Clinically relevant enhancement of human sperm motility using compounds with reported phosphodiesterase inhibitor activity

STUDY QUESTION: Can we identify compound(s) with reported phosphodiesterase inhibitor (PDEI) activity that could be added to human spermatozoa in vitro to enhance their motility without compromising other sperm functions? SUMMARY ANSWER: We have identified several compounds that produce robust and effective stimulation of sperm motility and, importantly, have a positive response on patient samples. WHAT IS KNOWN ALREADY: For >20 years, the use of non-selective PDEIs, such as pentoxifylline, has been known to influence the motility of human spermatozoa; however, conflicting results have been obtained. It is now clear that human sperm express several different phosphodiesterases and these are compartmentalized at different regions of the cells. By using type-specific PDEIs, differential modulation of sperm motility may be achieved without adversely affecting other functions such as the acrosome reaction (AR). STUDY DESIGN, SIZE, DURATION: This was a basic medical research study examining sperm samples from normozoospermic donors and subfertile patients attending the Assisted Conception Unit (ACU), Ninewells Hospital Dundee for diagnostic semen analysis, IVF and ICSI. Phase 1 screened 43 commercially available compounds with reported PDEI activity to identify lead compounds that stimulate sperm motility. Samples were exposed (20 min) to three concentrations (1, 10 and 100 µM) of compound, and selected candidates (n = 6) progressed to Phase 2, which provided a more comprehensive assessment using a battery of in vitro sperm function tests.  PARTICIPANTS/MATERIALS, SETTING, METHODS: All healthy donors and subfertile patients were recruited at the Medical Research Institute, University of Dundee and ACU, Ninewells Hospital Dundee (ethical approval 08/S1402/6). In Phase 1, poor motility cells recovered from the 40% interface of the discontinuous density gradient were used as surrogates for patient samples. Pooled samples from three to four different donors were utilized in order to reduce variability and increase the number of cells available for simultaneous examination of multiple compounds. During Phase 2 testing, semen samples from 23 patients attending for either routine diagnostic andrology assessment or IVF/ICSI were prepared and exposed to selected compounds. Additionally, 48 aliquots of prepared samples, surplus to clinical use, were examined from IVF (n = 32) and ICSI (n = 16) patients to further determine the effects of selected compounds under clinical conditions of treatment. Effects of compounds on sperm motility were assessed by computer-assisted sperm analysis. A modified Kremer test using methyl cellulose was used to assess sperm functional ability to penetrate into viscous media. Sperm acrosome integrity and induction of apoptosis were assessed using the acrosomal content marker PSA-FITC and annexin V kit, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: In Phase 1, six compounds were found to have a strong effect on poor motility samples with a magnitude of response of ≥60% increase in percentage total motility. Under capacitating and non-capacitating conditions, these compounds significantly (P ≤ 0.05) increased the percentage of total and progressive motility. Furthermore, these compounds enhanced penetration into a cervical mucus substitute (P ≤ 0.05). Finally, the AR was not significantly induced and these compounds did not significantly increase the externalization of phosphatidylserine (P = 0.6, respectively). In general, the six compounds maintained the stimulation of motility over long periods of time (180 min) and their effects were still observed after their removal. In examinations of clinical samples, there was a general observation of a more significant stimulation of sperm motility in samples with lower baseline motility. In ICSI samples, compounds #26, #37 and #38 were the most effective at significantly increasing total motility (88, 81 and 79% of samples, respectively) and progressive motility (94, 93 and 81% of samples, respectively). In conclusion, using a two-phased drug discovery screening approach including the examination of clinical samples, 3/43 compounds were identified as promising candidates for further study. LIMITATIONS, REASONS FOR CAUTION: This is an in vitro study and caution must be taken when extrapolating the results. Data for patients were from one assessment and thus the robustness of responses needs to be established. The n values for ICSI samples were relatively small. WIDER IMPLICATIONS OF THE FINDINGS: We have systematically screened and identified several compounds that have robust and effective stimulation (i.e. functional significance with longevity and no toxicity) of total and progressive motility under clinical conditions of treatment. These compounds could be clinical candidates with possibilities in terms of assisted reproductive technology options for current or future patients affected by asthenozoospermia or oligoasthenozoospermia

Association between proton pump inhibitor therapy and clostridium difficile infection: a contemporary systematic review and meta-analysis.

Abstract Introduction Emerging epidemiological evidence suggests that proton pump inhibitor (PPI) acid-suppression therapy is associated with an increased risk of Clostridium difficile infection (CDI). Methods Ovid MEDLINE, EMBASE, ISI Web of Science, and Scopus were searched from 1990 to January 2012 for analytical studies that reported an adjusted effect estimate of the association between PPI use and CDI. We performed random-effect meta-analyses. We used the GRADE framework to interpret the findings. Results We identified 47 eligible citations (37 case-control and 14 cohort studies) with corresponding 51 effect estimates. The pooled OR was 1.65, 95% CI (1.47, 1.85), I2 = 89.9%, with evidence of publication bias suggested by a contour funnel plot. A novel regression based method was used to adjust for publication bias and resulted in an adjusted pooled OR of 1.51 (95% CI, 1.26–1.83). In a speculative analysis that assumes that this association is based on causality, and based on published baseline CDI incidence, the risk of CDI would be very low in the general population taking PPIs with an estimated NNH of 3925 at 1 year. Conclusions In this rigorously conducted systemic review and meta-analysis, we found very low quality evidence (GRADE class) for an association between PPI use and CDI that does not support a cause-effect relationship

Specific loss of CatSper function is sufficient to compromise fertilizing capacity of human spermatozoa

STUDY QUESTION Are significant abnormalities of CatSper function present in IVF patients with normal sperm concentration and motility and if so what is their functional significance for fertilization success?SUMMARY ANSWER Sperm with a near absence of CatSper current failed to respond to activation of CatSper by progesterone and there was fertilization failure at IVF.WHAT IS KNOWN ALREADY In human spermatozoa, Ca2+ influx induced by progesterone is mediated by CatSper, a sperm-specific Ca2+ channel. A suboptimal Ca2+ influx is significantly associated with, and more prevalent in, men with abnormal semen parameters, and is associated with reduced fertilizing capacity. However, abnormalities in CatSper current can only be assessed directly using electrophysiology. There is only one report of a CatSper-deficient man who showed no progesterone potentiated CatSper current. A CatSper 2 genetic abnormality was present but there was no information on the [Ca2+]i response to CatSper activation by progesterone. Additionally, the semen samples had indicating significant abnormalities (oligoasthenoteratozoospermia) multiple suboptimal functional responses in the spermatozoon. As such it cannot be concluded that impaired CatSper function alone causes infertility or that CatSper blockade is a potential safe target for contraception.STUDY DESIGN, SIZE, DURATION Spermatozoa were obtained from donors and subfertile IVF patients attending a hospital assisted reproductive techniques clinic between January 2013 and December 2014. In total 134 IVF patients, 28 normozoospermic donors and 10 patients recalled due to a history of failed/low fertilization at IVF took part in the study.PARTICIPANTS/MATERIALS, SETTING, METHODS Samples were primarily screened using the Ca2+ influx induced by progesterone and, if cell number was sufficient, samples were also assessed by hyperactivation and penetration into viscous media. A defective Ca2+ response to progesterone was defined using the 99% confidence interval from the distribution of response amplitudes in normozoospermic donors. Samples showing a defective Ca2+ response were further examined in order to characterize the potential CatSper abnormalities. In men where there was a consistent and robust failure of calcium signalling, a direct assessment of CatSper function was performed using electrophysiology (patch clamping), and a blood sample was obtained for genetic analysis.MAIN RESULTS AND THE ROLE OF CHANCE A total of 101/102 (99%) IVF patients and 22/23 (96%) donors exhibited a normal Ca2+ response. The mean (±SD) normalized peak response did not differ between donors and IVF patients (2.57 ± 0.68 [n = 34 ejaculates from 23 different donors] versus 2.66 ± 0.68 [n = 102 IVF patients], P = 0.63). In recall patients, 9/10 (90%) showed a normal Ca2+ response. Three men were initially identified with a defective Ca2+ influx. However, only one (Patient 1) had a defective response in repeat semen samples. Electrophysiology experiments on sperm from Patient 1 showed a near absence of CatSper current and exon screening demonstrated no mutations in the coding regions of the CatSper complex. There was no increase in penetration of viscous media when the spermatozoa were stimulated with progesterone and importantly there was failed fertilization at IVF.LIMITATIONS, REASONS FOR CAUTION A key limitation relates to working with a specific functional parameter (Ca2+ influx induced by progesterone) in fresh sperm samples from donors and patients that have limited viability. Therefore, for practical, technical and logistical reasons, some men (∼22% of IVF patients) could not be screened. As such the incidence of significant Ca2+ abnormalities induced by progesterone may be higher than the ∼1% observed here. Additionally, we used a strict definition of a defective Ca2+ influx such that only substantial abnormalities were selected for further study. Furthermore, electrophysiology was only performed on one patient with a robust and repeatable defective calcium response. This man had negligible CatSper current but more subtle abnormalities (e.g. currents present but significantly smaller) may have been present in men with either normal or below normal Ca2+ influx.WIDER IMPLICATIONS OF THE FINDINGS These data add significantly to the understanding of the role of CatSper in human sperm function and its impact on male fertility. Remarkably, these findings provide the first direct evidence that CatSper is a suitable and specific target for human male contraception

Measurement of healthcare quality : a mixed-methods comparative study of accredited and non-accredited hospitals in Saudi Arabia

Saudi Arabia was one of the first countries in the middle east to adopt an accreditation programme in its healthcare sector in forming the Central Board of Accreditation for Healthcare Institutions (CBAHI) in 2005. Even though accreditation has implied positive effects on quality of healthcare, as addressed in the literature, the literature search revealed a dearth of published studies concerned with the relationship between accreditation and improved quality of healthcare in Saudi Arabia. The main aim of this research was to examine any potential differences in the quality of care provided by accredited and non-accredited Ministry of Health hospitals in Saudi Arabia. A mixed-method approach was adopted with the intention of gathering both quantitative and qualitative data to answer the research objectives. Quantitative data was collected through extraction from the reports on quality of care indicators provided by the participating Ministry of Health hospitals. Qualitative data incorporated social and behavioural thinking regarding the quality of accredited and non-accredited hospitals. Qualitative data was collected through semi-structured interviews with senior hospital management of a selection of Ministry of Health hospitals. A total of 88 MoH hospitals provided data, of which 46 were accredited and 42 were non-accredited. When quality of care indicators were compared between accredited and non-accredited hospitals, a significant difference was found in 12 separate quality of care indicators. The significant difference was that, the indicators in the accredited hospitals had a higher score, which showed that the quality of care in non-accredited hospitals was better. Three themes emerged from the interview data: knowledge, practice, and attitude, with findings showing a similarity of perspective towards quality from both accredited and non-accredited hospital staff. Non-accredited hospital staff had a different attitude towards quality than accredited hospital staff. Conclusion: This study clearly demonstrated the superiority of non-accredited hospitals in the overall results of the indicators under study. Moreover, the behaviour and attitude of the employee demonstrate that some of the hospitals members are not able to strike a balance between their basic duties as healthcare practitioners and their participation in quality initiatives

The morphometric anatomy and clinical importance of the radial artery

Background: The radial forearm flap (RFF), including the radial artery and venous components, is used for hand reconstruction surgery. Updating the knowledge of the vascular anatomy in the forearm and associated flaps, such as the RFF, is useful in bringing innovations into reconstructive surgery. This study aimed to describe the morphometric anatomy of the radial artery (RA) and the associated RFF in human cadavers. Materials and methods: A total of 16 forearms from 8 human cadavers were dissected. The group consisted of 5 men and 3 women with a mean age at death of 59.05 ± 14.06 years. The inclusion criteria consisted of no history of trauma or surgery; thus, only apparently normal cadavers were included. The measurement of the following parameters was performed on these human cadavers: the mean diameter of the RA, the length of the RA, the average diameter of the cephalic vein, the length of the pedicle of the flap, and the average area of the radial forearm flap. Results: In males, the mean diameter of the radial artery at the wrist was 2.58 ± 1.1 mm. In females, the mean diameter of the radial artery was 2.60 ± 0.99 mm, and the mean length of the radial artery was 20.55 ± 1.7 cm. The average diameter of the cephalic vein was 1.8 ± 0.8 mm. The length of the pedicle of the flap was 8.88 ± 1.6 cm. The average area of the radial forearm flap was 5 X 7 cm2. Conclusions: This study demonstrates the morphometric anatomy of the RA and lateral forearm radial artery flaps in human cadavers, which could be useful in improving the success rate during transradial coronary interventions and performing complex hand injuries

Meningococcal vaccination and travel health in Hajj pilgrims – A study of pilgrims to Mecca, Saudi Arabia

Background: Hajj brings millions of pilgrims from different countries into a confined place. A number of outbreaks of meningococcal disease have been reported after the Hajj. All pilgrims are required to receive a quadrivalent meningococcal vaccine at least 10 days before the Hajj. They are also advised to follow travel health advice to reduce the risk of acquiring infections. We conducted a study to investigate the association between time of meningococcal vaccination and carriage of Neisseria meningitidis pathogenic serogroups A, C, W, and Y. Patterns of health problems encountered by pilgrims and preventive measures adopted during the Hajj were also investigated. Methods: A cross-sectional oropharyngeal carriage survey was conducted in 2973 Hajj pilgrims in 2017. A two stage sampling method was used to select departing flights. An electronic data collection tool (‘Open Data Kit’ (ODK)), was used to gather demographic, health and exposure data through questionnaires. Real-time polymerase chain reaction (rt-PCR) was used to identify N. meningitidis and serogroups. Results: The overall prevalence of N. meningitidis carriage was 4·6%. Meningococcal carriage of pathogenic serogroups A, C, W, and Y was not significantly associated with time of vaccination. A total 22·58 % were likely unvaccinated against meningococcal disease. 38.7% reported symptoms of upper respiratory tract infections and 5.4% of travel 4 diarrhoea. Compliance with facemask use was 50.2%. Changing facemask every 4 hours was found to be a significant protective factor for URTI’s. No significant association was found between having a chronic disease and seeking pre-travel advice. Conclusion: Whilst this study did not find any association between timing of meningococcal vaccination and carriage of N. meningitidis, it did highlight the issue of unvaccinated pilgrims and a need to strengthen compliance with the current vaccination policy. Early pre-travel health advice should continue to be enforced

The association between histamine 2 receptor antagonist use and Clostridium difficile infection: a systematic review and meta-analysis.

Background Clostridium difficile infection (CDI) is a major health problem. Epidemiological evidence suggests that there is an association between acid suppression therapy and development of CDI. Purpose We sought to systematically review the literature that examined the association between histamine 2 receptor antagonists (H2RAs) and CDI. Data source We searched Medline, Current Contents, Embase, ISI Web of Science and Elsevier Scopus from 1990 to 2012 for all analytical studies that examined the association between H2RAs and CDI. Study selection Two authors independently reviewed the studies for eligibility. Data extraction Data about studies characteristics, adjusted effect estimates and quality were extracted. Data synthesis Thirty-five observations from 33 eligible studies that included 201834 participants were analyzed. Studies were performed in 6 countries and nine of them were multicenter. Most studies did not specify the type or duration of H2RAs therapy. The pooled effect estimate was 1.44, 95% CI (1.22–1.7), I2 = 70.5%. This association was consistent across different subgroups (by study design and country) and there was no evidence of publication bias. The pooled effect estimate for high quality studies was 1.39 (1.15–1.68), I2 = 72.3%. Meta-regression analysis of 10 study-level variables did not identify sources of heterogeneity. In a speculative analysis, the number needed to harm (NNH) with H2RAs at 14 days after hospital admission in patients receiving antibiotics or not was 58, 95% CI (37, 115) and 425, 95% CI (267, 848), respectively. For the general population, the NNH at 1 year was 4549, 95% CI (2860, 9097). Conclusion In this rigorous systematic review and meta-analysis, we observed an association between H2RAs and CDI. The absolute risk of CDI associated with H2RAs is highest in hospitalized patients receiving antibiotics

Outcomes of fixed partial dentures fabricated in AFHSR before 3 years

Objectives: This study was done to determine the length of service of FPDs delivered to the patients with specific clinical, radiographic, and laboratory procedures. Methods: A total of 110 patients were examined 65 of the participants were females and 45 males, with a total of 175 prostheses. Patient was selected randomly, all of them having a single crown or fixed partial dentures done at the Dental Specialty Centre King Fahad Armed forced hospital Khamis Mushait KSA, between 2016 and 2019. Patients were informed and written consents were obtained. Age, gender and the duration of prosthesis placement were being recorded. Clinical and radiographic analysis was done. Results: Out of 200 patients participated satisfying the criteria for inclusion in this study were identified. 110 responded positively with a total of 175 prostheses (91 single crowns, 84 FPDs). The male patients were 45 and the female patients were 65, with age ranging from 25 to 65 years. The most frequent failure was due to debonding in both types of prosthesis. Conclusion : Within the limitation of this study, secondary caries and debonding of the single crowns and FPDs were the most frequent complication

Awareness of the General population about Influenza Vaccine in Tabuk, Saudi Arabia

Objectives: Increasing national influenza vaccination rates continues to be a challenge for Saudi Arabia. Therefore, the purpose of this study was to explore the Saudi public perceptions toward seasonal influenza vaccination and their association with the rate of vaccination. Methods: This is a descriptive cross-sectional study. The study includes the general population in Tabuk, Northern Saudi Arabia. The study includes Saudi and none Saudi who speaks Arabic or English, from any age group (18-60 years), male or female, any level of education (from primary to university or more) and low, moderate or high socioeconomic level. Results: Regarding to gender, the study showed that the largest percentage of the study members are male with a percentage of (63.3 %), while there is a percentage of (36.6%) females. According to” Received influenza vaccine” there are (63.3%) of the respondents chose (Yes) and (36.6%) of the respondents chose (No). according to” Influenza vaccination is effective in preventing influenza infection” there are (53.3%) of the respondents chose (Yes), (26.66%) of the respondents chose (No) and (20%) chose (Don’t Know). Conclusion: The findings of this study suggest that the rate of seasonal influenza vaccination is moderate among the Saudi population, which necessitates the launching of public awareness campaigns about the importance of the seasonal influenza vaccine