Achieving global equity for COVID-19 vaccines: Stronger international partnerships and greater advocacy and solidarity are needed.

Peter Figueroa and co-authors advocate for equity in the worldwide provision of COVID-19 vaccines.

The effects of bariatric surgeries on nonalcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is associated with obesity. Bariatric surgery has been shown to be the most effective method for weight reduction. However, no conclusive data exists on the effects of weight reduction surgery on NAFLD. This study aimed to characterize liver histology, metabolic status, and liver function changes in patients who underwent bariatric surgery, before and after the weight-reduction procedure. This is a phase 1 report of a prospective cohort study of patients who underwent bariatric surgery. Biopsies were obtained at baseline (intraoperatively) and 3 months postoperatively. Clinical characteristics, biochemical profile, and histopathological data [steatosis, NAFLD activity score (NAS), hepatocyte ballooning, lobular inflammation, and degree of fibrosis] were obtained at each time point. Twenty-seven patients were included (9 men and 18 women), and the median age was 35 ± 8 years old. At baseline, 3 patients had dyslipidemia, 4 had diabetes, and 5 patients had hypertension, which did not change at follow-up. The average body mass index decreased from 44.6 ± 7.8 to 34.2 ± 6.3 kg/m2 at follow-up (P < 0.001). On histopathology, 12 of the 18 patients with preoperative steatosis (median score 2) had reduced steatosis scores postoperatively (P = 0.025); fibrosis (median score 1) was also reduced in 17 patients (P = 0.012), and NAS was decreased from 4 (3-5) to 2 (1-3) (P = 0.004). The changes in lobular inflammation and hepatocyte ballooning were not statistically significant on follow-up. The phase 1 results of this study described the histopathological changes following weight reduction surgery and suggested that hepatic steatosis, fibrosis, and NAFLD activity score were reduced 3 months after surgery. This clinical trial is financially supported by the National Plan for Science, Technology and Innovation Program grant number (11-MED1910-02).

Use of Lean methodology to improve operating room efficiency in hospitals across the Kingdom of Saudi Arabia.

OBJECTIVE: The objective of this study was to assess whether an intervention on process efficiency using the Lean methodology leads to improved utilization of the operating room (OR), as measured by key performance metrics of OR efficiency. DESIGN: A quasi-experimental design was used to test the impact of the intervention by comparing pre-intervention and post-intervention data on five key performance indicators. SETTING: The ORs of 12 hospitals were selected across regions of the Kingdom of Saudi Arabia (KSA). PARTICIPANTS: The participants were patients treated at these hospitals during the study period. INTERVENTION(S): The intervention comprised the following: (i) creation of visual dashboards that enable starting the first case on time; (ii) use of computerized surgical list management; (iii) optimization of time allocation; (iv) development of an operating model with policies and procedures for the pre-anesthesia clinic; and (iv) creation of a governance structure with policies and procedures for day surgeries. MAIN OUTCOME MEASURE(S): The following were the main outcome measures: on-time start for the first case, room turnover times, percent of overrun cases, average weekly procedure volume and OR utilization. RESULTS: The hospital exhibited statistically significant improvements in the following performance metrics: on-time start for the first case, room turnover times and percent of overrun cases. A statistically significant difference in OR utilization or average weekly procedure volumes was not detected. CONCLUSIONS: The implementation of a Lean-based intervention targeting process efficiency applied in ORs across various KSA hospitals resulted in encouraging results on some metrics at some sites, suggesting that the approach has the potential to produce significant benefit in the future. Copyright © 2016 John Wiley & Sons, Ltd.

Neoadjuvant chemotherapy does not impair liver regeneration following hepatectomy or portal vein embolization for colorectal cancer liver metastases.

BACKGROUND AND OBJECTIVES: Treatment strategies for colorectal cancer liver metastasis (CRCLM) such as major hepatectomy and portal vein embolization (PVE) rely on liver regeneration. We aim to investigate the effect of neoadjuvant chemotherapy on liver regeneration occurring after PVE and after major hepatectomy. METHODS: CRCLM patients undergoing PVE or major resection were identified retrospectively from our database. Liver regeneration data (expressed as future liver remnant [FLR] and percentage of liver regeneration [%LR]), total liver volume (TLV) and clinical characteristics were collected. RESULTS: Between 2003 and 2013, 226 patients were included (85 major resection, 141 PVE). The median chemotherapy cycles was six in both groups. The median time interval between the last chemotherapy and the intervention was 51 days in the PVE group and 79 days in the hepatectomy group. In the PVE group, chemotherapy was not associated with altered liver regeneration (number of cycles [P = 0.435], timing [P = 0.563], or chemotherapy agent [P = 0.116]). Similarly in the major hepatectomy group, preoperative chemotherapy (number of cycles [P = 0.114]; agent [P = 0.061], timing [P = 0.126]) were not significantly associated with differences in liver regeneration (P = 0.592). In both groups, the predicted FLR% was inversely correlated with the %LR (P < 0.001). CONCLUSION: Chemotherapy does not affect liver regeneration following PVE or major resection. J. Surg. Oncol. 2016;113:449-455. © 2016 Wiley Periodicals, Inc.

Trends in brain-dead organ donor characteristics: a 13-year analysis.

BACKGROUND: Driven by disease trends, such as obesity and metabolic syndrome, that are increasingly prevalent in the general population, we aimed to evaluate the comorbidities and attributes of the brain-dead organ donor population over time in a longitudinal study. METHODS: We compared overall health and baseline attributes of organ donors between 2000-2005 and 2006-2012 using our prospective transplant database. Descriptive and comparative analyses of the 2 historical cohorts were performed. RESULTS: A total of 1040 brain-dead organ donors were included in our analysis: 496 from the 2000-2005 period and 544 from the 2006-2012 period. Our analysis revealed that donors from the recent (2006-2012) period were more likely to have increased body mass index (26.4 ± 6.0 v. 25.0 ± 4.8, p = 0.003), smoking history (57.0% v. 27.2%, p < 0.001), coronary artery disease (14.3% v. 3.2%, p = 0.015) and dyslipidemia (19.1% v. 4.2%, p < 0.001), but less likely to have concurrent infection (1.1% v. 7.9%, p < 0.001) than those from the earlier period. CONCLUSION: Our data suggest that the characteristics and comorbidities of brain-dead organ donors have somewhat deteriorated over the last decade. Further studies are needed to evaluate the impact of these health attributes on donated organ utilization and outcomes.

CONTEXTE: Comme la prévalence de l'obésité et du syndrome métabolique est actuellement en hausse dans la population générale, nous avons voulu évaluer, dans une étude longitudinale, les comorbidités et les caractéristiques de la population de donneurs d'organes en état de mort cérébrale au fil du temps. MÉTHODES: Nous avons comparé la santé globale et les caractéristiques de base des donneurs d'organes de 2000-2005 et de 2006-2012 au moyen de notre base de données prospective sur les greffes. Des analyses descriptives et comparatives des 2 cohortes ont été effectuées. RÉSULTATS: Au total, 1040 donneurs d'organes en état de mort cérébrale ont été inclus dans notre analyse : 496 de la période de 2000-2005 et 544 de la période de 2006-2012. Notre analyse a révélé que les donneurs de la période récente (2006-2012) étaient plus susceptibles d'avoir un indice de masse corporelle élevé (26,4 ± 6,0 c. 25,0 ± 4,8, p = 0,003), des antécédents de tabagisme (57,0 % contre 27,2 %, p < 0,001), une coronaropathie (14,3 % c. 3,2 %, p = 0,015) et une dyslipidémie (19,1 % c. 4,2 %, p < 0,001), mais moins susceptibles d'avoir une infection concomitante (1,1 % c. 7,9 %, p < 0,001) que ceux de la période antérieure. CONCLUSION: Nos données semblent indiquer que les caractéristiques et les comorbidités des donneurs d'organes en état de mort cérébrale se sont quelque peu détériorées au cours de la dernière décennie. D'autres études sont nécessaires pour évaluer l'incidence de ces caractéristiques de santé sur l'utilisation des organes donnés et les résultats.

Decreased PCSK9 expression in human hepatocellular carcinoma.

BACKGROUND: The management of hepatocellular carcinoma (HCC) is limited by the lack of adequate screening biomarkers and chemotherapy. In response, there has been much interest in tumor metabolism as a therapeutic target. PCSK9 stimulates internalization of the LDL-receptor, decreases cholesterol uptake into hepatocytes and affects liver regeneration. Thus, we investigated whether PCSK9 expression is altered in HCC, influencing its ability to harness cholesterol metabolism. METHODS: Thirty-nine patients undergoing partial hepatectomy or liver transplantation for HCC were consented for use of HCC tissue to construct a tissue microarray (TMA). The TMA was immunostained for PCSK9. Imagescope software was used to objectively determine staining, and assess for pathological and clinical correlations. PCSK9 and LDL receptor mRNA levels in flash-frozen HCC and adjacent liver tissue were determined by quantitative RT-PCR. Serum PCSK9 levels were determined by ELISA. RESULTS: By immunohistochemistry, there was significantly lower expression of PCSK9 in HCC as compared to adjacent cirrhosis (p-value < 0.0001, wilcoxon signed-rank test). Significantly greater staining of PCSK9 was present in cirrhosis compared to HCC (p value <0.0001), and positivity (percentage of positive cells) was significantly greater in cirrhosis compared to HCC (p-value < 0.0001). Conversely, significantly higher expression of LDL-R was present in HCC as compared to the adjacent cirrhosis (p-value < 0.0001). There was no significant correlation of PCSK9 staining with grade of tumor, but there were significant correlations between PCSK9 staining and stage of fibrosis, according to spearman correlation test. PCSK9 mRNA levels were relatively less abundant within HCC compared to adjacent liver tissue (p-value =0.08) and normal control tissue (p-value =0.02). In contrast, serum PCSK9 levels were significantly increased among patients with HCC compared to those with chronic liver disease without HCC (p-value =0.029). LDL receptor mRNA was consistantly greater in HCC when compared to normal control tissue (p-value = 0.06) and, in general, was significantly greater in HCC when compared to adjacent liver (p-value = 0.04). CONCLUSIONS: The decreased expression of PCSK9 and conversely increased LDL-R expression in HCC suggests that HCC modulates its local microenvironment to enable a constant energy supply. Larger-scale studies should be conducted to determine whether PCSK9 could be a therapeutic target for HCC.

Treatment Patterns and Recommendations for Improving the Management of Hepatocellular Carcinoma in Saudi Arabia.

Hepatocellular carcinoma (HCC) is the sixth most common type of cancer in the world associated with high morbidity and mortality. Despite being a significant healthcare burden there is limited information on the unmet needs and current treatment practices for intermediate and advanced-stage HCC in Saudi Arabia. This article analyzes the gaps and provides expert consensus on the management strategies for unresectable HCC in Saudi Arabia. A pre-meeting online questionnaire, comprising 20 objective questions about the treatment landscape and diagnosis of HCC in Saudi Arabia, was distributed to experts in the field of HCC management. An advisory board meeting including a panel of 13 experts was held in September 2022 where the responses to the survey questionnaire were reviewed and discussed. The survey results and experts' discussion highlighted the growing incidence of liver cancer in Saudi Arabia. HCC comprised the majority of all liver cancer cases due to rising rates of chronic viral infections and lifestyle-related risk factors. Most physicians in Saudi Arabia follow the Barcelona Clinic Liver Cancer guidelines as a prognostic tool for the detection and staging of patients with HCC. Most of the patients with HCC in Saudi Arabia are diagnosed in the intermediate or advanced stages with poor prognoses and limited therapeutic options. Establishing evidence-based surveillance techniques, a multidisciplinary approach to diagnosis, and better accessibility of treatment options is vital for the management of HCC in Saudi Arabia.

ACE2-Fc and DPP4-Fc decoy receptors against SARS-CoV-2 and MERS-CoV variants: a quick therapeutic option for current and future coronaviruses outbreaks.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and the Middle East respiratory syndrome coronavirus (MERS-CoV) are highly pathogenic human coronaviruses (CoVs). Anti-CoVs mAbs and vaccines may be effective, but the emergence of neutralization escape variants is inevitable. Angiotensin-converting enzyme 2 and dipeptidyl peptidase 4 enzyme are the getaway receptors for SARS-CoV-2 and MERS-CoV, respectively. Thus, we reformatted these receptors as Fc-fusion decoy receptors. Then, we tested them in parallel with anti-SARS-CoV (ab1-IgG) and anti-MERS-CoV (M336-IgG) mAbs against several variants using pseudovirus neutralization assay. The generated Fc-based decoy receptors exhibited a strong inhibitory effect against all pseudotyped CoVs. Results showed that although mAbs can be effective antiviral drugs, they might rapidly lose their efficacy against highly mutated viruses. We suggest that receptor traps can be engineered as Fc-fusion proteins for highly mutating viruses with known entry receptors, for a faster and effective therapeutic response even against virus harboring antibodies escape mutations.

Pancreatic cancer and predictors of survival: comparing the CA 19-9/bilirubin ratio with the McGill Brisbane Symptom Score.

INTRODUCTION: Few tools predict survival from pancreatic cancer (PAC). The McGill Brisbane Symptom Score (MBSS) based on symptoms at presentation (weight loss, pain, jaundice and smoking) was recently validated. The present study compares the ability of four strategies to predict 9-month survival: MBSS, carbohydrate antigen 19-9 (CA 19-9) alone, CA19-9-to-bilirubin ratio and a combination of MBSS and the CA19-9-to-bilirubin ratio. METHODOLOGY: A retrospective review of 133 patients diagnosed with PAC between 2005 and 2011 was performed. Survival was determined from the Quebec civil registry. Blood CA 19-9 and bilirubin values were collected (n = 52) at the time of diagnosis. Receiver-operating characteristic (ROC) curves were used to determine a cutoff for optimal test characteristics of CA 19-9 and CA19-9-to-total bilirubin ratio in predicting survival at 9 months. Predictive characteristics were then calculated for the four strategies. RESULTS: Of the four strategies, the one with the greatest negative predictive value was the MBSS: negative predictive value (NPV) was 90.2% (76.9-97.3%) and the positive likelihood ratio (LR) was the greatest. The ability of CA 19-9 levels alone, at baseline, to predict survival was low. For the CA19-9-to-bilirubin ratio, the test characteristics improved but remained non-significant. The best performing strategy according to likelihood ratios was the combined MBSS and CA19-9 to the bilirubin ratio. CONCLUSION: CA19-9 levels and the CA19-9-to-bilirubin ratio are poor predictors of survival for PAC, whereas the MBSS is a far better predictor, confirming its clinical value. By adding the CA19-9-to-bilirubin ratio to the MBSS the predictive characteristics improved.

Hepatitis C infection and hepatocellular carcinoma in liver transplantation: a 20-year experience.

BACKGROUND: Hepatitis C infection (HCV) and hepatocellular carcinoma (HCC), the two main causes of liver transplantation (LT), have reduced survival post-LT. The impact of HCV, HCC and their coexistence on post-LT survival were assessed. METHODOLOGY: All 601 LT patients from 1992 to 2011 were reviewed. Those deceased within 30 days (n = 69) and re-transplants (n = 49) were excluded. Recipients were divided into four groups: (a) HCC-/HCV-(n = 252) (b) HCC+/HCV- (n = 58), (c) HCC-/HCV+ (n = 106) and (d) HCC+/HCV+ (n = 67). Demographics, the donor risk index (DRI), Model for End-Stage Liver Disease (MELD) score, survival, complications and tumour characteristics were collected. Statistical analysis included anova, chi-square, Fisher's exact tests and Cox and Kaplan-Meier for overall survival. RESULTS: Groups were comparable with regards to baseline characteristics, but HCC patients were older. After adjusting for age, MELD, gender and the donor risk index (DRI), survival was lower in the HCC+/HCV+ group (59.5% at 5 yrs) and the hazard ratio (HR) was 1.90 [95% confidence interval (CI),1.24-2.95, P = 0.003] and 1.45 (95% CI, 0.99-2.12, P = 0.054) for HCC-/HCV+. HCC survival was similar to controls (HR 1.18, 95% CI, 0.71-1.93, P = 0.508). HCC+/HCV- patients exceeded the Milan criteria (50% versus 31%, P < 0.04) and had more micro-vascular invasion (37.5% versus 20.6%, P = 0.042). HCC+/HCV+ versus HCC+/HCV- survival remained lower (HR 1.94, 95% CI, 1.06-3.81, P = 0.041) after correcting for tumour characteristics and treatment. CONCLUSION: HCV patients had lower survival post-LT. HCC alone had no impact on survival. Patient survival decreased in the HCC+/HCV+ group and this appears to be as a consequence of HCV recurrence.

Vaccines and therapeutics for immunocompromised patients with COVID-19.

The COVID-19 pandemic has disproportionately impacted immunocompromised patients. This diverse group is at increased risk for impaired vaccine responses, progression to severe disease, prolonged hospitalizations and deaths. At particular risk are people with deficiencies in lymphocyte number or function such as transplant recipients and those with hematologic malignancies. Such patients' immune responses to vaccination and infection are frequently impaired leaving them more vulnerable to prolonged high viral loads and severe complications of COVID-19. Those in turn, have implications for disease progression and persistence, development of immune escape variants and transmission of infection. Data to guide vaccination and treatment approaches in immunocompromised people are generally lacking and extrapolated from other populations. The large clinical trials leading to authorisation and approval of SARS-CoV-2 vaccines and therapeutics included very few immunocompromised participants. While experience is accumulating, studies focused on the special circumstances of immunocompromised patients are needed to inform prevention and treatment approaches.

Predictors of response to radio-embolization (TheraSphere®) treatment of neuroendocrine liver metastasis.

BACKGROUND: Neuroendocrine tumours (NET) frequently metastasize to the liver. NET liver metastasis has been shown to respond to Yttrium-90 microspheres therapy. The aims of the present study were to define factors that predict the response to radio-embolization in patients with NET liver metastases. METHODS: From January 2006 until March 2009, all patients with NET liver metastasis that received radio-embolization using TheraSphere® (glass microspheres) were reviewed. The response was determined by a change in the percentage of necrosis (ΔN%) after the first radio-embolization based on the modified RECIST criteria (mRECIST) criteria. The following confounding variables were measured: age, gender, size of the lesions, liver involvement, World Health Organization (WHO) classification, the presence of extra-hepatic metastasis, octereotide treatment and previous operative [surgery and (RFA)] and non-operative treatments (chemo-embolization and bland-embolization). RESULTS: In all, 25 patients were identified, with a median follow-up of 21.7 months. The median age was 64.6 years, 28% had extra-hepatic metastasis and 56% were WHO stage 2. Post-treatment, the mean ΔN% was 48.4%. Previous surgical therapy was a significant predictor of the response with a response rate of 66.7 ΔN% vs. 31.5 ΔN% (P= 0.02). Bilateral liver disease, a high percentage of liver involvement and large metastatic lesions were inversely related to the degree of tumour response although did not reach statistical significance. CONCLUSION: Radio-embolization increased the necrosis of NET liver metastasis mainly in patients with less bulky disease. This may imply that surgical therapy before radio-embolization would increase the response rates.

Portal vein embolization stimulates tumour growth in patients with colorectal cancer liver metastases.

OBJECTIVES: Portal vein embolization (PVE) can facilitate the resection of previously unresectable colorectal cancer (CRC) liver metastases. Bevacizumab is being used increasingly in the treatment of metastatic CRC, although data regarding its effect on post-embolization liver regeneration and tumour growth are conflicting. The objective of this observational study was to assess the impact of pre-embolization bevacizumab on liver hypertrophy and tumour growth. METHODS: Computed tomography scans before and 4 weeks after PVE were evaluated in patients who received perioperative chemotherapy with or without bevacizumab. Scans were compared with scans obtained in a control group in which no PVE was administered. Future liver remnant (FLR), total liver volume (TLV) and total tumour volume (TTV) were measured. Bevacizumab was discontinued ≥ 4 weeks before PVE. RESULTS: A total of 109 patients and 11 control patients were included. Portal vein embolization induced a significant increase in TTV: the right lobe increased by 33.4% in PVE subjects but decreased by 34.8% in control subjects (P < 0.001), and the left lobe increased by 49.9% in PVE subjects and decreased by 33.2% in controls (P= 0.022). A total of 52.8% of the study group received bevacizumab and 47.2% did not. There was no statistical difference between the two chemotherapy groups in terms of tumour growth. Median FLR after PVE was similar in both groups (28.8% vs. 28.7%; P= 0.825). CONCLUSIONS: Adequate liver regeneration was achieved in patients who underwent PVE. However, significant tumour progression was also observed post-embolization.

Staged hepatectomy for bilobar colorectal hepatic metastases.

OBJECTIVES: This study describes the management of patients with bilobar colorectal liver metastases (CRLM). METHODS: A retrospective collection of data on all patients with CRLM who were considered for staged resection (n= 85) from January 2003 to January 2011 was performed. Patients who underwent one hepatic resection were considered to have had a failed staged resection (FSR), whereas those who underwent a second or third hepatic resection to produce a cure were considered to have had a successful staged resection (SSR). Survival was calculated from the date of diagnosis of liver metastases. Complete follow-up and dates of death were obtained from the Government of Quebec population database. RESULTS: Median survival was 46 months (range: 30-62 months) in the SSR group and 22 months (range: 19-29 months) in the FSR group. Rates of 5-year survival were 42% and 4% in the SSR and FSR groups, respectively. Fifteen of the 19 patients who remained alive at the last follow-up date belonged to the SSR group. CONCLUSIONS: In patients in whom staged resection for bilobar CRLM is feasible, surgery would appear to offer benefit.

SARS-CoV-2 Reinfection Rate and Outcomes in Saudi Arabia: A National Retrospective Study.

BACKGROUND: The characterization of reinfection with SARS-CoV-2 has been a subject of concern and controversy, especially with the surge of infections with highly transmissible variants worldwide. METHODS: This retrospective national study used comorbidities, vaccination status, SARS-CoV-2 variants of concern, and demographics data to profile participants who were reinfected with SARS-CoV-2, defined as having two reverse transcriptase-polymerase chain reaction-positive SARS-CoV-2 tests within at least 90 days apart. A multivariate logistic regression model assessed the risk factors associated with reinfection . Two control groups were selected: nonreinfected participants reporting a positive test (control group one) and those reporting a negative test (control group two). RESULTS: Between March 2020 and December 2021, 4454 reinfected participants were identified in Saudi Arabia (0.8%, 95% confidence interval [CI] 0.7-0.8). The majority (67.3%) were unvaccinated (95% CI 65.9-68.7) and 0.8% (95% CI 0.6-1.1) had severe or fatal SARS-CoV-2 disease. COVID-19 vaccines were 100% effective against mortality in reinfected individuals who received at least one dose, whereas it conferred 61% (odds ratio [OR] 0.4, 95% CI 0.1-1.0) additional protection against severe disease after the first dose and 100% after the second dose. In the risk factor analysis, reinfection was highly associated with comorbidities, such as HIV (OR 2.5, 95% CI 1.3-5.2; P = 0.009), obesity (OR 2.3, 95% CI 1.3-3.9; P = 0.003), pregnancy (OR 3.2, 95% CI 1.4-7.4; P = 0.005), and working in health care facilities (OR 6.1, 95% CI 3.1-12.9; P <0.0001). The delta variant (B.1.617.2) was the most frequent variant of concern among the reinfected cohort. CONCLUSION: This in-depth study of the reinfection profile identified risk factors and highlighted the associated SARS-CoV-2 variants. Results showed that naturally acquired immunity to SARS-CoV-2 through multiple reinfections together with vaccine-induced immunity provided substantial protection against severe SARS-CoV-2 disease and mortality.

Epidemiology of Pancreatic Cancer in Saudi Arabia: A Retrospective Analysis of Pancreatic Cancer Diagnosed in Saudi Arabia Between 2004 and 2015.

PURPOSE: Over the last decades, the incidence of pancreatic cancer has increased, particularly in countries with a higher socioeconomic status. The present work aimed to provide detailed epidemiological data on the incidence of pancreatic cancer in Saudi Arabia. PATIENTS AND METHODS: In this retrospective descriptive study, the epidemiological data on pancreatic cancer cases diagnosed in 13 administrative regions of Saudi Arabia between January 2004 and December 2015 were extracted from the Saudi Cancer Registry. The frequency, the crude incidence rate (CIR), and the age-standardized incidence rate (ASIR), stratified by geographical region, gender, and the year of diagnosis, were analyzed. RESULTS: From January 2004 to December 2015, a total of 2338 cases of pancreatic cancer were registered, including 1443 males and 895 females. The overall CIR was 1.28/100,000 among males and 0.80/100,000 in females, with an overall ASIR of 2.26 and 1.41/100,000 for males and females, respectively. Higher ASIR and CIR were observed among males than females (ratio 1.6). In both genders, the ASIR of pancreatic cancer increased with increasing age, with the highest incidence in patients aged 70 years or more. The ASIR in the Eastern Region (3.2/100,000) and the regions of Riyadh (3.0/100,000) and Tabuk (2.6/100,000) proved to be significantly higher than in the other regions of the country. Among women, the ASIR was significantly higher in Riyadh (2.3/100,000), the northern region (2.2/100,000), and Tabuk (2.0/100,000). CONCLUSION: This study revealed a slight increase of the CIR and ASIR of pancreatic cancer among males and females of the Saudi population. Eastern region, Riyadh, and Tabuk had the highest overall ASIRs of pancreatic cancer among males, Riyadh, Northern region, and Tabuk among Saudi females. The area least affected by pancreatic cancer was observed in Jazan among male and female Saudis. The rates of pancreatic cancer in Saudi Arabia were significantly higher among males compared with female Saudis. Further analytical studies are needed to identify the potential risk factors for pancreatic cancer among the Saudi population.

Cellular and Humoral Immunogenicity of a Candidate DNA Vaccine Expressing SARS-CoV-2 Spike Subunit 1.

The urgent need for effective, safe and equitably accessible vaccines to tackle the ongoing spread of COVID-19 led researchers to generate vaccine candidates targeting varieties of immunogens of SARS-CoV-2. Because of its crucial role in mediating binding and entry to host cell and its proven safety profile, the subunit 1 (S1) of the spike protein represents an attractive immunogen for vaccine development. Here, we developed and assessed the immunogenicity of a DNA vaccine encoding the SARS-CoV-2 S1. Following in vitro confirmation and characterization, the humoral and cellular immune responses of our vaccine candidate (pVAX-S1) was evaluated in BALB/c mice using two different doses, 25 µg and 50 µg. Our data showed high levels of SARS-CoV-2 specific IgG and neutralizing antibodies in mice immunized with three doses of pVAX-S1. Analysis of the induced IgG subclasses showed a Th1-polarized immune response, as demonstrated by the significant elevation of spike-specific IgG2a and IgG2b, compared to IgG1. Furthermore, we found that the immunization of mice with three doses of 50 µg of pVAX-S1 could elicit significant memory CD4+ and CD8+ T cell responses. Taken together, our data indicate that pVAX-S1 is immunogenic and safe in mice and is worthy of further preclinical and clinical evaluation.

Synthetic SARS-CoV-2 Spike-Based DNA Vaccine Elicits Robust and Long-Lasting Th1 Humoral and Cellular Immunity in Mice.

The ongoing global pandemic of coronavirus disease 2019 (COVID-19) calls for an urgent development of effective and safe prophylactic and therapeutic measures. The spike (S) glycoprotein of severe acute respiratory syndrome-coronavirus (SARS-CoV-2) is a major immunogenic and protective protein and plays a crucial role in viral pathogenesis. In this study, we successfully constructed a synthetic codon-optimized DNA-based vaccine as a countermeasure against SARS-CoV-2, denoted VIU-1005. The design was based on a codon-optimized coding sequence of a consensus full-length S glycoprotein. The immunogenicity of the vaccine was tested in two mouse models (BALB/c and C57BL/6J). Th1-skewed systemic S-specific IgG antibodies and neutralizing antibodies (nAbs) were significantly induced in both models 4 weeks after three injections with 100 µg of the VIU-1005 vaccine via intramuscular needle injection but not intradermal or subcutaneous routes. Such immunization induced long-lasting IgG and memory T cell responses in mice that lasted for at least 6 months. Interestingly, using a needle-free system, we showed an enhanced immunogenicity of VIU-1005 in which lower or fewer doses were able to elicit significantly high levels of Th1-biased systemic S-specific immune responses, as demonstrated by the significant levels of binding IgG antibodies, nAbs and IFN-γ, TNF and IL-2 cytokine production from memory CD8+ and CD4+ T cells in BALB/c mice. Furthermore, compared to intradermal needle injection, which failed to induce any significant immune response, intradermal needle-free immunization elicited a robust Th1-biased humoral response similar to that observed with intramuscular immunization. Together, our results demonstrate that the synthetic VIU-1005 candidate DNA vaccine is highly immunogenic and capable of inducing long-lasting Th1-skewed humoral and cellular immunity in mice. Furthermore, we show that the use of a needle-free system could enhance the immunogenicity and minimize doses needed to induce protective immunity in mice, supporting further preclinical and clinical testing of this candidate vaccine.

Global public health security and justice for vaccines and therapeutics in the COVID-19 pandemic.

A Lancet Commission for COVID-19 task force is shaping recommendations to achieve vaccine and therapeutics access, justice, and equity. This includes ensuring safety and effectiveness harmonized through robust systems of global pharmacovigilance and surveillance. Global production requires expanding support for development, manufacture, testing, and distribution of vaccines and therapeutics to low- and middle-income countries (LMICs). Global intellectual property rules must not stand in the way of research, production, technology transfer, or equitable access to essential health tools, and in context of pandemics to achieve increased manufacturing without discouraging innovation. Global governance around product quality requires channelling widely distributed vaccines through WHO prequalification (PQ)/emergency use listing (EUL) mechanisms and greater use of national regulatory authorities. A World Health Assembly (WHA) resolution would facilitate improvements and consistency in quality control and assurances. Global health systems require implementing steps to strengthen national systems for controlling COVID-19 and for influenza vaccinations for adults including pregnant and lactating women. A collaborative research network should strive to establish open access databases for bioinformatic analyses, together with programs directed at human capacity utilization and strengthening. Combating anti-science recognizes the urgency for countermeasures to address a global-wide disinformation movement dominating the internet and infiltrating parliaments and local governments.

Perioperative glucose and insulin administration while maintaining normoglycemia (GIN therapy) in patients undergoing major liver resection.

BACKGROUND: Although hyperglycemia is a well-recognized risk factor in the context of cardiac surgery, the relevance of perioperative glycemic control for patients undergoing major noncardiac operations has received little attention. We designed this study to assess the hyperglycemic response to liver resection, and to test the hypothesis that perioperative glucose and insulin administration while maintaining normoglycemia (GIN therapy) provides glycemic control superior to that achieved by the conventional use of insulin. METHODS: Patients were randomly assigned to GIN therapy or standard therapy (control group). In the GIN therapy group, insulin was administered at 2 mU . kg(-1) . min(-1) during surgery. At the end of surgery, the insulin infusion was decreased to 1 mU . kg(-1) . min(-1) and continued for 24 hours. Dextrose 20% was infused at a rate adjusted to maintain blood glucose within the target range of 3.5 to 6.1 mmol . L(-1) (63-110 mg . dL(-1)). Patients in the standard therapy group received a conventional insulin sliding scale during and after surgery. The mean and SD of blood glucose as well as the percentage of blood glucose values within the target range were calculated. To evaluate intrasubject variability, the coefficient of variability (CV) of blood glucose was calculated for each patient. Episodes of severe hypoglycemia, i.e., blood glucose <2.2 mmol . L(-1) (40 mg . dL(-1)), were recorded. The primary outcome was the proportion of normoglycemic measurements. RESULTS: We studied 52 patients. The mean blood glucose value in patients receiving GIN therapy always remained within the target range. The blood glucose levels were lower in the GIN therapy group than in the standard therapy group (during surgery, P < 0.01; after surgery, P < 0.001). In nondiabetic patients receiving GIN therapy (n = 19), target glycemia was achieved in 90.1% of the blood glucose measurements during surgery and in 77.8% of the measurements after surgery. In diabetic patients receiving GIN therapy (n = 7), target glycemia was achieved in 81.2% of the blood glucose measurements during surgery and in 70.5% of the measurements after surgery. In nondiabetic patients receiving standard therapy (n = 19), target glycemia was achieved in 37.4% of the blood glucose measurements during surgery and in 18.3% of the measurements after surgery. In diabetic patients receiving standard therapy (n = 7), target glycemia was achieved in 4.3% of the blood glucose measurements during surgery and in 2.9% of the measurements after surgery. The SD and CV of blood glucose were smaller in the GIN therapy group than in the standard therapy group, especially in nondiabetic patients after surgery (SD, P < 0.001; CV, P = 0.027). No patients receiving GIN therapy experienced severe hypoglycemia during surgery. One patient receiving GIN therapy experienced hypoglycemia in the intensive care unit after surgery without neurological sequelae. CONCLUSIONS: GIN therapy effectively provides normoglycemia in patients undergoing liver resection (clinicaltrials.gov, NCT00774098).