Epigenetic effects of folate and related B vitamins on brain health throughout life: Scientific substantiation and translation of the evidence for health improvement strategies.

Suboptimal status of folate and/or interrelated B vitamins (B12 , B6 and riboflavin) can perturb one-carbon metabolism and adversely affect brain development in early life and brain function in later life. Human studies show that maternal folate status during pregnancy is associated with cognitive development in the child, whilst optimal B vitamin status may help to prevent cognitive dysfunction in later life. The biological mechanisms explaining these relationships are not clear but may involve folate-related DNA methylation of epigenetically controlled genes related to brain development and function. A better understanding of the mechanisms linking these B vitamins and the epigenome with brain health at critical stages of the lifecycle is necessary to support evidence-based health improvement strategies. The EpiBrain project, a transnational collaboration involving partners in the United Kingdom, Canada and Spain, is investigating the nutrition-epigenome-brain relationship, particularly focussing on folate-related epigenetic effects in relation to brain health outcomes. We are conducting new epigenetics analysis on bio-banked samples from existing well-characterised cohorts and randomised trials conducted in pregnancy and later life. Dietary, nutrient biomarker and epigenetic data will be linked with brain outcomes in children and older adults. In addition, we will investigate the nutrition-epigenome-brain relationship in B vitamin intervention trial participants using magnetoencephalography, a state-of-the-art neuroimaging modality to assess neuronal functioning. The project outcomes will provide an improved understanding of the role of folate and related B vitamins in brain health, and the epigenetic mechanisms involved. The results are expected to provide scientific substantiation to support nutritional strategies for better brain health across the lifecycle.

FcyRIIB is a novel immune checkpoint in the tumor microenvironment limiting activity of Treg-targeting antibodies.

Despite pre-clinical murine data supporting T regulatory (Treg) cell depletion as a major mechanism by which anti-CTLA-4 antibodies function in vivo, the two main antibodies tested in patients (ipilimumab and tremelimumab) have failed to demonstrate similar effects. We report analogous findings in an immunocompetent murine model humanized for CTLA-4 and Fcy receptors (hCTLA-4/hFcyR mice), where both ipilimumab and tremelimumab fail to show appreciable Treg depletion. Immune profiling of the tumor microenvironment (TME) in both mice and human samples revealed upregulation of the inhibitory Fcy receptor, FcyRIIB, which limits the ability of the antibody Fc fragment of human anti-CTLA-4 antibodies to induce effective antibody dependent cellular cytotoxicty/phagocytosis (ADCC/ADCP). Blocking FcyRIIB in humanized mice rescues Treg depleting capacity and anti-tumor activity of ipilimumab. For another target, CC motif chemokine receptor 8 (CCR8), which is selectively expressed on tumor infiltrating Tregs, we show that Fc engineering to enhance binding to activating Fc receptors, while limiting binding to the inhibitory Fc receptor, leads to consistent Treg depletion and single-agent activity across multiple tumor models, including B16, MC38 and MB49. These data reveal the importance of reducing engagement to the inhibitory Fc receptor to optimize Treg depletion by TME targeting antibodies. Our results define the inhibitory FcyRIIB receptor as a novel immune checkpoint limiting antibody-mediated Treg depletion in tumors, and demonstrate Fc variant engineering as a means to overcome this limitation and augment efficacy for a repertoire of antibodies currently in use or under clinical evaluation in oncology.

Association between testosterone and cognitive performance in postmenopausal women: a systematic review of observational studies.

This review was conducted to explore the association between endogenous testosterone blood concentrations and cognitive performance among community dwelling postmenopausal women. We searched Ovid MEDLINE, EMBASE, PsycINFO and Web of Science databases for observational studies with at least 100 postmenopausal participants. The results were categorized by study design, reporting of total or free testosterone and risk of bias assessments, narratively. Ten of the 26 articles retrieved for full-text review met the inclusion criteria, six provided cross-sectional data, seven provided longitudinal data and one provided case-control data. Cognitive performance tests differed between studies. Eight studies measured testosterone by immunoassay, one by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and one did not specify their methodology. Eleven different cognitive domains were tested by 37 different instruments. Irrespective of the study design, the findings were inconsistent and inconclusive. Both positive and inverse associations were reported for each of global cognition and immediate and delayed verbal recall. The majority of studies reported no association between total or free testosterone and cognitive performance. Although this review did not demonstrate an association between testosterone and cognitive performance in postmenopausal women, the findings should be considered inconclusive due to the imprecision of testosterone measurement and the methodological heterogeneity of the included studies.

Chemoradiation therapy alters the PD-L1 score in locoregional recurrent squamous cell carcinomas of the head and neck.

PD-L1 testing guides therapeutic decision-making for head and neck squamous cell carcinoma (HNSCC). We sought to understand whether chemoradiation therapy (CRT) influences the PD-L1 combined positive score (CPS) and other biomarkers of response to immunotherapy. PD-L1 expression was assessed using immunohistochemistry, and bulk RNA sequencing was performed on 146 HNSCC patients (65 primary sites, 50 paired local recurrences, and 31 paired regional recurrences). PD-L1 was scored using the CPS of ≥1, ≥20, and ≥50. Overall, 98 %, 54 %, and 17 % of HNSCCs had a CPS ≥1, ≥20, and ≥50, respectively. When using a cut-off of ≥1, CRT did not significantly change CPS at the locoregional recurrent site. However, there were significant changes when using CPS ≥20 or ≥50. The CPS changed for 32 % of patients when using a CPS ≥20 (p < 0.001). When using a CPS ≥50, there was a 20-23 % (p = 0.0058-0.00067) discordance rate at the site of locoregional recurrence. Oral cavity cancers had a significantly higher discordant rate than other primary sites for CPS ≥50, 44 % (8/18, p = 0.0058) and 58 % (7/12, p = 0.00067) discordance at the site of local and regional recurrence, respectively. When evaluating the 18 gene IFN-É£ signature predictive of response to anti-PD-1 blockade, there was a statistically significant increase in the IFN-É£ signature in recurrent larynx cancer (p = 0.02). Our study demonstrates that when using a higher cut-off of CPS ≥20 and ≥50, a repeat biopsy may be warranted after CRT for local and regional recurrent HNSCCs.

Corrigendum to 'Diuretics and the kidney'[BJA Education 22 (2022) 216-23].

[This corrects the article DOI: 10.1016/j.bjae.2022.02.003.].

Moving beyond the T cell synapse for combination neoadjuvant immunotherapy in head and neck cancer.

Patients with HPV-unrelated head and neck squamous cell carcinoma (HPV-unrelated HNSCC) show only modest benefit from treatment with PD-1 inhibitors (PD-1i). Targeting transforming growth factor ß (TGF-ß) may make PD-1i more effective by inducing T cell responses. In this issue of the JCI, Redman et al. performed a clinical trial in 14 patients with HPV-unrelated HNSCC using bintrafusp alfa, a bifunctional fusion protein that blocks PD-L1 and TGF-ß. Primary tumors displayed pathologic responses with 5 of 14 patients having at least a partial response. While no primary tumor or metastatic lymph node demonstrated a complete pathologic response, the findings suggest that concurrent neoadjuvant inhibition of PD-L1 and TGF-ß may provide a rational strategy to improve pathologic response and clinical outcome in patients with HPV-unrelated HNSCC.

Immunotherapy in head and neck squamous cell carcinoma: a narrative review.

Objective: Provide a narrative review of the literature describing immunological concepts and novel approaches in the treatment of head and neck squamous cell carcinoma. Background: In 2016, two anti-PD1 antibodies, nivolumab and pembrolizumab, were shown to improve overall survival in patients with recurrent/metastatic HNSCC and were approved by the US Food and Drug Administration (FDA) for use in the second line, cisplatin-resistant setting, although the overall response rates were only about 15%. More recently, pembrolizumab was approved for use in the first-line R/M setting as monotherapy in patients with CPS >1 or in combination with chemotherapy regardless of PD-L1 expression. Interestingly, while response rates with combination therapy were increased compared to pembrolizumab alone, the duration of response was shorter than might be expected. Based on a growing amount of evidence in other types of cancer treated with various combinations of immunotherapy, similar concepts are being studied in HNSCC, both in pre-clinical models and in clinical trials. Methods: A review of the literature was conducted using the Medline-PubMed and ClinicalTrials.gov databases. Main topics were selected for review, including basic immunology background, checkpoint inhibition, neoadjuvant immunotherapy, the combination of immunotherapy with radiation therapy and chemotherapy, intratumoral immunotherapy, and future prospects. Conclusions: There is an ongoing effort, which is supported by an increasing body of evidence, to enhance response rates with combinations of immunotherapy with other immunotherapy agents, targeted small molecules, chemotherapy, radiation therapy, and surgery. The clinician and the scientist should be familiarized with basic immunologic concepts, key findings in recent clinical trials, and current indications for administering immunotherapy.

Remote ischaemic conditioning: defining critical criteria for success-report from the 11th Hatter Cardiovascular Workshop.

The Hatter Cardiovascular Institute biennial workshop, originally scheduled for April 2020 but postponed for 2 years due to the Covid pandemic, was organised to debate and discuss the future of Remote Ischaemic Conditioning (RIC). This evolved from the large multicentre CONDI-2-ERIC-PPCI outcome study which demonstrated no additional benefit when using RIC in the setting of ST-elevation myocardial infarction (STEMI). The workshop discussed how conditioning has led to a significant and fundamental understanding of the mechanisms preventing cell death following ischaemia and reperfusion, and the key target cyto-protective pathways recruited by protective interventions, such as RIC. However, the obvious need to translate this protection to the clinical setting has not materialised largely due to the disconnect between preclinical and clinical studies. Discussion points included how to adapt preclinical animal studies to mirror the patient presenting with an acute myocardial infarction, as well as how to refine patient selection in clinical studies to account for co-morbidities and ongoing therapy. These latter scenarios can modify cytoprotective signalling and need to be taken into account to allow for a more robust outcome when powered appropriately. The workshop also discussed the potential for RIC in other disease settings including ischaemic stroke, cardio-oncology and COVID-19. The workshop, therefore, put forward specific classifications which could help identify so-called responders vs. non-responders in both the preclinical and clinical settings.

Adjuvant and Neoadjuvant Therapies in Cutaneous Melanoma.

Melanoma is the most common cause of skin cancer-related death in the United States. Cutaneous melanoma is most prevalent in the head and neck. The long-term prognosis has been poor and chemotherapy is not curative. Complete surgical resection with locally advanced disease can be challenging and melanoma is resistant to radiation. Advances made in immunotherapy and genomically targeted therapy have transformed the treatment of metastatic melanoma; as of 2021, the 5-year survival for metastatic melanoma is greater than 50%. Ongoing clinical studies are underway to integrate these life-saving therapies into the presurgical or postsurgical settings. This article reviews that effort.

Genomic Epidemiology of Salmonella enterica Circulating in Surface Waters Used in Agriculture and Aquaculture in Central Mexico.

Salmonella enterica can survive in surface waters (SuWa), and the role of nonhost environments in its transmission has acquired increasing relevance. In this study, we conducted comparative genomic analyses of 172 S. enterica isolates collected from SuWa across 3 months in six states of central Mexico during 2019. S. enterica transmission dynamics were assessed using 87 experimental and 112 public isolates from Mexico collected during 2002 through 2019. We also studied genetic relatedness between SuWa isolates and human clinical strains collected in North America during 2005 through 2020. Among experimental isolates, we identified 41 S. enterica serovars and 56 multilocus sequence types (STs). Predominant serovars were Senftenberg (n = 13), Meleagridis, Agona, and Newport (n = 12 each), Give (n = 10), Anatum (n = 8), Adelaide (n = 7), and Infantis, Mbandaka, Ohio, and Typhimurium (n = 6 each). We observed a high genetic diversity in the sample under study, as well as clonal dissemination of strains across distant regions. Some of these strains are epidemiologically important (ST14, ST45, ST118, ST132, ST198, and ST213) and were genotypically close to those involved in clinical cases in North America. Transmission network analysis suggests that SuWa are a relevant source of S. enterica (0.7 source/hub ratio) and contribute to its dissemination as isolates from varied sources and clinical cases have SuWa isolates as common ancestors. Overall, the study shows that SuWa act as reservoirs of various S. enterica serovars of public health significance. Further research is needed to better understand the mechanisms involved in SuWa contamination by S. enterica, as well as to develop interventions to contain its dissemination in food production settings. IMPORTANCE Surface waters are heavily used in food production worldwide. Several human pathogens can survive in these waters for long periods and disseminate to food production environments, contaminating our food supply. One of these pathogens is Salmonella enterica, a leading cause of foodborne infections, hospitalizations, and deaths in many countries. This research demonstrates the role of surface waters as a vehicle for the transmission of Salmonella along food production chains. It also shows that some strains circulating in surface waters are very similar to those implicated in human infections and harbor genes that confer resistance to multiple antibiotics, posing a risk to public health. This study contributes to expand our current knowledge on the ecology and epidemiology of Salmonella in surface waters.

Cancer case trends following the onset of the COVID-19 pandemic: A community-based observational study with extended follow-up.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has impacted health care delivery worldwide. Cancer is a leading cause of death, and the impact of the pandemic on cancer diagnoses is an important public health concern. METHODS: This cross-sectional study retrospectively analyzed the electronic medical records of 80,138 cancer patients diagnosed between January 1, 2019, and May 31, 2021. Outcome measures included weekly number of new cancer cases and trends in weekly cancer cases, before and after the pandemic; patient demographics; and positive COVID-19 test rates. RESULTS: Beginning March 4, 2020, defined as the onset of the pandemic, weekly cancer cases declined precipitously (-110.0 cases per week [95% confidence interval, -190.2 to -29.8]) for 4 weeks, followed by a moderate recovery (+23.7 cases per week [9.1 to 38.4]) of 10 weeks duration. Thereafter, weekly cancer cases trended slowly back toward pre-COVID-19 baseline levels. Following the pandemic onset, there was a cumulative year-over-year decline in cancer cases overall of 7.3%, including a 20.2%, 14.3%, and 12.8% decline in nonmelanoma skin cancer, breast cancer, and prostate cancer, respectively. Changes in case volumes were accompanied by variations in patient characteristics, including region, age, gender, race, insurance coverage, and COVID-19 positive test rates (P < .01 for all). Among patients tested for COVID-19, 5.3% had a positive result. CONCLUSIONS: The data in this study demonstrate a substantial reduction in cancer diagnoses following the onset of COVID-19, which appear to reach expected pre-COVID norms 12 months later. The largest reduction was noted among cancers that are typically screen-detected or identified as part of a routine wellness examination.

"Custom" Plate in a Day-Accurate Predictive Hole Fabrication Using Point-of-Care 3-Dimensional Printing.

PURPOSE: In computer surgical planned (CSP) fibular reconstructions of the mandible, custom plates facilitate accurate and efficient transfer of the digital plan intraoperatively by a way of predrilled fixation holes. Stock plates are more easily accessible and are more economical but typically preclude the utilization of these predictive holes. The purpose of this article is to describe an accurate and economical alternative to custom plates, while still having the ability to create predictive holes for plate alignment and execution of a digital surgical plan. METHODS: An in vitro accuracy study was performed on a point-of-care resin-printed predictive hole guide termed "prebent plate analog" (PPA). Twenty stock 2.0 reconstruction plates prebent against a 3-dimensional printed mandibular model reconstructed with a 2-piece fibula were used to fabricate 20 PPAs. The proximal and distal 4 holes of each prebent plate and corresponding PPA were assessed using a heat map overlay, measuring difference in millimeters between matching points of the predictive hole segments. The median distance from the points of reference in the PPA versus the prebent plate was calculated for each predictive hole position in addition to the average error of the PPA to the stock plate. RESULTS: Eighteen PPAs were used for statistical analysis; 2 were damaged in transport. The mean error between the body (-0.265) and condylar segments (-0.116 mm) and mean difference in error between the proximal predictive holes (-0.124 mm) and distal predictive holes (-0.215 mm) on the PPA were not statistically different (P = .061, P = .314 general estimating equation regression, respectively). The mean error across the PPA predictive holes and corresponding holes of the prebent plates was -0.194 mm (P < .001, general estimating equation regression). CONCLUSIONS: The PPA is a precise and accurate analog that faithfully replicates the position of proximal and distal components of a prebent stock plate, thereby allowing for predictive hole placement in lieu of a custom plate in fibula mandibular reconstruction cases.

Adolescent opioid abuse: Role of glial and neuroimmune mechanisms.

Opioids are widely prescribed for pain management, and prescription opioid misuse in adolescents has become a major epidemic in the United States and worldwide. Emerging data indicate that adolescence represents a critical period of brain development, and exposure to opioids during adolescence may increase the risk of addiction in adulthood. There is growing evidence that disruptions in brain glial function may be implicated in numerous chronic neuropathologies. Evidence suggests that glial mechanisms have an important role in the development and maintenance of opioid abuse and the risk for addiction. This review will describe glial and neuroimmune mechanisms involved in opioid use disorders during adolescence, which may increase substance use disorder liability later in life. Moreover, this review will identify some important neuro-glial targets, involved in opioid abuse and addiction, to develop future preventions and treatment strategies.

Phase II Randomized Trial of Transoral Surgery and Low-Dose Intensity Modulated Radiation Therapy in Resectable p16+ Locally Advanced Oropharynx Cancer: An ECOG-ACRIN Cancer Research Group Trial (E3311).

PURPOSE: Definitive or postoperative chemoradiation (CRT) is curative for human papillomavirus-associated (HPV+) oropharynx cancer (OPC) but induces significant toxicity. As a deintensification strategy, we studied primary transoral surgery (TOS) and reduced postoperative radiation therapy (RT) in intermediate-risk HPV+ OPC. METHODS: E3311 is a phase II randomized trial of reduced- or standard-dose postoperative RT for resected stage III-IVa (American Joint Committee on Cancer-seventh edition) HPV+ OPC, determined by pathologic parameters. Primary goals were feasibility of prospective multi-institutional study of TOS for HPV+ OPC, and oncologic efficacy (2-year progression-free survival) of TOS and adjuvant therapy in intermediate-risk patients after resection. TOS plus 50 Gy was considered promising if the lower limit of the exact 90% binomial confidence intervals exceeded 85%. Quality of life and swallowing were measured by functional assessment of cancer therapy-head and neck and MD Anderson Dysphagia Index. RESULTS: Credentialed surgeons performed TOS for 495 patients. Eligible and treated patients were assigned as follows: arm A (low risk, n = 38) enrolled 11%, intermediate risk arms B (50 Gy, n = 100) or C (60 Gy, n = 108) randomly allocated 58%, and arm D (high risk, n = 113) enrolled 31%. With a median 35.2-month follow-up for 359 evaluable (eligible and treated) patients, 2-year progression-free survival Kaplan-Meier estimate is 96.9% (90% CI, 91.9 to 100) for arm A (observation), 94.9% (90% CI, 91.3 to 98.6]) for arm B (50 Gy), 96.0% (90% CI, 92.8 to 99.3) for arm C (60 Gy), and 90.7% (90% CI, 86.2 to 95.4) for arm D (66 Gy plus weekly cisplatin). Treatment arm distribution and oncologic outcome for ineligible or step 2 untreated patients (n = 136) mirrored the 359 evaluable patients. Exploratory comparison of functional assessment of cancer therapy-head and neck total scores between arms B and C is presented. CONCLUSION: Primary TOS and reduced postoperative RT result in outstanding oncologic outcome and favorable functional outcomes in intermediate-risk HPV+ OPC.

Updates in Management of Craniomaxillofacial Gunshot Wounds and Reconstruction of the Mandible.

This article includes updates in the management of mandibular trauma and reconstruction as they relate to maxillomandibular fixation screws, custom hardware, virtual surgical planning, and protocols for use of computer-aided surgery and navigation when managing composite defects from gunshot injuries to the face.