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We performed the first integrative single-cell and spatial transcriptomic analysis on HPV-negative oral squamous cell carcinoma (OSCC) to comprehensively characterize tumor core (TC) and leading edge (LE) transcriptional architectures. We show that the TC and LE are characterized by unique transcriptional profiles, cellular compositions, and ligand-receptor interactions. We demonstrate that LE regions are conserved across multiple cancers while TC states are more tissue specific. Additionally, we found our LE gene signature is associated with worse clinical outcomes while the TC gene signature is associated with improved prognosis across multiple cancer types. Finally, using an in silico modeling approach, we describe spatially-regulated patterns of cell development in OSCC that are predictably associated with drug response. Our work provides pan-cancer insights into TC and LE biologies, a platform for data exploration (http://www.pboselab.ca/spatial_OSCC/) and is foundational for developing novel targeted therapies.

SummaryBackgroundWe aimed to systematically review the magnitude and duration of the protective effectiveness of prior infection (PE) and hybrid immunity (HE) against Omicron infection and severe disease.MethodsWe searched pre-print and peer-reviewed electronic databases for controlled studies from January 1, 2020, to June 1, 2022. Risk of bias (RoB) was assessed using the Risk of Bias In Non-Randomized Studies of Interventions (ROBINS-I)-Tool. We used random-effects meta-regression to estimate the magnitude of protection at 1-month intervals and the average change in protection since the last vaccine dose or infection from 3 months to 6 or 12 months. We compared our estimates of PE and HE to previously published estimates of the magnitude and durability of vaccine effectiveness (VE) against Omicron.FindingsEleven studies of prior infection and 15 studies of hybrid immunity were included. For prior infection, there were 97 estimates (27 at moderate RoB and 70 at serious RoB), with the longest follow up at 15 months. PE against hospitalization or severe disease was 82·5% [71·8-89·7%] at 3 months, and 74·6% [63·1-83·5%] at 12 months. PE against reinfection was 65·2% [52·9-75·9%] at 3 months, and 24·7% [16·4-35·5%] at 12 months. For HE, there were 153 estimates (78 at moderate RoB and 75 at serious RoB), with the longest follow up at 11 months for primary series vaccination and 4 months for first booster vaccination. Against hospitalization or severe disease, HE involving either primary series vaccination or first booster vaccination was consistently >95% for the available follow up. Against reinfection, HE involving primary series vaccination was 69·0% [58·9-77·5%] at 3 months after the most recent infection or vaccination, and 41·8% [31·5-52·8%] at 12 months, while HE involving first booster vaccination was 68·6% [58·8-76·9%] at 3 months, and 46·5% [36·0-57·3%] at 6 months. Against hospitalization or severe disease at 6 months, hybrid immunity with first booster vaccination (effectiveness 95·3% [81·9-98·9%]) or with primary series alone (96·5% [90·2-98·8%]) provided significantly greater protection than prior infection alone (80·1% [70·3-87·2%]), first booster vaccination alone (76·7% [72·5-80·4%]), or primary series alone (64·6% [54·5-73·6%]). Results for protection against reinfection were similar.InterpretationPrior infection and hybrid immunity both provided greater and more sustained protection against Omicron than vaccination alone. All protection estimates waned quickly against infection but remained high for hospitalisation or severe disease. Individuals with hybrid immunity had the highest magnitude and durability of protection against all outcomes, reinforcing the global imperative for vaccination.FundingWHO COVID-19 Solidarity Response Fund and the Coalition for Epidemic Preparedness Innovations.Research in contextEvidence before this studyThe global emergence and rapid spread of Omicron (B.1.1.529) variant of concern, characterized by their ability to escape immunity, has required scientists and policymakers to reassess the population protection against Omicron infection and severe disease. So far, few systematic reviews have incorporated data on Omicron, and none have examined the protection against Omicron conferred by hybrid immunity (i.e. the immunity gained from the combination of vaccination and prior infection) which is now widespread globally. While one preprint has recently reported protection from prior infection over time, no systematic review has systematically compared the magnitude and duration of vaccination, prior infection, and hybrid immunity. A large single-country study has reported that protection from either infection or hybrid immunity against Omicron infection wanes to low levels at 15 months, but is relatively stable against severe disease.Added value of this studyPrior infection and hybrid immunity both provided greater and more sustained protection against Omicron than vaccination alone. Individuals with hybrid immunity had the highest magnitude and durability of protection against all outcomes; protection against severe disease remained above 95% until the end of available follow-up at 11 months after hybrid immunity with primary series and 4 months after hybrid immunity with booster vaccination, and was sustained at these high levels of protection in projections to 12 months and 6 months, respectively.Implications of all the available evidenceThese results may serve to tailor guidance on the optimal number and timing of vaccinations. At the public health level, these findings can be combined with data on local infection prevalence, vaccination rates, and their timing. In settings with high seroprevalence, limited resources, and competing health priorities, it may be reasonable to focus on achieving high coverage rates with primary series among individuals who are at higher risk of poor outcome, as this will provide a high level of protection against severe disease for at least one year among those with prior infection. Furthermore, given the waning protection for both infection-and vaccine induced immunity against infection or reinfection, mass vaccination could be timed for roll-out prior to periods of expected increased incidence, such as the winter season. At the individual level, these results can be combined with knowledge of a person’s infection and vaccination history. A six-month delay in booster may be justified after the last infection or vaccination for individuals with a known prior infection and full primary series vaccination. Further follow-up of the protective effectiveness of hybrid immunity against hospitalization or severe disease for all vaccines is needed to clarify how much waning of protection might occur with longer duration since the last infection or vaccination. Producing estimates of protection for new variant-containing vaccines will be crucial for COVID-19 vaccine policy and decision-making bodies. Policy makers considering the use and timing of vaccinations should include the local extent of past infection, the protection conferred by prior infection or hybrid immunity, and the duration of this protection as key considerations to inform their decision-making.

Miniaturization and portable devices have reshaped the electronic device landscape, emphasizing the importance of high performance while maintaining energy efficiency to ensure long battery life. FinFET and Tunnel-FET technologies have emerged as attractive alternatives to overcome the limitations of supply voltage scaling for ultra-low power applications. This work compares the performance of 10 nm FinFET- and TFET-based digital circuits from basic logic gates up to an 8k gates low-power microprocessor. When compared with their FinFET-based counterparts, the TFET-based logic gates have lower leakage power when operated below 300 mV, show higher input capacitance, and exhibit a reduced propagation delay under different fan-in and fan-out conditions. Our comparative study was extended to the synthesis of an MSP-430 microprocessor through standard cell libraries built particularly for this work. It is demonstrated that the TFET-based synthesized circuits operating at ultra-low voltages achieve a higher performance in terms of speed at the cost of increased power consumption. When the speed requirements are relaxed, the TFET-based designs are the most energy-efficient alternative. It is concluded that the TFET is an optimal solution for ultra-low voltage design.

IntroductionEstimating COVID-19 cumulative incidence in Africa remains problematic due to challenges in contact tracing, routine surveillance systems and laboratory testing capacities and strategies. We undertook a meta-analysis of population-based seroprevalence studies to estimate SARS-CoV-2 seroprevalence in Africa to inform evidence-based decision making on public health and social measures (PHSM) and vaccine strategy.MethodsWe searched for seroprevalence studies conducted in Africa published 1 January 2020–30 December 2021 in Medline, Embase, Web of Science and Europe PMC (preprints), grey literature, media releases and early results from WHO Unity studies. All studies were screened, extracted, assessed for risk of bias and evaluated for alignment with the WHO Unity seroprevalence protocol. We conducted descriptive analyses of seroprevalence and meta-analysed seroprevalence differences by demographic groups, place and time. We estimated the extent of undetected infections by comparing seroprevalence and cumulative incidence of confirmed cases reported to WHO.PROSPERO: CRD42020183634.ResultsWe identified 56 full texts or early results, reporting 153 distinct seroprevalence studies in Africa. Of these, 97 (63%) were low/moderate risk of bias studies. SARS-CoV-2 seroprevalence rose from 3.0% (95% CI 1.0% to 9.2%) in April–June 2020 to 65.1% (95% CI 56.3% to 73.0%) in July–September 2021. The ratios of seroprevalence from infection to cumulative incidence of confirmed cases was large (overall: 100:1, ranging from 18:1 to 954:1) and steady over time. Seroprevalence was highly heterogeneous both within countries—urban versus rural (lower seroprevalence for rural geographic areas), children versus adults (children aged 0–9 years had the lowest seroprevalence)—and between countries and African subregions.ConclusionWe report high seroprevalence in Africa suggesting greater population exposure to SARS-CoV-2 and potential protection against COVID-19 severe disease than indicated by surveillance data. As seroprevalence was heterogeneous, targeted PHSM and vaccination strategies need to be tailored to local epidemiological situations.

BackgroundRisk of bias (RoB) assessments are a core element of evidence synthesis but can be time consuming and subjective. We aimed to develop a decision rule-based algorithm for RoB assessment of seroprevalence studies.MethodsWe developed the SeroTracker-RoB algorithm. The algorithm derives seven objective and two subjective critical appraisal items from the Joanna Briggs Institute Critical Appraisal Checklist for Prevalence studies and implements decision rules that determine study risk of bias based on the items. Decision rules were validated using the SeroTracker seroprevalence study database, which included non-algorithmic RoB judgements from two reviewers. We quantified efficiency as the mean difference in time for the algorithmic and non-algorithmic assessments of 80 randomly selected articles, coverage as the proportion of studies where the decision rules yielded an assessment, and reliability using intraclass correlations comparing algorithmic and non-algorithmic assessments for 2,070 articles.ResultsA set of decision rules with 61 branches was developed using responses to the nine critical appraisal items. The algorithmic approach was faster than non-algorithmic assessment (mean reduction 2.32 minutes [SD 1.09] per article), classified 100% (n=2,070) of studies, and had good reliability compared to non-algorithmic assessment (ICC 0.77, 95% CI 0.74-0.80). We built the SeroTracker-RoB Excel Tool which embeds this algorithm for use by other researchers.ConclusionsThe SeroTracker-RoB decision-rule based algorithm was faster than non-algorithmic assessment with complete coverage and good reliability. This algorithm enabled rapid, transparent, and reproducible RoB evaluations of seroprevalence studies and may support evidence synthesis efforts during future disease outbreaks. This decision rule-based approach could be applied to other types of prevalence studies.

The trade-offs of the Tunnel-FETs (TFETs) in terms of delay, energy per cycle, and noise margin are compared with 10 nm FinFETs for a wide voltage supply ranging from 200 to 600 mV with a specific focus on the ultra-low voltage domain. A calibration process is carried out to ensure the same off-current and extrinsic capacitance in both devices. The TFETs presented a high advantage in terms of delay as well as a penalty in energy consumed. As a result, the TFET circuits show a better Energy-Delay trade-off in voltages as low as 350 m V. This is explained by a larger capacitance caused by the nature of the intrinsic materials chosen of the device modelling.

Population-level immune surveillance, which includes monitoring exposure and assessing vaccine-induced immunity, is a crucial component of public health decision-making during a pandemic. Serosurveys estimating the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in the population played a key role in characterizing SARS-CoV-2 epidemiology during the early phases of the pandemic. Existing serosurveys provide infrastructure to continue immune surveillance but must be adapted to remain relevant in the SARS-CoV-2 vaccine era. Here, we delineate how SARS-CoV-2 serosurveys should be designed to distinguish infection- and vaccine-induced humoral immune responses to efficiently monitor the evolution of the pandemic. We discuss how serosurvey results can inform vaccine distribution to improve allocation efficiency in countries with scarce vaccine supplies and help assess the need for booster doses in countries with substantial vaccine coverage.

e18043 Background: Head and neck cancer is the 6th most common cancer worldwide. Oral squamous cell carcinoma (OSCC) is the most prevalent head and neck cancer that is characterized by aggressive local invasion and metastasis. Despite the leading edge (invasive front) of the tumor being a driver of OSCC pathophysiology, its biology and clinical relevance have not been fully characterized. We used spatial transcriptomics to explore signaling patterns within the leading edge and tumor core. Methods: Fresh-frozen, surgically resected OSCC samples from three HPV-negative OSCC patients were profiled using the 10x Genomics Visium Spatial Gene Expression platform. Leading edge and tumor core regions were defined by pathologist annotations and expression of previously identified edge and core gene signatures from the literature. Spatial differential gene expression (DGE) analysis and pathway analysis was performed using the Seurat package and Ingenuity Pathway Analysis (IPA), respectively. Cell-cell interaction networks were reconstructed using the CellChat package. Results: The leading edge and tumor core displayed unique transcriptional and signaling profiles that were conserved across all three OSCC patient samples. DEG analysis revealed 31 genes enriched in the leading edge and 62 genes enriched in the tumor core with a log2FC > 0.58 and adjusted p-value < 0.01. The top genes upregulated in the leading edge were FN1, COL1A1, COL1A2, IFITM3, and SPARC. Top tumor-core genes included CRCT1, LCE3D, DEFB4A, SPRR2A, and CNFN. IPA analysis of upregulated DEGs in the leading edge and tumor core predicted the activation of wound healing and GP6 signaling pathways, and activation of intrinsic prothrombin activation and MSP-RON signaling pathways, respectively. Cell communication analysis revealed that the leading edge had higher intercellular signaling than the tumor core. Upregulated leading edge cell signaling modules included collagen, CD99, CSPG4, and non-canonical WNT pathways, which have been linked to tumor invasion, metastasis, and adhesion. COL1A1 and COL1A2 ligands and CD44 and SDC1 receptors were upregulated in leading edge signaling. The tumor core was enriched for ANGPTL and PERIOSTIN cell signaling modules. Conclusions: This is the first study to characterize the tumor core and leading edge of OSCC tumors using spatial transcriptomics. Further investigation of the therapeutic potential of identified signaling pathways may improve OSCC outcomes.

BackgroundMany studies report the seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies. We aimed to synthesize seroprevalence data to better estimate the level and distribution of SARS-CoV-2 infection, identify high-risk groups, and inform public health decision making.MethodsIn this systematic review and meta-analysis, we searched publication databases, preprint servers, and grey literature sources for seroepidemiological study reports, from January 1, 2020 to December 31, 2020. We included studies that reported a sample size, study date, location, and seroprevalence estimate. We corrected estimates for imperfect test accuracy with Bayesian measurement error models, conducted meta-analysis to identify demographic differences in the prevalence of SARS-CoV-2 antibodies, and meta-regression to identify study-level factors associated with seroprevalence. We compared region-specific seroprevalence data to confirmed cumulative incidence. PROSPERO: CRD42020183634.ResultsWe identified 968 seroprevalence studies including 9.3 million participants in 74 countries. There were 472 studies (49%) at low or moderate risk of bias. Seroprevalence was low in the general population (median 4.5%, IQR 2.4–8.4%); however, it varied widely in specific populations from low (0.6% perinatal) to high (59% persons in assisted living and long-term care facilities). Median seroprevalence also varied by Global Burden of Disease region, from 0.6% in Southeast Asia, East Asia and Oceania to 19.5% in Sub-Saharan Africa (pDiscussionMost of the population remains susceptible to SARS-CoV-2 infection. Public health measures must be improved to protect disproportionately affected groups, including racial and ethnic minorities, until vaccine-derived herd immunity is achieved. Improvements in serosurvey design and reporting are needed for ongoing monitoring of infection prevalence and the pandemic response.

BackgroundMany studies report the seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies. We aimed to synthesize seroprevalence data to better estimate the level and distribution of SARS-CoV-2 infection, identify high-risk groups, and inform public health decision making.MethodsIn this systematic review and meta-analysis, we searched publication databases, preprint servers, and grey literature sources for seroepidemiological study reports, from January 1, 2020 to December 31, 2020. We included studies that reported a sample size, study date, location, and seroprevalence estimate. We corrected estimates for imperfect test accuracy with Bayesian measurement error models, conducted meta-analysis to identify demographic differences in the prevalence of SARS-CoV-2 antibodies, and meta-regression to identify study-level factors associated with seroprevalence. We compared region-specific seroprevalence data to confirmed cumulative incidence. PROSPERO: CRD42020183634.ResultsWe identified 968 seroprevalence studies including 9.3 million participants in 74 countries. There were 472 studies (49%) at low or moderate risk of bias. Seroprevalence was low in the general population (median 4.5%, IQR 2.4-8.4%); however, it varied widely in specific populations from low (0.6% perinatal) to high (59% persons in assisted living and long-term care facilities). Median seroprevalence also varied by Global Burden of Disease region, from 0.6 % in Southeast Asia, East Asia and Oceania to 19.5% in Sub-Saharan Africa (pDiscussionMost of the population remains susceptible to SARS-CoV-2 infection. Public health measures must be improved to protect disproportionately affected groups, including racial and ethnic minorities, until vaccine-derived herd immunity is achieved. Improvements in serosurvey design and reporting are needed for ongoing monitoring of infection prevalence and the pandemic response.FundingPublic Health Agency of Canada through the COVID-19 Immunity Task Force.

Background Use of sodium-glucose cotransporter-2 (SGLT2) inhibitors has been associated with Fournier gangrene (FG), a rare urologic emergency characterized by necrotizing infection of the external genitalia, perineum, and perianal region. Objective To describe and compare reported cases of FG in diabetic adults receiving treatment with SGLT2 inhibitors or other antiglycemic agents. Design Descriptive case series. Setting U.S. Food and Drug Administration (FDA) Adverse Event Reporting System and published case reports. Patients Adults receiving SGLT2 inhibitors or other antiglycemic agents. Measurements Clinical and laboratory data. Results The FDA identified 55 unique cases of FG in patients receiving SGLT2 inhibitors between 1 March 2013 and 31 January 2019. The patients ranged in age from 33 to 87 years; 39 were men, and 16 were women. Time to onset after initiation of SGLT2-inhibitor therapy ranged from 5 days to 49 months. All patients had surgical debridement and were severely ill. Reported complications included diabetic ketoacidosis (n = 8), sepsis or septic shock (n = 9), and acute kidney injury (n = 4). Eight patients had fecal diversion surgery, 2 patients developed necrotizing fasciitis of a lower extremity that required amputation, and 1 patient required a lower-extremity bypass procedure because of gangrenous toes. Three patients died. For comparison, the FDA identified 19 FG cases associated with other antiglycemic agents between 1984 and 31 January 2019: metformin (n = 8), insulin glargine (n = 6), short-acting insulin (n = 2), sitagliptin plus metformin (n = 2), and dulaglutide (n = 1). These patients ranged in age from 42 to 79 years; 12 were men, and 7 were women. Two patients died. Limitation Inability to establish causality or incidence, variable quality of reports, possible underreporting, and confounding by indication. Conclusion FG is a newly identified safety concern in patients receiving SGLT2 inhibitors. Physicians prescribing these agents should be aware of this possible complication and have a high index of suspicion to recognize it in its early stages. Primary funding source None.

Cu capping layer deposition plays an important role in BEOL plasma induced damage. In this paper, PID issue by Cu capping layer deposition process studied. The PID performance was studied with Cu capping layer deposition recipe optimization. And, the impact on PID performance of different Cu capping layer equipment was also compared. The PID performance is different with antenna ratio increase, both NMOS and PMOS PID performance with different antenna ratio have been investigated. In order to get clear supporting evidence for plasma damage, plasma charged voltage of wafer surface is also studied by Quantax in this paper. Finally we developed an optimized Cu capping layer deposition process with acceptable PID performance and without any reliability degradation.

As the development of technology node, ULK was used as isolation material in Cu damascene integration. ULK is a porous material with low mechanical strength and low adhesion. During CMP process, slurry additive and moisture will enter the hole of ULK material and result in the increasing of ULK K value, and also ULK film is easily damaged by mechanical force. To solve this problem, a capping layer is designed in Cu integration. In this paper, a novel barrier is developed to meet this integration need. Slurry chemistry/additives effect on RR selectivity and topo is evaluated in this paper.

As the technology node is advanced to 28nm and below, several new materials are introduced such as ultra low-k dielectric and metal hard mask. This presents critical chalenges to Cu-CMP in terms of k-shift, poor within-die uniformity and deteriorated breakdown voltage. Such issues must be resolved before moving to mass production. This paper presents a practical solution with improved barrier slurry and process for high performance of ULK/Cu interconnects at the advacned technology node. Through balancing the removal rates of various films, the reasonable topography is obtained. Slurry formulation refinement and post-CMP treatment are applied together to recover k value and to improve within-die range under optimized process conditions. While the surface property and breakdown voltage of the metal layer have been studied, it’s found that post-polish cleaning in combination with CMP slurry plays a major role to enhance reliability.