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Congenital cytomegalovirus (cCMV) is the most common intrauterine infection, leading to infant neurodevelopmental disabilities. An improved knowledge of correlates of protection against cCMV is needed to guide prevention strategies. Here, we employ an ex vivo model of human CMV (HCMV) infection in decidual tissues of women with and without preconception immunity against CMV, recapitulating nonprimary vs. primary infection at the authentic maternofetal transmission site. We show that decidual tissues of women with preconception immunity against CMV exhibit intrinsic resistance to HCMV, mounting a rapid activation of tissue-resident memory CD8+ and CD4+ T cells upon HCMV reinfection. We further reveal the role of HCMV-specific decidual-tissue-resident CD8+ T cells in local protection against nonprimary HCMV infection. The findings could inform the development of a vaccine against cCMV and provide insights for further studies of the integrity of immune defense against HCMV and other pathogens at the human maternal-fetal interface. [Display omitted] • Primary vs. nonprimary HCMV infections are studied in human decidual organ culture model • Nonprimary infected decidual tissues exhibit significant resistance to HCMV infection • HCMV-specific resident memory CD8+ T cells protect against nonprimary decidual infection • The identified correlates of protection can guide the development of HCMV vaccine Alfi et al. use an ex vivo model of HCMV infection in the maternal-fetal interface to identify correlates of protection against transplacental HCMV transmission. HCMV-specific decidual-tissue-resident memory CD8+ T cells drive the protection, lacking in primary-infected tissues of HCMV-seronegative women, against nonprimary infection of decidual tissues of HCMV-seropositive women. [ABSTRACT FROM AUTHOR]

Highlights: [•] APOE*4 allele is associated with increased risk of dementia in Pakistani population. [•] Stressful life events are also associated with dementia risk in Pakistani population. [•] No significant interaction was observed between APOE*4 and stress in Pakistani population. [ABSTRACT FROM AUTHOR]

Abstract: We prove that the Riemann functional equation can be recovered by the Mellin transforms of essentially all the absolutely integrable functions. The present analysis shows also that the Riemann functional equation is equivalent to the Fourier inversion formula. We introduce the notion of a -pair of absolutely integrable functions and show that the components of the -pair satisfy an identity involving convolution type products. [ABSTRACT FROM AUTHOR]

Abstract: Pakistan is an energy-deficient country. This paper accentuates the importance and challenges of new era technologies. The renewable energy sources like wind energy, solar energy, geothermal energy, ocean energy, biomass energy and fuel cell technology can be used to overcome energy shortage in Pakistan. Renewable energy sources and technologies have the potential to provide solutions to the long-standing energy problems being faced by the developing countries. The expansion of existing energy resources and exploration of new sources is an important exercise to be considered in order to sustain their development initiatives. [Copyright &y& Elsevier]

Abstract: A closed form representation of the Mertens function, without assuming simplicity of the non-trivial zeros of the zeta function, is proved and the Titchmarsh representation of the function is recovered as a special case. We exploit a representation of the Mertens function and provide numerical support of the Riemann hypothesis and the simplicity of the zeros of the zeta function. [Copyright &y& Elsevier]

Abstract: Weed management studies in transplanted onion were conducted during 2004 and 2005 at the National Agricultural Research Centre, Islamabad, Pakistan. Pendimethalin and oxadiazon were applied post-emergence 2 days and 4 week after transplanting and their efficacy alone and in combination with one manual weeding was evaluated to reduce weed competition and its effects on marketable bulb yield. Hand weeded and weedy check were included. Compared to weed free condition, weed crop competition caused 71% and 76% reduction in the marketable bulb yield during the first and second year, respectively. Cyprus rotundus (41%) and Coronopus didymus (19%) were the dominant weeds recorded in the field. Both pendimethalin and oxadiazon when applied 2 DAT in combination with one weeding at 60 DAT were found more effective in enhancing marketable bulb yield and recorded higher net returns than other treatments. [Copyright &y& Elsevier]

An extension of the beta function by introducing an extra parameter, which proved to be useful earlier, is applied here to extend the hypergeometric and confluent hypergeometric functions. Since the latter functions contain many of the familiar special functions as sub-cases, this extension is expected to prove to be useful. The object of the present paper is to study this extension and its relationship with the hypergeometric and confluent hypergeometric functions. [Copyright &y& Elsevier]

The response of cells to ionizing radiation has long been known to result in alterations in gene expression. Here we examined the expression patterns of synchronized HeLa cells in G1 or G2, after exposure to 2 Gy of X-rays on microarrays allowing evaluation of over 12,000 human genes. The analysis showed induction of at least twofold for 257 different genes, after irradiation of cells in G1 and down-regulation of 42. The altered transcription patterns involved genes belonging to cell cycle pathways, DNA repair, oncogenes, histones, heat shock genes, mitochondrial and ribosomal proteins, transcription and translational regulators and genes encoding cytoskeleton components. HeLa cells are deficient in p53 and none of the induced genes have previously been identified as regulated by p53. One hundred and seventy-seven genes were up-regulated and 26 genes were down-regulated after irradiation in G2. Surprisingly most of the up-regulated genes in both phases of the cell cycle encode ribosomal proteins. These studies have revealed cell cycle dependence on radiation-induced gene induction and have permitted the identification of previously known as well as unknown genes associated with radiation-induced altered expression. [Copyright &y& Elsevier]

The novel betacoronavirus severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) causes a form of severe pneumonia disease called coronavirus disease 2019 (COVID-19). To develop human neutralizing anti-SARS-CoV-2 antibodies, antibody gene libraries from convalescent COVID-19 patients were constructed and recombinant antibody fragments (scFv) against the receptor-binding domain (RBD) of the spike protein were selected by phage display. The antibody STE90-C11 shows a subnanometer IC 50 in a plaque-based live SARS-CoV-2 neutralization assay. The in vivo efficacy of the antibody is demonstrated in the Syrian hamster and in the human angiotensin-converting enzyme 2 (hACE2) mice model. The crystal structure of STE90-C11 Fab in complex with SARS-CoV-2-RBD is solved at 2.0 Å resolution showing that the antibody binds at the same region as ACE2 to RBD. The binding and inhibition of STE90-C11 is not blocked by many known emerging RBD mutations. STE90-C11-derived human IgG1 with FcγR-silenced Fc (COR-101) is undergoing Phase Ib/II clinical trials for the treatment of moderate to severe COVID-19. [Display omitted] • Human antibody selected from convalescent COVID-19 patients by phage display • In vivo neutralization of SARS-CoV-2 is demonstrated in two animal models • Crystal structure of STE90-C11 in complex with SARS-CoV-2-RBD • Antibody with silenced Fc part is in clinical Phase Ib/II trial Bertoglio et al. describe the anti-SARS-CoV-2 antibody generation by phage display and development of the human antibody COR-101. In vitro and in vivo neutralization in two animal models is demonstrated. The structure is solved in complex with RBD. COR-101 with silenced Fc part is in clinical Phase Ib/II trial. [ABSTRACT FROM AUTHOR]

Abstract: Two hundred patients received hematopoietic stem cell transplantation (HSCT) from matched sibling donors (MSD) after myeloablative conditioning including fludarabine (Flu) and once-daily intravenous busulfan (Bu). Thymoglobulin (TG) was added to methotexate (MTX) and cyclosporine (CsA) as graft-versus-host disease (GVHD) prophylaxis. For low-risk (acute leukemia CR1/CR2, CML CP1) patients projected 5-year nonrelapse mortality (NRM) and overall survival (OS) were 4% and 76% for those ≤45 years old (n = 54) and 6% and 83% for those >45 (n = 31). For high-risk (HR) patients NRM was 6% versus 27% (18% at 1 year) (P = .04) and OS 64% versus 37% (P = .47) in younger (n = 40) and older (n = 75) patients, respectively. To correct for imbalance in HR diagnoses each of 17 younger HR patients were matched with 2 older HR (OHR) patients by diagnosis and details of stage, and thereafter for other risk factors. For the younger HR and OHR patients, respectively, OS was 70% versus 37% (P = .02) and NRM 0 versus 34% (P = .02). When outcomes of OHR patients were compared with the other 3 groups combined NRM was 27% versus 5%, respectively (P = .002). Incidence of acute graft-versus-host disease (aGVHD) grade II-IV, aGVHD grade III-IV, and chronic GVHD (cGVHD) was 23% versus 10% (P = .02), 4% versus 2% (P = ns), and 66% versus 41% (P = .001), respectively. Nine of 14 nonrelapse deaths in the OHR group were related to GVHD or its treatment compared with 3 of 6 in all others (P value for GVHD related death = .01). Multivariate analysis of OS and DFS correcting for potentially confounding pretransplant factors identified only the OHR patients as having significantly increased risk (relative risk [RR] 3.32, confidence interval [CI] 1.71-6.47, P < .0001, and RR 3.32, CI 1.71-6.43, P < .0001, respectively). The effect of age on NRM is only apparent in HR patients, and is not explained by heterogeneity in diagnoses. Older HR patients experience more GVHD and more GVHD-related death than others, but NRM is no higher than reported with many nonmyeloablative regimens. [Copyright &y& Elsevier]

Research on general health service delivery in urban areas of Canada shows that Aboriginal people face formidable barriers in accessing culturally appropriate and timely care. Over the past decade, Urban Aboriginal Health Centres (UAHCs) have emerged to address the unmet health concerns of Aboriginal people living in metropolitan areas of the country. The purpose of this research was to address the gap in social science literature on how the health care concerns of Aboriginal women are being met by UAHCs. The research aimed to give voice to Aboriginal women by asking them whether the appropriate professional services and educational programs they need to address their health care needs were being provided in the inner city. A case-study approach was used whereby three separate focus groups were conducted with Aboriginal women who were clients of the Vancouver Native Health Society (VNHS), its sister organization, Sheway, or residents of Vancouver's Downtown Eastside (DTES). In addition, twenty-five semi-structured interviews were conducted with VNHS staff, health providers, government representatives, and community leaders in health care (total n=61). The findings indicate that despite efforts from various quarters to articulate the health and social concerns of the country's marginalized populations, such has not been the case for Aboriginal women living in one of Canada's most prosperous cities. Many Aboriginal women expressed a strong desire for a Healing Place, based on a model of care where their health concerns are addressed in an integrated manner, where they are respected and given the opportunity to shape and influence decision-making about services that impact their own healing. [ABSTRACT FROM AUTHOR]

The management of slipped upper femoral epiphysis is controversial and evolving as insight into the condition develops. Loder introduced the concept of slip stability and demonstrated a strong association between poor outcome and instability. Almost half of patients with unstable slip developed femoral head osteonecrosis. This has been influential in surgeons' choice of treatments. Some surgeons have adopted a minimal intervention approach such as pinning in situ or gentle reduction and pinning whereas others advocated an urgent open reduction and stabilisation of slip using various surgical techniques. In this review we analysed the influence of various interventions, timing of surgery and severity of the slip on the outcome of unstable slip. [ABSTRACT FROM AUTHOR]

A solid-state technique was used to synthesize ceria-based (CDC−xT, in which x=0–1mol%) solid electrolyte ceramics. The effects of doping the ceramic solid electrolyte (CDC) with titanium oxide were studied with regard to densification, crystal structure, morphology, electro-impedance spectroscopy and fuel cell performance. TiO2 doping afforded materials a 95% relative density at 940°C, approximately 200°C lower than the temperature required without titanium oxide. The addition of titanium oxide (TiO2) reduced the CDC sintering temperature and significantly improved the grain boundary conduction. The minimum grain boundary resistivity was obtained at 0.8mol% TiO2. X-ray diffraction (XRD) results showed that the lattice parameters enhanced with increased titanium oxide concentrations up to 0.8mol%, revealing the solubility limit for Caria׳s fluorite structure. The optimum doping level (0.8mol%) is provided maximum conductivity. Conductivities were measured using EIS (Electrochemical Impedance Spectroscopy) with a two-probe method, and the activation energies were calculated using the Arrhenius plots. The maximum power density (660mW/cm2) was achieved with CDC−0.8T electrolyte at 650°C using LiCuZnNi oxide electrodes. [ABSTRACT FROM AUTHOR]

Abstract: Ceria-based electrolyte materials have great potential in low and intermediate temperature solid oxide fuel cell applications. In the present study, three types of ceria-based nano-composite electrolytes (LNK-SDC, LN-SDC and NK-SDC) were synthesized. One-step co-precipitation method was adopted and different techniques were applied to characterize the obtained ceria-based nano-composite electrolyte materials. TGA, XRD and SEM were used to analyze the thermal effect, crystal structure and morphology of the materials. Cubic fluorite structures have been observed in all composite electrolytes. Furthermore, the crystallite sizes of the LN-SDC, NK-SDC, LNK-SDC were calculated by Scherrer formula and found to be in the range 20 nm, 21 nm and 19 nm, respectively. These values emphasize a good agreement with the SEM results. The ionic conductivities were measured using EIS (Electrochemical Impedance Spectroscopy) with two-probe method and the activation energies were also calculated using Arrhenius plot. The maximum power density was achieved 484 mW/cm2 of LNK-SDC electrolyte at 570 °C using the LiCuZnNi oxide electrodes. [Copyright &y& Elsevier]

Abstract: A combination of fludarabine (Flu) and daily i.v. busulfan (Bu) is well tolerated and effective in patients undergoing allogeneic hematopoietic stem cell transplantation. Although there is some evidence that Bu exposures exceeding 6000 μM/min may lead to excessive toxicity, there is little information on the effect of exposures below this level on outcomes. We studied Bu exposure, as measured by area under the concentration-time curve (AUC), in 158 patients with various hematologic malignancies in an attempt to identify an optimal range for targeted therapy. The preparative chemotherapy regimen comprised Flu 50 mg/m2 on days -6 to -2 and i.v. Bu 3.2 mg/kg on days -5 to -2 inclusive. Graft-versus-host disease (GVHD) prophylaxis included methotrexate, cyclosporin A, and antithymocyte globulin. Patients with Bu exposures below the median AUC of 4439 μM/min were at increased risk for acute GVHD grade II-IV (hazard ratio [HR], 2.30; 95% confidence interval [CI], 1.19 to 4.49; P = .014). Those in the highest and lowest Bu exposure quartiles (daily AUC <3814 μM/min and >4993 μM/min) had an increased risk of nonrelapse mortality (subdistribution HR, 3.32; 95% CI, 1.46 to 7.54; P = .004), as well as worse disease-free survival (HR, 1.81; 95% CI, 1.09 to 2.99; P = .021) and overall survival (HR, 1.94; 95% CI, 1.12 to 3.37; P = .018). Bu exposures between 4440 and 4993 μM/min were accompanied by the lowest risk of both nonrelapse mortality and acute GVHD. [Copyright &y& Elsevier]

Intravenous (i.v.) busulfan (Bu) administered once daily in myeloablative transplant regimens is convenient, effective, and relatively well tolerated. Therapeutic drug monitoring is recommended as nonrelapse mortality increases when daily exposure, as determined by the area under the plasma concentration versus time curve (AUC), exceeds 6000 μM·min. We describe sequential studies to achieve accurate prediction of treatment doses of Bu based on the kinetics of a smaller test dose. A total of 335 patients with hematologic malignancies were given daily i.v. Bu 3.2 mg/kg × 4 and fludarabine 50 mg/m2 × 5. Pharmacokinetic monitoring was conducted for both the test dose and first treatment dose of Bu (day −5). Three different test dose schedules were evaluated: 12 mg Bu administered over 20 minutes, 0.8 mg/kg over 3 hours, and 0.8 mg/kg infused at 80 mg/h. The 3.2 mg/kg treatment doses were infused over a fixed time of 3 hours for the first 2 test dose trials and at a fixed rate of 80 mg/h for the final protocol. All test dose infusions were on day −7. In the first 2 schedules, Bu administered over a fixed time had significantly higher clearance for the test dose compared with the treatment dose. However, when both the test and the treatment doses were administered at the same infusion rate, clearance of the drug between the 2 dosing days was equivalent. Predicted day −5 AUC (AUC−5) showed a high linear correlation (r2 = 0.74) to the actual AUC−5. The error of these predictions was <20% in 98% of patients and <10% in 80%. In 24 individuals, the test dose predicted an AUC >5500 μM·min; therefore, the first Bu treatment dose was reduced to a desired target AUC. All adjusted doses fell within 20% of the targeted exposure. We conclude that a test dose strategy for therapeutic drug monitoring of daily i.v. Bu is accurate if the test and treatment doses are infused at the same rate. This approach allows targeting of therapeutic doses of Bu to desired levels and the potential for improved safety and efficacy. [ABSTRACT FROM AUTHOR]

A combination of fludarabine (Flu) and daily i.v. busulfan (Bu) is well tolerated and effective in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for acute myelogenous leukemia (AML). The addition of rabbit antithymocyte globulin (ATG) may reduce morbidity and mortality from graft-versus-host disease (GVHD), but lead to increased relapse. To compensate for this effect, we added 400 cGy of total body irradiation (TBI) to the Flu/Bu regimen in 89 patients, and compared outcomes with those achieved in 90 patients who received the drug combination alone. Although nonrelapse mortality (NRM) at 3 years did not differ between the groups, the inclusion of TBI significantly reduced relapse (hazard ratio [HR] = 0.29; 95% confidence interval [CI] = 0.15-0.54; P = .0001). Consequently, both overall survival (OS; HR = 0.50; 95% CI = 0.3-0.84; P = .009) and disease-free survival (DFS; HR = 0.43; 95% CI = 0.26-0.72; P = .001) were improved with the inclusion of TBI. This study confirms the importance of regimen intensity in allogeneic HSCT for AML. The combination of daily i.v. Bu, Flu, 400 cGy TBI, and ATG provides a well-tolerated regimen with antileukemic activity in AML comparable to that of other, conventional myeloablative (MA) regimens. [Copyright &y& Elsevier]

Abstract: We have reported a lower incidence of acute graft-versus-host disease (aGVHD) with a novel conditioning regimen using low-dose rabbit antithymocyte globulin (ATG; Thymoglobulin [TG]) with fludarabine and intravenous busulfan (FluBuTG). To assess further this single-center experience, we performed a retrospective matched-pair analysis comparing outcomes of adult patients transplanted using the FluBuTG conditioning regimen with matched controls from patients reported to the CIBMTR receiving a first allogeneic hematopoietic stem cell transplant (HCT) after standard oral busulfan and cyclophosphamide (BuCy). One hundred twenty cases and 215 matched controls were available for comparison. Patients receiving FluBuTG had significantly less treatment related mortality (TRM; 12% versus 34%, P < .001) and grades II-IV aGVHD (15% versus 34%, P < .001) compared to BuCy patients. The risk of relapse was higher in the FluBuTG patients (42% versus 20%, P < .001). The risks of chronic GVHD (cGVHD) and disease free survival (DFS) were similar in the cases and controls. These results suggest that the novel regimen FluBuTG decreases the risk of aGVHD and TRM after HLA-identical sibling HSCT, but is associated with an increased risk of relapse, resulting in similar DFS. Whether these conditioning regimens may be more suitable for specific patient populations based on relapse risk requires testing in prospective randomized trials. [Copyright &y& Elsevier]

Abstract: Low plasma busulfan (Bu) area under the concentration-time curve (AUC) is associated with graft failure and relapsed leukemias, and high AUC with toxicities when Bu is used orally or i.v. 4 times daily combined with cyclophosphamide in myeloablative hematopoietic stem cell transplantation (SCT) conditioning regimens. We report Bu AUC and its association with clinical outcomes in 130 patients with hematologic malignancies given a once-daily i.v. Bu (3.2 mg/kg days −5 to −2) and fludarabine (Flu, 50 mg/m2 days −6 to –2) regimen. Total-body irradiation (TBI) 200 cGy × 2 was added for 51 patients with acute leukemias. Plasma AUC varied 3.6-fold (2184-7794 μM·min, median 4699 μM·min). Patients with an AUC >6000 μM·min had lower overall survival (OS) than those with AUC ≤6000 μM·min at 12 months (38% versus 74%) and 36 months (23% versus 68%, P < .001). This effect was apparent in patients with standard-risk and high-risk disease, and persisted when potential confounders were considered (hazard ratio 3.2, 95% confidence interval 1.7-6.3). Nonrelapse mortality (NRM) at 100 days (6% versus 19%) and progression free survival (PFS; 58% versus 16%) at 3 years were better with AUC ≤6000 μM·min. These data support a role for therapeutic dose monitoring and dose adjustment with daily i.v. busulfan. [Copyright &y& Elsevier]

Abstract: A myeloablative conditioning regimen incorporating daily intravenous busulfan, fludarabine, and 400 cGy total-body irradiation was given before allogeneic stem cell transplantation (SCT) to 64 adults with acute leukemia in first and second remission. Graft-versus-host disease (GVHD) prophylaxis included methotrexate, cyclosporine A, and rabbit antithymocyte globulin (Thymoglobulin). For 31 matched related (MRD) and 33 alternate donor (AD) SCT the incidence of acute GVHD grade II-IV was 11% ± 6% versus 35% ± 9% (P = .047), acute GVHD grade III-IV was 0% versus 10% ± 6% (P = .09), and chronic GVHD was 40% ± 9% versus 66% ± 9% (P = NS), respectively. Overall transplant-related mortality (TRM) was 3% ± 2%. Projected disease-free (DFS) and overall survival (OS) at 3 years for acute myelogenous leukemia (AML) (n = 36) are the same at 83% ± 6%, and for acute lymphoblastic leukemia (ALL) (n = 28) are 65% ± 10% and 78% ± 8%, respectively. For MRD SCT DFS is 77% ± 9%, OS 87% ± 6%, for AD SCT the respective figures are 71% ± 8% and 74% ± 8%. OS and DFS in patients without and with high-risk features are 100% versus 71% ± 7% (P = .007) and 88% ± 8% versus 68% ± 7% (P = .04), respectively. This combination appears relatively well tolerated, gives equivalent final outcomes from MRD and AD, and may be a reasonable alternative to conventional myeloablative regimens. [Copyright &y& Elsevier]

Co-precipitation technique using chlorides of constituents was used to prepare fine particles Ni–Zn ferrites. The particle size was estimated from X-ray diffraction data using Sherrer''s formula. The dc electrical resistivity and thermo-power was measured in the temperature range 300–450 K and it was found that all the samples are degenerate type semi-conductors. The results of dc resistivity and thermo-electric power confirm that the conduction mechanism in these ferrites is due to small polaron hopping. [Copyright &y& Elsevier]