In February 2021 Kazakhstan began offering COVID-19 vaccines to adults. Breakthrough SARS-CoV-2 infections raised concerns about real-world vaccine effectiveness. We aimed to evaluate effectiveness of four vaccines against SARS-CoV-2 infection.N = 565,390). We separately calculated daily cumulative hazards for COVID-19 breakthrough among vaccinated persons by age and vaccination month.We conducted a retrospective cohort analysis among adults in Almaty using aggregated vaccination data and individual-level breakthrough COVID-19 cases (≥14 days from 2nd dose) using national surveillance data. We ran time-adjusted Cox-proportional-hazards model with sensitivity analysis accounting for varying entry into vaccinated cohort to assess vaccine effectiveness for each vaccine (measured as 1-adjusted hazard ratios) using the unvaccinated population as reference (p < 0.001), and 1.2% for people vaccinated in February–May versus 3.3% in June–August (p < 0.001).From February 22 to September 1, 2021, in Almaty, 747,558 (57%) adults were fully vaccinated (received 2 doses), and 108,324 COVID-19 cases  were registered. Vaccine effectiveness against infection was 79% [sensitivity estimates (SE): 74%–82%] for QazVac, 77% (SE: 71%–81%) for Sputnik V, 71% (SE: 69%–72%) for Hayat-Vax, and 70% (SE: 65%–72%) for CoronaVac. Among vaccinated persons, the 90-day follow-up cumulative hazard for breakthrough infection was 2.2%. Cumulative hazard was 2.9% among people aged ≥60 years versus 1.9% among persons aged 18–39 years (Our analysis demonstrates high effectiveness of COVID-19 vaccines against infection in Almaty similar to other observational studies. Higher cumulative hazard of breakthrough among people ≥60 years of age and during variant surges warrants targeted booster vaccination campaigns. From March 2020 to December 17, 2021 in Kazakhstan, over one million people were diagnosed with coronavirus disease 2019 (COVID-19); ~18,000 died  were listed for emergency use globally by the World Health Organization (WHO) by end of 2021. The WHO pre-qualifies, and lists vaccines based on several guidelines  includinAlthough not listed by the WHO, Sputnik V and QazVac vaccines have received emergency use authorization from the Kazakhstan Ministry of Healthcare. Both have >90% efficacy and safety in phase II and III clinical trials –10. AddiIncreasing breakthrough COVID-19 infections among vaccinated people raised concerns about the real-world effectiveness of available vaccines. This was especially concerning in Kazakhstan where vaccine hesitancy was high, and there was distrust in the newly developed vaccines offered in the country. By the end of 2021, there were no real-world effectiveness studies on QazVac vaccine and limited data on the effectiveness of Sputnik V. Understanding how vaccines are performing outside of clinical trials is important for healthcare system preparedness. Additionally, it is important to continually monitor effectiveness of vaccines in different geographic regions, time periods, populations, to best inform targeted local mitigation measures that are needed for a novel virus that is continually mutating.Policy makers in Kazakhstan needed data to create evidence-based vaccine guidelines, including policies for booster vaccine doses for different populations. We aimed to estimate daily hazard of breakthrough SARS-CoV-2 infection among vaccinated people in Almaty, to identify groups at higher risk for breakthrough infection, and to evaluate the overall effectiveness of four vaccines against infection. Vaccine efficacy and effectiveness studies can be costly and resource intensive, we therefore aimed to demonstrate an approach to assess real-world effectiveness using existing data collected routinely by the public health system.We conducted a retrospective, observational population-based cohort study of the effectiveness of four different vaccines against SARS-CoV-2 infection among the entire adult population (18 years or older) of Almaty, Kazakhstan between February 1, and September 1, 2021. Sinopharm vaccine was excluded from this assessment because only 20 participants received this two-dose vaccine during this period in Almaty. Almaty is the economic capital and largest city of Kazakhstan with the population of 1,928,000. Adults constituted 68%  of Almaty and ~10% of the national adult population in 2021 .All healthcare providers in Kazakhstan are mandated to report all COVID-19 cases and vaccines into national registries. Our study uses the routinely collected data from these national registries. The national case-based COVID-19 surveillance system in Kazakhstan is managed by the Ministry of Healthcare. Everyone tested for COVID-19, regardless of test result, is registered in the system. COVID-19 PCR testing is provided free of charge to all persons with symptoms and all contacts of cases. This testing is conducted at all primary health care facilities, in home-based visits, and in hospitals. COVID-19 testing is also widely available at private laboratories in Kazakhstan for a fee. All persons traveling internationally and unvaccinated people in different settings were required to test. Home-based COVID-19 antigen testing was not available during the period covered by this study. In addition, the COVID-19 positivity rate during this study ranged from 5% to 7%.During the study period COVID-19 vaccination was also provided free of charge to all adults 18 years and older. All vaccinations are registered in a national vaccine registry. Adverse effect experience in the first 3 days after vaccination are registered.Community mitigation strategies in place during this time were masking, contact tracing, isolation and quarantine of cases and contacts which was monitored by a nationwide mobile phone app linked to peoples’ national identification number.A breakthrough COVID-19 infection was defined as having confirmed or probable COVID-19, including people with asymptomatic disease, ≥14 days after receiving the 2nd dose of a COVID-19 vaccine.A confirmed COVID-19 case was defined as the detection of SARS-CoV-2 ribonucleic acid (RNA) in a respiratory specimen collected from a person aged ≥18 years, including those with asymptomatic disease.A probable COVID-19 case was a patient who met clinical criteria , did not have a positive SARS-CoV-2 PCR test, and was a contact of a probable or confirmed case or linked to a COVID-19 cluster.Fully vaccinated was defined as having received two COVID-19 vaccine doses (there were no single dose COVID-19 vaccines offered in Kazakhstan). Unvaccinated was defined as never having received any COVID-19 vaccine.People who received only 1 dose or got COVID-19 <14 days after their second dose are considered not fully immune and are censored  from analysis at date of 1st vaccine dose.We classified people into four groups. People who were:unvaccinated (never received any COVID-19 vaccine) and diagnosed with COVID-19,unvaccinated (never received any COVID-19 vaccine) and not diagnosed with COVID-19,fully vaccinated (two doses) and diagnosed with breakthrough COVID-19, and.fully vaccinated (two doses) and not diagnosed with breakthrough COVID-19.Our analysis included Almaty residents ages 18 years and older. The following people were excluded from the time-dependent Cox proportional hazards regression analysis :People whose records were inconsistent with national vaccination guidelines .People who received the Sinopharm vaccine (only 20 people).Data on history of COVID-19 prior to the study period was not available; therefore, we do not exclude based on prior disease.Individual-level data on COVID-19 cases among anyone who had ever received a COVID-19 vaccine from February 1 to September 1, 2021 were provided by the Emergency Operational Center (EOC) of the National Center of Public Health of the Ministry of Healthcare in Kazakhstan. Data on all COVID-19 cases from testing centers, laboratories, hospitals, and healthcare providers are collected by the EOC. This clinical record dataset included age, comorbidities, dates of COVID-19 vaccination, vaccine name, date of SARS-CoV-2 PCR test result or diagnosis, hospitalization, death, and disease severity. Disease severity was based on the WHO Scale adapted by the Kazakhstan clinical protocol of diagnosis and treatment. People with critical disease had acute respiratory distress, those with severe disease had severe pneumonia, those with moderate disease had pneumonia, and those with mild disease did not have pneumonia. Data aggregated per day on SARS-CoV-2 polymerase chain reaction (PCR) testing, which included the number of people testing positive per day for the same period, were also provided.Aggregated data on vaccination were received from the Salidat Kairbekova National Research Center for Health Development of the Ministry of Healthcare in Kazakhstan. Variables in this dataset were given to us aggregated by date and included the number of people vaccinated per day per age groups  and vaccine type.Analyses were performed using R statistical software, version 4.0.3 . We calculated and plotted attack rates for the vaccinated and unvaccinated populations for each day of our analysis for each vaccine type. As is commonly used in vaccine effectiveness analysis –16, we fN = 1,313,040) was classified into the unvaccinated group at-risk for COVID-19 group. People contributed person-time to the unvaccinated population until they either received a COVID-19 diagnosis or a COVID-19 vaccine. Persons receiving a COVID-19 diagnosis were censored at their time of diagnosis. After people received their first vaccine, they did not contribute person-time to either population (vaccinated or unvaccinated) from their first dose to 14 days after their second dose after which they contributed person-time to the vaccinated population. We performed sensitivity analysis by changing the dates at which people entered the vaccinated population  and the dates of definition of a COVID-19 breakthrough case . We tested for the proportional hazards (PH) assumption using Schoenfeld residuals, which tests whether there is a relationship between residuals and time, using cox.zph function from the survival package in R . The entire population of adults ≥18 years old in Almaty  vaccine effectiveness for each vaccine as per the WHO guidance , 23.We also estimated the crude (unadjusted) number of COVID-19 cases prevented by multiplying the number of vaccinated people by the overall incidence among the unvaccinated population and subtracting the number of breakthrough cases.Lastly, we conducted sub analysis on the vaccinated population. We calculated the cumulative hazard (the estimate of the expected number of COVID-19 cases that has been observed for the given amount of time) of getting COVID-19 using survfit and plotted Kaplan–Meyer cumulative hazard curves using ggsurvplot function and by vaccine name, age group, and month. The log-rank test was used to test difference in hazard curves , Hayat-Vax , CoronaVac , or QazVac  and met inclusion criteria. During this time, Almaty had 108,324 probable and confirmed COVID-19 cases among people ≥18 years old, including 23,858 cases among people with at least one COVID-19 vaccination record . Of thesAmong fully vaccinated people with breakthrough SARS-CoV-2 infections , 24% werp < 0.001). Vaccine effectiveness was similar across models that adjusted for time, daily cumulative proportion of vaccinated people that were ≥60 years old, and daily COVID-19 positive test rate :71.1%–80.0%] . Adjusteest rate . The proest rate .For all vaccines, the attack rate for COVID-19 per 100,000 was consistently higher over the 7 days moving average for unvaccinated persons than for vaccinated persons . The 7 dn = 747,558), the 90 days cumulative hazard of developing a SARS-CoV-2 breakthrough infection was 2.2%, ranging from 2.0% for Sputnik V to 3.5% for Hayat-Vax (Among people who were fully vaccinated (ayat-Vax . The cump < 0.001) (p < 0.001) when comparing people who were vaccinated in March to May 2021 to those vaccinated in June to September 2021 (the period when the SARS-CoV-2 Delta variant was active in the region). However, in vaccine-specific analysis, this difference was only significant for QazVac and Sputnik V.This divergence in hazard by age group over follow-up time was observed across the four vaccines (< 0.001) . CumulatOur study provides a snapshot of vaccine effectiveness in a specific population at specific point in time in the pandemic. We found that at the population-level the four vaccines against COVID-19 used in Kazakhstan were effective at preventing SARS-CoV-2 infection. Vaccination reduced the risk of infection by 76% and prevented over 100,000 cases of SARS-CoV-2 infection in Almaty, the country’s most populous city. The vaccine effectiveness for all four vaccines exceeded the 50% vaccine efficacy minimum threshold set by the WHO for approving vaccines. Vaccine effectiveness also remained relatively stable over the period, despite a slight decrease observed during the months when the SARS-CoV-2 Delta variant became the predominant circulating strain worldwide.QazVac had 79% vaccine effectiveness in our study but accounted for only 2% of people vaccinated. Vaccine effectiveness for QazVac in our analysis was similar to the vaccine efficacy reported in phase III clinical trials (81%) .It is difficult to compare vaccine effectiveness results across countries, settings and populations because studies are conducted in different phases of the pandemic. Different phases have had different non-pharmaceutical interventions in place and different circulating strains. The predominant vaccine given in Kazakhstan during the period of analysis was Sputnik V (89% of vaccinated people) and our observed vaccine effectiveness of 73% compares to (79% and 86%) vaccine effectiveness from limited observational studies, but lower than 92% vaccine efficacy estimate from phase III clinical trials , 25. HowCoronaVac had the lowest vaccine effectiveness in our analysis, and the estimate fell within the range of vaccine efficacy phase III trials (51 to 84%) in several countries , 26–29. Although COVID-19 vaccines used globally are highly effective, people who are fully vaccinated may experience breakthrough SARS-CoV-2 infections, especially when the incidence is high, and the proportion of people vaccinated in a population is low. In Kazakhstan, population vaccination began shortly before the Delta surge. As expected, breakthrough cases occurred among vaccinated people, increasing as SARS-CoV-2 incidence increased in the country. However, out of every 100 people fully vaccinated in Almaty during our study period less than 2 had breakthrough infections. The low proportion of people getting breakthrough COVID-19 in our study is within the range of that reported in other settings (<1% to 8%) , 34. NotProportion of breakthrough infections increased over time, especially among people ≥60 years of age and during the SARS-CoV-2 Delta variant surge . This inAlthough the COVID-19 picture has changed and will continue to change, globally we are still experiencing daily cases of COVID-19, including high burden of COVID-19 associated mortality. Vaccination has been proven to be an effective tool in preventing severe illness, hospitalization, and death caused by COVID-19. With the decrease in the incidence rate, it is crucial to continue vaccinating as many people as possible to ensure that the virus does not have a resurgence. It is also critical to continually monitor effectiveness of vaccines during these resurgences. Our study demonstrates a cost-effective way of doing this using data that is already being routinely collected by the Ministry of Health.During data cleaning, we found 1,204 cases where the dates of vaccination and disease onset conflicted with national vaccine administration directives. While some of these incongruencies could be data entry errors, they could also be from falsification of vaccine records. Falsification of vaccine records was known to be a problem in the Central Asia Region and in Kazakhstan where vaccination was compulsory for certain populations –41. FalsVaccine confidence can also be boosted through increased global recognition of efficacious vaccines. Despite trials showing high vaccine efficacy and studies showing real-world vaccine effectiveness in several countries, only one of the four vaccines in our study, CoronaVac, is accepted as proof of vaccination in several countries. The other vaccines, two of which have been used widely globally, have not completed submission of all requirements for WHO approval.This is the first study from Kazakhstan reporting the real-world effectiveness of fours available vaccines based on the retrospective cohort analysis in the largest city of the country using aggregated vaccination data and individual-level breakthrough case national surveillance data. This is also the first study to estimate vaccine effectiveness for QazVac, an inactivated vaccine developed in Kazakhstan, in real-world conditions. Our results are relevant for planning and scale-up of COVID-19 vaccination efforts in the region.Our study is subject to at least five important limitations. First, we could not assess vaccine effectiveness against severe disease, hospitalization, and death because individual level data on unvaccinated people who died or were hospitalized were not available for our analysis. Second, we were not able to adjust for potential confounders, such as gender, age or underlying medical conditions, because this data was not available in the reference group. Our analysis is likely not biased by age because the population proportion ages 60 years and older among vaccinated people (12%) approximates  that proWe conducted a retrospective cohort study in Almaty to evaluate effectiveness of Sputnik V, QazVac, Hayat-Vax, and CoronaVac COVID-19 vaccines using aggregated vaccination data and individual-level COVID-19 case data from ongoing surveillance. We found that four vaccines used in Almaty had good effectiveness against SARS-CoV-2 infection vaccine effectiveness of 76.4% (range 69.5% to 78.6% across vaccine types). Vaccine effectiveness studies have known limitations regarding the outcome studied, confounders, and misclassification, however, we minimized the biases in our analysis and interpreted our results considering these limitations. Our results can be used to increase vaccine confidence in Kazakhstan and the region. Scale-up of efforts to fully vaccinate all eligible unvaccinated persons and to provide booster doses to persons already fully vaccinated, people ≥60 years of age and during variant surges, will help reduce SARS-CoV-2 incidence. The methodology used for this analysis can be adopted for ongoing monitoring of vaccine effectiveness nationally and regionally.hny5@cdc.gov.The data analyzed in this study is subject to the following licenses/restrictions: deidentified data might be made available for authorized researchers after application to the Ministry of Healthcare of the Republic of Kazakhstan. The authors confirm that the manuscript is an honest, accurate, and transparent account of the investigation being reported; and that no important aspects of the study have been omitted. Requests to access these datasets should be directed to The study was deemed non-research public health activity by the Ministry of Healthcare of Kazakhstan and the institutional review board of the CDC and conducted in accordance with the CDC policy (project ID # 0900f3eb81e4b259).DN, RH, MS, GN, AY, DS, AH, and AT: conceptualization and writing—review and editing. DN, RH, MS, GN, AH, and AY: methodology. DN, RH and GN: software, validation, and formal analysis. DN, RH, AH, and GN: investigation. DN, MS, GN, AY, and AT: resources and data curation. DN, RH, AH, and DS: writing—original draft preparation. DN and RH visualization. AY, DS, and AT: supervision. MS and DN: project administration. All authors contributed to the article and approved the submitted version.None for study implementation. The cost of publication will be funded by the CDC (TEPHINET cooperative agreement # GH000044).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Gastrointestinal stromal tumours (GISTs) are soft-tissue sarcomas of the gastrointestinal tract. Surgery is the standard treatment for localised disease, but the risk of relapse and progression to more advanced disease is substantial. Following the discovery of the molecular mechanisms underlying GISTs, targeted therapies for advanced GIST were developed, with the first being the tyrosine kinase inhibitor (TKI) imatinib. Imatinib is recommended in international guidelines as first-line therapy to reduce the risk of GIST relapse in high-risk patients, and for locally advanced, inoperable and metastatic disease. Unfortunately, imatinib resistance frequently occurs and, therefore, second-line (sunitinib) and third-line (regorafenib) TKIs have been developed. Treatment options are limited for patients with GIST that has progressed despite these therapies. A number of other TKIs for advanced/metastatic GIST have been approved in some countries. Ripretinib is approved as fourth-line treatment of GIST and avapritinib is approved for GIST harbouring specific genetic mutations, while larotrectinib and entrectinib are approved for solid tumours (including GIST) with specific genetic mutations. In Japan, pimitespib, a heat shock protein 90 (HSP90) inhibitor, is now available as a fourth-line therapy for GIST. Clinical studies of pimitespib have indicated that it has good efficacy and tolerability, importantly not displaying the ocular toxicity of previously developed HSP90 inhibitors. Additional approaches for advanced GIST have been investigated, including alternative uses of currently available TKIs (such as combination therapy), novel TKIs, antibody–drug conjugates, and immunotherapies. Given the poor prognosis of advanced GIST, the development of new therapies remains an important goal. Gastrointestinal stromal tumours (GISTs) are the most frequent soft-tissue sarcoma of the gastrointestinal (GI) tract. They are usually found in the stomach (60–65% of cases) and small intestine (20–35% of cases), with the rectum, colon and oesophagus more rarely involved . GISTs uPopulation-based studies from various European countries and data from the United States (US) National Cancer Institute estimate the incidence of GISTs  to be approximately 6–22 cases per million per year . GISTs aKIT) . There were three responders in the imatinib plus BSC group and one in the BSC alone group.The reintroduction of a TKI that had previously been well tolerated and effective has proven beneficial in several studies. A retrospective, non-randomised study suggested that imatinib rechallenge combined with best supportive care (BSC) may have advantages over BSC alone in Japanese patients with locally advanced or metastatic GIST who had previously received both imatinib and sunitinib . After aP = 0.005).Encouraging effects have also been seen with TKI rechallenge as fourth-line treatment. The phase 3 Rechallenge of Imatinib in GIST Having no effective Treatment (RIGHT) study assessed the efficacy and safety of imatinib (n = 41) versus placebo (n = 40) in patients with metastatic and/or unresectable GIST who had experienced initial benefit from imatinib but had subsequently evolved to progression of GIST despite receiving treatment with at least imatinib and sunitinib (40% of patients had received ≥ 3 prior TKIs) . After aA larger, but uncontrolled, Italian real-world study investigated the effects of imatinib rechallenge in 71 patients with advanced GIST whose disease had progressed after treatment with imatinib, sunitinib and regorafenib . The medHeat shock proteins (HSPs) are a class of adenosine triphosphate (ATP)-dependent proteins that act as molecular ‘chaperones’. They assist in a number of events that are essential for normal cellular functioning and survival, such as the folding of ‘client’ proteins . The levA number of HSP90 inhibitors have been developed  and invePimitespib -4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-1H-pyrazolo pyridin-1-yl] benzamide) is a selective inhibitor of HSP90α and HSP90β. Pimitespib was approved in June 2022 in Japan for the treatment of GIST that has progressed after other lines of treatment . Unlike Administration schedule The dose and administration schedule for pimitespib was determined from a first-in-human phase 1 study that aimed to identify the maximum tolerated dose , and assess the safety, efficacy, pharmacokinetics and pharmacodynamics of pimitespib ) than with placebo (7.6 months [95% CI 5.3–14.9]) . The results of the other secondary endpoints, including OS, investigator-assessed PFS, response rate, DCRs, time to progression and secondary PFS, are summarised in Table KIT mutations of exons 13/14 and 17/18, as well as in the overall patient population. No significant difference was observed in health-related quality of life (HRQOL) [exploratory endpoint] between pimitespib- and placebo-treated patients  mAb) in 28 patients with advanced GIST (refractory to or intolerant of imatinib and sunitinib) and other sarcomas . No patiA phase 2 trial is ongoing to assess the efficacy and safety of the combination of the TKI axitinib and the anti-PD-L1 antibody avelumab in patients with unresectable/metastatic GIST who have received no more than 3 lines of treatment, including imatinib and sunitinib (NCT04258956) .A further phase 1/2 study is assessing the effects of avelumab and regorafenib in patients with advanced or metastatic solid tumours, including GIST (NCT03475953) .Immunotherapy combinations are also being investigated, including several studies of ipilimumab plus nivolumab (a mAb targeting PD-1/PDCD-1) . To datePDGFRA exon 18-mutated GIST, while pimitespib is now approved as fourth-line treatment for GIST in Japan. Although it may be expected that the establishment of pimitespib in the treatment armamentarium will improve patient prognosis in Japan, there are still very limited options for patients with this stage of disease. As such, the development of new drugs and combination therapies remains an important goal.In Japan and internationally, treatments have been established for GIST that has not responded to up to two lines of treatment. In many countries, ripretinib can be used as a fourth-line treatment and avapritinib has been approved for


Bariatric and metabolic surgery (BMS) may adversely affect noninvasive stool tests for colorectal cancer (CRC) screening through several mechanisms. Multitarget stool DNA (mt-sDNA) is approved for CRC screening; however, performance in post-BMS patients is unknown. As the rates of BMS are anticipated to increase with rising incidence of obesity, it is important to evaluate mt-sDNA test performance among these patients.In a multisite academic and community-based practice, we obtained mt-sDNA results from 10/2014 to 12/2019 through electronic records and an institutional BMS registry. Average CRC risk patients with BMS prior to a positive mt-sDNA underwent a detailed chart review. Follow-up colonoscopy findings were compared to those among BMS patients screened with colonoscopy alone and a historical cohort of patients without BMS, screened by mt-sDNA. The primary study endpoint was the positive predictive value (PPV) for advanced colorectal neoplasia.P = .86). Among those who had prior BMS, the rate of advanced neoplasia was higher after mt-sDNA compared to screening colonoscopy alone.Among 336 average-risk patients who had mt-sDNA after BMS, mt-sDNA was positive in 49 (14.6%), 47/49 (96%) underwent follow-up colonoscopy, and the PPV for advanced neoplasia was 12/47 (25.5%). This is similar to the PPV for advanced colorectal neoplasia  in a historical cohort of persons without prior BMS, screened by mt-sDNA at our center (Despite anatomic and physiologic mechanisms that could alter blood or DNA content in stool, BMS does not appear to adversely affect the PPV of mt-sDNA.  Among those with BMS, iron deficiency is also common28 and classically warrants diagnostic colonoscopy to exclude CRC as the source. Additionally, post-BMS diarrhea from dumping, bile acid malabsorption, or bacterial overgrowth could uniquely affect mt-sDNA. The mt-sDNA collection kit provides a buffer solution that stabilizes the stool sample for molecular processing.29 Voluminous stool may exceed the buffering capacity of the solution and altered bowel transit may influence exfoliation of tumor markers, altering test performance.Enthusiasm for noninvasive CRC screening may be dampened by consideration of anatomic and physiologic consequences of BMS could theoretically alter stool blood or DNA content . Margina32 the impact of BMS on this test has not been directly studied. With the increased utilization of BMS,33 it is important to evaluate whether BMS adversely affects mt-sDNA performance as this could lead to costly overutilization of colonoscopy. We therefore aimed to describe factors leading to mt-sDNA selection among those with BMS and report findings at follow-up colonoscopy to estimate positive predictive value (PPV). The PPV was then compared to a historical cohort of patients from the same institution34 who were at average risk for CRC, utilized mt-sDNA, and had no history of BMS. While this comparison provides a direct way to evaluate whether BMS changes mt-sDNA test performance, in the real world those with a negative mt-sDNA do not undergo colonoscopy. To account for rates of neoplasia among those with BMS, the PPV among those with BMS and subsequent utilization of colonoscopy alone (no use of mt-sDNA) was also compared.Although patients with prior BMS have not been excluded from key studies evaluating mt-sDNA,After institutional review board approval, we reviewed records to identify patients with prior BMS who had an mt-sDNA test between 10/2014 and 12/2019 at any of the Mayo Clinic sites ). In accordance with Minnesota law, patients who had not consented to research (including chart review) were excluded.We identified patients who had BMS using 2 search strategies. The first queried a database maintained by the Division of Bariatric Surgery of their operations since May 1, 2008 . Second,Then, the Mayo Clinic central data warehouse was utilized to search mt-sDNA lab/order, procedure, and diagnosis codes to identify patients with an mt-sDNA test result. The collective list of patients with a suspected history of BMS was cross-referenced to mt-sDNA testing over the study period. Patients without mt-sDNA use or mt-sDNA testing dated before a known surgical date for BMS were excluded. The remaining cohort underwent a chart review.mt-sDNA after BMS cohort) in comparison to BMS patients with screening colonoscopy only (screening colonoscopy after BMS cohort) and historical data from persons screened by mt-sDNA and no history of BMS (non-BMS mt-sDNA cohort). Secondary analyses included stratification of the primary endpoints for presence of anemia, history of marginal ulcers, and current nonsteroidal anti-inflammatory drug (NSAID) use. Where possible, we abstracted any record of patient/provider decision-making for mt-sDNA use.The primary study endpoint was the overall test positivity rate and the PPV for mt-sDNA among post-BMS patients at average CRC risk  were excluded (Review of each patient’s EMR was done by one reviewer (D.W.E.) and the data were recorded and stored using REDCap . For the excluded .30 Anemia within 3 months of mt-sDNA was also recorded and classified . Given the high prevalence of iron deficiency among those with BMS those with iron deficiency were included in the composite analysis and subsequently evaluated as a subgroup.Baseline characteristics included patient demographics, tobacco use, and past medical and family history to assess average vs increased risk for CRC.CRC screening by colonoscopy prior to mt-sDNA use and reports of any history of neoplasia were evaluated  and the highest-graded lesion was recorded. The date and type of BMS were recorded including presurgical body mass index (BMI), history of revision, marginal ulcerations, NSAID use, or features of malabsorption  within 3 months prior to mt-sDNA.The date of mt-sDNA and result (positive or negative) were noted. In review of encounter notes, the indication for mt-sDNA use was determined based on available notation. Broadly, these were categorized as: 1) shared decision-making, if specific notation was available reviewing the various options for CRC screening; 2) patient choice, if there was notation that the patient specifically requested the mt-sDNA test in the absence of reviewing alternative methods; 3) provider preference, given a concern for tolerance of colon preparation or opinion the patient was not suitable for colonoscopy; or 4) unknown.screening colonoscopy after BMS and non-BMS mt-sDNA).The findings at follow-up colonoscopy were also enumerated . Hyperplastic polyps, irrespective of size, were excluded as neoplasia when determining PPV. Test PPV for neoplasia  was then compared to 2 independent patient cohorts . Those with a colonoscopy indication of average risk screening during the study period (10/2014 through 12/2019) were included. The colonoscopy indication at our institution is entered by the performing endoscopist and accuracy has been internally validated using manual chart review.35 Therefore, manual chart review did not revalidate patient risk or evaluate prior screening history. All available patients were manually reviewed to verify BMS history, absence of mt-sDNA results, and detailed results of colonoscopy screening.A second comparison was to patients with BMS history who underwent screening colonoscopy during the study period. To generate the mt-sDNA after BMS, screening colonoscopy after BMS, and non-BMS mt-sDNA were compared using the Wilcoxon rank sum test for continuous variables (summarized as a median with corresponding 25th and 75th percentiles) whereas proportions were compared by the Fisher’s exact test. PPV was calculated as the number of positive findings (excluding hyperplastic polyps) relative to the total number of patients undergoing follow-up colonoscopy with corresponding 95% confidence intervals. The required sample size to detect an odds ratio of 2 (absolute difference of ±15%) between 2 independent cohorts with 80% power was estimated to be 150 patients per group assuming a reference PPV of 60% and a two-sided significance level of 0.05. However, the actual number of BMS patients with a positive (+) mt-sDNA test who underwent colonoscopy was less than anticipated. Given the observed sample sizes, the minimum detectable odds ratio with the same level of power, significance, and reference PPV increased to 2.6 (absolute difference of ±20%).Patient characteristics among the cohorts mt-sDNA after BMS) consisted of 365 average-risk patients, with or without iron deficiency 90 days prior to mt-sDNA use . The final cohort (sDNA use .36 The median BMI prior to BMS was 44 (40–49) kg/m2 and the median time from BMS to mt-sDNA was 8.9 (4.9–14.7) years. Roux-en-Y gastric bypass was conducted for 297/365 (81%). A history of marginal ulcers was seen 27/365 (7%), and 22/361 (6%) had prior surgical revision. Additional patient characteristics are noted , white (99%), and 209 (57%) had a history of colonoscopy prior to mt-sDNA. Among 14 with findings at prior colonoscopy; most were hyperplastic lesions and only 3 patients had precancerous polyps, all of which were low-risk.re noted .There were some differences in patient characteristics . Those smt-sDNA after BMS cohort, independent of CRC risk, was 59/381 (15.5%). Among the final study cohort of 365 otherwise average risk post-BMS patients, 29 had iron deficiency anemia. Of the 336 average-risk patients without iron deficiency anemia, mt-sDNA was positive in 49 (14.6%), 47/49 (96%) underwent follow-up colonoscopy, and most had a Roux-en-Y . For the 47 patients who underwent follow-up colonoscopy bowel preparation was not reported for one and was otherwise adequate for all but 5/46 (11%). Cecal intubation was achieved for 46/47 (98%). At least one neoplasm was found in 29 of the 47 patients who had a follow-up colonoscopy . Of total neoplasia detected, most included findings in the right colon . The PPV for advanced neoplasia was 12/47 .The mt-sDNA positivity rate for the mt-sDNA after BMS were compared to the non-BMS mt-sDNA cohort, there were no differences in the diagnosis of CRC, advanced, or non-advanced neoplasia . The majority of these were secondary to iron deficiency 29/41 (71%). Among those with iron deficiency, 5 (17%) had a +mt-sDNA; 4/5 underwent follow-up colonoscopy; and 1/4 had non-advanced neoplasia only. Of the 29 patients with iron deficiency, 5 had a history of marginal ulceration and mt-sDNA testing was negative for each of those patients. For the 27/365 patients with a history of marginal ulcers, mt-sDNA was positive for 3/27 (11%); follow-up colonoscopy detected an advanced adenoma for one patient and colonoscopy was normal for the other 2 patients.Of the additional potential confounders, malabsorption was only suggested for 4% (15/365) of the cohort; additionally, NSAID use within 3 months of mt-sDNA was observed in 32% (115/365). Among the 115 NSAID users, 10 (9%) had iron deficiency anemia and 23 (20%) had a +mt-sDNA. Follow-up colonoscopy was pursued for 20/23 (87%) and neoplasia was diagnosed for 12/20 (60%). Among those with neoplasia, advanced neoplasia was diagnosed for 5/12 (42%). An additional patient had 2 polyps removed but the tissue was not retrieved and was therefore not counted as neoplasia.A process of shared decision-making about the modalities for CRC screening was documented prior to mt-sDNA screening in 315/381 (82.6%). Specific notation of patient or provider concerns about bowel preparation tolerance was recorded for 17/381 (4%) of those with BMS who were screened by mt-sDNA.34 and prospective evaluation of average-risk individuals.30 Thus, mt-sDNA does not appear to generate a meaningful increase in false positive mt-sDNA tests in patients with prior BMS, who are otherwise at average risk for CRC.There is theoretical concern regarding the use of mt-sDNA among those with a history of BMS given the high prevalence of iron deficiency, risk for marginal ulceration with subsequent gastrointestinal hemorrhage, and increased risk for CRC. We observed that the test positivity (14.6%) and PPV of 25.5% and 61.7% for advanced precursors and any colorectal neoplasia, respectively, are highly consistent with values observed in patients without BMS. The test positivity of mt-sDNA has ranged from 14% to 16% in real-world observational study among patients with mixed risk for CRC34 However, there was significantly higher neoplasia at prior screening colonoscopy among the non-BMS group compared to those with BMS, and the non-BMS mt-sDNA screened patients were significantly older. Despite these differences in patient characteristics, mt-sDNA test performance was similar. Of note, in the BMS cohort, there were 156 average-risk patients without a history of colonoscopy prior to mt-sDNA use and 122 were overdue to start CRC screening. We observed that the rate of attendance for follow-up colonoscopy after a +mt-sDNA for those with BMS history  is similar to published reports that range 85%–96%.38 Among the BMS cohort, mt-sDNA detected high rates of right-sided and sessile serrated neoplasia, similar to previous reports.40 In the pivotal prospective study of mt-sDNA with criterion colonoscopy among average-risk individuals, the test positivity rate was 16% and advanced neoplasia PPV was 23.6%30; in the present study, the test positivity among average-risk BMS was 14.6% and advanced neoplasia PPV was 25.5%. When patients with BMS and iron deficiency anemia are included, test positivity is essentially the same . We reinforce that mt-sDNA should not be used and is not approved as a test for evaluating the underlying cause of iron deficiency anemia.The rate of mt-sDNA use after prior colonoscopy among those with prior BMS appears to mirror non-BMS patients at our institution; the mt-sDNA after BMS cohort rate of prior colonoscopy was 57% compared to 59% at our institution for average-risk adults.42 Additionally, more women in the BMS group and older patients in the non-BMS group would both bias toward a lower rate of colorectal neoplasia diagnosis in those having BMS before mt-sDNA, which was not observed. This may suggest that the history of obesity or BMS may independently raise the prevalence of colorectal neoplasia. However, this observation may also reflect the low diagnosis rate of neoplasia at historic colonoscopy prior to the use of mt-sDNA, which is beyond the aim of study to evaluate further. Despite an extensive search heuristic rendering the largest cohort of patients with BMS undergoing mt-sDNA, we acknowledge the sample size of test-positive patients is small. Lastly, our study population was mostly white; this potential barrier to generalizability is mitigated, at least in part, by multiple prior studies which show that race does not appear to influence the markers and results of the mt-sDNA test.44While our evaluation comes from the detailed chart review, this was a retrospective cohort study, which can introduce biases and limitations. As patients with a negative mt-sDNA do not undergo colonoscopy in real-world conditions, our primary analysis focused on test positivity and the PPV; negative predictive value could not be calculated. To address this limitation, we compared neoplasia rates among post-BMS patients undergoing colonoscopy alone. In an effort to account for colonoscopy performance that can otherwise change overtime, the BMS cohorts  were evaluated over the same study period. Our retrospective study design limits our ability to elaborate on the lower rate of advanced neoplasia among the screening colonoscopy after BMS group when compared to mt-sDNA after BMS. However, this observation may be related to increased post-test probability after a positive mt-sDNA, variability in prior CRC screening between the groups or other patient-level factors. For example, we did not have control over which patients utilized mt-sDNA and were unable to measure BMI at the time of screening. We were able to determine that shared decision-making between patients and providers was a key driver in mt-sDNA use, but we cannot account for all reasons that influenced use. The manner in which BMI at the time of CRC screening influences patient decision-making on invasive vs noninvasive testing warrants further study. These data could help inform strategies for CRC screening across a community and help tailor dialogue surrounding screening strategies to optimize utilization. Our findings are most applicable to patients with a history of Roux-en-Y gastric bypass ; subgrouBMS is a key strategy in the management of obesity. While there are theoretical concerns that post-BMS anatomy and physiology may alter the performance of mt-sDNA, contribute to false-positive tests, and overutilization of follow-up colonoscopy; these concerns were not supported. The performance of mt-sDNA is similar to that observed among average-risk adults and can be reliably utilized for CRC screening.123


Long-term kidney replacement therapy and critical illness are independently linked to acute and prolonged cognitive impairment, and structural brain pathology. Poor regional cerebral oxygenation  Intensive Care Unit (ICU).2 was monitored during the first 72 hours of continuous kidney replacement therapy or throughout each intermittent hemodialysis session. We measured acute neurological impairment by daily delirium screening and long-term neurocognitive outcomes using the Kinarm robot, Repeatable Battery for the Assessment of Neuropsychological Status, and brain magnetic resonance imaging.rSO2/vitals (91.3%), and delirium screening and demographics (100%). Longitudinal testing was completed in 50% (1 of 2) of survivors.Of 484 ICU patients, 26 met the screening criteria. Two declined, and 13 met at least one exclusion criteria. Eleven patients were enrolled. Eight died in ICU, one died 2 months after discharge, and one declined follow-up. Data capture rates were high: rSOEnrollment was low due to a variety of factors, limiting our ability to evaluate long-term outcomes.2 and delirium data collection is feasible in critically ill patients undergoing kidney replacement therapy; high mortality limits follow-up.rSO Long-term kidney replacement therapy (KRT) and critical illness are independently linked to acute and prolonged cognitive impairment, and structural brain pathology.2) may be related to both acute and long-term neurological impairments in this vulnerable cohort of patients; long-term follow-up of these patients is needed to further understand this relationship.Low regional cerebral oxygen saturation  was feasible in our single center, as a first step toward being able to understand the neurological issues facing this cohort, and ultimately develop targeted interventions to improve neurological complications in this population.It is feasible to collect regional cerebral oxygenation and delirium data in critically ill patients undergoing kidney replacement therapy. Long-term follow-up may be challenging in this cohort due to high mortality. Although KRT may be a lifesaving intervention for individuals with kidney failure, long-term  KRT is associated with poor neurocognitive outcomes and reduced quality of life. Critical illness has also independently been linked to prolonged cognitive impairment and structural brain pathology. Therefore, adults on short-term KRT for AKI in the ICU may be at risk for superimposed impairments associated with both critical illness and dialysis-requiring AKI. Unfortunately, the neurocognitive and structural neurological impact of KRT in this population remains largely unknown.The prevalence of acute kidney injury (AKI) is increasing among critically ill patients admitted to the intensive care unit (ICU), with over half of adult ICU patients meeting the criteria for AKI at some point during their admission, and up to 13% receiving treatment with kidney replacement therapy (KRT). and has been associated with increased brain atrophy. Delirium is common among ICU patients, particularly in those with AKI. Regional cerebral oxygen saturation (rSO2) is associated with delirium in critically ill adults, and duration of disturbed cerebral autoregulation is correlated with the duration of delirium. Therefore, rSO2 may provide an early marker of neurocognitive impairment.Delirium is one of the most consistent and reliable risk factors for cognitive impairment among critically ill adultsThe rationale for this program of research is the lack of data examining the association between KRT, delirium, and long-term structural and cognitive outcomes in critically ill patients. Prior to embarking on the full study, this feasibility study was conducted to assess participant enrollment rates, data fidelity, and long-term follow-up. We identified barriers to enrollment or data collection to design mitigation strategies to ensure adherence to a complex protocol involving longitudinal multimodal data collection. Briefly, participants were eligible for inclusion if they met the following criteria: age ≥18 years; diagnosis of severe AKI Stage 2/3 requiring KRT (per KDIGO criteria); and within 12 hours of initiation of KRT via intermittent hemodialysis (IHD) or continuous kidney replacement therapy (CKRT). Exclusion criteria were as follows: acquired/congenital neurological disorders ; contraindication to testing with cerebral oximetry, Kinarm, or magnetic resonance imaging (MRI)30); KRT via peritoneal dialysis ; life expectancy <24 hours (impeding follow-up); clinical suspicion of renal obstruction, rapidly progressive glomerulonephritis or interstitial nephritis (which could independently affect outcomes); or prehospitalization estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 .This study was approved by the Queen’s University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board (DMED-2424-20). The methodological details for the full study have been published.Baseline illness severity was evaluated using the Acute Physiology and Chronic Health Evaluation II (APACHE II) scoring system. Baseline cognition was measured using the Clinical Dementia Rating (CDR) scale. Baseline frailty was assessed via the Clinical Frailty Scale (CFS). All assessments were performed by a trained member of the research team at the time of enrollment (N.A.J.).https://www.bedmaster.net/) or MediCollector (https://www.medicollector.com/) depending on the availability for the patient.Participants on CKRT underwent continuous cerebral oximetry using the FORESIGHT Elite cerebral oximeter  during the first 72 hours of CKRT. Post-CKRT oximetry was measured for 1 hour following CKRT. Participants on IHD underwent oximetry beginning 1 hour prior to each session, continuously throughout every session, and ending 1 hour following session completion, up to a maximum of 30 days. Heart rate, peripheral oxygen saturation, blood pressure, and mean arterial pressure were continuously captured alongside cerebral oximetry. Data were extracted from the patient’s bedside vitals monitor using either BedMaster Solutions (The presence and severity of delirium was assessed daily using the Confusion Assessment Method (CAM)-ICU-7. Assessments were performed by a trained research team member (N.A.J.) for up to 30 days of ICU admission.Supplemental Table 1.Follow-up data collection is described in  Feasibility for long-term follow-up data collection was defined as a rate of 70% of ICU survivors, as refusal rates for participation in follow-up research among this group are known to be high, with over one third of participants refusing participation. Reasons for missing data were determined to optimize data collection in the future larger study.Feasibility was assessed through (1) participant enrollment, (2) data capture rates, and (3) follow-up rates at 3 and 12 months after ICU discharge. Based on our existing population of potential candidates in the Kingston Health Sciences Centre (KHSC) ICU, feasibility of enrollment was defined as a rate of 1 patient per month. Feasibility of data capture was defined as a data capture rate of 80%, in accordance with the literature on similar existing studies.Supplemental Table 2. Seven of 11 patients met the CAM screening criteria for delirium during their ICU admission. The mean length of time that patients were delirious was 4.57 (SD ± 4.12) days.Participant enrollment is summarized in Supplemental Figure 1. Daily CAM-ICU-7 delirium screening and chart review were performed for all patients with 100% data capture rate.The baseline data capture rate, including CDR, CFS, and APACHE II, was 100%. For all 11 patients we recorded continuous vitals and cerebral oximetry with a mean capture rate of 91.3%. Missing data was primarily due to the near-infrared spectroscopy sensor being removed for surgical interventions, procedures, or imaging that was not compatible with the oximeter. Data illustrating the feasibility of collection of continuous vitals and cerebral oximetry during participants’ admissions are shown in Three- and 12-month follow-up testing was completed on only 1 of 3 patients who survived to ICU discharge and included structural T1- and diffusion-weighted brain MRI, Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and Kinarm assessments. Reasons for lack of follow-up are described in 2 and ICU delirium. However, we have identified barriers and resource planning issues that need to be considered for our larger study. The high mortality rate in our study cohort  is a notable barrier to long-term follow-up. Importantly, performing this early assessment of feasibility has allowed us to identify strategies to ensure that we can obtain sufficient sample sizes, follow-up rates, and data quality to address our outcomes of interest.Our work demonstrates the feasibility of this study for the primary aim of examining the relationship between intradialytic rSOOur enrollment rate was 0.61 patients per month. As this was less than our expected 1 per month, strategies to increase our enrollment will need to be implemented to make a larger study feasible. One of the major barriers to participant enrollment in our feasibility study was the inability to enroll patients within the 12-hour window from their time of KRT initiation. This was primarily due to the inability to reach substitute decision-makers if patients initiated KRT overnight, as well as late notification of new eligible patients to the study team. As we begin our larger study, we plan to implement a deferred consent model, with well-described written study materials for participants/proxies to aid in the conversation to notify patients of their enrollment. To address the issue of lack of awareness of eligible patients admitted after hours, we plan to more closely integrate charge nurses into the enrollment process, to ensure that our study team is notified early on of eligible patients. Due to the COVID-19 pandemic, increased ICU admission rates created the need for subsidiary ICU beds that did not have the ability to perform continuous vitals monitoring, thus excluding potentially eligible patients. Due to the decreasing number of COVID-19-related ICU admissions, we expect this issue to diminish over time. Furthermore, our center is currently implementing bedside monitors that can continuously capture data throughout all beds in the hospital, which will permanently resolve this problem. Furthermore, we plan to onboard additional centers with the infrastructure available to support this study across Canada, which will enable us to achieve the sample size required to adequately answer our research aims.As our expected follow-up rate was 70%, our follow-up data collection in its current form was determined not to be feasible. Longitudinal research in this population is challenging due to high mortality rates both in ICU and following discharge, high study withdrawal rates, and loss to follow-up. Participants’ poor physical, financial, emotional, psychiatric, and neurocognitive states all contribute to their inability or unwillingness to return for assessment. To reduce attrition, our larger INCOGNITO-AKI study will employ a multifaceted approach, including pairing clinical and research visits, enhancing feasibility of participant attendance at appointments and visit completion, increasing study visibility through regular telephone communications, building rapport between participants and study teams, and employing multiple methods for contacting participants. When employing a combination of these strategies, studies have achieved follow-up rates of 70% to 80%.Click here for additional data file.Supplemental material, sj-docx-1-cjk-10.1177_20543581231192743 for Neurological Impairment in Critically Ill Patients on Dialysis: Research Letter for the INCOGNITO-AKI Feasibility Study by Natasha A. Jawa, Samuel A. Silver, Rachel M. Holden, Stephen H. Scott, Andrew G. Day, Patrick A. Norman, Benjamin Y. M. Kwan, David M. Maslove, John Muscedere and J. Gordon Boyd in Canadian Journal of Kidney Health and Disease


Binding antibody levels against SARS-CoV-2 have shown to be correlates of protection against infection with pre-Omicron lineages. This has been challenged by the emergence of immune-evasive variants, notably the Omicron sublineages, in an evolving immune landscape with high levels of cumulative incidence and vaccination coverage. This in turn limits the use of widely available commercial high-throughput methods to quantify binding antibodies as a tool to monitor protection at the population-level. Here we show that anti-Spike RBD antibody levels, as quantified by the immunoassay used in this study, are an indirect correlate of protection against Omicron BA.1/BA.2 for individuals previously infected by SARS-CoV-2. Leveraging repeated serological measurements between April 2020 and December 2021 on 1083 participants of a population-based cohort in Geneva, Switzerland, and using antibody kinetic modeling, we found up to a three-fold reduction in the hazard of having a documented positive SARS-CoV-2 infection during the Omicron BA.1/BA.2 wave for anti-S antibody levels above 800 IU/mL . However, we did not detect a reduction in hazard among uninfected participants. These results provide reassuring insights into the continued interpretation of SARS-CoV-2 binding antibody measurements as an independent marker of protection at both the individual and population levels. Binding antibody levels correlate with protection against infection with the ancestral SARS-CoV-2 strain, but it is not clear whether this relationship extends to the Omicron variant. Here, the authors characterise antibody dynamics and their relationship with Omicron infection in a longitudinal cohort from Geneva, Switzerland. Neutralizing antibodies may provide a reliable correlate of protection against both infection and severe disease7. Neutralization assays are, however, labor-intensive and challenging to use at a large scale, despite advances in high-throughput surrogate assays8.While by mid-2022, a large fraction of the global population had developed anti-SARS-CoV-2 binding antibodies through infection and/or vaccination10. Evidence for their more general use as a correlate of protection is mounting both from population-level9, as well as individual-level studies in the context of vaccine trials13. These studies suggest that higher antibody titers after infection and/or vaccination tend to reduce subsequent infection risk14. However, most of these studies focused on the ancestral SARS-CoV-2 strain, and only a few reports have explored the extension of these results to the Omicron subvariants18.Binding antibody measurements have been found to correlate with neutralization capacity against the ancestral SARS-CoV-2 strain at different degrees depending on time post infection/vaccination and on immunoassay22. Characterization of long-term antibody kinetics provides an opportunity for leveraging serological cohort studies to complement vaccine trials in evaluating binding antibody levels as a correlate of protection against future infections. By relying on binding antibody immunoassays that are simple, standardized, and widely used worldwide, the results of these studies have the potential to be generalized to other settings despite their functional limitation. These cohort studies might therefore contribute by assessing the extension of results to different commercially available immunoassays and a wider range of infection/vaccination histories, in particular to non-vaccinated individuals.The evaluation of binding antibody levels as correlates of protection are challenged by the constant evolution of the anti-SARS-CoV-2 immune landscape through vaccination and successive epidemic waves driven by different virus variants. Longitudinal antibody studies up to 14 months follow-up have shown that antibody levels change with time since infection and/or vaccination across individuals and depending on the immunoassays used for detectionIn this study, we aim to evaluate the use of a widely available immunoassay as a correlate of protection in the Omicron era. We do so by leveraging repeated serological measurements and reported infections on a population-based longitudinal cohort followed for up to 20 months in the state of Geneva, Switzerland. We first characterize antibody dynamics during the longitudinal serology period (April 2020 to December 2021) using kinetic models fit to observed antibody measurements. We then project each individual’s antibody trajectories into the Omicron exposure period (December 2021 to March 2022) to explore the relationship between projected antibody levels and having a SARS-CoV-2 positive test.The cohort included in this study was composed of 1083 adult participants recruited during the longitudinal serology period , and then plateaued for higher antibody level thresholds Fig. . In sensWe, however, found that measured antibody levels do not have the same meaning in terms of a correlate of protection whether a participant had a history of infection or not, independently of antibody level Fig. . SimilarThis longitudinal antibody study with follow-up times up to 20 months provided the opportunity to understand long-term anti-SARS-CoV-2 antibody dynamics and to evaluate binding antibody levels from a commercial widely available immunoassay as a correlate of protection against infections during the Omicron BA.1/BA.2 era. Anti-S antibodies persisted up to 20 months after the probable date of infection, with decay dynamics determined by infection and vaccination history. The strongest and longest-lasting antibody boosts occurred with vaccine doses following prior infection. Modeled antibody trajectories enabled the evaluation of binding antibody levels as a correlate of protection against Omicron BA.1/BA.2 infections, for which we found an overall three-fold reduction in the hazard of reporting a positive test for antibody levels above 800 IU/mL. Hazard reduction was, however, not observed for non-infected participants, indicating that the validity of anti-S binding antibody levels as correlates of protection for Omicron BA.1/BA.2 depends on infection history.22. Our kinetic modeling results support previous findings indicating that antibody boost is strongest and longest lasting in vaccinees with a history of infection24. In contrast with previous findings, we found no significant difference in antibody boosting between age groups and slower decay rates in adults 65 years and older25. The slower decay rates may be due to age-specific differences in disease severity that we did not account for in these models, thus limiting the comparability of these findings with previous studies due to differences in disease severity profiles. Furthermore, we had a small number of participants over 65 years of age in our study, and these age-stratified results should be interpreted with caution. Finally, our results highlight the strong individual-level variability in antibody dynamics, which has been shown in previous antibody kinetic studies26.This study extends our previous work showing that anti-SARS-CoV-2 spike antibodies remain detectable after 22 months past probable infection as measured with the Roche anti-S immunoassay12. These trials had found similar effect sizes of around a fivefold reduction in risk of Alpha infections at anti-S antibody levels of 600 IU/mL12 and a halving of hazard by a 10-fold increase in anti-S titers for ancestral strain infections5. Moreover, our results are in line with available studies on Omicron BA.1/BA.2 subvariants, which have also found binding antibody levels to be correlates of protection against infection using in-house immunoassays18. In particular, one study using the same immunoassay found similar effect size estimates in a prospective study design using measured antibody levels, although not differentiating between infection/vaccination statuses and finding large confidence intervals16. On the other hand, we did not find differences in the hazard of having an Omicron BA.1/BA.2 infection with anti-S antibody levels below or above a certain threshold in the non-infected vaccinated group, as opposed to results reported for Delta infections13. Notably, this finding is supported by our recent work on neutralization capacity in the Geneva population2. Using the same immunoassay as in this study and a cell-free Spike trimer-ACE2 binding-based surrogate neutralization assay8, we did not observe any significant correlation between anti-S binding and neutralizing antibody levels against Omicron subvariants in uninfected participants, as opposed to previously infected participants2. These results can be linked to growing evidence that hybrid immunity (infection plus vaccination) provides the strongest protection against Omicron subvariant infections27. This infection history-specificity thus warrants care in the interpretation of binding antibodies as correlates of protection against Omicron sublineages and could be immunoassay-dependent.Survival analysis results on Omicron BA.1/BA.2 infections are in line with previous findings from vaccine trials targeting the ancestral strain and the Alpha variant, showing that binding antibody levels are an informative correlate of protection against SARS-CoV-2 infection29. Changes in immune evasion capacity may, theoretically if multiple mutations accumulate on the spike protein, impact the level of binding antibodies at which hazard reduction occurs, as well as its effect size. Moreover, our longitudinal serology follow-up was conducted before the circulation of the Omicron lineage in Geneva. The interpretation of anti-S antibody levels measured with this immunoassay following Omicron infections might need to be revisited in light of the evidence of reduced test sensitivity towards antibodies targeting the Omicron Spike protein30.We note that it remains unclear whether these correlate of protection results extend to subsequent Omicron subvariants , which have been found, thanks to specific mutations, to have stronger immune evasion capacity than the parent BA.1 strain10. Secondly, analyses in the 65+ subgroup are limited by the small number of participants. Thirdly, our survival analysis to assess correlates of protection was based on modeled antibody trajectories and not on measurements at defined time points as done in studies available from vaccine trails5. Although modeled trajectories matched well with antibody participant-level measurements, the survival analysis results are subject to modeling uncertainty. While sensitivity analysis using the 2.5% and 97.5% prediction quantiles yielded qualitatively similar correlations of protection results, other sources of modeling uncertainty cannot be excluded. A further modeling limitation relates to the immunoassay’s limit of quantification at the 1:10 dilution level used in this study, which for logistical constraints, could not be further diluted. We addressed this issue through censoring within our modeling framework. We further note that we could not account for unreported infections between the last serology for each participant and the exposure period, given that exclusion criteria for the survival analysis relied on reported infections. This may have resulted in the miss-classification of participants as falsely below the antibody threshold, thus leading to an underestimation of the reduction in infection hazard . Fourthly, a large proportion of virologically confirmed infections  were self-reported as opposed to the other 56%, which were directly extracted from the state COVID-19 test registry (ARGOS). Reassuringly, of the 1083 participants in our longitudinal sample for whom tests in the registry were available, self-reported positive tests with matching dates were reported in 82% (491/599) of cases, thus suggesting a reasonable sensitivity of self-reporting. Moreover, we note that a proportion of Omicron infections during the exposure period were not reported due to subclinical infections, individual (self-)testing, and test reporting practices. As our outcome measure of reported infections is mainly composed of symptomatic infections, it may probably be more representative of more severe BA.1/BA.2 infections than infections across the clinical spectrum of the disease. Finally, both Omicron BA.1 and BA.2 subvariants circulated in the canton of Geneva during the study exposure period, and sequencing information on infection was not available, thus precluding a differential correlation of protection analysis for both subvariants.This study has several limitations. Firstly, we only used the Roche Elecsys assay, which measures total anti-S antibodies (IgA/M/G), whose levels may correlate differently with overall immune function following infection or vaccination; other immunoassays may have different antibody binding characteristics. In particular, changes in the assay’s antibody avidity with time since infection may impact the interpretation of antibody levels prior to infection related to functional immune capacityOverall, this study extends findings against previous SARS-CoV-2 variants showing that anti-S binding antibody levels measured by a widely distributed immunoassay are a valid correlate of protection against Omicron BA.1/BA.2 infections. Importantly, we found that the validity of antibody levels as a correlate of protection depends on infection history as quantified with the immunoassay used in this study. Our results highlight the imperfect nature of protection after vaccination and/or infection. Even with perfect knowledge of infection and vaccination histories, inference about population-level immunity continues to pose challenges. Future studies may benefit from the modeling framework developed in this study to leverage longitudinal measurements to epidemiological outcomes. Taken together, these conclusions motivate further investigation of how immune landscape and immunoassay characteristics determine the interpretation of serological surveys into population levels of protection to inform public health decisions.34. Following their baseline serology, participants in this cohort are regularly invited to complete online questionnaires, where they report SARS-CoV-2 test results, disease severity, and vaccination status and can be proposed one or several serological tests during the follow-up. Each participant coming for a follow-up serology provided a venous blood sample and filled in a short paper questionnaire on-site to update/complete their information on infection and vaccination statuses.This study uses data from the population-based Specchio-COVID19 cohort, composed of adult participants recruited through serological surveysIn this study, our main analysis consisted of two steps. Firstly, we analyzed antibody trajectories during the longitudinal serology period, when serological testing follow-up was conducted . Secondly, we evaluated correlates of protection against infection during the “exposure period”, using information on SARS-CoV-2 infections from the surge of the Omicron BA.1 subvariant in the state of Geneva until the end of the study period  Fig. . During This study was approved by the Geneva Cantonal Commission for Research Ethics (CCER project number 2020-00881), and written informed consent was obtained from all participants.For this study, we used the quantitative Elecsys anti-SARS-CoV-2 RBD immunoassay, which measures total antibodies (IgG/A/M) against the receptor binding domain of the virus spike (S) protein . Seropositivity was defined using the cut-off provided by the manufacturer of ≥0.8 U/mL. Output test values were transformed to WHO international standard units by multiplying by a factor of 1.184. We calculated the intra-lot coefficient of variation (CV) for each batch of our internal positive control serum, and the maximum CV 7.3%) was used to define uncertainty in serological measurements in the kinetic model described below  as self-reported by the participants through regular questionnaires.For the correlation of protection analysis, results of PCR and antigenic tests were extracted from the ARGOS database up to March 20th, 2022. The ARGOS database consists of a general register of COVID-19 diagnostic tests performed in the state of Geneva since February 2020 and is maintained by the state directorate for health26. These models assume an initial post-infection/vaccination antibody boost (increase in antibody levels at a given time post-exposure) followed by initially fast then slower exponential decay. We here expanded these models to account for multiple boosting events due to infection and/or vaccination. The size of antibody boosts and decay in time are determined by age, sex, and boosting history (the sequence of infections and vaccine doses). We further accounted for observed individual-level variability in anti-SARS-CoV-2 antibody kinetics. Inference was performed in a Bayesian hierarchical framework incorporating uncertainty of the timing of infection events in the absence of information on COVID-19 diagnostic tests. Model details are given in the Supplementary Material (Section SIn the first step of the analysis (“longitudinal serology” period in Fig. Section S.36.In the second step of the analysis, we evaluated binding antibody levels as a correlate of protection against Omicron BA.1/BA.2 infections during the “exposure period” Fig. . Given tSupplementary InformationPeer Review File


We assessed the clinical results of irrigation and debridement (I&D) with antibiotic-impregnated calcium hydroxyapatite (CHA) as a novel antibiotic delivery system for the treatment of prosthetic-joint-associated infection (PJI) after total hip arthroplasty (THA). Thirteen patients (14 hips) treated with I&D for PJI after THA at our institution between 1997 and 2017 were retrospectively evaluated. The study group included four men (five hips) and nine women, with an average age of 66.3 years. Four patients (five hips) had symptoms of infection within less than 3 weeks; however, nine patients had symptoms of infection over 3 weeks. All patients received I&D with antibiotic-impregnated CHA in the surrounding bone. In two hips (two cups and one stem), cup and/or stem revision were performed with re-implantation because of implant loosening. In ten patients (11 hips), vancomycin hydrochloride was impregnated in the CHA. The average duration of follow-up was 8.1 years. Four patients included in this study died of other causes, with an average follow-up of 6.7 years. Eleven of thirteen patients (12 of 14 hips) were successfully treated, and no signs of infection were observed at the latest follow-up. In two patients (two hips) for whom treatment failed, infection was successfully treated with two-stage re-implantation. Both patients had diabetes mellitus and symptoms of infection over 3 weeks. Eighty-six percent of patients were successfully treated. No complications were observed with this antibiotic-impregnated CHA. I&D treatment with antibiotic-impregnated CHA produced a higher rate of success in patients with PJI after THA. After removing implants in patients with prosthetic-joint-associated infection (PJI), clinicians prefer to insert antibiotic-impregnated bone cement in the form of beads or spacers. However, antibiotic-impregnated bone cement is also associated with certain disadvantages, including a short duration of drug release , very loInfection after total hip arthroplasty (THA) remains a severe and costly complication ,4. A regChronic infections follow a persistent and undulating course with frequent exacerbations, are generally not fully responsive to systemic antibiotics, and often recur when treatment regimens are discontinued. Therefore, as the only strategy, topical and systemic antibiotics fail to successfully manage bacteria with a biofilm phenotype and must be combined with other approaches .Antibiotic-impregnated calcium hydroxyapatite (CHA) ceramic has been developed as a new drug delivery system A 7,8] a,8 a7,8] Accordingly, in this study, we aimed to evaluate the clinical results of antibiotic-impregnated CHA used for I&D treatment of infected hips.Soft tissue was normal in eight patients (nine hips) and abscessed with fistula in four hips . One of S. aureus (one hip). In two patients, the causative microorganism was Escherichia coli, and Enterococcus faecalis and an unknown microorganism were the causative agents in one patient each. One patient in whom no bacteria were detected showed the presence of purulent fluid and pus during pre-operative hip aspiration and intra-operative findings. We diagnosed PJI based on clinical and intra-operative macroscopic and histological findings. We assumed that the reason for the negative culture was that the patient was taking sulfamethoxazole trimethoprim regularly after kidney transplant  culture were performed in all patients. In 13 aspirates, the culprit bacterium was identified in all but one sample. In nine patients (10 hips), the microorganisms were Staphylococcus aureus, including methicillin-resistant  Case11, .Four patients (five hips) had symptoms of infection for less than 3 weeks, whereas nine patients had symptoms of infection for more than 3 weeks .Open debridement was performed using the previous incision and approach. Synovectomy with all abscessed and necrotic joints and periprosthetic regions was performed via large regions , with thorough lavage using antibiotic-laden saline. The implant was dislocated in order to treat all interfaces and was then tested intra-operatively for loosening. The modular components  and loosening component were replaced, whereas the fixed components were retained. Ten patients (11 hips) underwent exchange of the liner and head, excluding the first two patients. In two hips (two cups and one stem), cup and/or stem revision were performed with one-stage re-implantation because of implant loosening .All patients underwent I&D with antibiotic-impregnated CHA applied to the surrounding bone A,B. CHA The operative antibiotherapy was systematically initiated following pre-operative hip aspiration. This treatment consisted of intravenous (i.v.) antibiotherapy at the effective dose, which was quickly adapted based on the aspiration findings. CHA was administered as local antibiotherapy, and i.v. antibiotherapy was maintained for 4–9 weeks, followed by oral administration for 6 weeks. Tolerance was satisfactory. Treatment outcomesThe average duration of follow-up was 8.1 years . No patients were lost to follow-up. Four patients included in this study died of other causes, with an average follow-up of 6.7 (4.0–12.5) years before death. There was no evidence of recurrent infections in these four patients.Eleven of thirteen patients (12 of 14 hips) were successfully treated with no signs of infection at most recent follow-up. In two of thirteen patients (two of 14 hips) for whom treatment failed, infection was successfully treated with two-stage re-implantation with antibiotic-impregnated CHA. Both patients had diabetes mellitus and had symptoms of infection for more than 3 weeks. However, seven of nine patients who showed symptoms of infection for more than 3 weeks were successfully treated with I&D with antibiotic-impregnated CHA. Eighty-six percent of patients were successfully treated by I&D with antibiotic-impregnated CHA. No complications, such as excessive postoperative drainage, erythema, bone damage from friction, or any particle disease, were observed following treatment with this antibiotic-impregnated CHA. However, one patient had a greater trochanteric fracture after PJI surgery. There was no pain or dysfunction in this patient, and he followed up normally. These patients were free of infection at the time of the most recent follow-up. Radiographically, there was no loosening or migration of the components in any of the 13 patients.Eleven of thirteen patients (12 of 14 hips) were comprehensively rated using JOA hip scores at the most recent follow-up. Overall, the median and mean JOA hip scores were 70 and 69.3 (42–97), respectively. For two hips (two patients) that underwent two-stage revision, the JOA hip scores were 59 and 46.Total joint arthroplasty is a widely used treatment modality for advanced osteoarthritis of the hip and knee. Although this procedure is highly successful, PJI is a relatively uncommon but devastating complication following total joint arthroplasty. The average reported incidence of PJI is 0.5–2% ,10,11. PPrimary surgical management strategies for PJI differ among institutions but include I&D with modular component exchange, one-stage revision arthroplasty, and two-stage revision arthroplasty. However, two-stage revision is associated with significant morbidity and mortality and is poorly tolerated by patients. Additionally, when associated with a period without a hip implant, the tissue changes can lead to important functional deficits after re-implantation .In appropriate patients, single-stage revision appears to be associated with similar reinfection rates when compared with two-stage revision with superior functional outcomes . One optMultiple factors influence the outcomes of I&D. For example, the causative microorganisms, applied antimicrobial regimen, soft tissue envelope, timing of intervention, and duration of symptoms have all been shown to influence the outcome of I&D ,18,19,20Moreover, several studies have demonstrated that the I&D failure rate increases when the infection persists for a longer period of time ,20. In cBiofilms related infections are recalcitrant to antibiotic strategies. It has already been published in the literature that the antimicrobial concentrations needed to eradicate biofilms are higher than the concentrations required to eradicate the same bacterial clones in a planktonic state. To be able to decide on an appropriate empirical antimicrobial therapy, the common microbiological causes of periprosthetic joint infections should be known. In orthopedic surgeries, the most common causative organisms are Staphylococcus aureus and coagulase-negative staphylococci (CNS) . In the Indications for determining eligibility for I&D have been suggested in recent years as the arthroplasty community has developed a greater understanding of the risk factors that predispose patients to treatment failure. Success can be achieved in over 70% of cases when patients with favorable factors are selected, such as those with a short duration of symptoms (less than 3–4 weeks), a stable implant, and healthy soft tissues surrounding the prosthesis ,18,26. FIn this retrospective study, we investigated the efficacy of antibiotic-impregnated CHA used in conjunction with irrigation and debridement for the treatment of PJI with attempted prosthetic retention for determination of long-term efficacy and safety. PJI could be treated successfully using antibiotic-impregnated CHA, even for more advanced cases. All patients with infective symptoms for less than 3 weeks were successfully treated with I&D using antibiotic-impregnated CHA. Moreover, seven of nine patients who had symptoms of infection for more than 3 weeks were successfully treated by I&D with antibiotic-impregnated CHA. Both of the two patients for whom I&D treatment failed had diabetes mellitus and symptoms of infection over 3 weeks. Supporting our results, Katakam A et al. have suggested that morbidly obese patients face an increased risk of DAIR failure .The success of I&D in early PJI largely depends on the presence of a mature biofilm. Infected artificial joints are often unresponsive to antibiotic treatment owing to poor vascular supply and biofilm formation. In most cases, reconstruction was performed with cemented implants, and antibiotic-impregnated cement was used. At the time of revision surgery with the cemented prosthesis, the success rate with antibiotic-impregnated bone cement has been reported to be higher than that without antibiotic-impregnated bone cement . HoweverPrevious studies, including our study, reported successful two-stage reconstruction surgery using CHA in patients with intractable PJI, with good clinical outcomes without any cases of reinfection during follow-up ,30. ImpoThere were several limitations to the current study. First, this study was retrospective, and randomized trials are needed to conclusively determine whether the use of CHA could improve infection-free survival when used as part of an attempt at implant retention in the setting of PJI. Furthermore, because the study was retrospective in nature, it is possible that there may have been some selection bias owing to selection of CHA in more challenging cases. Second, in early PJI, there may be cases that can be treated with only I&D. However, recurrent infection may be a physical and mental burden on patients. Therefore, antibiotic-impregnated CHA can be used to lower the possibility of recurrence. Finally, our study cohort lacked a direct control group to compare irrigation and debridement with component retention with or without the addition of antibiotic-impregnated CHA.This research was a retrospective study and was approved by the Institutional Review Board of our institution. Thirteen patients (14 hips) treated with I&D for PJI after THA at our institution between 1997 and 2017 were retrospectively enrolled in this study and followed for more than 2 years after treatment. The study group consisted of four men (five hips) and nine women, with an average age of 66.3 years . The initial diagnoses were osteoarthritis in six patients, rheumatoid arthritis in four patients (five hips), idiopathic osteonecrosis in two patients, and neck fracture in one patient .The diagnosis of infection was based on clinical criteria, including the presence of discharging sinus, frank purulent fluid, or pus found on pre-operative hip aspiration or positive findings on laboratory and histopathological tests. The criteria to define PJI were the presence of a sinus tract communicating with the prosthesis and/or at least two identical positive cultures.The primary outcome measure was the presence or absence of PJI at the most recent clinical follow-up and the final follow-up date. At the most recent follow-up visit, the patients were clinically assessed, and blood tests were performed, including analysis of erythrocyte sedimentation rate and C-reactive protein.Functional outcomes were assessed based on the Japanese Orthopedic Association (JOA) hip score, with a maximum score of 100 points (representing no disability).The criterion for success was apparent resolution of the initial infection after a minimum follow-up of 2 years, defined as the absence of clinical, biological, and radiological implant infection signs or death directly related to the infection or treatment . TreatmeIn conclusion, our findings suggested that I&D treatment with antibiotic-impregnated CHA produced high success rates for the treatment of PJI after THA, even in cases of advanced disease, with adequate functional outcomes after surgery.