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Simple Summary: Glioblastoma is a highly aggressive and lethal brain tumor that has seen marginal improvement in patient outcomes despite decades of concerted efforts. This study investigated the impact of tumor molecular features, sex, and their interaction on the survival of patients with newly diagnosed glioblastoma. Our findings show that females are more often found to have silencing of the MGMT promoter, but that they also receive a greater survival benefit, which is more clinically and statistically significant, associated with MGMT promoter silencing that is not reflected in males. These findings may significantly impact both our understanding as well as the clinical management of the disease. Rather than the established practice of using temozolomide to treat MGMT promoter methylated patients as a whole, our findings suggest that females accrue a disproportionate survival benefit compared to males who, regardless of methylation status, may experience better survival outcomes from alternative treatment options. Introduction: Sex differences in glioblastoma (GBM) have been observed in incidence, genetic and epigenetic alterations, and immune response. These differences have extended to the methylation of the MGMT promoter, which critically impacts temozolomide resistance. However, the association between sex, MGMT methylation, and survival is poorly understood, which this study sought to evaluate. Methods: A retrospective cohort study was conducted and reported following STROBE guidelines, based on adults with newly diagnosed GBM who received their first surgical intervention at Cleveland Clinic (Ohio, USA) between 2012 and 2018. Kaplan–Meier and multivariable Cox proportional hazards models were used to analyze the association between sex and MGMT promoter methylation status on overall survival (OS). MGMT was defined as methylated if the mean of CpG 1-5 ≥ 12. Propensity score matching was performed on a subset of patients to evaluate the effect of individual CpG site methylation. Results: A total of 464 patients had documented MGMT methylation status with a mean age of 63.4 (range 19–93) years. A total of 170 (36.6%) were female, and 133 (28.7%) received gross total resection as a first intervention. A total of 42.5% were MGMT methylated, with females more often having MGMT methylation than males (52.1% vs. 37.4%, p = 0.004). In univariable analysis, OS was significantly longer for MGMT promoter methylated than un-methylated groups for females (2 yr: 36.8% vs. 11.1%; median: 18.7 vs. 9.5 months; p = 0.001) but not for males (2 yr: 24.3% vs. 12.2%; median: 12.4 vs. 11.3 months; p = 0.22, p for MGMT–sex interaction = 0.02). In multivariable analysis, MGMT un-methylated versus methylated promoter females (2.07; 95% CI, 1.45–2.95; p < 0.0001) and males (1.51; 95% CI, 1.14–2.00; p = 0.004) had worse OS. Within the MGMT promoter methylated group, males had significantly worse OS than females (1.42; 95% CI: 1.01–1.99; p = 0.04). Amongst patients with data on MGMT CpG promoter site methylation values (n = 304), the median (IQR) of CpG mean methylation was 3.0% (2.0, 30.5). Females had greater mean CpG methylation than males (11.0 vs. 3.0, p < 0.002) and higher per-site CpG methylation with a significant difference at CPG 1, 2, and 4 (p < 0.008). After propensity score matching, females maintained a significant survival benefit (18.7 vs. 10.0 months, p = 0.004) compared to males (13.0 vs. 13.6 months, p = 0.76), and the pattern of difference was significant (P for CpG–sex interaction = 0.03). Conclusions: In this study, females had higher mean and individual CpG site methylation and received a greater PFS and OS benefit by MGMT methylation that was not seen in males despite equal degrees of CpG methylation. [ABSTRACT FROM AUTHOR]

• Formulations and thermal stress uniquely alter dmLT biochemical stability. • Biochemical stability poorly predicts immunity in mouse dmLT vaccine models. • Delivery route and antigen impact vaccine outcomes more than dmLT stability. • Biochemical and immunity testing are needed for vaccine formulation optimization. A key aspect to vaccine efficacy is formulation stability. Biochemical evaluations provide information on optimal compositions or thermal stability but are routinely validated by ex vivo analysis and not efficacy in animal models. Here we assessed formulations identified to improve or reduce stability of the mucosal adjuvant dmLT being investigated in polio and enterotoxigenic E. coli (ETEC) clinical vaccines. We observed biochemical changes to dmLT protein with formulation or thermal stress, including aggregation or subunit dissociation or alternatively resistance against these changes with specific buffer compositions. However, upon injection or mucosal vaccination with ETEC fimbriae adhesin proteins or inactivated polio virus, experimental findings indicated immunization route and co-administered antigen impacted vaccine immunogenicity more so than dmLT formulation stability (or instability). These results indicate the importance of both biochemical and vaccine-derived immunity assessment in formulation optimization. In addition, these studies have implications for use of dmLT in clinical settings and for delivery in resource poor settings. [ABSTRACT FROM AUTHOR]

Skin and soft-tissue infections (SSTIs) are a common reason for hospital admission. Severe SSTIs, particularly necrotizing infections, often require intensive care. Source control (often with surgical debridement) and broad-spectrum antimicrobials are paramount for minimizing significant morbidity and mortality. Rapid diagnostic tests may help in selection and de-escalation of antimicrobials for SSTIs. Besides early source control and early effective antimicrobial therapy, other patient-level factors such as comorbidities and immune status play a role in clinical outcomes. Intravenous immunoglobulin continues to be studied for severe SSTI, though recruitment in trials continues to be an issue. Severe SSTIs are complex to manage, due in part to regional variation in predominant pathogens and antimicrobial resistance patterns, as well as variations in host immune responses. This review includes descriptions of source control, antimicrobial therapies, intravenous immunoglobulin, and hyperbaric oxygen therapy, as well as host factors in severe SSTIs. [ABSTRACT FROM AUTHOR]

In high-resolution ion mobility spectrometry-mass spectrometry (IMS-MS)-based separations individual, pure, oligosaccharide species often produce multiple IMS peaks presumably from their α/β anomers, cation attachment site conformations, and/or other energetically favorable structures. Herein, the use of high-resolution traveling wave-based cyclic IMS-MS to systematically investigate the origin of these multiple peaks by analyzing α1,4- and β1,4-linked d-glucose homopolymers as a function of their group I metal adducts is presented. Across varying degrees of polymerization, and for certain metal adducts, at least two major IMS peaks with relative areas that matched the ~40:60 ratio for the α/β anomers of a reducing-end d-glucose as previously calculated by NMR were observed. To further validate that these were indeed the α/β anomers, rather than other substructures, the reduced versions of several maltooligosaccharides were analyzed and all produced a single IMS peak. This result enabled the discovery of a mobility fingerprint trend: the β anomer was always higher mobility than the α anomer for the cellooligosaccharides, while the α anomer was always higher mobility than the β anomer for the maltooligosaccharides. For maltohexaose, a spurious, high mobility, fourth peak was present. This was hypothesized to potentially be from a highly compacted conformation. To investigate this, α-cyclodextrin, a cyclic oligosaccharide, produced similar arrival times as the high mobility maltohexaose peak. It is anticipated that these findings will aid in the data deconvolution of IMS-MS-based glycomics workflows and enable the improved characterization of biologically relevant carbohydrates. [ABSTRACT FROM AUTHOR]

Recruitment of winter tick larvae (Dermacentor albipictus) was studied in a forest opening and a closed canopy deciduous forest to evaluate their potential as sources of tick infestation to moose (Alces alces). Engorged female ticks were set out in early May at each site and monitored to measure the proportions of females producing larvae and the number of larvae recruited per g of surviving female. Recruitment was higher in the forest during the hotter, drier summer of 1983, primarily due to fewer engorged females producing larvae in the opening, and was much higher (>2 x) in the opening during the cooler, damper summer of 1984. Recruitment in the field was 20–40% of that under laboratory conditions. Desiccation of eggs and/or larvae was the probable cause for the annual variation in recruitment in the opening. Most larvae were recruited earlier in the opening than in the forest site. Neither weight nor date of detachment of engorged female ticks influenced when larvae first ascended vegetation. Weather, especially temperature, and site structure and composition affect abundance of the free-living stages of the winter tick and larvae available for transmission to moose. Open sites should support more winter tick larvae than densely forested sites except in years of particularly hot and dry weather. [ABSTRACT FROM AUTHOR]

The results of previous studies on directed forgetting effects in implicit memory have led to the conclusion that the underlying mechanism for such effects is an inhibition of retrieval or an encoding difficulty. Differences in procedure and stimuli may contribute to these different conclusions. In 2 studies we standardized the procedure while varying the stimuli. As in previous research, directed forgetting results were obtained for direct memory tasks. However, the magnitude of the directed forgetting effect varied with the stimuli. In Experiments 1 and 2, medium- and low-frequency to-be-remembered (R) and to-be-forgotten (F) words appeared to be equally accessible using the indirect task. In Experiment 3, we devised a procedure in which a single stem could lead to an R-word or F-word, but space was provided for only one word. In that way, we could examine the relative accessibility of R- and F-words. Results are discussed in light of Mandler's (1980) conceptualization of the contributions of identification and familiarity to memory retrieval processes. [ABSTRACT FROM AUTHOR]

Triggering receptor expressed on myeloid cells 2 (TREM2) is a single-pass transmembrane receptor of the immunoglobulin superfamily that is secreted in a soluble (sTREM2) form. Mutations in TREM2 have been linked to increased risk of Alzheimer's disease (AD). A prominent neuropathological component of AD is deposition of the amyloid-β (Aβ) into plaques, particularly Aβ40 and Aβ42. While the membrane-bound form of TREM2 is known to facilitate uptake of Aβ fibrils and the polarization of microglial processes toward amyloid plaques, the role of its soluble ectodomain, particularly in interactions with monomeric or fibrillar Aβ, has been less clear. Our results demonstrate that sTREM2 does not bind to monomeric Aβ40 and Aβ42, even at a high micromolar concentration, while it does bind to fibrillar Aβ42 and Aβ40 with equal affinities (2.6 ± 0.3 µM and 2.3 ± 0.4 µM). Kinetic analysis shows that sTREM2 inhibits the secondary nucleation step in the fibrillization of Aβ, while having little effect on the primary nucleation pathway. Furthermore, binding of sTREM2 to fibrils markedly enhanced uptake of fibrils into human microglial and neuroglioma derived cell lines. The disease-associated sTREM2 mutant, R47H, displayed little to no effect on fibril nucleation and binding, but it decreased uptake and functional responses markedly. We also probed the structure of the WT sTREM2-Aβ fibril complex using integrative molecular modeling based primarily on the cross-linking mass spectrometry data. The model shows that sTREM2 binds fibrils along one face of the structure, leaving a second, mutation-sensitive site free to mediate cellular binding and uptake. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): The COVID-19 pandemic has direct and indirect impact on patients with cancer. Low- and middle-income regions, especially sub-Saharan Africa, are especially vulnerable to a negative impact on cancer resources and outcomes. We report the initial indirect impact of COVID-19 on cancer care in the sub-Saharan Africa region approximately 14 months into the pandemic.Materials/methods: At the start of the pandemic, we created a consortium of African and North American cancer centers and NGOs for the distribution of factual and timely information and data on COVID-19 and cancer care. A survey was distributed to consortium members and other colleagues from the sub-Saharan Africa region to understand the impact of COVID-19 in cancer care resources. Survey respondents represent cancer experts from 8 centers in Ghana, Nigeria, Kenya, Ethiopia, South Africa, Rwanda, and Zimbabwe.Results: All sites report SARS-COv-2 transmission amongst cancer patients and staff. A total of 48 staff developed COVID-19 infection with one site reporting a single death. Additionally, 62.5% of sites report loss of oncology physician or nursing staff due to redeployment for COVID-19 care resulting in minimal (20%), moderate (60%), or other (20%) impact on cancer care. All 8 sites report a government mandated lockdown with a median duration of 2.3 months (IQR .9-4.2 months). Impact of the lockdown on cancer care was reported as none (12.5%), minimal (12.5%), moderate (50%) and severe (25%). Additionally, we surveyed the impact of COVID-19 on resources in radiation, medical and surgical oncology services. A total of 25% of responders reported decreases in radiation resources while 37.5% reported changes in medical and surgical oncology resources. For radiation oncology, the most common impact was access to CT imaging for 3D-conformal planning (25%), access to brachytherapy (12.5%), and medical physics support (12.5%). For medical oncology, the most frequent impact was access to chemotherapy (37.5%) and blood products (12.5%), and loss of oncology ward space (12.5%). The most frequent impact for surgical oncology was access to operating rooms (37.5%), ventilators (12.5%), anesthesia (25%), blood products (25%), and other supply chain issues (25%). Of centers who reported impact on cancer care, severity of impact was none (50%) and moderate (50%) for radiation oncology; mild (25%) and moderate (75%) for medical oncology; and moderate (75%) and severe (25%) for surgical oncology.Conclusion: Our survey identified diffuse impact of COVID-19 on all facets of cancer care across sub-Saharan Africa. Based on physician assessment of impact, the discipline of surgical oncology may be impacted the greatest. Additional studies measuring the impact of COVID-19 on cancer outcomes are ongoing. [ABSTRACT FROM AUTHOR]

Introduction: Peterborough Care Home Support Team (CHST) have worked on a small pilot of 4 care homes with a local GP and an interface geriatrician to address the complex needs of the residents within those care homes to improve patient experience, quality of care and reduce attendances and admissions to hospital in a geographical area of 5000 care home beds. Methods: The multidisciplinary team (MDT) consisted of a General Practitioner, Interface Geriatrician, Pharmacist from the medicine optimisation team and Care Home Support Team member with once a month meeting in the selected Care Home. We measure the impact of our intervention comparing the data predating our intervention comparing 4 selected care homes with high A&E attendances in each period 2017 and 2018. Results: 50% reduction in hospital attendances with £4985.48 cost saving following medication review in the 4 care homes under study. Conclusions: Commissioners, Local Authorities and Care Home Providers have started to look towards more innovative solutions to improve patient experience, quality of care and reduce attendances and admissions to hospital. Our experience and results aim to consider enhance GP-Geriatrician Care Homes MDT as a good model of care. [ABSTRACT FROM AUTHOR]