Immunometabolic Adaptation of CD19-Targeted CAR T Cells in the Central Nervous System Microenvironment of Patients Promotes Memory Development.

Metabolic reprogramming is a hallmark of T-cell activation, and metabolic fitness is fundamental for T-cell-mediated antitumor immunity. Insights into the metabolic plasticity of chimeric antigen receptor (CAR) T cells in patients could help identify approaches to improve their efficacy in treating cancer. Here, we investigated the spatiotemporal immunometabolic adaptation of CD19-targeted CAR T cells using clinical samples from CAR T-cell-treated patients. Context-dependent immunometabolic adaptation of CAR T cells demonstrated the link between their metabolism, activation, differentiation, function, and local microenvironment. Specifically, compared with the peripheral blood, low lipid availability, high IL15, and low TGFß in the central nervous system microenvironment promoted immunometabolic adaptation of CAR T cells, including upregulation of a lipolytic signature and memory properties. Pharmacologic inhibition of lipolysis in cerebrospinal fluid led to decreased CAR T-cell survival. Furthermore, manufacturing CAR T cells in cerebrospinal fluid enhanced their metabolic fitness and antileukemic activity. Overall, this study elucidates spatiotemporal immunometabolic rewiring of CAR T cells in patients and demonstrates that these adaptations can be exploited to maximize the therapeutic efficacy of CAR T cells. SIGNIFICANCE: The spatiotemporal immunometabolic landscape of CD19-targeted CAR T cells from patients reveals metabolic adaptations in specific microenvironments that can be exploited to maximize the therapeutic efficacy of CAR T cells.

The robotic NICE procedure outperforms conventional laparoscopic extracorporeal-assisted colorectal resection: results of a matched cohort analysis.

INTRODUCTION: We introduced the robotic NICE procedure for left-sided colorectal resection in 2018 in which the entire procedure is performed without loss of pneumoperitoneum and without an abdominal wall incision by performing natural orifice-assisted transrectal extraction of the specimen and intracorporeal anastomosis. We compare the results of the NICE procedure versus conventional laparoscopic resection, which was our standard approach prior to 2018. METHODS: A matched pair case-control study compared patients following the NICE procedure versus those who underwent laparoscopic left-sided colorectal resection with conventional extracorporeal-assisted technique. Cases were performed at an Academic Medical Center and recorded in a prospective database to analyze perioperative outcomes. RESULTS: From a total cohort of 352 patients, 83 were matched in each group. When comparing the NICE procedure vs. the Extracorporeal-Assisted laparoscopic group, there were no significant differences in age (58.5 vs. 59.3 years old), sex (47 vs. 42 Female), body mass index (27.4 vs. 27.5 kg/m2), ASA, diagnosis, or type of surgery. Operative time (198.8 vs. 197.7 min), blood loss (56.0 vs. 53.3 ml), intraoperative complications (0.0% vs. 0.0%), and conversion rates (0.0% vs. 0.0%) were similar in both groups. The NICE procedure was associated with significantly earlier return of bowel function (40.7 vs. 23.6 h), shorter length of stay (3.1 vs. 2.2 days), and lower total opioid use (94.6 vs. 70.5 morphine milligram equivalents). Overall, there were no differences in postoperative abscess formation, complications, readmission, or reoperation rates. CONCLUSION: When compared to conventional laparoscopic resection, the NICE procedure is associated with short-term benefits including earlier recovery and less opioid use without increased operative time or increased risk of complications. Multicenter studies are recommended to validate benefits and limitations of this technique.

Success rates and outcomes of the robotic NICE procedure across complicated and uncomplicated diverticulitis cases.

INTRODUCTION: We implemented the NICE procedure as a robotic natural orifice colorectal resection utilizing the rectum to extract the specimen and complete an intracorporal anastomosis for diverticulitis in 2018. Although complicated diverticulitis is associated with higher rates of conversion and post-operative morbidity, we hypothesized that the stepwise approach of the NICE procedure can be equally successful in this cohort. We aimed to compare feasibility and outcomes of the NICE procedure for uncomplicated and complicated diverticulitis. METHODS: Consecutive patients presenting with diverticulitis who underwent robotic NICE procedure from May 2018 through June 2021 were included. Cases were stratified into uncomplicated and complicated diverticulitis (fistula, abscess, or stricture). Demographic, clinical, disease, intervention, and outcomes data were analyzed. The main outcome measures were return of bowel function, length of stay, opioid consumption, and postoperative complications. RESULTS: Of a total of 190 patients, those presenting with uncomplicated diverticulitis (53.2%) were compared to those with complicated diverticulitis (47.8%). Uncomplicated diverticulitis had fewer low anterior resections (15.8% vs 49.4%; p < 0.001) and shorter median operative time (186 vs 220 min; p < 0.001). Both cohorts had equal rates of successful intracorporeal anastomosis (100%) and successful transrectal extraction (100% vs 98.9%; p = 0.285). Both cohorts had similar return of bowel function (median 21 h and 18.5; p = 0.149), median length of hospital stay (2 days, p = 0.015) and mean total opioid use (68.4 MME vs 67.3; p = 0.91). There were also no significant differences in overall postoperative complication rate over a 30-day time period (8.9% vs 12.5%; p = 0.44), readmission (6.9% vs 5.6%; p = 0.578) and reoperation (3% vs 4.5%; p = 0.578). CONCLUSION: Despite being inherently more complex and technically challenging, complicated diverticulitis patients have similar success rates and post-operative outcomes compared to uncomplicated diverticulitis patients when undergoing the NICE procedure. These results implicate the benefits of robotic natural orifice techniques may be even more pronounced in complicated diverticulitis patients.

Beyond Cellular Immunity: On the Biological Significance of Insect Hemocytes.

Insect immunity is assorted into humoral and cellular immune reactions. Humoral reactions involve the regulated production of anti-microbial peptides, which directly kill microbial invaders at the membrane and intracellular levels. In cellular immune reactions, millions of hemocytes are mobilized to sites of infection and replaced by hematopoiesis at a high biological cost after the immune defense. Here, we considered that the high biological costs of maintaining and replacing hemocytes would be a better investment if hemocytes carried out meaningful biological actions unrelated to cellular immunity. This idea allows us to treat a set of 10 hemocyte actions that are not directly involved in immunity, some of which, so far, are known only in Drosophila melanogaster. These include (1) their actions in molting and development, (2) in surviving severe hypoxia, (3) producing phenoloxidase precursor and its actions beyond immunity, (4) producing vitellogenin in a leafhopper, (5) recognition and responses to cancer in Drosophila, (6) non-immune actions in Drosophila, (7) clearing apoptotic cells during development of the central nervous system, (8) developing hematopoietic niches in Drosophila, (9) synthesis and transport of a lipoprotein, and (10) hemocyte roles in iron transport. We propose that the biological significance of hemocytes extends considerably beyond immunity.

The success rate of robotic natural orifice intracorporeal anastomosis and transrectal extraction (NICE procedure) in a large cohort of consecutive unselected patients.

BACKGROUND: The Robotic NICE procedure is a total intracorporeal natural orifice approach in which specimen extraction and anastomosis is accomplished without an abdominal wall incision other than the port sites themselves. We aim to present the success rate of the NICE procedure in a large cohort of unselected consecutive patients presenting with colorectal disease using a stepwise and reproducible robotic approach. METHODS: Consecutive patients who presented with benign or malignant disease requiring left-sided colorectal resection and anastomosis between May 2018 and June 2021 were evaluated. Data abstracted included demographic, clinical data, disease features, intervention data, and outcomes data. The main outcome was success rate of Intracorporeal anastomosis (ICA), transrectal extraction of specimen (TRSE), and conversion rate. RESULTS: A total of 306 patients underwent NICE procedure. Diverticulitis was the main diagnosis (64%) followed by colorectal neoplasm (27%). Median operative time was 219 min, and the median estimated blood loss was 50 ml. ICA was achieved in all cases (100%). TRSE was successfully achieved in 95.4% of cases. In 14 patients (4.6%), an abdominal incision was required due to inability to extract a bulky specimen through the rectum. There overall postoperative complications rate was 12.4%. Eight patients (2.6%) experienced postoperative ileus. There were no superficial or deep surgical site infection (SSI). Eleven patients (3.6%) developed organ SSI space including 5 patients with intra-abdominal abscess and 4 patients with anastomotic leak. There was one mortality (0.3%) due to toxic megacolon from resistant Clostridium difficile. The 30-day reoperation rate was 2.9% (n = 9) including six patients presenting with organ space SSI and three patients with postoperative obstruction at the diverting loop ileostomy site. CONCLUSION: The NICE procedure is associated with a very high success rate for both intracorporeal anastomosis and transrectal specimen extraction in a large cohort of unselected patients.

Why can insects not biosynthesize cholesterol?

Two aspects of insect lipid biochemistry differ from the mammalian background. In one aspect, nearly a hundred years ago scientists demonstrated that the polyunsaturated fatty acid (PUFAs), linoleic acid (LA; 18:2n-6) is an essential nutrient in the diets of all mammals that have been studied in that regard. An unknown number of insect species are able to biosynthesize LA de novo. Some species take the biosynthesized LA into fatty acid elongation/desaturation pathways to produce other PUFAs, 18:3n-6, 20:3n-6 and 20:4n-6. A couple of species use the de novo produced LA to biosynthesize prostaglandins and other eicosanoids, short-lived signal moieties that mediate important physiological actions in immunity and reproduction. Insects differ from mammals, also, in their lack of genes that encode enzymes acting in biosynthesis of cholesterol. Insects require dietary cholesterol to meet their cellular, physiological, developmental, and reproductive needs. Looking at a broader view of invertebrate biochemistry, most protostomes lost all or most genes involved in cholesterol biosynthesis. The massive gene loss occurred during the Ediacaran Period, which lasted 96 million years, from the end of the Cryogenian Period (635 million years ago; MYA) to the beginning of the Cambrian Period (538.6 MYA). The key point here is that the inability to biosynthesize cholesterol is not limited to insects; it occured in most protostomes. We address the protostome need and benefits of acquiring exogenous sterols.

A national evaluation of the predictors of compliance and survival from adjuvant chemotherapy in high-risk stage II colon cancer: A National Cancer Database (NCDB) analysis.

BACKGROUND: Guidelines recommend adjuvant chemotherapy for stage II colon cancer with high-risk features, but there has been little study on compliance with guidelines. This work sought to evaluate compliance with adjuvant chemotherapy and factors associated with compliance in high-risk stage II colon cancer. This work's hypothesis was that compliance with adjuvant chemotherapy recommendations is low, but improves overall survival when used. METHODS: The National Cancer Database was reviewed for stage II high-risk colon cancers that underwent curative resection from 2010 to 2017. The cases were stratified into adjuvant chemotherapy and no adjuvant chemotherapy cohorts. A multivariate logistic regression identified factors associated with adjuvant chemotherapy compliance. Propensity-score matching was performed to balance the cohorts and Kaplan-Meier analysis assessed overall survival. The main outcome measures were adjuvant chemotherapy compliance, factors associated with compliance, and overall survival in high-risk stage II colon cancer. RESULTS: A total of 52,609 patients were evaluated, and 23.2% received adjuvant chemotherapy. The factors associated with noncompliance included older age (odds ratio 0.919; 95% confidence interval 0.915-0.922; P < .001), Medicaid (odds ratio 0.720; 95% confidence interval 0.623-0.832; P < .001) payor, greater comorbidities (odds ratio 0.423; 95% confidence interval 0.334-0.530; P < .001), and residing in the Midwest (odds ratio 0.898; 95% confidence interval 0.812-0.994; P = .037). All of the known high-risk features were significantly independently associated with compliance. In a matched cohort, adjuvant chemotherapy significantly improved the 5-year overall survival (78.1% vs 66.6%; P < .001). CONCLUSION: Nationally, there is low compliance with adjuvant chemotherapy in high-risk stage II colon cancer. Despite the low compliance, adjuvant chemotherapy was associated with improved overall survival. Demographic variables were associated with poor compliance, whereas tumor factors were associated with increased compliance. These results highlighted the disparities in care and opportunities to improve outcomes in high-risk stage II colon cancer.

Land Use Influences the Composition and Antimicrobial Effects of Propolis.

Honey bee propolis is a complex, resinous mixture created by bees using plant sources such as leaves, flowers, and bud exudates. This study characterized how cropland surrounding apiaries affects the chemical composition and antimicrobial effects of propolis. The chemical composition and compound abundance of the propolis samples were analyzed using Gas Chromatography-Mass Spectrometry (GC-MS) and the antimicrobial effects were analyzed using the 50% minimum inhibitory concentration (MIC50) assay against four relevant bee pathogens, Serratia marcescens, Paenibacillus larvae, Lysinibacillus sphaericus, and Klebsiella pneumoniae. Propolis composition varied significantly with apiary, and cropland coverage predicted mean sum abundance of compounds. The apiary with the highest cropland coverage exhibited significantly higher MIC50 values for S. marcescens and K. pneumoniae compared to other apiaries. These results demonstrate that agricultural land use surrounding honey bee apiaries decreases the chemical quality and antimicrobial effects of propolis, which may have implications for the impacts of land use on hive immunity to potential pathogens.

Robotic NICE Procedure Using Handsewn Technique.

INTRODUCTION: In 2018, we described a robotic natural orifice-assisted left-sided colorectal resection with intracorporeal anastomosis and transrectal extraction of the specimen and termed it the natural orifice intracorporeal anastomosis with transrectal extraction procedure. More recently, we have explored the feasibility, safety, and utility of performing total handsewn intracorporeal anastomosis. We present a technical video and initial experience depicting the unique steps to accomplish this procedure with colorectal end-to-end handsewn anastomosis. TECHNIQUE: Twenty natural orifice intracorporeal anastomosis with transrectal extraction procedures with end-to-end handsewn intracorporeal anastomosis were performed. A video depicting the essential steps with 2 variations of the handsewn techniques is presented along with short-term outcomes. RESULTS: The most common indication was complicated diverticulitis followed by rectal cancer and deep infiltrative endometriosis of the rectum. The mean operative time was 235 minutes (99-294 min), and there were no intraoperative complications or conversions. Handsewn end-to-end intracorporeal anastomosis was successful in all patients. Natural orifice transrectal extraction was successful in 17 of 20 (85%) patients. The mean postoperative length of stay was 2.1 days (±1.05 SD). There were 3 major complications. One patient developed a deep surgical site infection, and another patient had an organ space abscess. Both patients required readmission and were treated with antibiotics alone. One patient, who had a diverting ileostomy performed at the time of the index procedure, developed subclinical dehiscence of the anastomosis, which healed without intervention but resulted in a delay in ileostomy reversal. There were no additional readmissions and no reoperations or mortalities. CONCLUSIONS: Robotic natural orifice intracorporeal anastomosis with transrectal extraction procedure and colorectal end-to-end handsewn anastomosis was feasible and safe in this initial series. This technique can be successfully performed in a total intracorporeal manner without the need for an abdominal wall extraction incision or any circular stapling devices.

Single-cell analysis by mass cytometry reveals CD19 CAR T cell spatiotemporal plasticity in patients.

The adaptive T cell immune response requires cellular plasticity to generate distinct subsets with diverse functional and migratory capacities. Studies of CAR T cells have primarily focused on a limited number of phenotypic markers in blood, representing an incomplete view of CAR T cell complexity. Here, we adapted mass cytometry to simultaneously analyze trafficking and functional proteins expression in CD19 CAR T cells across patients' tissues, including leukapheresis T cells, CAR product, CAR T cells in peripheral blood, bone marrow, and cerebrospinal fluid post infusion and correlate them with phenotypes. This approach revealed spatiotemporal plasticity of CAR T cells. Patients' CAR product revealed upregulation in many trafficking and activation molecules compared to leukapheresis T cells as baseline. Including statistically significant upregulation in CD4 and CD8 integrin-ß7, CD4 granzyme B, and CD11a as well as CD8 CD25 and CD95. Moreover, patients' tissues showed spatiotemporal alteration in trafficking, activation, maturation, and exhaustion features, with a distinct signature in the central nervous system niche. Compared to peripheral blood samples, cerebrospinal fluid samples were statistically significant enriched in CD4 and CD8 trafficking and memory phenotype proteins integrin ß7, CCR7, CXCR4, and CD8 CD69. Our data provide a potential framework to remodel CAR T cells and enhance immunotherapy efficacy.

Real-World Data on Liposomal Bupivacaine and Inpatient Hospital Costs After Colorectal Surgery.

INTRODUCTION: This study compared costs of care among colorectal surgery patients who received liposomal bupivacaine versus those who did not (control) from a health institution perspective. MATERIAL AND METHODS: This pharmacoeconomic evaluation was conducted among adults undergoing open or minimally invasive colorectal resection at an academic medical center from May 2016 to February 2018. Healthcare resource utilization was derived from the electronic health record. Total cost of care (2018 USD) was analyzed using a generalized linear model adjusted for American Society of Anesthesiologists score, enhanced recovery after surgery management, open surgery, opioid use before surgery, height, cancer, and age. The primary analysis used public costs. A sensitivity analysis used internal costs from the hospital to maximize internal validity. RESULTS: Of 486 included patients, 286 (59%) received liposomal bupivacaine. Total cost of care using public costs included perioperative local anesthetics (mean ± standard deviation [SD]: $392 ± 74 liposomal bupivacaine versus $8 ± 13 control), analgesics within 48 h after surgery (mean ± SD: $132 ± 99 liposomal bupivacaine versus $117 ± 127 control), postoperative ileus management (mean ± SD: $5 ± 51 liposomal bupivacaine versus $65 ± 284 control), and hospital length of stay (mean ± SD: $4459 ± 3576 liposomal bupivacaine versus $7769 ± 7082 control). Liposomal bupivacaine was associated with an adjusted absolute difference in total cost of care of -$1435 (95% confidence interval -$2401 to -$470; P = 0.004) using public costs and -$1345 (95% confidence interval -$2215 to -$476; P = 0.002) using internal costs. CONCLUSIONS: Use of liposomal bupivacaine in colorectal surgery was associated with a significant reduction in total cost of care that was predominately driven by reduced costs for hospital stay and postoperative ileus management despite higher medication costs.

A national evaluation of the use and survival impact of adjuvant chemotherapy in Stage II colon cancer from the national cancer database.

AIM: Stage II colon cancers are a heterogeneous category, with controversy over use of adjuvant chemotherapy (AC). Patients with high-risk features may benefit from AC to improve overall survival (OS). Current guidelines do not routinely recommend AC in low-risk cases, but the actual use and benefit on OS in this cohort have not been fully examined on a national scale. We aimed to evaluate the use and impact of AC on OS in low-risk Stage II colon cancer. METHODS: The national cancer database was reviewed for Stage II colon cancers undergoing curative resection (2010-2015). Cases with preoperative radio-chemotherapy or high-risk features were excluded. Cases were stratified into 'AC' and 'no AC' cohorts, and then propensity score matched. Kaplan-Meier and Cox regression analysed OS. The main outcome measures were the incidence and impact of AC on OS in low-risk Stage II colon cancer. RESULTS: Of 39 926 patients evaluated, 8.2% (n = 3275) received AC. Matching resulted in 3275 cases per cohort. AC significantly improved 1-, 3- and 5-year OS versus no AC (P = 0.0017). The 5-year absolute risk reduction was 2.6%, relative risk reduction 12%, with a number needed to treat of 38. In the Cox model, AC remained significantly associated with increased OS (hazard ratio 0.816; 95% CI 0.713-0.934; P < 0.003). CONCLUSIONS: From this dataset, AC was associated with improved OS in low-risk Stage II disease. These findings from a large-scale sample question current guidelines and the need for better risk stratification. Further study with more robust variables is warranted to determine AC best practices.

Infections, hospitalisations, and deaths averted via a nationwide vaccination campaign using the Pfizer-BioNTech BNT162b2 mRNA COVID-19 vaccine in Israel: a retrospective surveillance study.

BACKGROUND: On Dec 20, 2020, Israel initiated a nationwide COVID-19 vaccination campaign for people aged 16 years and older and exclusively used the Pfizer-BioNTech BNT162b2 mRNA COVID-19 vaccine (tozinameran). We provide estimates of the number of SARS-CoV-2 infections and COVID-19-related admissions to hospital (ie, hospitalisations) and deaths averted by the nationwide vaccination campaign. METHODS: In this retrospective surveillance study, we used national surveillance data routinely collected by the Israeli Ministry of Health from the first 112 days (Dec 20, 2020, up to our data cutoff of April 10, 2021) of Israel's vaccination campaign to estimate the averted burden of four outcomes: SARS-CoV-2 infections and COVID-19-related hospitalisations, severe or critical hospitalisations, and deaths. As part of the campaign, all individuals aged 16 years and older were eligible for inoculation with the BNT162b2 vaccine in a two-dose schedule 21 days apart. We estimated the direct effects of the immunisation programme for all susceptible individuals (ie, with no previous evidence of laboratory-confirmed SARS-CoV-2 infection) who were at least partly vaccinated (at least one dose and at least 14 days of follow-up after the first dose). We estimated the number of SARS-CoV-2 infection-related outcomes averted on the basis of cumulative daily, age-specific rate differences, comparing rates among unvaccinated individuals with those of at least partly vaccinated individuals for each of the four outcomes and the (age-specific) size of the susceptible population and proportion that was at least partly vaccinated. FINDINGS: We estimated that Israel's vaccination campaign averted 158 665 (95% CI 144 640-172 690) SARS-CoV-2 infections, 24 597 (18 942-30 252) hospitalisations, 17 432 (12 770-22 094) severe or critical hospitalisations, and 5532 (3085-7982) deaths. 16 213 (65·9%) of 24 597 hospitalisations and 5035 (91·0%) of 5532 of deaths averted were estimated to be among those aged 65 years and older. We estimated 116 000 (73·1%) SARS-CoV-2 infections, 19 467 (79·1%) COVID-19-related hospitalisations, and 4351 (79%) deaths averted were accounted for by the fully vaccinated population. INTERPRETATION: Without the national vaccination campaign, Israel probably would have had triple the number of hospitalisations and deaths compared with what actually occurred during its largest wave of the pandemic to date, and the health-care system might have become overwhelmed. Indirect effects and long-term benefits of the programme, which could be substantial, were not included in these estimates and warrant future research. FUNDING: Israel Ministry of Health and Pfizer.

A proposed service model for early identification of autism spectrum disorder in ethnic communities in Southern Israel.

Early autism spectrum disorder (ASD) detection is a precondition for effective intervention and facilitates significant improvements in functioning. In Israel, toddlers undergo general developmental screening by public health nurses (PHNs) at maternal and child health centres (MCHCs). Nevertheless, there are disparities among ethnic groups in the reported incidence of ASD. By means of an ecological model (EM), we identified strategies that improve ASD detection in the Bedouin community by investigating the social and policy factors that affect diagnosis. We conducted in-depth interviews with 18 policy makers and service providers and three focus groups of PHNs and paediatricians. We mapped the strategies for identifying toddlers with ASD based on the three EM levels. Correlations were established by comparing the codes within and between the EM levels. At the macro-level, the policy makers' strategy for improving ASD detection in the Bedouin community reflected the ideology, values and goals of the PHNs and included the MCHCs as the sole institution involved in detecting ASD. At the meso-level of the service providers, the key elements of the strategy consisted of actualising the professional potential of PHNs and patients' case management. At the micro-level was the population that utilises the services and complies with recommendations. A correlation was established between the PHNs' values and goals and patients' case management. Actualising their professional potential influenced the population's compliance. To reduce gaps in ASD diagnosis between Bedouin communities and the general population, it is necessary to identify and change the policy factors that influence access to services for children with ASD at every EM level while incorporating PHNs from the Bedouin community in future services. Culturally appropriate policies, screening policies and interventions must be developed to serve the needs of Bedouin children.

Colorectal cancer in the 45-to-50 age group in the United States: a National Cancer Database (NCDB) analysis.

BACKGROUND: Amid increasing awareness of early-onset colorectal cancer (CRC), guidelines in the United States (US) recently lowered the recommended routine CRC screening age from 50 to 45 in average-risk individuals. There are little data on the number of patients in this age group diagnosed with CRC prior to these changes. Our objective was to audit the historic CRC case trends and impact of CRC in the 45-to-50-year-old category prior to new screening recommendations. METHODS: Colorectal adenocarcinoma cases in 45-to-50-year-old patients were queried from the NCDB (2004-2017). Cases were stratified by sex, race, and site. The disability-adjusted lost years (DALY) and lost earnings were estimated. The average annual percentage changes (AAPC) of CRC incidence were estimated using jointpoint analysis. The main outcome measures were DALY and lost earnings. Secondary outcome measures were the 2004-2017 AAPC and the cumulative incidence of potential CRC cases in the 45-to-50 cohort through 2030 without guideline changes. RESULTS: 67,442 CRC patients in the 45-to-50 demographic were identified. The CRC burden resulted 899,905 DALY and $17 billion in lost earnings. The 2004-2017 AAPC was 1.6%, with an estimated 13-year increase of 25%. There were sex-, race-, and anatomic site-specific discrepancies with estimated 13-year increases of 30% for males, 110% for American Indian/ Alaska Natives/ Asian American/ Pacific Islander races, and 31% for rectal cancer by 2030. CONCLUSION: CRC has been steadily increasing in the 45-to-50 age group, with tremendous disability and cost ensuing. There is great potential benefit from lowering the recommended routine CRC screening age to 45. Targeted intervention could ensure the most vulnerable segments benefit from the new guidelines, in both reducing the incidence and improving survivorship in CRC patients.

Effectiveness of BNT162b2 mRNA COVID-19 vaccine against SARS-CoV-2 variant Beta (B.1.351) among persons identified through contact tracing in Israel: A prospective cohort study.

BACKGROUND: SARS-CoV-2 variant Beta (B.1.351) was designated as a Variant of Concern (VoC) after becoming the dominant strain in South Africa and spreading internationally. BNT162b2 showed lower levels of neutralizing antibodies against Beta than against other strains raising concerns about effectiveness of vaccines against infections caused by Beta. We estimated BNT162b2 vaccine effectiveness (VE) against Beta infections in Israel, a country with high vaccine uptake. METHODS: The Ministry of Health (MoH) identified Beta cases through mandatory reporting of SARS-CoV-2 cases and whole genome sequencing (WGS) of specimens from vaccination-breakthrough infections, reinfections, arriving international travelers, and a selection of other infected persons. A cohort analysis was conducted of exposure events of contacts of primary Beta cases. WGS was conducted on available PCR-positive specimens collected from contacts. VE estimates with 95% confidence intervals (CIs) against confirmed and probable Beta infections were determined by comparing infection risk between unvaccinated and fully-vaccinated (≥7 days after the second dose) contacts, and between unvaccinated and partially-vaccinated (<7 days after the second dose) contacts. FINDINGS: MoH identified 310 Beta cases through Jun 27, 2021. During the study period (Dec 11, 2020 - Mar 25, 2021), 164 non-institutionalized primary Beta cases, with 552 contacts aged ≥16 years, were identified. 343/552 (62%) contacts were interviewed and tested. 71/343 (21%) contacts were PCR-positive. WGS was performed on 7/71 (10%) PCR-positive specimens; all were Beta. Among SARS-CoV-2-infected contacts, 48/71 (68%) were symptomatic, 10/71 (14%) hospitalized, and 2/71 (3%) died. Fully-vaccinated VE against confirmed or probable Beta infections was 72% (95% CI -5 - 97%; p=0·04) and against symptomatic confirmed or probable Beta infections was 100% (95% CI 19 - 100%; p=0·01). There was no evidence of protection in partially-vaccinated contacts. INTERPRETATION: In a prospective observational study, two doses of BNT162b2 were effective against confirmed and probable Beta infections. Through the end of June 2021, introductions of Beta did not interrupt control of the pandemic in Israel. FUNDING: Israel Ministry of Health and Pfizer.

Waning Immunity after the BNT162b2 Vaccine in Israel.

BACKGROUND: In December 2020, Israel began a mass vaccination campaign against coronavirus disease 2019 (Covid-19) by administering the BNT162b2 vaccine, which led to a sharp curtailing of the outbreak. After a period with almost no cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, a resurgent Covid-19 outbreak began in mid-June 2021. Possible reasons for the resurgence were reduced vaccine effectiveness against the delta (B.1.617.2) variant and waning immunity. The extent of waning immunity of the vaccine against the delta variant in Israel is unclear. METHODS: We used data on confirmed infection and severe disease collected from an Israeli national database for the period of July 11 to 31, 2021, for all Israeli residents who had been fully vaccinated before June 2021. We used a Poisson regression model to compare rates of confirmed SARS-CoV-2 infection and severe Covid-19 among persons vaccinated during different time periods, with stratification according to age group and with adjustment for possible confounding factors. RESULTS: Among persons 60 years of age or older, the rate of infection in the July 11-31 period was higher among persons who became fully vaccinated in January 2021 (when they were first eligible) than among those fully vaccinated 2 months later, in March (rate ratio, 1.6; 95% confidence interval [CI], 1.3 to 2.0). Among persons 40 to 59 years of age, the rate ratio for infection among those fully vaccinated in February (when they were first eligible), as compared with 2 months later, in April, was 1.7 (95% CI, 1.4 to 2.1). Among persons 16 to 39 years of age, the rate ratio for infection among those fully vaccinated in March (when they were first eligible), as compared with 2 months later, in May, was 1.6 (95% CI, 1.3 to 2.0). The rate ratio for severe disease among persons fully vaccinated in the month when they were first eligible, as compared with those fully vaccinated in March, was 1.8 (95% CI, 1.1 to 2.9) among persons 60 years of age or older and 2.2 (95% CI, 0.6 to 7.7) among those 40 to 59 years of age; owing to small numbers, the rate ratio could not be calculated among persons 16 to 39 years of age. CONCLUSIONS: These findings indicate that immunity against the delta variant of SARS-CoV-2 waned in all age groups a few months after receipt of the second dose of vaccine.

Myocarditis after BNT162b2 mRNA Vaccine against Covid-19 in Israel.

BACKGROUND: Approximately 5.1 million Israelis had been fully immunized against coronavirus disease 2019 (Covid-19) after receiving two doses of the BNT162b2 messenger RNA vaccine (Pfizer-BioNTech) by May 31, 2021. After early reports of myocarditis during adverse events monitoring, the Israeli Ministry of Health initiated active surveillance. METHODS: We retrospectively reviewed data obtained from December 20, 2020, to May 31, 2021, regarding all cases of myocarditis and categorized the information using the Brighton Collaboration definition. We analyzed the occurrence of myocarditis by computing the risk difference for the comparison of the incidence after the first and second vaccine doses (21 days apart); by calculating the standardized incidence ratio of the observed-to-expected incidence within 21 days after the first dose and 30 days after the second dose, independent of certainty of diagnosis; and by calculating the rate ratio 30 days after the second dose as compared with unvaccinated persons. RESULTS: Among 304 persons with symptoms of myocarditis, 21 had received an alternative diagnosis. Of the remaining 283 cases, 142 occurred after receipt of the BNT162b2 vaccine; of these cases, 136 diagnoses were definitive or probable. The clinical presentation was judged to be mild in 129 recipients (95%); one fulminant case was fatal. The overall risk difference between the first and second doses was 1.76 per 100,000 persons (95% confidence interval [CI], 1.33 to 2.19), with the largest difference among male recipients between the ages of 16 and 19 years (difference, 13.73 per 100,000 persons; 95% CI, 8.11 to 19.46). As compared with the expected incidence based on historical data, the standardized incidence ratio was 5.34 (95% CI, 4.48 to 6.40) and was highest after the second dose in male recipients between the ages of 16 and 19 years (13.60; 95% CI, 9.30 to 19.20). The rate ratio 30 days after the second vaccine dose in fully vaccinated recipients, as compared with unvaccinated persons, was 2.35 (95% CI, 1.10 to 5.02); the rate ratio was again highest in male recipients between the ages of 16 and 19 years (8.96; 95% CI, 4.50 to 17.83), with a ratio of 1 in 6637. CONCLUSIONS: The incidence of myocarditis, although low, increased after the receipt of the BNT162b2 vaccine, particularly after the second dose among young male recipients. The clinical presentation of myocarditis after vaccination was usually mild.