel treatments from the patient perspective.

Gymnema sylvestre (GS) is a perennial woody vine native to tropical Asia, China, the Arabian Peninsula, Africa and Australia. GS has been used as a medicinal plant with potential anti-microbial, anti-inflammatory and anti-oxidant properties. This study was conceptualized to evaluate the cytotoxicity potential of Gymnema sylvestre saponin rich fraction (GSSRF) on breast cancer cell lines (MCF-7 and MDA-MB-468) by SRB assay. The anti-tumor activity of GSSRF was assessed in tumor-bearing Elrich ascites carcinoma (EAC) and Dalton’s lymphoma ascites (DLA) mouse models. The anti-oxidant potential of GSSRF was assessed by DPPH radical scavenging assay. The acute toxicity of GSSRF was carried out according to OECD guideline 425. The yield of GSSRF was around 1.4% and the presence of saponin content in GSSRF was confirmed by qualitative and Fourier transform infrared spectroscopic (FTIR) analysis. The in vitro cytotoxic effects of GSSRF on breast cancer cell lines were promising and found to be dose-dependent. An acute toxicity study of GSSRF was found to be safe at 2000 mg/kg body weight. GSSRF treatment has shown a significant increase in the body weight and the life span of EAC-bearing mice in a dose-dependent manner when compared with the control group. In the solid tumor model, the doses of 100 and 200 mg/kg body weight per day have shown about 46.70% and 60.80% reduction in tumor weight and controlled the tumor weight until the 30th day when compared with the control group. The activity of GSSRF in both models was similar to the cisplatin, a standard anticancer agent used in the study. Together, these results open the door for detailed investigations of anti-tumor potentials of GSSRF in specific tumor models, mechanistic studies and clinical trials leading to promising novel therapeutics for cancer therapy.

Background: Fabry disease (FD) is a rare, genetic disease, that if untreated, progresses to irreversible and life-threatening renal, cardiac, and cerebrovascular events. FD symptoms impact daily functioning and quality of life, but no disease-specific measure of these symptoms has been psychometrically tested. Methods: The Fabry Disease Patient-Reported Outcome (FD-PRO) consists of 19 items that measure neuropathic symptoms (pain, tingling, numbness and burning in upper/lower extremities), headache, abdominal pain, heat intolerance, swelling, tinnitus, fatigue, hearing/vision impairment, hypohidrosis (diminished sweating) and difficulty engaging in regular physical activities in the past 24 h. Measurement properties of the instrument were evaluated among 139 adult (≥ 18 years) FD diagnosed patients (enzyme deficiency in males; GLA genotyping in females) including enzyme replacement (ERT) treated or treatment-naïve patients, classic or late-onset phenotypes from ten countries and eighteen sites. Patients completed the FD-PRO daily on a handheld electronic diary for 4 weeks; demographic, other patient and clinician reported outcomes were also collected. Results: The mean age of patients was 43 years; with even sex distribution (female: 53%) and majority was ERT treated (72%). Patient compliance was high; ≥ 87% completed at least 4 FD-PRO entries each week (mean completion time: < 3 min in week one). Empirical evaluation of item properties via inter-item correlations, exploratory factor analysis and item-response theory models suggested that a total symptom score (TSS) could be calculated. Due to redundancy among items, a “neuropathy parcel” and an “audiovisual parcel” were created in generating the TSS (items within a parcel averaged and treated as a single item). Two items were excluded from TSS: sweating (did not correlate with other items) and difficulty engaging in regular physical activities (measure of impact, not symptoms). Internal consistency (Cronbach's alpha) of the TSS was ≥0.89 across weeks; test-retest reliability (intraclass correlation coefficient) was ≥0.91. The TSS was correlated with conceptually similar clinical and patient reported assessments as expected (r > |0.4|) and discriminated moderate/severe from least severe FD groups in known-groups validity analyses. Conclusions: The FD-PRO instrument is a novel disease-specific instrument that assesses classic and non-classic symptoms, with strong psychometric properties and appropriate for use in clinical studies.

Abstract Background In order to set research priorities for reproductive health in the occupied Palestinian territory, it is vital to know what current research has been done in the field of reproductive health. The purpose of this scoping review is to examine the range and nature of reproductive health research in the occupied Palestinian territory and to identify research gaps in the existing literature. Methods We searched four databases: EMBASE, PubMed, CINAHL, and Popline. We included studies that: (i) are published (with an abstract); (ii) relevant to reproductive health; (iii) Palestinians living in Palestine; (iv) participants over the age of 15 years; and (v) restricted to human research. Three independent reviewers screened title and abstracts, and extracted data from included articles. We conducted quantitative and qualitative analyses. Results Of 1025 titles and abstracts screened, 145 articles were included. 52 (36%) articles were conducted in community setting and 34 (24%) were conducted in hospitals. There were 5 (3%) experimental studies. 15 articles had more than one main theme; 160 subthemes overall were identified. The most frequently studied theme was labor and delivery (n = 19; 12%). One article discussed adolescent reproductive health and menopause while no articles discussed men’s reproductive health. Conclusions 91% of the research conducted is observational. The focus of reproductive health research was to understand the topic, community and providers’ perceptions and knowledge. Articles related to the quality of services were limited. It is also important to research the reproductive health of women outside of reproductive age, men, and adolescents.

The association of COVID-19 with neurological complications is a well-known fact, and researchers are endeavoring to investigate the mechanistic perspectives behind it. SARS-CoV-2 can bind to Toll-like receptor 4 (TLR-4) that would eventually lead to α-synuclein aggregation in neurons and stimulation of neurodegeneration pathways. Olive leaves have been reported as a promising phytotherapy or co-therapy against COVID-19, and oleuropein is one of the major active components of olive leaves. In the current study, oleuropein was investigated against SARS-CoV-2 target (main protease 3CLpro), TLR-4 and Prolyl Oligopeptidases (POP), to explore oleuropein potency against the neurological complications associated with COVID-19. Docking experiments, docking validation, interaction analysis, and molecular dynamic simulation analysis were performed to provide insight into the binding pattern of oleuropein with the three target proteins. Interaction analysis revealed strong bonding between oleuropein and the active site amino acid residues of the target proteins. Results were further compared with positive control lopinavir (3CLpro), resatorvid (TLR-4), and berberine (POP). Moreover, molecular dynamic simulation was performed using YASARA structure tool, and AMBER14 force field was applied to examine an 100 ns trajectory run. For each target protein-oleuropein complex, RMSD, RoG, and total potential energy were estimated, and 400 snapshots were obtained after each 250 ps. Docking analyses showed binding energy as −7.8, −8.3, and −8.5 kcal/mol for oleuropein-3CLpro, oleuropein-TLR4, and oleuropein-POP interactions, respectively. Importantly, target protein-oleuropein complexes were stable during the 100 ns simulation run. However, an experimental in vitro study of the binding of oleuropein to the purified targets would be necessary to confirm the present study outcomes.

Abstract Background This study aimed to obtain UK societal-based utility values for health states related to treatment mode of administration using Gaucher disease as the background condition. Methods A review of relevant literature and expert clinical input informed the development of five health states characterising the impact of Gaucher disease and its management on patients’ lives. A base-state characterising the “controlled disease” was developed as well as four subsequent health states which varied in description of the method (intravenous versus oral) and frequency of treatment administration. Health state utilities were obtained using the time trade-off (TTO) method via face-to-face interviews with 100 members from the UK general population. Before the valuation exercise, participants provided informed consent, completed a demographic form and the EQ-5D, and ranked the health states from best to worst on a 0–100 visual analogue scale (VAS). Results Mean age of the participants (n = 100) was 35 years and 66% were female. Participants reported high EQ-5D VAS (86.1) and index scores (0.95) indicating very good health status. The “controlled disease” state had the highest mean TTO-derived utility value (0.89). There was only a marginal reduction in utility for the generic state for “Oral treatment” (0.85), while the reduction was more pronounced for the generic state for “Intravenous treatment” (0.73). Conclusions The findings suggest that the avoidance of the need for intravenous treatment administration is associated with a notable positive increase in health-related quality of life. Patient benefit arising from less invasive treatment could be an important consideration when undertaking economic evaluation of future therapies for Gaucher disease.

Abstract Background The Disease Severity Scoring System (DS3) is a validated measure for evaluating Gaucher disease type 1 (GD1) severity. We developed a new framework, consisting of health states, transition probabilities between those states, and preferences for those states (utilities) based on the DS3 to predict long-term outcomes of patients starting treatment. We defined nine mutually exclusive (alive) health states based on three DS3 categories: mild (0 ≤ DS3 ≤ 3.5) without symptoms of bone disease; mild with bone pain, mild with severe skeletal complications (SSC) defined as lytic lesions, avascular necrosis, or fracture; moderate (3.5

Abstract—Social justice, broadly defined as providing equal access to liberties, rights, and opportunities especially for the least advantaged members of society, is a priority of several governments in the Middle East and North Africa (MENA) post−Arab Spring as well as globally. Achieving social justice in the field of health care is consistent with the principles of universal health coverage and is an important means to achieve this aim. To translate this abstract concept into concrete action, we propose a novel diagnostic method and then apply it to the case of Egypt, a country with a stated goal of achieving social justice in health care. This allows us to assess progress and then suggest targeted recommendations through which to improve social justice in health care. Through a comprehensive analysis of primary and secondary qualitative and quantitative data sources, we first identify six disadvantaged groups in Egypt and then analyze the status of these groups with respect to the three objectives of a health system—improving health outcomes, financial protection, and public satisfaction. Our results suggest that Egypt faces 11 challenges to achieving social justice in health care that can be addressed through 14 short- and medium-term recommendations drawn from global evidence of what works. Implementing these health system changes can help advance social justice in health care in Egypt.

Objective: To compare three-dimensional ultrasound (3D US) examination of the uterus to office hysteroscopy as a method of diagnosing cause of pain and bleeding associated with intrauterine contraceptive device (IUCD). Design: Prospective comparative study. Patients and methods: Ninety patients with a copper IUCD inserted complaining of pain, bleeding or both, underwent 3D US examination of the uterus and adnexa. The coronal view of the three orthogonal planes of the 3D volume was used to assess site and position of the IUCD. Other abnormalities such as fibroids, adenomyosis and ovarian cysts were recorded as well. This was followed by office hysteroscopy, after control of any bleeding or infection. Results: By 3D US; 15 IUCDs (16.6%) were found displaced; 2 laterally displaced, 13 displaced downward, sensitivity, specificity, NPV, PPV and accuracy of 3D US in diagnosing displaced IUCD compared to hysteroscopy were 93.3%, 84%, 63.6%, 97.7%, and 86.2%. Additional findings detected by hysteroscopy; 2 embedded IUCDS, one missed polyp one missed intrauterine synechiae, one polypoid endometrium revealed endometrial hyperplasia. Seventeen patients (18%) had abnormalities of the ovaries and adnexa confirmed by ultrasound; 13 functional cysts, one endometrioma, one dermoid cyst, one case with polycystic ovaries and one hydrosalpinx. Conclusions: Patients with abnormal bleeding and pain with IUCD have frequent abnormally positioned IUCD and associated ovarian pathology. 3D US has high diagnostic accuracy and should be the first line of investigation. Office hysteroscopy should be performed only in suspected embedded IUCD or other endometrial abnormality.