Rabbit anti-thymocyte globulin (rATG) induction in HIV-infected kidney transplant recipients has been associated with a lower risk of acute rejection, but data on the rates of de novo malignancy. Secondary outcomes included the development of BK viremia, infections requiring hospitalization, HIV progression, biopsy-proven acute rejection, and patient and allograft survival.We performed a single-center retrospective cohort study of adult HIV-infected individuals who underwent kidney transplantation with rATG induction between January 2006 and December 2016. The primary outcome was the development of Twenty-seven HIV-infected individuals with end-stage kidney disease received deceased (n=23) or living (n=4) donor kidney transplants. The cumulative rate of malignancy at five years was 29%, of whom 29% died because of advanced malignancy. BK viremia was detected in six participants (22%), of whom one had biopsy-proven BK virus-associated nephropathy and all of whom cleared the BK viremia. Five-year acute rejection rates, patient survival and death-censored allograft survival were 17%, 85% and 80% respectively.de novo malignancies and BK viremia in this cohort. Screening strategies to closely monitor for BK virus infection and malignancy post-transplantation may improve outcomes in HIV-infected kidney transplant recipients receiving rATG induction.rATG induction in HIV-infected kidney transplant recipients was associated with a low risk of acute rejection, but a potentially higher risk of  Highly active antiretroviral therapy (HAART) has had a major impact on reducing the mortality of people living with human immunodeficiency virus (HIV) with their survival now being similar to patients not infected with HIV . Despitede novo malignancy and BK viremia, are limited.While there may have been a reluctance to prescribe potent immunosuppressive agents in the early experience of KT in PWH given concerns about infection and malignancy risk, paradoxically, a landmark study in KT in PWH demonstrated a higher rejection rate at one-year of 31% when compared to the 12% reported in the US Scientific Registry of Transplant Recipients , 8. The The objective of this study was to investigate the neoplastic and infectious complications following rATG induction in PWH after KT.This is an IRB-approved (protocol #19-04020110) retrospective cohort study of all adult HIV-infected patients who received a KT with rATG induction (1.5mg/Kg daily x4 doses) at our center between January 2006 and December 2016. Intravenous methylprednisolone was administered starting on post-operative day (POD) 0 and either tapered off by POD4 or continued at a low maintenance dose per our center’s protocol. All patients were started on maintenance immunosuppression therapy with tacrolimus and mycophenolate. Opportunistic infection prophylaxis was initiated post-transplant per our center’s protocol for oral candidiasis, pneumocystis pneumonia, and cytomegalovirus (CMV) infection using clotrimazole, sulfamethoxazole-trimethoprim, and valganciclovir or acyclovir, respectively. There were no restrictions on the use of antiretroviral medications. Only for-indication biopsies were performed during follow-up. No protocol biopsies were performed. Details of post-transplant immunosuppression, infection prophylaxis and monitoring are described in de novo malignancy within five years after transplantation. Secondary outcomes included the development of BK viremia, infection requiring hospitalization, HIV progression, biopsy-proven acute rejection within five years of transplantation, and patient and graft survival at one and five years. Graft failure was defined as return to maintenance dialysis. We used Kaplan-Meier analysis to estimate patient and allograft survival, time to first episode of rejection, and infection requiring hospitalization. Patients who did not reach their primary outcomes were censored at their last follow up. We used GraphPad Prism version 8.4.3 for statistical analyses. The study was conducted in compliance with the Declaration of Helsinki and all data are reported in compliance with STROBE guidelines. The clinical and research activities being reported are consistent with the Principles of the Declaration of Istanbul as outlined in the ‘Declaration of Istanbul on Organ Trafficking and Transplant Tourism’.The primary outcome was the development of Between January 1, 2006, and December 31, 2016, 27 PWH received deceased (n=23) and living (n=4) KTs and induction immunosuppression with rATG at our center. de novo malignancies during the first five years after KT  and both patients underwent kidney biopsies. One patient had tubular injury that did not improve, and the other patient had mixed acute rejection that did not improve with treatment. Both patients had to resume maintenance hemodialysis. Five-year Kaplan-Meier survival estimate was 80% for allograft survival  developed acute rejection. One patient (discussed above) developed a mixed acute rejection  at three weeks post transplantation. The patient was treated with pulse methylprednisolone, intravenous immunoglobulins and plasmapheresis but did not recover kidney function. The patient was re-started on hemodialysis and underwent a transplant nephrectomy.The second patient developed acute T-cell mediated rejection (Banff grade IB) three months post-transplantation with an increase in serum creatinine from 1.78 to 3.25 mg/dL. The patient was treated with pulse intravenous methylprednisolone followed by an oral prednisone taper with improvement in allograft function to a serum creatinine of 1.76 mg/dL two weeks after treatment. At five years, the Kaplan-Meier estimate for acute rejection was 17% for the entire cohort (de novo DSAs after transplantation and at their last follow up (median follow up 27 months) had stable allograft function and no proteinuria. Glomerular filtration rates estimated using the 4-parameter Modification of Diet in Renal Disease (MDRD) formula (eGFR), at 1, 3, 6, 9, 12, 18, 24, 36, 48 and 60 months after transplantation are shown in At the time of transplant, none of the patients had a positive T or B crossmatch by complement-dependent cytotoxicity assay. Results of the flow cytometric crossmatch were available in five patients; all were negative for T and B cell crossmatch. Luminex platform test to detect circulating IgG directed against donor human leukocyte antigen (HLA) using single antigen beads was done in 26 of the 27 (96%) recipients. Three were positive at the time of transplant based on our threshold of 2000 mean fluorescence intensity value. After transplant, these three recipients tested negative for donor-specific antibodies (DSAs) and at the last follow up (median follow up 63 months) had no DSAs, stable allograft function and no proteinuria. Three patients developed de novo malignancy and BK viremia has not been studied thoroughly yet in this patient population, we aimed to evaluate these risks in this study.Kidney transplantation for HIV-infected patients with ESKD is associated with improved survival compared to dialysis . The optAn important finding in our study was that the incidence of malignancy after transplant was high (29% within five years) and about half of these patients had pre-transplant malignancies. Five of the seven patients who developed post-transplant malignancies remain alive with no evidence of recurrence or progression of their malignancies. Two of the seven malignancies were metastatic, resulting in death. While this rate of malignancy is high, it is difficult to interpret as there is little data on the risk of post-transplant malignancies in this group of patients and its impact on mortality . Nissen 3 soon after rATG induction in our transplant recipients. Contrary to the tenet of preserving the CD4 count when managing non-transplant HIV-infected patients, it is alarming that the CD4 count did not recover to 200 cells per mm3 until almost 12 months after induction therapy. Despite that, only one patient developed an opportunistic infection during the first 12 months post-transplant (Pneumocystis jirovecii pneumonia at 4.5 months) and there were no cases of progressive multifocal leukoencephalopathy. BK viremia, however, developed in 22% of patients, which is higher than the 11.5-12.6% reported in non-HIV-infected kidney transplant recipients  database (83% vs 87% at five years for DDRTs). Rates of death-censored allograft failure while similar at one year between our study and SRTR data (9% vs 5% for DDRTs) but were higher in our HIV-infected patient cohort at five years (23% vs 12% for DDRTs). Rates of acute rejection were also similar at one-year . The five-year rate of acute rejection in our cohort was 17% but was not specified in the SRTR data , due to de novo malignancy appear higher in this group of patients, this needs to be weighed against the benefit of lower risk of acute rejection in this population. Therefore, our findings should not discourage the use of rATG induction immunosuppression in this population given its clear benefits in lowering the risk of acute rejection. Rather, these patients should be considered for more frequent screening for malignancy and BK viremia to mitigate these risks. Prospective studies with larger cohorts are needed to investigate both the incidence and prevention strategies for BK virus infection and de novo malignancy in HIV-infected KT recipients receiving rATG induction.Our study has several limitations including its retrospective single-center design, lack of a matched control group managed without rATG induction and the small sample size of our cohort. Despite that, our study demonstrates the efficacy of rATG induction immunosuppression in high-risk HIV-infected KT recipients with similar long-term patient survival and one-year acute rejection rates when compared to non-HIV infected KT recipients. Rates of death-censored allograft survival are similar to non-HIV infected KT recipients at one year but are lower at five years. While rates of BK viremia and The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Weill Cornell Medicine IRB protocol #19-04020110. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.AJ, EL, AD, CS, SK, CH, and TM designed the research project. AJ, EL, TS, AD, and TM collected the data. AJ, EL, MA, ML, AD, CS, CH, and TM analyzed the data. AJ, EL, CH, and TM wrote the manuscript and reviewed the final version. All authors contributed to the article and approved the submitted version.


People with coronary heart disease are at an increased risk of morbidity and mortality even if they attend cardiac rehabilitation. High sedentary behavior levels potentially contribute to this morbidity. Smartphone apps may be feasible to facilitate sedentary behavior reductions and lead to reduced health care use.We aimed to test the effect of a sedentary behavior change smartphone app (Vire app and ToDo-CR program) as an adjunct to cardiac rehabilitation on hospital admissions and emergency department (ED) presentations over 12 months.A multicenter, randomized controlled trial was conducted with 120 participants recruited from 3 cardiac rehabilitation programs. Participants were randomized 1:1 to cardiac rehabilitation plus the fully automated 6-month Vire app and ToDo-CR program (intervention) or usual care (control). The primary outcome was nonelective hospital admissions and ED presentations over 12 months. Secondary outcomes including accelerometer-measured sedentary behavior, BMI, waist circumference, and quality of life were recorded at baseline and 6 and 12 months. Logistic regression models were used to analyze the primary outcome, and linear mixed-effects models were used to analyze secondary outcomes. Data on intervention and hospital admission costs were collected, and the incremental cost-effectiveness ratios (ICERs) were calculated.P=.39) and cardiac-related  hospital admissions and ED presentations  than the control group. Despite this, cardiac-related hospital admission costs were lower in the intervention group over 12 months . There were no significant between-group differences in sedentary behavior minutes per day over 12 months, although the intervention group completed 22 minutes less than the control group . The intervention group had a lower BMI , waist circumference , waist-to-hip ratio , and quality of life  than the control group. The intervention was more effective but more costly in reducing sedentary behavior (ICER Aus $351.77) and anxiety  at 12 months. The intervention was also more effective yet costly in increasing quality of life  at 12 months.Participants were, on average, aged 62 (SD 10) years, and the majority were male . The intervention group were more likely to experience all-cause  ACTRN12619001223123; https://australianclinicaltrials.gov.au/anzctr/trial/ACTRN12619001223123RR2-10.1136/bmjopen-2020-040479 Cardiovascular disease, including coronary heart disease (CHD), is the leading cause of death in Australia and globally -3. ExercCardiac rehabilitation aims to reduce morbidity through positive lifestyle changes, including increasing physical activity and decreasing sedentary behavior ,7. DespiP=.04) reductions in weight and blood pressure and a 28% reduction in rehospitalizations and emergency department (ED) presentations compared with those who received traditional cardiac rehabilitation only. We hypothesized that better secondary prevention management of risk factors through cardiac rehabilitation plus the digital health intervention can lead to reduced hospital admissions. Similarly, smartphone apps that reduce sedentary behavior may be a feasible option to reduce hospital admissions. Few studies have targeted sedentary behavior change through smartphone apps in people with CHD [Evidence suggests that cardiac rehabilitation participants are interested in support via the internet and mobile phones ,23, and with CHD -29. Theswith CHD . Effect with CHD , and in Using an assessor-blind, parallel randomized controlled trial design, participants were recruited from 3 phase-2 hospital-based cardiac rehabilitation programs in Canberra, Australia, between January 2020 and December 2021. The study duration for each participant was 12 months . FollowiAll participants provided written informed consent. Ethics approval was obtained from the Australian Capital Territory Health (2019.ETH.00162), Calvary Public Hospital Bruce (20-2019), and the University of Canberra HREC-2325) Human Research Ethics Committees. Reporting was informed by the CONSORT –EHEALTH 5 Human R and guidDo Something Different approach focusing on breaking existing sedentary behavior habits and becoming behaviorally flexible [Do’s in the form of push notifications 2 to 3 times per week at random over 6 months. The Do’s targeted sedentary behavior, suggesting microbehavioral alternatives designed to disrupt usual habits and encourage small lifestyle changes. Participants were encouraged to download the app, and technological support was provided throughout the trial.The Vire app and ToDo-CR behavior change program was informed by the flexible ,35,36. TThe primary outcome was the total number of all-cause hospital admissions  and ED presentations within the 12 months after commencing cardiac rehabilitation. Data on cardiac-related hospital admissions and time frames to admission were also collected. Participants self-reported hospital admissions, which were verified by a comprehensive hospital patient records audit for all participants, regardless of self-report admission.Sedentary behavior and physical activity were measured using a triaxial commercial accelerometer (ActiGraph wGT3X-BT) worn by participants on the right hip for 7 consecutive days during waking hours. ActiLife software (ActiLife V.6.13.4) was used to download raw data (30 Hz), which were converted to 15-second epochs and counts per minute (cpm) ,16. All 2); waist circumference; waist-to-hip ratio; blood pressure; exercise capacity ; healthdistance ,43); anxdistance ); and thdistance ).Do’s. The total number of completed Do’s across the study was recorded.For those in the intervention group, the usability and acceptance of the Vire app and ToDo-CR program were assessed using the Unified Theory of Acceptance and Use of Technology questionnaire . EngagemThe costs of implementing and delivering the intervention were recorded prospectively, including payment for the Vire app and maintenance of the server, the purchase of Fitbit Inspire wearable activity trackers, and phone call and email support related to the app from a cardiac rehabilitation clinician.A hospital patient records audit was completed for all participants to obtain the associated Australian Refined Diagnosis Related Group (AR-DRG) classification code for any nonelective admissions and the Urgent Related Group classification codes for any ED presentation. The Independent Health and Aged Care Pricing Authority Australian version of the National Weighted Activity Unit calculators were used to obtain hospital cost information ,48. CostP<.05 and power of 88% , a minimum of 108 participants were needed. Accounting for a 25% dropout rate, 72 participants per group  were calculated.Sample size was based on detecting a significant difference in hospital admissions and ED presentations between usual care and a digital health intervention. A similar study  noted a To comply with public health recommendations, there were variations in the methods used in the protocol . The triData were analyzed according to group assignment using intention-to-treat analyses. Missing data were handled by bringing the last value forward (carryover approach). An on-protocol analysis was also performed. All descriptive statistics were reported using means and SDs, medians, and IQRs or proportions, as appropriate. Normality was assessed using the Kolmogorov-Smirnov test for samples ≥50.The primary analysis was the comparison of rates of nonelective hospital admissions and ED presentations. Binary logistic regression for “yes” versus “no” admissions (odds ratios) and negative binomial with log link regression for the rate or number of admissions (incidence rate ratio) were completed. Survival analyses (Cox regression) were completed to consider the time frame to admission (hazard ratios). Adjustments were made for sociodemographic variables  and other covariates .Linear mixed-effects models for repeated measures were used to analyze all other secondary outcomes. The maximum likelihood method was used for parameter estimation. Time and between-group comparisons were explored as fixed effects while adjusting for demographic characteristics  and other covariates  -51. PartSensitivity analyses were completed for outcomes self-administered by participants under telehealth conditions  and for participants wearing their accelerometer belt during COVID-19 pandemic lockdowns and restrictions. Subanalyses were completed for participants excluded versus participants consented, dropouts versus those who completed the study, and those with prior experience with a physical activity tracker versus those with no experience. Data were analyzed using SPSS .Effectiveness was measured in terms of the secondary outcomes. The incremental cost-effectiveness ratios (ICERs) were calculated using the following formula:t tests with 95% CIs. From these analyses, the additional cost per unit of health benefit gained  was determined.The mean difference in health care resource use costs included the costs of implementing the intervention plus the indirect costs associated with health care use . The difference in effects was calculated as the change from baseline to 6 months and from baseline to 12 months for each secondary outcome per individual participant. The mean difference of these individual differences was then calculated using 2-tailed independent samples P=.003), from public hospitals (P=.001), and less likely to have had a percutaneous coronary intervention and more likely to have had a myocardial infarction  but no difference in characteristics  of all-cause or cardiac-related admissions or ED presentations . The admResults of the Cox regression analysis to determine if there were differences in time to admission or ED presentation between the intervention and control groups are presented in Table S4 in d=0.11) and 12 months (Cohen d=0.21) in favor of the intervention group compared with the control group. At 6 and 12 months, the control group engaged in 15 minutes (P=.54) and 22 minutes (P=.33) more sedentary behavior than the intervention group when adjusted for age, sex, VM counts, employment, and education (P=.02), had shorter sedentary bouts , and had lower overall sedentary minutes per day  at 6 months on the completion of the intervention , waist circumference (Cohen d=0.43), and waist-to-hip ratio (Cohen d=0.33) at 6 and 12 months  over 6 months. There were 27% (16/60) of participants who engaged with the app for the entire 6 months , 33% (20/60) of participants who engaged with the app less than once per month, and 40% (24/60) of participants who did not complete any Dos. In logistic regression modeling, those who had used apps or wearable activity trackers before were 1.04 times (P=.01) more likely to complete Dos (χ21=7.1). Those who were employed full time or part time were 0.97 times (P=.01) less likely to complete Dos (χ21=6.6). There were no statistically significant correlations among the total number of Dos completed and age , sedentary behavior , physical activity , quality of life , anxiety  or depression  at 6 months (Table S10 in The median completion rate of The usability of the Vire app (Unified Theory of Acceptance and Use of Technology) is presented in Table S11 in P=.04).On average, the cost of implementing the intervention per participant was Aus $1086.55 . Presenting to the ED for chest pain is particularly relevant with advice given in the Vire app and ToDo-CR program to seek medical attention if participants experienced these symptoms. These participants may have become more proactive in self-managing their CHD because of the education provided. Public education campaigns to raise awareness of the signs and symptoms of acute chest pain have been shown to be effective in increasing the rate of ED presentations for early medical intervention ,58. DespAlthough the effect size for reduction in sedentary behavior was small in this study, an approximate 20-minute reduction may still be clinically meaningful. In the limited studies available that test the effect of smartphone apps on sedentary behavior , greater2) significantly reduced in the intervention group; however, they were unlikely to be clinically significant changes. The intervention also had a statistically significant 6-cm reduction in waist circumference, which could be considered clinically significant after accounting for measurement error (≥2 cm) [The waist-to-hip ratio (0.03) and BMI (1.64 kg/m (≥2 cm) . These r (≥2 cm) .Do message , which was used as the marker of engagement. There may have been a misunderstanding of the need to tick off the Dos after viewing them or, alternatively, the intervention did not appeal to them. Previous studies on cardiovascular disease and smartphone apps have reported similarly low engagement and adherence levels [A high percentage of the intervention group did not complete a single e levels ,62,69-71e levels . Similare levels ,72. Low e levels , with ine levels -77.In line with the feasibility trial preceding this study , not havAlthough smartphone apps have the potential to be a cost-effective solution , furtherThis study has several strengths being one of the first published studies to explore the impact of a sedentary behavior change smartphone app on hospital admissions and its cost-effectiveness. Device-measured sedentary behavior was analyzed, personalization and clinical guidelines were championed, and the study included both public and private hospitals. This is critical for improving the implementation of research apps in real-world settings.Despite these strengths, there were several limitations. First, this trial was interrupted during the COVID-19 pandemic, impacting the recruitment and follow-up of participants and ultimately resulting in incomplete data. The number of participants who completed outcomes remotely have been reported, and sensitivity analyses were completed in line with guidelines for reporting trials affected by the pandemic . No partIt does not appear that the Vire app and ToDo-CR program targeting sedentary behavior is an outcome-effective or cost-effective solution to reduce all-cause hospital admissions or ED presentations in cardiac rehabilitation participants. Although those using the Vire app and the ToDo-CR program had more hospital admissions, these admissions were less costly. Further research is warranted to improve engagement and implementation with age appearing to be less of an impacting factor and prior experience with apps correlating more with engagement. This type of intervention may work as a better resource for those not already attending cardiac rehabilitation, who are at greater risk of hospitalizations, to influence sedentary behavior and potentially reduce costs associated with cardiac-related hospital admissions.


Adenovirus-based COVID-19 vaccines are extensively used in low- and middle-income countries (LMICs). Remarkably, cases of cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT) have rarely been reported from LMICs.We studied the frequency, manifestations, treatment, and outcomes of CVST-VITT in LMICs.We report data from an international registry on CVST after COVID-19 vaccination. VITT was classified according to the Pavord criteria. We compared CVST-VITT cases from LMICs to cases from high-income countries (HICs).p = 0.039).Until August 2022, 228 CVST cases were reported, of which 63 were from LMICs . Of these 63, 32 (51%) met the VITT criteria, compared to 103 of 165 (62%) from HICs. Only 5 of the 32 (16%) CVST-VITT cases from MICs had definite VITT, mostly because anti-platelet factor 4 antibodies were often not tested. The median age was 26 (interquartile range [IQR] 20–37) versus 47 (IQR 32–58) years, and the proportion of women was 25 of 32 (78%) versus 77 of 103 (75%) in MICs versus HICs, respectively. Patients from MICs were diagnosed later than patients from HICs (1/32 [3%] vs. 65/103 [63%] diagnosed before May 2021). Clinical manifestations, including intracranial hemorrhage, were largely similar as was intravenous immunoglobulin use. In-hospital mortality was lower in MICs  11–40]) than in HICs (44/102 , The number of CVST-VITT cases reported from LMICs was small despite the widespread use of adenoviral vaccines. Clinical manifestations and treatment of CVST-VITT cases were largely similar in MICs and HICs, while mortality was lower in patients from MICs. Meanwhile, low- and middle-income countries (LMICs) had a delayed start to their vaccination campaigns. In response to the VITT occurrences, most HICs restricted, or outright banned, the use of adenovirus-based vaccines, relying on mRNA vaccines instead. In stark contrast, adenovirus-based vaccines remain vital for the vaccination campaigns in LMICs, as these vaccines generally are cheaper and easier to transfer and store. By 22 September 2022, 530 million doses of adenovirus-based COVID-19 vaccines have been secured through COVAX, which is a global collaboration for equitable access to COVID-19 vaccines. Moreover, in India alone, 1.67 billion ChAdOx1 nCoV-19 vaccines were administered by 23 August 2022.Almost all reports on VITT originated from high-income countries (HICs), which was initially not surprising, as these countries had preferential access to COVID-19 vaccines.10 However, despite the widespread use of adenovirus-based COVID-19 vaccines for millions of individuals in these countries, there are almost no reports on VITT from LMICs.12 A PubMed search on 15 December 2022 identified only nine CVST-VITT cases reported from LMICs . This apparent contradiction may be due to under-recognition of the condition in LMICs, for instance, due to limited availability of diagnostic tests such as vascular neuroimaging, or because some LMICs have a more nascent infrastructure for pharmacovigilance. Alternatively, or in combination with under-ascertainment, it may be that susceptibility to CVST-VITT differs across populations, as has, for instance, also been observed for the association between the Pandemrix H1 N1 vaccine and narcolepsy.Vaccination campaigns in LMICs have accelerated in the past months and are still in full swing. Immunomodulation by intravenous immunoglobulins (IVIGs) is effective but also expensive, and global shortages of IVIG have been well-documented even prior to the COVID-19 pandemic.17 In LMICs, access to these therapies might be limited, which could lead to a worse outcome for patients with CVST-VITT.The treatment of CVST-VITT in the acute phase is mainly based on administration of immunomodulatory agents.The aims of this study were to gain insight into rates and characteristics of CVST-VITT reported from LMICs and to determine if its clinical manifestations, treatment, and outcome differ from CVST-VITT cases reported from HICs.15 Briefly, participating investigators were instructed to report consecutive cases of CVST developing within 4 weeks after any COVID-19 vaccine. For this particular study, we purposefully approached investigators from LMICs on multiple occasions through the International Cerebral Venous Thrombosis Consortium with the request to extend the invitation to as many colleagues in their country as possible. Detailed information on the search for eligible patients in the participating middle-income countries (MICs) is provided in Supplemental Table 2. Relevant patient data were extracted from the medical records.Data were collected as part of an international observational study on CVST after COVID-19 vaccination. Details about the study methods have been published.The Medical Ethical Review Committee of Amsterdam University Medical Centers gave a waiver for formal approval of this study (reference W21_171#21.186). Informed consent was obtained from the patient or patient’s relatives if required by local law and/or hospital regulations. For this analysis, we included all data collected until 15 August 2022. . We considered the criterion for positive anti-PF4 antibodies to be met if the treating physician indicated that the patient tested positive for anti-PF4 antibodies, regardless of the antibody test type. Thrombocytopenia was defined as a platelet count < 150 × 103/µL. In the main analysis, we focused on the cases classified as definite, probable, or possible VITT. The CVST cases with unlikely VITT were explored in a sensitivity analysis to investigate if CVST-VITT cases had potentially been misclassified as unlikely VITT, due to insufficient diagnostic resources in LMICs.CVST cases were categorized into definite, probable, possible, or unlikely VITT based on the criteria from Pavord et al. Ethnicity and sex were as investigator reported. The date of CVST diagnosis was divided into three timeframes  based on the timing of the first publication on VITT, which included treatment recommendations.15 If follow-up data after the initial hospital discharge were unavailable, the modified Rankin Scale (mRS) score at discharge was considered the final follow-up data. Functional independence was defined as having an mRS score of 0–2. Because the mortality rate due to CVST-VITT declined over time, we performed a sensitivity analysis to compare outcomes of patients diagnosed with CVST-VITT after May 2021 from MICs and HICs.Countries were classified as low-income country, MIC, or HIC according to the World Bank definition.p values less than 0.05 were considered significant. Analyses were conducted using IBM SPSS Statistics for Windows, version 28.0.1.0  and RStudio version 1.3.1093  using the “Hmisc” package.We used descriptive statistics to report study outcomes. We calculated 95% confidence intervals (95% CI) for proportions using the Wilson score method. We compared patient characteristics using the Mann–Whitney U test for non-normally distributed numerical variables, the chi-square test for binary and nominal categorical variables, and the chi-square test for trend for ordinal categorical variables. Fisher’s exact test for binary categorical variables and the Fisher–Freeman–Halton test for nominal categorical variables were used if any cells had an expected count less than five. Supplemental Figure 1 and Supplemental Table 4). Of these, 63 cases (28%) came from seven MICs, and 165 cases (72%) from 18 HICs. There were no cases from low-income countries. Cases from MICs originated from Brazil, China, India, Iran, Mexico, Pakistan, and Turkey.Between 31 March 2021 and 15 August 2022, 228 cases of CVST within 4 weeks of COVID-19 vaccination were reported from 25 countries (p = 0.110). The median age of CVST-VITT patients from MICs at diagnosis was 26 years (IQR 20–37 years), compared with 47 years (IQR 32–58 years) for CVST-VITT patients from HICs . Anti-PF4 antibodies were frequently not tested in patients from MICs (missing in 21/32 [66%] cases vs. 9/103 [9%] cases from HICs). D-dimer levels were not tested or were unknown in 5 of the 32 (16%) CVST-VITT cases from MICs compared with 6 of the 103 (6%) cases from HICs.Of the 63 CVST cases from MICs, 32 (51%) fulfilled the criteria for definite, probable, or possible VITT, compared with 103 of the 165 (62%) cases from HICs (p = 0.047), and the median platelet count at presentation was higher  in the MICs group than in the HICs group. The nadir platelet count was also higher in cases from MICs than that in cases from HICs . In MICs, 14 of 27 (52%) patients were treated with a non-heparin as the first anticoagulant, compared with 56 of 90 (62%) patients in HICs . In both the MICs group and the HICs group, one additional patient died after hospital discharge . Mortality at 30 days after CVT diagnosis was 7 of 22 (32%) in MICs versus 43 of 100 (43%) in HICs. Most patients with a missing vital status at 30 days after diagnosis were discharged from the hospital before the 30-day mark without any follow-up . Functional independence at the latest follow-up was achieved by 21 of 29 (72%) CVST-VITT patients from MICs compared with 50 of 102 (49%) patients from HICs (p = 0.026).A new concomitant VTE diagnosed during hospitalization was reported in 1 of 30 (3%) CVST-VITT patients from MICs and in 16 of 96 (17%) patients from HICs. Major bleeding events occurred in 6 of 28 (21%) patients from MICs during hospitalization compared with 30 of 100 (30%) patients from HICs. The in-hospital mortality rate was lower in the MICs group than in the HICs group . In MICs, 21 of 30 (70%) CVST-VITT patients were discharged home compared with 16 of 38 (42%) patients in HICs (p = 0.022). Functional independence at the latest follow-up was achieved by 20 of 28 (71%) patients from MICs and 23 of 38 (61%) patients from HICs (p = 0.358).When comparing patients with CVST-VITT who were diagnosed after May 2021, the in-hospital mortality rate in the MICs group was 7 of 30 (23%) compared with 12 of 38 (32%) in the HICs group . Thrombocytopenia was present in 2 of 30 (7%) and 4 of 62 (6%) CVST patients with unlikely VITT from MICs and HICs, respectively. Patients with unlikely VITT from both MICs and HICs infrequently had a concomitant VTE at baseline (2/29 [7%] and 2/61 [3%]) and had low mortality rates at follow-up .CVST patients from MICs with unlikely VITT had a similar clinical profile to unlikely VITT patients from HICs (The main results of this study are (1) CVST-VITT cases were less often reported from MICs than from HICs; (2) cases from MICs less often could be classified as definite VITT, mostly because anti-PF4 antibodies were not tested; (3) clinical presentation of CVST-VITT cases was comparable between MICs and HICs, except that patients from MICs were younger and less often had a concomitant VTE at presentation; (4) frequencies of use of IVIG and non-heparin anticoagulants were similar between MICs and HICs; and (5) mortality rate due to CVST-VITT was lower among cases from MICs than among cases from HICs. In India alone, 1.67 billion ChAdOx1 nCoV-19  vaccines have been administered by 23 August 2022. Theoretically, CVST-VITT might be underdiagnosed or underreported in LMICs because of more limited access to imaging and laboratory tests and poorer quality of and access to health care. However, if the risk of CVST-VITT is the same across populations, that is, around one per 250,000 ChAdOx1 nCoV-19 vaccinations,20 thousands of cases should have occurred in India alone by now. It is unlikely that under-ascertainment and underreporting alone can fully explain the apparently strikingly lower incidence of CVST-VITT in LMICs. Even more so because CVST not related to COVID-19 vaccinations is more common in LMICs in the Middle East and South Asia than in HICs, and neurologists in these regions generally have ample experience with diagnosing CVST. Instead, these observations, in combination with the low reporting rate outside this study, could indicate that the risk of CVST-VITT differs between populations. This hypothesis is in line with findings from a study based on data from the AstraZeneca global safety database for the AZD1222 (ChAdOx1 nCoV-19) vaccine. The reporting rate of thrombosis with thrombocytopenia in this study was 88 times higher in Nordic countries than in Asian countries and Brazil, suggesting differences in the risk of thrombosis with thrombocytopenia after AZD1222 vaccination between the observed populations. There could be several explanations for a difference in risk of CVST-VITT between populations. First, there could be a genetic predisposition for VITT that varies across ethnicities, as has been described for the association between narcolepsy and the Pandemrix H1 N1 vaccine.24 Second, environmental factors could play a role, for instance, exposure to certain viruses or medications in the general population. Third, it has been proposed that manufacturing differences between batches of vaccines or different factories may explain discrepancies in rates of VITT. The consistency of the low rates of VITT reported from LMICs over time across multiple regions, however, makes this less likely, and no evidence to date has supported this hypothesis. Unfortunately, as far as the authors are aware of, no (inter)national pharmacovigilance data are available besides the data from the AstraZeneca global safety database to confirm the low incidence of CVST-VITT in LMICs.The low reporting rate of CVST cases after COVID-19 vaccination from LMICs is remarkable since, by first of July 2022, 9.61 billion COVID-19 vaccines were administered in LMICs compared with 2.51 billion COVID-19 vaccines in HICs. Moreover, further investigations into the possible difference in the incidence of CVST-VITT across populations may help to shed further light on the pathophysiology of VITT and possibly similar conditions such as heparin-induced thrombocytopenia.The results of this study can be of value to health care policy-makers to evaluate the role of adenovirus-based COVID-19 vaccines in vaccination campaigns in LMICs, which are still in full swing. As of June 2022, only 58 of 194 (30%) World Health Organization member states had reached the target of 70% vaccination coverage. These findings suggest that the VITT criteria by Pavord et al. might be less suitable for MICs. A more clinically based case definition for vaccine-related CVST such as the combination of CVST with new-onset thrombocytopenia within 28 days after COVID-19 vaccination, as proposed by the Brighton Collaboration, might be more suitable for MICs. Nevertheless, the clinical profile of unlikely VITT patients was very different from that of definite, probable, and possible CVST-VITT patients in both MICs and HICs, indicating that unlikely VITT patients in MICs were indeed non-VITT CVST patients instead of underdiagnosed CVST-VITT patients. In addition, the functional outcomes of the unlikely CVST-VITT patients from MICs and HICs were comparable to functional outcomes of CVST patients not related to vaccination, suggesting that these were spurious cases not related to vaccination.Anti-PF4 antibodies and, to a lesser extent, D-dimer levels were often not tested in CVST cases from MICs. Without these tests, a suspected CVST-VITT patient cannot meet the criteria for definite or probable VITT. Second, concomitant VTE at presentation was less frequently reported in cases from MICs than in those from HICs. Possible explanations for this difference might be under-ascertainment of subclinical thrombosis in MICs and less extensive screening for thrombosis at other sites, younger median age, or a true lower rate of VTE in cases from MICs. Third, the platelet count at presentation and the platelet count nadir were higher in MICs than in HICs. Theoretically, this might indicate that the general severity of CVST-VITT is lower in cases from MICs. This might be explained by the fact that CVST-VITT patients from MICs were diagnosed in a later time period than patients from HICs, when there was already global awareness and guidelines regarding diagnosis and treatment of CVST-VITT. However, the time from symptom onset to diagnosis and frequency of IVIG administration, non-heparin anticoagulants use, and platelet transfusions were similar between MICs and HICs.Although clinical characteristics of CVST-VITT cases were largely comparable between MICs and HICs, some differences between both groups should be noted. First, patients from MICs were younger than those from HICs, which is probably explained by differences in age groups that received adenoviral COVID-19 vaccines due to age restrictions on the use of these vaccines in many HICs.The observation that treatment of CVST-VITT cases did not differ between MICs and HICs is important because it suggests that knowledge on how to treat this condition is well disseminated in MICs and that access to, for example, IVIG is sufficient at the centers that contributed. Still, we should be careful to draw definitive conclusions on this issue, as the registry does not contain data on consecutive cases, or cases from low-income countries.In-hospital mortality due to CVST-VITT was lower among patients from MICs than among those from HICs. This difference might again be related to the fact that CVST-VITT cases from MICs were younger. The difference could also be partially attributed to the fact that cases from MICs were diagnosed in a later time period, as was suggested by the sensitivity analysis including only the cases diagnosed after May 2021. Alternatively, very severe CVST-VITT cases—which sometimes succumb within hours of hospital admission—may have been underdiagnosed in MICs. In addition, the diagnostic workup of patients with an unexplained death in the weeks following COVID-19 vaccination might be more limited in some MICs, which could lead to under-ascertainment of CVST-VITT.Our study has several limitations. Despite our multiple efforts to reach investigators from LMICs, local restrictions may have influenced the decision of investigators to participate in the study, and reporting within participating countries is almost certainly incomplete. We presume that our coverage of the poorest subpopulations of LMICs was likely worse than that of the more affluent parts of the population. Second, we did not receive any cases from low-income countries, so we cannot draw conclusions on the frequency and clinical manifestations of CVST-VITT in these countries. Third, all data collected in the study were gathered as part of routine medical care, and the data were not centrally adjudicated. and may possibly indicate that susceptibility of this condition varies between populations. Clinical presentation and treatment of CVST-VITT cases were largely similar in MICs and HICs, while mortality was lower in patients from MICs.In conclusion, the absolute number of CVST-VITT cases reported from LMICs was low despite the widespread use of adenoviral COVID-19 vaccines in these countries, which is consistent with previous pharmacovigilance reporting regarding VITTClick here for additional data file.Supplemental material, sj-docx-1-wso-10.1177_17474930231182901 for Cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia in middle-income countries by Anita van de Munckhof, Afshin Borhani-Haghighi, Sanjith Aaron, Katarzyna Krzywicka, Mayte Sánchez van Kammen, Charlotte Cordonnier, Timothy J Kleinig, Thalia S Field, Sven Poli, Robin Lemmens, Adrian Scutelnic, Erik Lindgren, Jiangang Duan, Yıldız Arslan, Eric CM van Gorp, Johanna A Kremer Hovinga, Albrecht Günther, Katarina Jood, Turgut Tatlisumak, Jukka Putaala, Mirjam R Heldner, Marcel Arnold, Diana Aguiar de Sousa, Mohammad Wasay, Antonio Arauz, Adriana Bastos Conforto, José M Ferro and Jonathan M Coutinho in International Journal of Stroke


Since the first appearance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019, the virus is still evolving and mutating until now. In this study, we collected 6 throat swabs from patients who diagnosed with COVID-19 in Inner Mongolia, China, to understand the entry of multiple SARS-CoV-2 variants into Inner Mongolia and analyze the relationships between variants and clinical features observed in infected patients. In addition, we performed a combined analysis of clinical parameters associated with SARS-CoV-2 variants of interest, pedigree analysis, and detection of single-nucleotide polymorphisms. Our results showed that the clinical symptoms were generally mild although some patients demonstrated some degree of liver function abnormalities, and the SARS-CoV-2 strain was related to the Delta variant (B.1.617.2), AY.122 lineage. The epidemiological investigations and clinical manifestations confirmed that the variant exhibits strong transmission, a high viral load, and moderate clinical symptoms. SARS-CoV-2 has undergone extensive mutations in various hosts and countries. Timely monitoring of virus mutation can help to monitor the spread of infection and characterize the diversity of genomic variants, thus limiting future waves of SARS-CoV-2 infection.The online version contains supplementary material available at 10.1007/s11262-023-01986-0. SARS-CoV-2 began a wave of infections during the Lantern Festival in 2022 in Hohhot, Inner Mongolia. The Hohhot has become the epicenter of viral spread because of the travel and reunion activities for the Spring Festival of  in Inner Mongolia. The emergence of SARS-CoV-2 variants is a key factor in the continued spread of the coronavirus disease 2019 (COVID-19) pandemic. SARS-CoV-2  established by the National Health Commission, PRC, the patients were diagnosed with one of four disease types. Patients with mild disease had mild clinical symptoms and did not exhibit pneumonia during imaging examinations. Patients with common disease had fever and respiratory symptoms, along with visible pneumonia during imaging examinations. Patients with severe disease exhibited any of the following conditions: shortness of breath ; oxygen saturation ≤ 93% at rest; arterial partial pressure of oxygen/oxygen concentration ≤ 300 mmHg; and progressive worsening of the clinical symptoms, with lung images that revealed > 50% lesion progression within 24 to 48 h. Patients with critical disease exhibited any of the following conditions: respiratory failure requiring mechanical ventilation, appearance of shock, and concurrent non-respiratory organ failure requiring intensive care unit monitoring and treatment.https://gisaid.org). MUMmer method [http://itol.embl.de/) tool for graphical display. Further confirmation of subvariant information was performed through a comparison of each sample with two subvariants on the Cov-Lineages website (https://cov-lineages.org/), specific mutations were analyzed to identify viral variant lineages. FASTQ files were analyzed by the ARTIC [Total RNA was extracted from the swab samples using a nucleic acid extraction kit , and amplified by multiplex polymerase chain reaction (PCR) according to the scheme recommended by WHO . A purifr method  was usedhe ARTIC  bioinforThe basic demographic and clinical characteristics of the six patients are shown in Table The genomes of SARS-CoV-2 isolates from the six infected patients were investigated by next-generation sequencing. After filtering, the total reads of the isolates were aligned against the reference genome NC_045512). Phylogenetic analysis Fig.  showed t5512. PhyThe result of mutation site analyses involving six SARS-CoV-2 isolates were shown Fig. . The virThe clusters of SARS-CoV-2 infections and rapid spread of COVID-19 attracted the attention of the Inner Mongolia government, it should be immediately implemented emergency measures to reduce the risk of transmission. Among the six positive patients, three had mild disease, two had moderate disease, and one had severe disease because of underlying chronic diseases . Although epidemiological investigations revealed that most patients had mild diseased during the current outbreak, SARS-CoV-2 infection continue to spread worldwide. These have led to additional increases in the number of confirmed cases and deaths with the emergence of new viral variants. Omicron and its subvariants have become the main pandemic strains. However, the virus identified in Inner Mongolia was a subvariant of B.1.617.2 (Delta).Amomum tsao-ko, Areca catechu, Mangnolia officinalis, salt-treated anemarrhena rhizome, Scutellaria baicalensis, Paeoniflorin, liquorice). The medicine was discontinued when the patient's condition improved, then the liver function gradually returned to normal. Thus, patient may have abnormal liver function during treatment, they should undergo frequent monitoring to ensure appropriate countermeasures can be performed in a timely manner. Another finding showed in our study that the six patients were cured within two weeks on average. As COVID-19 continues to develop, therapeutic schemes for various SARS-CoV-2 variants are constantly present and cure rates have increased. Aslam et al. [The clinical findings in the six patients included various degrees of liver damage during treatment, which has attracted interest from researchers. As reported in the literature, 14–53% of COVID-19 patients have liver dysfunction, but the etiology of the dysfunction  was unclear , 17. Thim et al. , 21.In this study, next-generation sequencing showed that the all six isolates were related to the Delta variant, which was originally identified in India in December 2020 . The staThe Delta variant exhibits numerous mutations of S protein . The D614G mutation was the first mutation identified in a variant of Wuhan SARS-CoV-2 strain. This mutation is located distal to the furin cleavage site and improves the efficiency of viral cell entry efficiency by increasing affinity for the ACE2 cell-surface receptor , it can Clinical assessment revealed that five of six patients, had completed vaccination in 2021. There is substantial evidence that antibodies produced after vaccination can neutralize the Delta variant. Data from global disease monitoring and infection surveillance programs data in 2021 showed that vaccination reduced the incidence of SARS-CoV-2 infection, as well as the incidences of hospitalization and mortality . Thus, eOur study found that the virus caused this epidemic in Inner Mongolia belongs to the Delta virus AY.122 lineage. Compared with reference genome, there are some mutation sites in the S protein region, which may be the reason for the increased virulence and transmission ability of the SARS-CoV-2. We also found that some of the patients infected with Delta virus had a certain degree of liver damage, thus we should timely detect the abnormal condition of the patient's test indicators during the treatment process and correctly guide the medication. The greatest limitation of this study was its small number of patients. Although more detailed immunological indicator data were recorded, the intra-group variation was substantial; thus, we could not conduct a systematicanalysis of immunological indicators. In subsequent studies, we plan to include additional patients to minimize the potential for measurement errors. The functions of mutation sites should be investigated in greater detail.Whole-genome sequences of the six samples were submitted to NCBI database under accession number SRR21312648 to SRR21312666.Supplementary file1 (XLSX 55 KB)Supplementary Table S2 Laboratory findings for six patients with SARS-CoV-2 infection 1 (DOC 110 kb)Below is the link to the electronic supplementary material.


Anterior cervical discectomy and fusion (ACDF) has long been the standard surgical treatment for cervical degenerative disc disease (DDD); however, cervical artificial total disc replacement (cTDR) has gained increasing recognition in recent years due to its ability to maintain a natural range of motion and lower the rate of adjacent segment disease. Although cTDR is only approved for one or two levels in the United States, it has been used for three or more levels in other countries. We present a case of a 59-year-old male patient who underwent three-level cTDR (C4-C7) in Germany and presented 10 years later with progressive paracervical pain and worsening dysphagia. Magnetic resonance imaging (MRI) and computed tomography (CT) scan showed hardware loosening, progressive loss of bone around the device, and a cyst ventral to C4-C5 with mass effect on the hypopharynx. The patient was successfully treated with posterior cervical fusion and showed improvement in neck pain. This case underscores the significance of long-term follow-up and thoughtful consideration when selecting an appropriate treatment modality for patients afflicted with cervical DDD. Cervical degenerative disc disease (DDD) is a commonly encountered condition in aging patients presenting with a spectrum of symptoms including neck pain, cervical radiculopathy, and myelopathy. In addition to these, patients may also suffer from other neurological symptoms and severe pain, which may require multimodal management. Initial management is usually conservative, including oral analgesics, physical therapy, or interventional pain procedures. Surgical intervention is required in cases where the patient is myelopathic or unresponsive to conservative management . The traHistory and examinationA 59-year-old male patient visited our office due to progressive paracervical pain, which was not radicular, and radiated to both shoulders but not to the arms. He reported no weakness in his upper extremities, and the motor strength of his deltoid, biceps, triceps, wrist flexion and extension, intrinsics, hip flexion, knee flexion and extension, dorsiflexion, and plantarflexion was all 5/5. The patient's reflexes, including biceps, triceps, brachioradialis, patellar, Achilles, Hoffman, and Babinski reflexes, were all 2+. Cranial nerves II-XII were also intact. The patient demonstrated normal gait and had no issues during the finger-to-nose testing, heel-to-shin testing, and pronator drift. The patient had undergone a three-level total disc replacement at C4-C7 10 years ago in Germany, and a one-level lumbar spine disc replacement in the past. The initial CT scan showed C5-C7 total disc replacement that had progressed to fusion around the disc replacement. Nonetheless, there was significant remodeling and sclerosis of bones at the C4-C5 level that had caused cavitation within the C5 body. A subsequent MRI with and without contrast revealed underlying sclerosis, but there was no significant neural compression Figure .After two years, the patient returned to our office with severe paracervical pain spreading to his shoulders and difficulty swallowing. An MRI revealed a large cyst that was moderately heterogeneous and hyperintense located ventral to the C4-C5 disc replacement Figure . The masTreatment and managementThe recommended course of action was fusion surgery to reduce the abnormal motion across C4-C7 disc replacement spacers. This involved performing a C4-C7 lateral mass screw fixation with fusion, utilizing MAGNUS allograft, ACTIFUSE allograft, and harvested autograft. The surgical procedure was closely monitored using fluoroscopy, somatosensory evoked potential (SSEP), and electromyography (EMG). To ensure a successful outcome, antibiotics were used for incision irrigation. The neurosurgical aspect of the surgery was completed without any issues Figure . FollowiIn this report, we presented a case of a patient who had undergone a three-level artificial disc replacement at the C4-C7 level in Germany and returned with severe and progressive paracervical pain 10 years later. The FDA recommendation in the United States limits the use of cTDR for up to two levels with a specific prosthesis, unlike in Europe and Asia. Only nine artificial discs have been approved by the FDA for single-level procedures, and three of them for two-level procedures. Proper device selection is critical to achieving positive postoperative outcomes, as certain devices have been associated with complications. Devices like PRESTIGE ST are associated with an increased incidence of dysphagia and hoarseness; hence, the device has been removed from the US market -8. WhileAlthough Heterotopic ossification (HO) is not prevalent in the early postoperative period, studies suggest that long-term HO is highly associated with cTDR, regardless of sex or age . HO can When treating multilevel degenerative disc disease (DDD), hybrid surgery can be considered as an alternative to using either cTDR or ACDF in isolation. Hybrid surgery combines cTDR and ACDF procedures at multiple levels in a single operation. Although there are no discernible differences between hybrid surgery and cTDR or ACDF alone in terms of early postoperative benefits or complications such as unintended intubation, pneumonia, or readmission rates, further research is needed to determine whether the same holds true for long-term postoperative outcomes .Our case is unique because the patient did not experience any perioperative or postoperative complications for 10 years. However, 10 years after the initial surgery, the patient reported paracervical pain without any neurological deficits. Over time, the pain worsened, and between the 10th and 12th year, the patient started experiencing progressive dysphagic symptoms due to soft tissue growth ventral to the C4-C5 level. This case emphasizes the importance of considering the long-term effects of multilevel cTDR. While previous studies have demonstrated the benefits of range of motion (ROM) preservation and reduced reoperation rates with the use of cTDR, these benefits become negligible if significant HO occurs. Previous studies have shown that the incidence of HO after cTDR has no clinical relevance during a two- or five-year follow-up period, highlighting the need for longer follow-up periods, such as the 10 years period as presented in our case , 14. TheWe present the case of a 59-year-old man who experienced worsening paracervical pain a decade after a three-level cTDR procedure performed in Germany, as the US FDA does not recommend cTDR beyond one or two levels. Over time, the patient's pain became more severe, and he developed dysphagia due to a cyst near the C4-C5 level. The patient was ultimately treated with a posterior cervical fusion procedure and has since made a good recovery. This case underscores the potential for long-term complications associated with multilevel cTDR procedures and highlights the importance of careful consideration when choosing a treatment option for patients. Including this case report in the current literature may help guide clinicians in making informed decisions when managing similar cases.


Cardiovascular disease (CVD) is a major cause of death in Malawi. In rural districts, heart failure (HF) care is limited and provided by non-physicians. The causes and patient outcomes of HF in rural Africa are largely unknown. In our study, non-physician providers performed focused cardiac ultrasound (FOCUS) for HF diagnosis and longitudinal clinical follow-up in Neno, Malawi.We described the clinical characteristics, HF categories, and outcomes of patients presenting with HF in chronic care clinics in Neno, Malawi.Between November 2018 and March 2021, non-physician providers performed FOCUS for diagnosis and longitudinal follow-up in an outpatient chronic disease clinic in rural Malawi. A retrospective chart review was performed for HF diagnostic categories, change in clinical status between enrollment and follow-up, and clinical outcomes. For study purposes, cardiologists reviewed all available ultrasound images.There were 178 patients with HF, a median age of 67 years (IQR 44 – 75), and 103 (58%) women. During the study period, patients were enrolled for a mean of 11.5 months (IQR 5.1–16.5), after which 139 (78%) were alive and in care. The most common diagnostic categories by cardiac ultrasound were hypertensive heart disease (36%), cardiomyopathy (26%), and rheumatic, valvular or congenital heart disease (12.3%).At follow-up, the proportion of New York Heart Association (NYHA) class I patients increased from 24% to 50% , and symptoms of orthopnea, edema, fatigue, hypervolemia, and bibasilar crackles all decreased (p < 0.05).Hypertensive heart disease and cardiomyopathy are the predominant causes of HF in this elderly cohort in rural Malawi. Trained non-physician providers can successfully manage HF to improve symptoms and clinical outcomes in limited resource areas. Similar care models could improve healthcare access in other rural African settings. Non-communicable diseases (NCDs) account for 32% of all deaths in Malawi 2, 10% ofMalawi is a landlocked Sub-Saharan African country bordering Tanzania, Zambia, and Mozambique . Ranked Access to NCD care in Malawi is limited – especially in primary care, which serves as the first point of contact for people living in rural areas. This is evidenced by the lack of first-line antihypertensive medications in health centers and minimal inconsistent supply at district-level hospitals . Poor poIn 2015, the Ministry of Health and Partners In Health, locally known as Abwenzi Pa Za Umoyo, established an Integrated Chronic Care Clinic (IC3)  which ofThe non-physician providers at PEN-Plus clinics are equipped with the knowledge, ongoing mentorship, and simplified algorithms for managing complex NCDs. Non-physician providers are involved in longitudinal patient care including initial evaluation, diagnosis, and categorization of HF, initiating treatment and establishing a follow-up plan, and linking patients requiring specialized care to specialists at a tertiary level of care.There is limited data on cardiovascular disease epidemiology and burden available in Malawi, and none available in rural Malawi. An important step in improving the care of chronic HF in this population is understanding the burden of disease and the feasibility and clinical outcomes of a decentralized strategy led by non-physician providers. Our study aims to describe the etiology and clinical outcomes in patients presenting with clinical HF who are longitudinally enrolled in PEN-Plus clinics in rural Malawi.This study was conducted at two PEN-Plus clinics based at Lisungwi Community Hospital and Neno District Hospital . Neno diThe PEN-Plus clinics are managed by a team of clinical officers (non-physician providers), nurses, pharmacy technicians, and clerks with routine supervision by a general physician and nurse mentor. Clinical officers in Malawi undergo four years of medical training. Additionally, the PEN-Plus clinical officers in Neno district underwent three months of bedside training in FOCUS for HF diagnosis and training on managing HF. These non-physician providers also treat a range of other NCDs in PEN-Plus clinics, including type 1 diabetes, sickle cell disease, and severe hypertension. The additional training and management of more complex NCDs separates the PEN-Plus non-physician providers from those working in IC3, who do not have the additional training in management of severe NCDs.Heart failure patients are identified in the inpatient wards, outpatient departments, or in IC3 using signs and symptoms as well as chest x-ray findings consistent with volume overload. Basic lab tests such as creatinine and electrolytes are mostly available, but B-type natriuretic peptide levels are not. Inpatient assessment and discharge planning are done by the ward team in conjunction with PEN-Plus providers. Upon discharge, medications are given and a follow-up appointment at the PEN-Plus clinic is assigned.An initial evaluation at the PEN-Plus clinic includes a complete history and physical examination. A focused cardiac ultrasound is performed  using a In the protocol , non-phyEach diagnostic category has a corresponding initial management plan to guide treatment with evidence-based medications and appropriate referral to specialists as outlined in the protocol . Diureti1516For study purposes, available cardiac ultrasound images were reviewed by board-certified cardiologists with specialization in echocardiography (SLK and GFK). Cardiologist interpretation was harmonized with non-physician providers’ interpretation. Following the flow of the diagnostic algorithm , cases oAt all clinical visits, the NYHA class was documented, volume status was determined by physical examination, and medications were adjusted to target doses. Counselling on the diagnosis, medication adherence, lifestyle modification, and when to return to the hospital was provided. Follow-up visits are scheduled every one to three months, depending on the clinical severity.To maximize patient retention, the PEN-Plus team performed home visits across Neno, for patients who missed scheduled appointments and those unable to attend PEN-Plus clinics due to long distances and cost of transportation. Home visits were performed for clinical evaluation and medication renewals. Older patients, patients with disability, and those with severe disease are prioritized for home visits.The district is covered by a network of community health workers (CHWs) that visit a group of pre-assigned households . CHWs reData from clinical charts in both PEN-Plus clinics between November 2018 and March 2021 was gathered retrospectively, including co-morbidities, clinical status at enrollment, FOCUS results, number of follow-up visits, and most recent clinical status at the time of chart review. Data was extracted by the primary author (BM) and electronic records were reviewed against paper charts to ensure accuracy. We performed a secondary review of the paper charts for instances of missing or discrepant data to ensure accuracy.Our primary outcome was the number of patients alive and actively followed at study closure. A patient was defined as lost to follow up when they were more than eight weeks late for their scheduled clinic appointment and attempts made to trace the patient were unsuccessful. Secondary outcomes were description of HF categories and change in patient clinical status from time of enrollment to most recent clinic visit: (1) change in signs and symptoms, and (2) change in NYHA class.We summarized categorical data as proportions and used Pearson Chi-square test or Fisher’s exact test to assess the association between two variables. We used the one-sample t-test to assess change in NYHA class between enrollment and follow-up among participants with available data. Loss to follow-up and mortality of patients stratified by NYHA class is described. We fitted the generalized linear model with binomial distribution to estimate the relative risk of death among NYHA class and further adjusted for sex and age. A p-value of <0.05 was considered significant. All data were analyzed using Stata version 15.1.Ethical approval was obtained from the Malawi College of Medicine Research and Ethics committee (COMREC); Brigham and Women’s Hospital, Harvard Medical School; and the Neno district health research committee. All data collected in the study was part of routine clinical care in PEN-Plus clinics. Patient consent was waived due to the retrospective nature of the chart review.2 and mean duration of follow-up in the clinic was 11.5 months (IQR 5.1–16.5). Hypertension was the most common comorbidity (44%), with prevalence slightly higher in women (57%) than men (42%). At enrollment, 33% had a systolic blood pressure of >140 mmHg, which decreased to 20% at follow up. Fourteen (8%) were HIV positive and on antiretroviral treatment.There were 178 patients with HF enrolled in the PEN-Plus clinics, 103 (58%) women, and 18 (10%) children under age 18 years during the study period . The medUpon enrollment in PEN-Plus clinics, more than 50% (n = 122) of the patients were symptomatic  and 64% were classified as NYHA II. Among the patients alive and in care at time of follow-up who had both baseline and follow-up data (n = 124), 2% were classified as NYHA III or IV. The proportion of patients with NYHA class II decreased from 61% to 48% (p < 0.0015), while the proportion of patients with NYHA class I increased from 24% to 50% (p < 0.001) .Cardiac ultrasound images for 154 patients were available for cardiologist review. The most common HF diagnostic categories were hypertensive heart disease in 56 (36.4%), cardiomyopathy in 40 (26.0%), and rheumatic mitral stenosis in 11 (7.1%) patients. There were 25 (16.2%) patients with other diagnoses or could not be classified . There wBy study closure, 50% of patients had attended five or more follow-up visits (IQR 3–9), 139 (78%) were alive and in care, 21 (12%) were lost to follow-up and 18 (10%) were known to have died. The crude relative risk of death was 3.94 for patients with enrollment NYHA III and IV vs. NYHA I & II (p < 0.005).Of the 124 patients that had documented NYHA class at both baseline and most recent follow-up, there was an improvement in symptoms . The proAt follow up, symptoms of orthopnea, edema, fatigue, hypervolemia, and bibasilar crackles all decreased (p < 0.05) There was no statistically significant improvement in chest pain and cough. .In our retrospective study of patients enrolled with HF in PEN-Plus clinics in rural Malawi over a two year period, non-physician providers play an important role in longitudinal care and categorization of patients with HF. There was a high rate of retention in clinical follow-up in PEN-Plus clinic (78%) when compared with the general NCD population in the IC3 clinic (72%) . In the Our retention in care (78%), was higher when compared to implementation of a similar model of care in Rwanda which had a retention rate of 42.8%. . A majorRegarding the causes of HF, our data differs from that of urban Malawi where 34% of HF was caused by rheumatic heart disease, 24% from hypertensive heart disease, and 19% from cardiomyopathy . The preOur loss to follow-up (12%) was lower than the loss to follow-up reported in IC3 clinic (25.5% over a 36-month follow-up period) even though both clinics are based in the same district . This coOur rate of known deaths at 10% was higher than that of IC3, which was 1.4% , but low23While our death rate is low when compared to other sub-Sahara African (SSA) countries, it is worth noting the difference in setting. Previous studies on an in-patient population 26272829 262728Our enrollment data showed small numbers of patients with peripheral edema and jugular venous distension, which may be due to patients being treated and stabilized in the hospital before enrollment into PEN-Plus clinics. This is suspected to underestimate the clinical severity of HF at the initial clinic enrollment visit.Out of 154 available FOCUS images, nine (5.8%) images were classified as normal despite presenting with clinical signs and symptoms of HF. This may be due to the nature of FOCUS, which does not incorporate more nuanced causes of HF such as diastolic dysfunction and constrictive pericarditis. In cases of valvular heart disease, when the murmur is soft or diastolic, these may be miscategorized as normal. In addition, due to limited diagnostic capacity such as absence of brain natriuretic peptide, patients may be misdiagnosed as having HF when their symptoms and physical exam findings are attributable to another cause.Due to the retrospective nature of our study and the limited-resource setting, there were several limitations of note. Cardiologists had access to and reviewed 154 images of the 178 enrolled HF patients. Images for the remaining 24 patients were unavailable and the diagnosis made by non-physician providers may have been inaccurate. Further study is required to assess the accuracy of clinicians in interpreting the images compared to cardiologist interpretation and evaluate quality of the care delivered. Our study described the implementation of a PEN-Plus clinic in Neno. No pre-implementation data or comparison group was available, thus the absolute effect of PEN-Plus clinics compared to usual care in rural Malawi could not be determined. Incomplete patient charting due to inconsistent staffing and other resource challenges affected data integrity and was present in all clinics. Heart failure categories were not confirmed by a cardiologist in real-time, thus broad categories such as ‘valvular and congenital heart disease’ were used with the recommendation to refer for cardiologist assessment. Our study sites were supported by a non-governmental organization (Abwenzi Pa Za Umoyo) with added social and financial support for patients. Dissemination of a PEN-Plus strategy including HF care to other regions of Malawi or other LMICs may face resource challenges not present at our site.Using a decentralized strategy of HF care led by non-physician providers, the PEN-Plus approach can make specialized cardiac care available to the rural poor in Malawi. A favorable retention in chronic care was seen in the setting of integration with community-based care. The common causes of HF are similar to rural regions of other LMICs including hypertensive heart disease, cardiomyopathy, and rheumatic heart disease. Longer term patient outcome and provider training data will help to refine the PEN-Plus approach and ensure that all rural patients can be reached. Contextually-adapted implementation of similarly integrated HF care strategies through training a decentralized workforce could further improve equity and accessibility to cardiac care in rural areas in sub-Saharan Africa.http://www.ncdipoverty.org.Endnote: Resources for PEN-Plus clinic implementation can be found at What is already known on this topic: Heart failure has been described in the Malawian urban setting, but in the majority rural population, HF data is scarce.What this study adds: In our retrospective study, of patients enrolled in PEN-Plus clinics in rural Malawi over a two year period, there was a high rate of retention in clinical follow-up and significant improvement in HF symptoms demonstrating that non-physician-led clinics in this setting are feasible and effective in reducing symptoms and implementing HF management employing FOCUS as a diagnostic tool.How this study might affect research, practice, or policy: Findings from our study support the decentralization of cardiac care from tertiary facilities to rural health facilities using simplified clinical algorithms and targeted training of non-physician providers. This approach, part of the PEN-Plus strategy, may be generalized to other clinics in sub-Saharan Africa.


Odontoid fractures are increasingly prevalent in older adults and associated with high morbidity and mortality. Optimal management remains controversial. Our study aims to investigate the association between surgical management of odontoid fractures and in-hospital mortality in a multi-center geriatric cohort. We identified patients 65 years or older with C2 odontoid fractures from the Trauma Quality Improvement Program database. The primary study outcome was in-hospital mortality. Secondary outcomes were in-hospital complications and hospital length of stay. Generalized estimating equation models were used to compare outcomes between operative and non-operative cohorts. Among the 13,218 eligible patients, 1100 (8.3%) were treated surgically. The risk of in-hospital mortality did not differ between surgical and non-surgical groups, after patient and hospital-level adjustment . The risks of major complications and immobility-related complications were higher in the operative cohort . Patients undergoing surgery had extended in-hospital length of stay compared to the non-operative group . These findings were supported by secondary analyses that considered between-center differences in rates of surgery. Among geriatric patients with odontoid fractures surgical management was associated with similar in-hospital mortality, but higher in-hospital complication rates compared to non-operative management. Surgical management of geriatric patients with odontoid fractures requires careful patient selection and consideration of pre-existing comorbidities. The number of individuals over 65 years of age in the United States is expected to increase faster than any other age group to over 70 million in the next decade5. Given the rapid expansion of this population and this high incidence of odontoid fractures, geriatric spine fractures have been described as an emerging health crisis6.Fractures of the C2 odontoid process are the most common isolated spine fracture in geriatric patients and are associated with high morbidity and mortality7. Non-operative treatment is associated with a risk of fibrous non-union and high 1-year mortality13. Surgery, however, is associated with high peri-operative risks given the prevalence of poor bone health and medical comorbidities in an elderly population16. Previous retrospective studies have found surgical treatment of geriatric odontoid fractures to be associated with lower mortality at 30 days when compared to non-operative treatment20. A prospective study comparing surgical fixation with non-operative treatment found a trend toward lower mortality in patients treated surgically21. In contrast others have advocated that non-operative management is an acceptable treatment option despite lower rates of osseous union18. While most previous studies have used data gathered at a single institution, few have examined a multi-center cohort17.Despite the increasing frequency of these fractures there remains uncertainty about the optimal management strategyIn this study we conducted a retrospective analysis using data from the American College of Surgeons (ACS) Trauma Quality Improvement Program (TQIP). The objective of this study was to determine the association between surgical management of odontoid fractures and in-hospital mortality and complications in a large multi-center cohort of geriatric patients.The study design was a multicenter retrospective cohort study. This study number 20–338 was approved by the Unity Health Toronto Research Ethics Board  in February of 2021. Study procedures were followed in accordance with the ethical standards of the institutional committee on human experimentation and with the Helsinki Declaration of 1975. This study used only de-identified retrospective patient data, and individual participant informed consent was waived by the Unity Health Toronto Research Ethics Board.We analyzed data from the ACS TQIP database from 2010 to 2018. The TQIP combines data from over 450 ACS and state verified Level 1 and 2 trauma centers across North America. Hospital and patient-level variables are collected for each included patient. The dataset excludes patients without signs of life on arrival to hospital, patients with pre-existing advanced directive to limit life sustaining interventions, patients who were discharged from the emergency department (ED), or patients who had severe burns. The dataset undergoes auditing procedures and internal and external validity checks.Patients aged ≥ 65 years with a diagnosis of fracture of the C2 odontoid process were identified using the Abbreviated Injury Scale (AIS) pre-dot code 650228. We excluded patients with non-survivable injury (AIS score of 6 in any body region), non-blunt mechanism of injury, and with severe injuries (AIS score of ≥ 3) in any non-spine body region. In addition, we excluded patients with spinal cord injury by excluding patients with another AIS score in the spine region of ≥ 3.23. We collected injury characteristics such as mechanism of injury, AIS score for each body region, total Injury Severity Score (ISS), the need for mechanical ventilation in the ED, shock (systolic blood pressure (SBP) < 90mm Hg) upon arrival to the ED, Glasgow Coma Scale (GCS) score on arrival, and alcohol and drug tests24. Hospital characteristics included trauma center level, number of adult beds, teaching status, year of injury, and the number of C2 odontoid fractures seen at the facility.We collected patient demographic characteristics including age, sex, race, insurance type, and comorbidities. Patient frailty was evaluated by a 5-factor modified Frailty Index (mFI-5)Surgical procedures for cervical fusion were identified using the International Classification of Diseases, 9th/10th revision, procedure classification system (ICD-9-PCS and ICD-10-PCS) codes  and discharge destination (dichotomized as routine versus non-routine). Major complication  was a composite outcome defined in the TQIP dataset as the occurrence of one or more of the following: acute kidney injury, cardiac arrest (with cardiopulmonary resuscitation), acute respiratory distress syndrome (ARDS), decubitus ulcer, surgical site infection, myocardial infarction, pneumonia, ventilator-associated pneumonia, pulmonary embolism, stroke, catheter-related bloodstream infection, unplanned return to the operating room, unplanned admission to the intensive care unit, or severe sepsis. Immobility-related complication was a composite outcome consisting of one or more of the following: decubitus ulcer, pneumonia, or pulmonary embolism. Subjects lost to follow-up or with missing outcome data were assumed to be missing completely at random.26. For binary outcomes, we assumed a binomial distribution and specified a logit link function. For hospital LOS, we assumed a gaussian distribution. Covariates included in the model were year of admission, hospital characteristics , patient demographics , and clinical characteristics .The baseline characteristics of the cohort were reported as counts with percentages for categorical variables. Hospital length of stay (LOS) and the proportion of patients enrolled and undergoing surgery at each facility were found to have positively skewed distributions and were thus presented as median with inter-quartile ranges (IQRs). In accordance with the STROBE recommendations we used Standardized Mean Differences (SMDs) to compare the baseline characteristics of the cohorts. We compared the outcomes between the surgically and non-surgically treated patients using a generalized estimating equation (GEE) model with facility used as a clustering identifier and an exchangeable working correlation structurep < 0125.We performed several secondary analyses. First, we included interaction terms in adjusted models to examine whether the effect of surgery varies with age, LOS and frailty. Next, we restricted the analysis to centers including at least 5 patients for three years of participation in TQIP. In a final analysis, we used a random effects (mixed-effects) logistic regression models to investigate whether there are substantial between-center differences in the outcomes that could not be explained by random variation or the patient and hospital characteristics included in the models. To ensure a family-wise type-1 error rate less than 0.05 in our primary and secondary analyses we used a Bonferroni correction, setting the significance cut-off at A total of 13,218 patients treated at 678 trauma centers met eligibility criteria Fig. .Figure 1p < .001). In unadjusted and adjusted models, the risk of primary complications was higher in the surgical group compared with the non-operative group . Similarly, the risk of immobility-related complications was higher in the surgical group than the group treated non-operatively . The patients undergoing surgery spent approximately 5.5 days longer in hospital than those treated non-operatively, after accounting for covariates .Estimates of the association between surgery and the outcomes are as shown in Table p = .002), and surgery with frailty index for primary complications (p = .007). Test of other interactions were not significant.We noted an interaction of surgery with age for immobility-related complications (There were 248 (36.6%) facilities enrolling at least 5 patients for at least 3 years of participation in TQIP  . The proportion of patients that had surgery varied between 0(0%)–32 (100%) per facility ; IQR:1 (1.9%), 6 (12.1%)) (Supplemental Table This study assesses the effect of surgery on in-hospital mortality and complications for a multi-center cohort of 13,218 geriatric patients with odontoid fractures. Patients treated surgically had similar in-hospital mortality as patients treated non-operatively after controlling for patient and hospital characteristics. Surgical management, however, was associated with higher rates of in-hospital complications.27. Chen et al. reported a 30-day mortality of 3.6% among geriatric patients treated surgically for type 2 odontoid fractures28. The study by Chapman et al. reported 30-day mortality of 7% among geriatric patients with odontoid fractures treated surgically17. We found 2.9% mortality among patients treated with surgery, which is comparable to previous reports. In our dataset 8.3% of patients underwent surgery, which is a lower incidence than that reported by other studies that have made use of registry data. The study by Robinson et al. reported an incidence of surgery of 22% in a cohort of patients aged ≥ 70 years29. In contrast the study by Dhall et al. reported an incidence of surgery of 10.3% in a cohort of octogenarians4. Our study included data from a broad range of Level 1 and 2 trauma hospitals across North America and the lower rate of surgery in our cohort may represent differing practice patterns. In addition, we included patients in our cohort based on the AIS predot code, which is not specific for type 2 odontoid fractures but includes all odontoid fractures.Our results are comparable to previous studies that have examined mortality among geriatric patients with odontoid fractures. White et al. performed a meta-analysis of geriatric patients treated surgically for type 2 odontoid fractures and reported an in-hospital mortality rate of 6.2%17. Vaccaro et al. prospectively followed 159 geriatric patients treated surgically or non-operatively and reported better functional outcomes and a trend towards lower mortality in the surgically treated patients at 1-year follow up but again, the reduction in mortality failed to meet statistical significance21. A multi-center retrospective study by Robinson et al. examined 3,375 elderly patients with C2 fractures and reported lower 1-year mortality among patients treated surgically when adjusting for covariates29. A systematic review by Robinson et al. included 1,284 cases of geriatric patients with odontoid fractures and found lower mortality among patients treated surgically30. We found no significant difference in in-hospital mortality between patients that were treated surgically and those treated non-operatively after adjusting for covariates. In addition, we conducted a secondary between-center analysis that confirmed these findings. It is important to note that these studies examined mortality at 1-year follow up, while we used in-hospital mortality as an outcome.Several studies comparing surgical and non-operative management of patients with odontoid fractures have been reported. One study retrospectively reviewed 322 geriatric patients with odontoid fractures and found that surgically treated patients had a trend towards lower mortality at 1-year follow up when compared to patients treated non-operatively, but this finding was not statistically significant21. Similarly, the systematic review by Robinson et al. reported similar complication rates between surgically treated and non-operative patients but noted that only a small number of studies in their analysis reported complications rates30. The retrospective analysis by Dhall et al. examined octogenarians with odontoid fractures and found higher rates of in-hospital complications such as pneumonia, decubitus ulcer, and ARDS among patients treated with surgery compared to non-operative management4. In our cohort the frequency of all complications and immobility-related complications were significantly higher in patients treated surgically when adjusting for covariates. These results suggest that while in-hospital complication rates are higher among surgically treated patients the absolute rate of complications is acceptable. Surgical decision making should thus consider the increased risk of complications with potential benefits and patient comorbidities. In addition, the interactions we found between surgery and age/frailty suggests that extra care should be taken when offering surgery to patients with higher age or greater frailty.Few studies have reported the association between surgical management of geriatric odontoid fractures and in-hospital complications. Vaccaro et al. reported similar rates of complications in surgically treated and non-operative patients31. Our dataset included data on in-hospital mortality and complications, but we were not able to assess patient outcomes after hospital discharge. We were not able to compare outcomes at a longer-term follow up period, which may have been more clinically meaningful33. Our dataset did not permit comparison of patient functional status and we were not able to assess the effect of surgical management on these outcomes. Lastly, we were not able to compare rates of non-union between patients treated surgically and non-operatively.Given this study’s observational nature, we are limited in controlling for baseline differences in the surgical and non-operative cohort. Although we made use of a multi-variate GEE model in our primary analysis, there may be unobserved imbalances between the cohorts that we cannot control for. For example, we were not able to control for fracture morphology on imaging studies, which can affect surgical decision making and success of treatmentTo our knowledge, this is the largest study to compare outcomes between geriatric patients with odontoid fractures treated surgically and non-operatively. In-hospital mortality did not differ between patients treated surgically and those treated non-operatively. In-hospital complications, however, were higher among patients treated surgically, especially in patients with higher age or frailty. These results emphasize that surgical management of geriatric patients with odontoid fractures is appropriate for certain patients but requires careful patient selection and consideration of pre-existing comorbidities. Future studies may attempt to examine outcomes at a longer follow up period and better understand specific patient level factors that affect outcomes in this population.Supplementary Information.