Social determinants of health inequalities in early phase clinical trials in Northern England.

BACKGROUND: Early phase clinical trials in Oncology represent a subspecialised area where UK patient selection is influenced by access to Experimental Cancer Medicine Centres (ECMCs). Equity of access with respect to social determinants of health (SDoH) were explored for two major ECMCs. METHODS: A retrospective cohort study including all referrals to Newcastle and Manchester ECMCs in 2021 was completed. Consent to screening or pre-screening was stratified against SDoH characteristics, including: Index of Multiple Deprivation (IMD) decile, ethnicity and distance to centre. RESULTS: 1243 patients were referred for trials. IMD quintile 1 (most deprived) patients had reduced likelihood of referral compared to expected population models (OR, 0.67; 95% CI: 0.55 to 0.80, p = <0.0001). IMD quintile 5 (least deprived) had increased likelihood of referral (OR, 1.46; 95% CI: 1.17 to 1.82, p = 0.0007). Living beyond median distance from Manchester reduced the likelihood of consenting to trials (OR, 0.72; 95% CI: 0.55 to 0.94, p = 0.015). Ethnicity data represented a White British propensity. CONCLUSIONS: Inequalities in socioeconomic and geographic factors influence referral and enrolment to early phase clinical trials in Northern England. This has implications for equity of access and generalisability of trial results internationally and warrants further study.

Study protocol: a pragmatic, cluster-randomized controlled trial to evaluate the effect of implementation of the Truenat platform/MTB assays at primary health care clinics in Mozambique and Tanzania (TB-CAPT CORE).

BACKGROUND: In 2020, the WHO-approved Molbio Truenat platform and MTB assays to detect Mycobacterium tuberculosis complex (MTB) and resistance to rifampicin directly on sputum specimens. This primary health care center-based trial in Mozambique and Tanzania investigates the effect of Truenat platform/MTB assays (intervention arm) combined with rapid communication of results compared to standard of care on TB diagnosis and treatment initiation for microbiologically confirmed TB at 7 days from enrolment. METHODS: The Tuberculosis Close the Gap, Increase Access, and Provide Adequate Therapy (TB-CAPT) CORE trial employs a pragmatic cluster randomized controlled design to evaluate the impact of a streamlined strategy for delivery of Truenat platform/MTB assays testing at primary health centers. Twenty-nine centers equipped with TB microscopy units were selected to participate in the trial. Among them, fifteen health centers were randomized to the intervention arm (which involves onsite molecular testing using Truenat platform/MTB assays, process process optimization to enable same-day TB diagnosis and treatment initiation, and feedback on Molbio platform performance) or the control arm (which follows routine care, including on-site sputum smear microscopy and the referral of sputum samples to off-site Xpert testing sites). The primary outcome of the study is the absolute number and proportion of participants with TB microbiological confirmation starting TB treatment within 7 days of their first visit. Secondary outcomes include time to bacteriological confirmation, health outcomes up to 60 days from first visit, as well as user preferences, direct cost, and productivity analyses. ETHICS AND DISSEMINATION: TB-CAPT CORE trial has been approved by regulatory and ethical committees in Mozambique and Tanzania, as well as by each partner organization. Consent is informed and voluntary, and confidentiality of participants is maintained throughout. Study findings will be presented at scientific conferences and published in peer-reviewed international journals. TRIAL REGISTRATION: US National Institutes of Health's ClinicalTrials.gov, NCT04568954. Registered 23 September 2020.

Tests of Lepton Universality Using B

Tests of lepton universality in B^{0}→K_{S}^{0}ℓ^{+}ℓ^{-} and B^{+}→K^{*+}ℓ^{+}ℓ^{-} decays where ℓ is either an electron or a muon are presented. The differential branching fractions of B^{0}→K_{S}^{0}e^{+}e^{-} and B^{+}→K^{*+}e^{+}e^{-} decays are measured in intervals of the dilepton invariant mass squared. The measurements are performed using proton-proton collision data recorded by the LHCb experiment, corresponding to an integrated luminosity of 9 fb^{-1} . The results are consistent with the standard model and previous tests of lepton universality in related decay modes. The first observation of B^{0}→K_{S}^{0}e^{+}e^{-} and B^{+}→K^{*+}e^{+}e^{-} decays is reported.

Observation of the Decay Λ_{b}

The first observation of the semileptonic b-baryon decay Λ_{b}^{0}→Λ_{c}^{+}τ^{-}ν[over ¯]_{τ}, with a significance of 6.1σ, is reported using a data sample corresponding to 3 fb^{-1} of integrated luminosity, collected by the LHCb experiment at center-of-mass energies of 7 and 8 TeV at the LHC. The τ^{-} lepton is reconstructed in the hadronic decay to three charged pions. The ratio K=B(Λ_{b}^{0}→Λ_{c}^{+}τ^{-}ν[over ¯]_{τ})/B(Λ_{b}^{0}→Λ_{c}^{+}π^{-}π^{+}π^{-}) is measured to be 2.46±0.27±0.40, where the first uncertainty is statistical and the second systematic. The branching fraction B(Λ_{b}^{0}→Λ_{c}^{+}τ^{-}ν[over ¯]_{τ})=(1.50±0.16±0.25±0.23)% is obtained, where the third uncertainty is from the external branching fraction of the normalization channel Λ_{b}^{0}→Λ_{c}^{+}π^{-}π^{+}π^{-}. The ratio of semileptonic branching fractions R(Λ_{c}^{+})≡B(Λ_{b}^{0}→Λ_{c}^{+}τ^{-}ν[over ¯]_{τ})/B(Λ_{b}^{0}→Λ_{c}^{+}µ^{-}ν[over ¯]_{µ}) is derived to be 0.242±0.026±0.040±0.059, where the external branching fraction uncertainty from the channel Λ_{b}^{0}→Λ_{c}^{+}µ^{-}ν[over ¯]_{µ} contributes to the last term. This result is in agreement with the standard model prediction.

Study of Z Bosons Produced in Association with Charm in the Forward Region.

Events containing a Z boson and a charm jet are studied for the first time in the forward region of proton-proton collisions. The data sample used corresponds to an integrated luminosity of 6 fb^{-1} collected at a center-of-mass energy of 13 TeV with the LHCb detector. In events with a Z boson and a jet, the fraction of charm jets is determined in intervals of Z-boson rapidity in the range 2.0

Observation of Two New Excited Ξ_{b}

Two narrow resonant states are observed in the Λ_{b}^{0}K^{-}π^{+} mass spectrum using a data sample of proton-proton collisions at a center-of-mass energy of 13 TeV, collected by the LHCb experiment and corresponding to an integrated luminosity of 6 fb^{-1}. The minimal quark content of the Λ_{b}^{0}K^{-}π^{+} system indicates that these are excited Ξ_{b}^{0} baryons. The masses of the Ξ_{b}(6327)^{0} and Ξ_{b}(6333)^{0} states are m[Ξ_{b}(6327)^{0}]=6327.28_{-0.21}^{+0.23}±0.12±0.24 and m[Ξ_{b}(6333)^{0}]=6332.69_{-0.18}^{+0.17}±0.03±0.22 MeV, respectively, with a mass splitting of Δm=5.41_{-0.27}^{+0.26}±0.12 MeV, where the uncertainties are statistical, systematic, and due to the Λ_{b}^{0} mass measurement. The measured natural widths of these states are consistent with zero, with upper limits of Γ[Ξ_{b}(6327)^{0}]<2.20(2.56) and Γ[Ξ_{b}(6333)^{0}]<1.60(1.92) MeV at a 90% (95%) credibility level. The significance of the two-peak hypothesis is larger than nine (five) Gaussian standard deviations compared to the no-peak (one-peak) hypothesis. The masses, widths, and resonant structure of the new states are in good agreement with the expectations for a doublet of 1D Ξ_{b}^{0} resonances.

Evidence for a New Structure in the J/ψp and J/ψp[over ¯] Systems in B_{s}

An amplitude analysis of flavor-untagged B_{s}^{0}→J/ψpp[over ¯] decays is performed using a sample of 797±31 decays reconstructed with the LHCb detector. The data, collected in proton-proton collisions between 2011 and 2018, correspond to an integrated luminosity of 9 fb^{-1}. Evidence for a new structure in the J/ψp and J/ψp[over ¯] systems with a mass of 4337_{-4}^{+7} _{-2}^{+2} MeV and a width of 29_{-12}^{+26} _{-14}^{+14} MeV is found, where the first uncertainty is statistical and the second systematic, with a significance in the range of 3.1 to 3.7σ, depending on the assigned J^{P} hypothesis.

Correlations of milk and serum element concentrations with production and management traits in dairy cows.

The present study investigated the potential consequences, positive or negative, that selection for favorable production-related traits may have on concentrations of vitamin B12 and key chemical elements in dairy cow milk and serum and the possible impact on milk healthiness, and associated benefits, for the dairy product consumer. Milk and serum samples (950 and 755, respectively) were collected from Holstein-Friesian dairy cows (n = 479) on 19 occasions over a 59-mo period, generating 34,258 individual records, and analyzed for concentrations of key trace and quantity elements, heavy metals, and milk vitamin B12. These data were then matched to economically important production data (milk, fat, and protein yield) and management data (dry matter intake, liveweight, and body condition score). Multivariate animal models, including full pedigree information, were used to analyze data and investigate relationships between traits of interest. Results highlighted negative genetic correlations between many quantity and trace elements in both milk and serum with production and management traits. Milk yield was strongly negatively correlated with the milk quantity elements Mg and Ca (genetic correlation between traits, ra = -0.58 and -0.63, respectively) as well as the trace elements Mn, Fe, Ni, Cu, Zn, and Mo (ra = -0.32, -0.58, -0.52, -0.40, -0.34, and -0.96, respectively); and in serum, Mg, Ca, Co, Fe, and Zn (ra = -0.50, -0.36, -0.68, -0.54, and -0.90, respectively). Strong genetic correlations were noted between dry matter intake with V (ra = 0.97), Fe (ra = -0.69), Ni (ra = -0.81), and Zn (ra = -0.75), and in serum, strong negative genetic correlations were observed between dry matter intake with Ca and Se (ra = -0.95 and -0.88, respectively). Body condition score was negatively correlated with serum P, Cu, Se, and Pb (ra = -0.45, -0.35, -0.51, and -0.64, respectively) and positively correlated with Mn, Fe, and Zn (ra = 0.40, 0.71, and 0.55, respectively). Our results suggest that breeding strategies aimed at improving economically important production-related traits would most likely result in a negative impact on levels of beneficial nutrients within milk for human consumption (such as Mg, Ca, Fe, Zn, and Se).

Acylated Ghrelin Administration Inhibits Sleeve Gastrectomy-Induced Hippocampal Oxidative Stress, Apoptosis and Tau-Hyperphosphorylation by Activating the PI3K/Akt Pathway.

This study investigated the impact of exogenous replacement therapy with acylated ghrelin (AG) post sleeve gastrectomy (SG) on the memory function in rats. In addition, we investigated the possible underlying mechanisms, including the effects on markers of oxidative stress, tau phosphorylation, and apoptosis. Adult male Wistar rats were divided into four groups (N = 18/group) as follows: sham (control), SG, SG+AG (100 µM), and SG+AG+LY294002 (0.25 µg/100 g). We continued all treatments daily for four weeks post-surgery. SG impaired the spatial, retention, and recognition memories as tested by the Morris water maze test, passive avoidance test, and novel object recognition test, respectively. Also, it enhanced the levels of reactive oxygen species and lipid peroxides, reduced glutathione and protein levels of Bcl-2, and increased the levels of Bax and cleaved caspase-3 in the hippocampus. In addition, SG reduced the hippocampal levels of acetylcholine and brain-derived neurotrophic factor. Concomitantly, it inhibited the hippocampal activity of Akt and increased the activity of glycogen synthase kinase 3ß and tau protein phosphorylation. Exogenous administration of acylated ghrelin to rats that had undergone SG prevented memory deficits. Also, it prevented the alteration in the above-mentioned biochemical parameters, an effect that was abolished by co-administration of LY294002 (phosphoinositide 3-kinase inhibitor). In conclusion, AG replacement therapy after SG in rats protects them against memory deficits and hippocampal damage by suppressing tau protein phosphorylation, mediated by activating PI3K/Aktinduced inhibition of glycogen synthase kinase 3ß.

Incidence and determinants of catastrophic health expenditures and impoverishment in Pakistan.

OBJECTIVES: Out-of-pocket (OOP) payment is a major health financing mechanisms across developing nations such as Pakistan. Private health expenditures are estimated to be 64.4%, of which 89% are OOP made by the households (National Health Accounts, 2015-16). These high health care expenditures cause households to face financial burden resulting in poverty. This study aims to estimate the incidence and determinants of catastrophic health expenditures and impoverishment for Pakistan. STUDY DESIGN: Household-based cross-section study. METHODS: We used the data from the Household Integrated Economic Survey (2015-16 and 2018-19), carried out by the Pakistan Bureau of Statistics. The well known methodology developed by Wagstaff and Doorslaer was used in this study for estimating the incidence and impoverishment effect of catastrophic health spending. RESULTS: It is found that at 10% threshold (out of total consumption expenditures), catastrophic health payments are incurred by 4.51% and 13.15% of households for 2015-16 and 2018-19, respectively. Moreover, following the 40% threshold (out of non-food expenditures), this incidence is 0.45% and 4.57%. Poverty headcount was 23.28% and 18.43% gross of health payments in both the considered years, respectively, whereas it turns out to be 24.68% and 22.02% net of healthcare payments for the respective years, representing an increase in poverty headcounts of 1.4% and 3.59%. CONCLUSION: OOP health payments exert pressure on household's capacity to pay and push them into poverty. This article recommends that the burden of OOP expenditures borne by households should be reduced to prevent them from falling into poverty by initiating some strategies (health financing policy reforms in terms of financial protection) with political support.

The reaction of propylene to propylene-oxide on CeO2: An FTIR spectroscopy and temperature programmed desorption study.

The potential of CeO2 as an epoxidation catalyst is studied for the reaction of propylene with hydrogen peroxide (H2O2) by Fourier transform infrared (FTIR) spectroscopy and temperature programmed desorption (TPD). Adsorption and decomposition of H2O2 and propylene oxide (PO) are also explored to determine their surface chemistry and thermal stability. Hydrogen peroxide adsorbed dissociatively on CeO2 forming adsorbed peroxo (O-O) species, as observed through vibrational features at 890 cm-1 and (830-855) cm-1 (FTIR). The signal at 890 cm-1 disappeared when a pulse of propylene was passed through the catalyst, and at the same time, adsorbed PO was observed (a sharp IR mode at 827 cm-1; ring deformation). The reaction between gas phase propylene and adsorbed peroxide species suggested the Eley-Rideal type mechanism. The absence of a ring opening reaction of PO at room temperature may indicate that CeO2 can be a suitable oxide for epoxidation of hydrocarbons. PO started to decompose above 323 K, as observed from FTIR and TPD results. TPD spectra of PO show its desorption at 365 K, with a small fraction decomposing into acetaldehyde and formaldehyde due to partial decomposition, while CO2 and CO are released at higher temperatures. Adsorbed acetate, formate, and carbonate species, formed due to further reactions of aldehydes, are observed during the thermal reaction (FTIR).

Follicle growth and endocrine dynamics in women with spontaneous luteinized unruptured follicles versus ovulation.

STUDY QUESTION: Do growth patterns and endocrine profiles differ between ovulatory follicles (OvFs) and luteinized unruptured follicles (LUFs) in women? SUMMARY ANSWER: Growth rates, diameters and associated endocrine profiles differed between OvFs and LUFs in unstimulated cycles. WHAT IS KNOWN ALREADY: Two-three waves of antral follicles develop during the menstrual cycle in ovulatory women of reproductive age, with the second or third wave terminating in ovulation. In contrast, some women can develop LUFs, where a preovulatory follicle fails to rupture and there is subsequent luteinization of the follicle wall. However, no study has compared OvFs and LUFs in unstimulated cycles. STUDY DESIGN, SIZE, DURATION: This retrospective observational study was conducted in 56 healthy women of reproductive age (range: 19-41 years) and with a history of regular menstrual cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants who met inclusion criteria were enrolled, as previously reported. Daily transvaginal ultrasonography was performed for one interovulatory interval (IOI) to measure the diameters of all follicles >2 mm. Blood samples were collected every 3 days during the IOI to measure serum concentrations of FSH, LH, estradiol and progesterone. MAIN RESULTS AND THE ROLE OF CHANCE: The interval from emergence to deviation (i.e. follicle selection) was shorter (P < 0.05) for LUFs compared to OvFs. However, the intervals from emergence to maximum diameter and deviation to maximum diameter were longer (P < 0.05) for LUFs compared to OvFs. Follicle deviation in LUFs occurred at a larger diameter (P < 0.05) compared to OvFs, and LUFs grew to larger (P < 0.0001) diameters compared to OvFs. Moreover, LUFs grew faster (P < 0.05) from emergence to deviation and from deviation to maximum diameter, compared to OvFs. LUFs were associated with low (P < 0.05) systemic LH levels at emergence and maximum diameter compared to OvFs. LUFs were also associated with low (P < 0.05) systemic FSH and high (P < 0.05) systemic progesterone at deviation and maximum diameter, respectively. Estradiol was higher (P < 0.05) at deviation and lower (P < 0.05) at maximum diameter for LUFs compared to OvFs. LIMITATIONS, REASONS FOR CAUTION: A 3-day interval of blood sampling for hormonal analyses was conducted, as a more frequent sampling interval was not considered acceptable by the study volunteers. A 3-day sampling interval did not allow characterization of acute changes in hormone production during the IOI. In addition, study visits were less frequent when LUFs persisted long after the expected day of the second ovulation of the IOI. WIDER IMPLICATIONS OF THE FINDINGS: Information about the growth and endocrine dynamics of OvFs and LUFs developing in unstimulated cycles in women may be applied to the early detection of LUF-associated anovulatory infertility and clinical management of women with this condition. STUDY FUNDING/COMPETING INTEREST(S): No external funding sources were used for this study. The authors have no conflicts of interest in publishing this manuscript. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT01389141.

In vivo antral follicle wall biopsy: a new research technique to study ovarian function at the cellular and molecular levels.

BACKGROUND: In vivo studies involving molecular markers of the follicle wall associated with follicular fluid (FF) milieu are crucial for a better understanding of follicle dynamics. The inability to obtain in vivo samples of antral follicle wall (granulosa and theca cells) without jeopardizing ovarian function has restricted advancement in knowledge of folliculogenesis in several species. The purpose of this study in mares was to develop and validate a novel, minimally invasive in vivo technique for simultaneous collection of follicle wall biopsy (FWB) and FF samples, and repeated collection from the same individual, during different stages of antral follicle development. We hypothesized that the in vivo FWB technique provides samples that maintain the normal histological tissue structure of the follicle wall layers, offers sufficient material for various cellular and molecular techniques, and allows simultaneous retrieval of FF. METHODS: In Experiment 1 (ex vivo), each follicle was sampled using two techniques: biopsy forceps and scalpel blade (control). In Experiment 2 (in vivo), FWB and FF samples from 10-, 20-, and 30-mm follicles were repeatedly and simultaneously obtained through transvaginal ultrasound-guided technique. RESULTS: In Experiment 1, the thickness of granulosa, theca interna, and theca externa layers was not influenced (P > 0.05) by the harvesting techniques. In Experiment 2, the overall recovery rates of FWB and FF samples were 97 and 100%, respectively. However, the success rate of obtaining samples with all layers of the follicle wall and clear FF varied according to follicle size. The expression of luteinizing hormone receptor (LHR) was mostly confined in the theca interna layer, with the estradiol-related receptor alpha (ERRα) in the granulosa and theca interna layers. The 30-mm follicle group had greater (P < 0.05) LHR expression in the theca interna and ERRα in the granulosa layer compared to the other groups. The overall expression of LHR and ERRα, and the intrafollicular estradiol were higher (P < 0.05 - P < 0.0001) in the 30-mm follicle group. CONCLUSION: The in vivo technique developed in this study can be repeatedly and simultaneously used to provide sufficient FWB and FF samples for various cellular and molecular studies without jeopardizing the ovarian function, and has the potential to be translated to other species, including humans.

In vitro quality of apheresis platelets divided into paediatric-sized units and stored in PVC bags plasticised with TOTM, BTHC or DINCH.

BACKGROUND AND OBJECTIVES: Two of the predictive factors of the quality of small volumes of platelets suitable for paediatric use are bag size and material. This study evaluated the storage properties of paediatric platelet aliquots in TOTM-, BTHC- or DINCH-PVC bags. METHODS/MATERIALS: (i) Three apheresis platelet concentrates (PC) were pooled and split into three units. One was retained as an adult unit (control; polyolefin bag). The second and third units were split into four MacoPharma TOTM-PVC and BTHC-PVC paediatric bags, respectively. (ii) Two apheresis PC were pooled and split into two units. One PC was retained as an adult unit, and the other was split into four Fresenius DINCH-PVC paediatric bags. Testing was performed on storage for pH, blood gases, hypotonic shock response, soluble CD62P, LDH, glucose and lactate, ATP, CD62P, CD63, platelet-derived microparticles and annexin V. RESULTS: The volumes, platelet yields and pH of all paediatric units met local specifications. The TOTM-PVC bag showed no worse quality than the adult bag up to day 7 for all parameters studied, and it maintained pH higher than BTHC-PVC and DINCH-PVC over storage. The BTHC-PVC bag was shown to be the most gas permeable; however, it had the highest glucose consumption rates and the highest platelet activation. CONCLUSION: All bags showed an acceptable in vitro quality. Overall, the TOTM-PVC paediatric bag showed better platelet quality compared to the other storage bags, whereas storage in the BTHC-PVC bag resulted in poorer platelet quality.

Follicle vascularity coordinates corpus luteum blood flow and progesterone production.

Colour Doppler ultrasonography was used to compare the ability of preovulatory follicle (POF) blood flow and its dimensions to predict the size, blood flow and progesterone production capability of the subsequent corpus luteum (CL). Cows (n=30) were submitted to a synchronisation protocol. Follicles ≥7mm were measured and follicular wall blood flow evaluated every 12h for approximately 3.5 days until ovulation. After ovulation, cows were scanned daily for 8 days and similar parameters were evaluated for the CL. Blood samples were collected and plasma progesterone concentrations quantified. All parameters were positively correlated. Correlation values ranged from 0.26 to 0.74 on data normalised to ovulation and from 0.31 to 0.74 on data normalised to maximum values. Correlations between calculated ratios of both POF and CL in data normalised to ovulation and to maximum values ranged from moderate (0.57) to strong (0.87). Significant (P<0.0001) linear regression analyses were seen in all comparisons. In conclusion, higher correlations were observed between the dimensions of POF and/or CL and blood flow of both structures, as well as POF and/or CL blood flow with plasma progesterone concentrations of the resultant CL. These findings indicate that follicle vascularity coordinates CL blood flow and progesterone production in synchronised beef cows.

The effect of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry instrumentation parameters on the matrix-assisted laser desorption/ionization simulated size exclusion chromatography number-mass, average-weight and polydispersity values of dextran against corresponding values obtained by size exclusion chromatography.

The matrix-assisted laser desorption/ionization simulated size exclusion chromatography (SECPC) average-number mass, weight average and polydispersity of dextran 1000 were determined by matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) mass spectrometry. The instrument parameters were varied and the SECPC value determined via the Bruker XMASS software was compared to the value obtained from aqueous-phase size exclusion chromatography. The aqueous-phase size exclusion chromatography values for average-number mass, weight average and polydispersity were 1223 Da, 1500 Da and 1.23 (1010 Da, 1270 Da and 1.26 from manufacturer), whereas the SECPC value varied on the instrumental parameters. The factors that had the greatest effect on the average-number mass, weight average and polydispersity were: (most effect on SECPC value) laser attenuation > matrix-analyte molar concentration > matrix-analyte molar ratios > delay extraction time > solvent-system composition > detector delay (least effect on SECPC value). The oligosaccharide signal distribution as a function of laser attenuation indicate that two distinct regions exist in dextran 1000, where one corresponds to the higher mass oligosaccharides (hexasaccharide or greater), while another region corresponds to lower oligosaccharides (tetra-saccharide). This distribution depends upon the crystallization of the biopolymer and the efficiency of desorption/ionization, which yields the SECPC value. There was broad agreement between the SECPC values and size exclusion chromatography values for dextran, although the polydispersity indicated by SECPC was less than size exclusion chromatography (1.10 vs. 1.26). It can be shown that for narrow polydisperse biopolymers the instrumental conditions are less critical in the determination of average-number mass, weight average and polydispersity, although the SECPC Mn, and weight average values are often higher than the corresponding values obtained by aqueous-phase size exclusion chromatography.

NORMALIZATION OF SERUM VITAMIN D IMPROVES SEMEN MOTILITY PARAMETERS IN PATIENTS WITH IDIOPATHIC MALE INFERTILITY.

CONTEXT: Idiopathic male infertility is evident in half of infertile males. Vitamin D receptors are expressed throughout male reproductive tract, including spermatozoa, promoting motility. Epidemiological studies revealed the positive association between serum vitamin D and semen quality. However, there are no clinical studies examining the differential role of vitamin D in idiopathic male infertility. OBJECTIVES: 1) To investigate the association between vitamin D deficiency and idiopathic male infertility, and 2) To determine whether vitamin D deficient males would show restoration of semen quality parameters upon supplementation with vitamin D. DESIGN: This was a year-long case-control study from November 2015 to November 2016. A therapeutic intervention cohort for 2 months was also performed. SUBJECTS AND METHODS: 117 Jordanian males were enrolled. Following a clinical evaluation by a urologist, baseline serum vitamin D and semen fluid analyses were collected. Participants were stratified into 3 groups: controls (n=30), idiopathic infertility (n=67), and secondary infertility (n=20). Idiopathic infertility patients with low vitamin D (n= 45) were supplemented with oral vitamin D, 5000 IU, once daily for two months. Thereafter, serum vitamin D and semen fluid analyses were reassessed (n= 34; 11 patients were lost to follow up). RESULTS: Vitamin D was significantly lower in patients with idiopathic infertility than in both controls and men with secondary infertility. Significant improvement of progressive and total sperm motility was observed after vitamin D treatment. Vitamin D correlated significantly with semen quality in the study population. However, no correlation was found between vitamin D and any of the semen quality parameters in the idiopathic infertility group. CONCLUSIONS: Vitamin D supplementation improves sperm motility in idiopathic male infertility patients with low vitamin D. Larger and longer clinical trials are warranted to validate the use of vitamin D in these cases.

The mare as a model for luteinized unruptured follicle syndrome: intrafollicular endocrine milieu.

Luteinized unruptured follicle (LUF) syndrome is a recurrent anovulatory dysfunction that affects up to 23% of women with normal menstrual cycles and up to 73% with endometriosis. Mechanisms underlying the development of LUF syndrome in mares were studied to provide a potential model for human anovulation. The effect of extended increase in circulating LH achieved by administration of recombinant equine LH (reLH) or a short surge of LH and decrease in progesterone induced by prostaglandin F2α (PGF2α) on LUF formation (Experiment 1), identification of an optimal dose of COX-2 inhibitor (flunixin meglumine, FM; to block the effect of prostaglandins) for inducing LUFs (Experiment 2), and evaluation of intrafollicular endocrine milieu in LUFs (Experiment 3) were investigated. In Experiment 1, mares were treated with reLH from Day 7 to Day 15 (Day 0=ovulation), PGF2α on Day 7, or in combination. In Experiment 2, FM at doses of 2.0 or 3.0 mg/kg every 12 h and human chorionic gonadotropin (hCG) (1500 IU) were administered after a follicle ≥32 mm was detected. In Experiment 3, FM at a dose of 2.0 mg/kg every 12 h plus hCG was used to induce LUFs and investigate the intrafollicular endocrine milieu. No LUFs were induced by reLH or PGF2α treatment; however, LUFs were induced in 100% of mares using FM. Intrafollicular PGF2α metabolite, PGF2α, and PGE2 were lower and the ratio of PGE2:PGF2α was higher in the induced LUF group. Higher levels of intrafollicular E2 and total primary sex steroids were observed in the induced LUF group along with a tendency for higher levels of GH, cortisol, and T; however, LH, PRL, VEGF-A, and NO did not differ between groups. In conclusion, this study reveals part of the intrafollicular endocrine milieu and the association of prostaglandins in LUF formation, and indicates that the mare might be an appropriate model for studying the poorly understood LUF syndrome.

Thrombin generation and coagulation factor content of thawed plasma and platelet concentrates.

BACKGROUND: We assessed the haemostatic capacity of thawed plasma produced after ambient storage of whole blood for 24 h (RTFP24), and the supernatant of buffy-coat derived platelet concentrates (PC). METHODS: Platelet concentrates (n = 20) were tested on days 1, 5 and 7 of storage at 22°C and RTFP24 (n = 10) immediately following thawing and after 4 and 6 days storage at 4°C. Coagulation factor activity, thrombin generation ± an activator of protein C (PROTAC) and rotational thromboelastometry (ROTEM) were assessed. RESULTS: In plasma and buffy-coat derived PC, there was a < 10% loss of factors II, IX and FX, but much higher loss of factors FV, FVII and FVIII. In plasma, the total or peak amount of thrombin generated was unaffected by storage for 6 days, with or without Protac, but there was an increase in lag time and decreased rate of clot formation by ROTEM. In PC, but not plasma, there was a 16% increase in FXII activity and increase in resistance to activated protein C, co-incidental to 30% loss of free protein S. CONCLUSIONS: These data suggest thrombin generation is relatively unaltered when RTFP24 is thawed and stored for 6 days, and that the supernatant of PC has significant haemostatic capacity.

The potential application of a transcriptionally regulated oncolytic herpes simplex virus for human cancer therapy.

BACKGROUND: Emerging studies have shown the potential benefit of arming oncolytic viruses with therapeutic genes. However, most of these therapeutic genes are placed under the regulation of ubiquitous viral promoters. Our goal is to generate a safer yet potent oncolytic herpes simplex virus type-1 (HSV-1) for cancer therapy. METHODS: Using bacterial artificial chromosome (BAC) recombineering, a cell cycle-regulatable luciferase transgene cassette was replaced with the infected cell protein 6 (ICP6) coding region (encoded for UL39 or large subunit of ribonucleotide reductase) of the HSV-1 genome. These recombinant viruses, YE-PC8, were further tested for its proliferation-dependent luciferase gene expression. RESULTS: The ability of YE-PC8 to confer proliferation-dependent transgene expression was demonstrated by injecting similar amount of viruses into the tumour-bearing region of the brain and the contralateral normal brain parenchyma of the same mouse. The results showed enhanced levels of luciferase activities in the tumour region but not in the normal brain parenchyma. Similar findings were observed in YE-PC8-infected short-term human brain patient-derived glioma cells compared with normal human astrocytes. intratumoural injection of YE-PC8 viruses resulted in 77% and 80% of tumour regression in human glioma and human hepatocellular carcinoma xenografts, respectively. CONCLUSION: YE-PC8 viruses confer tumour selectivity in proliferating cells and may be developed further as a feasible approach to treat human cancers.