Introduction: The COVID-19 pandemic resulted in substantial morbidity and mortality across the world. The prognosis was found to be poor in patients with co-morbidities such as diabetes, hypertension, interstitial lung disease, etc. Although biochemical studies were done in patient samples, no study has been reported from the Indian subcontinent about ultrastructural changes in the vital organs of COVID-19 patients. The present study was, therefore, conducted to understand the ultrastructural changes in the lung, liver, and brain of the deceased patients.Methods: The present study was conducted on samples obtained from reverse transcription-polymerase chain reaction (RT-PCR)-positive patients who were admitted to a tertiary care hospital in Western India. Core needle biopsies were done in eight fatal cases of COVID-19. The samples were taken from the lungs, liver, and brain and subjected to light microscopy, immunohistochemistry (IHC), and transmission electron microscopy (TEM). Clinical details and biochemical findings were also collected. Results: The study participants included seven males and one female. The presenting complaints included fever, breathlessness, and cough. Light microscopy revealed diffuse alveolar damage in the lungs. Further, a positive expression of SARS-CoV-2 nucleocapsid protein was observed in the pulmonary parenchyma of five patients. Also, the TEM microphotograph showed viral particles of size up to 80nm localized in alveolar epithelial cells. However, no viral particles were found in liver or brain samples. In the liver, macrovesicular steatosis and centrizonal congestion with loss of hepatocytes were observed in light microscopy.in-situ presence of viral particles in core biopsies from fatal cases of COVID-19. As evident from the results, histology and ultrastructural changes in the lung correlated with the presence of viral particles. The study revealed a positive correlation between the damage in the lungs and the presence of viral particles.Conclusion: This is the first study in the Indian population showing the  The COVID-19 pandemic resulted in substantial morbidity and mortality across the world with over six million deaths . Since tThere were no global guidelines for the management of COVID-19, and in most cases, the management varied with the severity of the illness. Significant heterogeneity was observed in the outcomes of these patients . SeveralFurther, inflammatory and biochemical parameters have been used to predict disease outcomes ,10. The Histological changes in various organs in autopsy studies have been reported -18. A feMaterialsImmunohistochemistry was performed for the SARS-CoV-2 nucleocapsid protein . Sodium cacodylate, osmium tetraoxide, and glutaraldehyde were purchased from Sigma-Aldrich . Dodecenyl Succinic Anhydride (DDSA) and 2,4,6 Tri-dimethylaminomethyl phenol (DMP-30) were purchased from Ladd’s Research . Uranyl acetate and lead citrate were purchased from Electron Microscopy Sciences . All other chemicals were purchased locally and were of analytical reagent grade.MethodsThe present study was conducted on samples obtained from RT-PCR-positive patients who were admitted to a tertiary care hospital in Western India. These samples were obtained from April 2020 to December 2020, which corresponds to the first wave of COVID-19 in India. Exclusion criteria included cases where samples could not be taken within six hours of death and cases where consent could not be obtained. Sample size calculation was not done. Samples were taken from eight cases of fatal COVID-19, in which the relative of the deceased had given informed consent. Clearance from the institutional ethics committee was also taken .Autopsy procedureIn the COVID-19 cases, open post-mortem autopsies were not performed due to the high risk involved. Therefore, samples of the lungs, liver, and brain from the deceased were obtained using core needle biopsies. Biopsies from each lung were taken with the aid of an antemortem chest radiograph from the most affected lobes. Core biopsies from the liver were taken blindly, while biopsies of the frontal lobe of the brain were obtained using a small-bore needle. The samples were immediately placed in 10% neutral buffered formalin (for light microscopy and IHC) and 2.5% glutaraldehyde (for TEM).Light microscopySamples fixed for 48 hours in 10% neutral buffered formalin were processed and the slides were prepared. The tissue sections were cut at 3µm thickness and staining was done as per the standard protocol. For hematoxylin and eosin staining, the slides were rehydrated through descending grades of alcohol to water. It was stained in alum hematoxylin for 20 minutes, followed by bluing in running tap water. The slides were then stained in 1% eosin for 10 minutes. Following this, the slides were washed in running tap water, dehydrated, and mounted. Additional stains  were used.Immunohistochemical studiesImmunohistochemistry was performed for SARS-CoV-2 nucleocapsid protein  in all cases and on all three organs. Pressure cooker antigen retrieval was performed in citrate buffer.Transmission electron microscopy3 pieces of lung, liver, and brain were cut and immersed in 2.5% glutaraldehyde vials separately. The sample was then transported to one of the reference centers of Central India within 24 hours while maintaining the cold chain. Once these TEM samples were received, all the samples were washed three times, each for 15 minutes, with 0.1 M sodium cacodylate buffer followed by adding 1% osmium tetraoxide (OsO4) to each sample. These samples were then stored at 4℃. The next day, the samples were washed with 0.1M sodium cacodylate buffer to remove OsO4. The samples were completely dehydrated using an ascending concentration of acetone. The samples were placed in the embedding media, which was prepared using Araldite 502, DDSA, and DMP-30. The sections were cut and stained with uranyl acetate and lead citrate and examined on TecnaiTM G2 Spirit .The TEM was performed in six cases for three organs: lungs, liver, and brain. For TEM, two to four 2mmPatient detailsFor all the cases, demographic details such as age and sex as well as comorbidities, presenting complaints, duration of hospital stay, duration of symptom onset to death, and results of laboratory investigations (including complete blood count (CBC), D-dimer, kidney function tests (KFTs), liver function tests (LFTs)) were taken from medical records and compiled.Clinical and laboratory findingsThe results showed a clear distinction between the changes observed in the lungs by comparison to that in the liver and brain. As evident from Table Haemogram, blood coagulation, serum inflammatory markers, liver function test (LFT), and kidney function test (KFT) are summarized in Table Histopathological findingsMarked histopathological changes observed in the lung are summarized in Table In the brain, corpora amylacea was observed in all cases while occasional hypoxic neurons were seen in three cases. One case showed a focus on an old healed infarct. No intra-parenchymal hemorrhage or perivascular/parenchymal inflammation was noted.Immunohistochemistry for SARS-CoV-2 nucleocapsid proteinThe IHC positivity for nucleocapsid protein of the SARS-CoV-2 virus was observed in the cytoplasm of alveolar epithelial cells of pulmonary parenchyma in five cases  and severe acute respiratory syndrome coronavirus (SARS-CoV) infections, and recently published reports of SARS-CoV-2 infection -18,31,32The present study is the first from India to use TEM to assess the ultrastructure of different tissues in SARS-CoV-2 infected patients. The result showed the presence of viral particles in the lung parenchyma, while the brain and liver did not harbor viral particles. Earlier studies using infected cell lines, organoids, and autopsies have reported morphological features of assembled virions and associated cytopathic changes ,34. The Apart from the lungs, viral particles were identified in the kidney tissue in a few studies ,16,38-40In the present study, SARS-CoV-2 IHC was positive in the alveolar pneumocytes, while no IHC expression was noted in hepatocytes and neural tissue. Our results are in confirmation with Rocha et al. who reported positive immunohistochemistry staining of SARS-CoV-2 antibodies in the lungs and placenta, while no expression was observed in kidney tissue . BradleyThe present study has several limitations. A complete autopsy was not undertaken due to safety limitations. The limited samples obtained using core biopsies during this study may be linked to false negative results in some cases. Another limitation was the small number of patients included in the study. Further studies may reveal that the consistent findings in this cohort are borne out in a large number of tissue samples.The specific tropism for SARS-CoV-2 viral particles in the respiratory system is demonstrated using transmission electron microscopy and restricted expression of SARS-CoV-2 nucleocapsid protein using immunohistochemistry in the lung. No viral particles in the liver and brain tissue were identified. Morphological changes observed in these organs may be attributed to the systemic effects of the inflammation.


All medicine and healthcare undergraduates were encountered with terminations and delays of professional examinations. These alterations were on topmost of other tasks the COVID-19 pandemic carried out for instance not roaming, covered faces with masks and specifically segregation. This interruption of normal life was a major cause of mental health disaster and it is no surprise that medicine and healthcare undergraduate has had high rates of psychological effects including hopelessness, stress and suicidal thoughts. This study aimed to investigate the unmediated connection of anxiety and stress related mental health decline and suicide among medical and nonmedical undergraduates during the pandemic of covid-19.A multidiscipline online cross-sectional comparative study design was chosen for this study conducted from November 2020 to January 2021 with a pre-validated questionnaire to collect responses from sample size 1290. SPSS- 21 used for descriptive analysis of means, S.D, ANOVA and spearman’s correlations. Forward step-wise model of linear regression applies for true significant bivariate relationship (p<.001)The result shows that all three cohorts were affected. Among the non-medical cohorts, B-Pharmacy students had the high level (p<.001) of anxiety with suicide ideation response , along with lowest level of envisions care  in pandemic. Control and independent variable had a strong negative effects on B-Pharmacy and medical students with p<.000.This study offered more data that the concerns, anxieties and uncertainties caused by pandemic COVID-19, don’t roll out alone but remain as long-lasting problems demanding ongoing attention. Covid-19 caused a worse mental health decline in all ages particularly undergraduates in Pakistan. Undergraduate’s medicine and healthcare final year students still were likely to start their internship.8COVID-19 pandemic reached Pakistan by March 2020 whereupon WHO confirmed the outbreak a worldwide pandemic.All medicine and healthcare undergraduates were encountered with terminations and delays of professional examination. These alterations were on topmost of other tasks the COVID-19 pandemic carried out for instance not roaming, covered faces with masks and specifically segregation.10In Pakistani social-and-ethnic context youth perspective and their mental health services may not be considered as a thoughtful alarms and may go unobserved. The negligence of such kinds may lead to increased recklessness emotional behavior and resultant suicide.13A multidiscipline online cross-sectional comparative study design was chosen for this study conducted from November 2020 to January 2021.The sample consist of all medical undergraduates  from M. Islam Medical and Dental College, Gujranwala; four sessional years of B-Pharm; n=480 from M. Islam college of pharmacy and 4-sessional years of DPT; n=350 students of M. Islam Institute of Rehabilitation and Physiotherapy with aged between 18-to-26-years .After the approval from Institutional Research Ethics Board (IREB letter #: 001/2020) all students were requested to log-in through their personal id allotment to avoid any repetition of responses. Anonymity and confidentiality of undergraduates were secured through specific number generating order, in this way record of each partaker was maintained for further correspondence. Information was collected in two rounds; first round or pilot study was before their final internal assessment exams during the month of November 2020 just to check the accuracy of data collection methods, and second round was collected in January before their professional external assessment exams in February 2021, which was used as empirical results.1. Data about Participant’s particulars: Details regarding their gender, age, and level of sessional years were collected from the survey. Students with medicine batches were classified as Med. cohorts, and others were categorized as Non-medical cohorts. Age and gender is not considered as variable.2. Dependent outcome variable:i) Anxiety and suicide ideation: In order to assess the pandemic COVID-19 generated sadness, anxiety, and suicide level of participants, State-Trait Anxiety Inventory (STAI) was used.153. Control variate:a) Certainty in Pandemic Switch: Certainty in pandemic switch included self-assurance concerning personal, town, and the institutional management in the pandemic condition. The Cronbach alpha was .83.16b) Sensitivity of Exposure to COVID-19 risk: The Cronbach value was .80.17c) To envision Care: Believed to get support detects perceived help from peers, teachers and families. The Cronbach was .69 of this 5-point Likert scale.184. Independent Covariates:a. Abundance of Means perceived to fights COVID-19: Sufficient resources of multiple means comprised of; information about COVID-19 situation; currency; approachable healthcare facility; personal protective equipment (PPE); and mental-health support. The Cronbach value was .76.19b. Delivering COVID-19 Facts and figures: Seeking evidence from several sources involved information from: The medical worker, Friends-or-families, and internet-based available data.20Descriptive and inferential statistics of mean and standard deviation calculated and applied Kolmogorov-Smirnov and ANOVA- test to examine the variances differences. That was followed by Post-hoc-Tukey HSD adjustments and spearman’s rho correlation to measure the true significant bivariate relationship among participants and all the variables. Thereafter, forward stepwise model used in regression analysis to find the significant effects of variables for multi-groups to address the role of independent covariates in anxiety and suicide ideation among cohorts. Considered P value < .001 was significant.Total sample size was 1290, out of which 38.1%  enrolled in medicine. Moreover, 37.2%  in B-Pharmacy. Whereas, 27.1%  in DPT respectively. The total female participants population was 64.1%  out of which 61.3% was studying medicine (282/460), 73.0% in B-Pharmacy (345/480) and 57.1% in DPT (200/350) respectively. Furthermore, 43.0% male participants were studying DPT (150/350), 40.0% in medicine (178/460) and very less (28.1%) enrolled in B-Pharmacy (135/480). Gender, age and years of undergraduate level were not considered in variable therefore it was not presented in the results. It was evident from Additionally, investigating the true nature of association between independent and control variable with outcomes variable, a forward-stepwise model using the information criterion was applied through linear regression analysis. The variables ’effects and coefficients are shown in The regression analysis tells us that control variable; i.e. certainty in pandemic COVID-19 switch and independent variable; i.e. information from internet had a strong negative effects on B-Pharmacy and medical students with p<.000 , whereasThe trajectory of decline mental health among students leading to extreme negative emotional behaviour in the form of suicide has been greatly emphasized in the past. This negative emotional behaviour or suicide idea is very impulsive because of unbearable stress, anxiety and depression due to multiple reasons while they were in their studentships. The data used in this study cover entire Islam group of three college population in Gujranwala, and we inspected whether anxiety and suicide ideation had a relationship with decline mental health wellbeing specifically near summative assessment of college and university under extreme circumstances during COVID-19 period. The results verifies the hypothesis that there was an unmediated connections of decline mental health wellbeing with suicidal ideation under strong stress and anxiety , .These findings strongly endorsed the results of another previous study22The sprouting of false or unclear knowledge from any sources is a lot of whistles for tsunami in psychiatric health care system in Pakistan which needs to be reforms and readdress. Regarding comparison of sources of COVID-19 information it was evident that DPT students had less information connections from medical health worker , internet , and friends or families  compared to B-Pharmacy and medical cohort. This represents that despite the fact that they were less informed but they are very anxious ) than medical students  and are also equally affected. These findings of medical and non-medical undergraduates of high education institutions support the outcomes of another study in university students.23Regarding the independent variables effects, it was obvious from outcomes that B-Pharmacy students had very weak envision cares from family; friends; peers; teachers; and medical worker . It could be due to the social distancing and online learning from home because of COVID-19 which is another invisible factor in the occurrence of anxiety and sadness resulting into stress-related-wrong-thoughts.24The results of this study emphasis that the risk of undergraduate student  with suicidal ideation during the pandemic of COVID-19 should not be ignored. Fear is adequate of vulnerability and magnifying the effects of social distancing, isolation and loss of outdoor college-gathering activities with friends and classmates, which ultimately results in by no means-ending anxiety and depression.This study is restricted to undergraduates related to medical field directly or indirectly and not every undergraduate of other subjects of other institutes. Another limitation was the removal of gender, age and study year. These could be possible mediator and could alter impacts of COVID-19 anxiety and suicide in outcomes. Thirdly the exclusion of any pre-existed mental health issue among undergraduates which may reoccurs during the COVID-19 pandemic and produces such negative effects.People connection and support even in the form of virtual setting is the key to fight unpredictable circumstances such as COVID-19. This study offered more data that the concerns, anxieties and uncertainties caused by pandemic COVID-19, don’t roll out alone but remain as long-lasting problems demanding ongoing attention.


Cardiac implantable electronic devices (CIEDs) may enable early identification of COVID-19 to facilitate timelier intervention.To characterize early physiologic changes associated with the onset of acute COVID-19 infection, as well as during and after acute infection, among patients with CIEDs.U tests.CIED sensor data from March 2020 to February 2021 from 286 patients with a CIED were linked to clinical data from electronic health records. Three cohorts were created: known COVID-positive (n = 20), known COVID-negative (n = 166), and a COVID-untested control group (n = 100) included to account for testing bias. Associations between changes in CIED sensors from baseline  and COVID-19 status were evaluated using logistic regression models, Wilcoxon signed rank tests, and Mann-Whitney P = .08]), respiratory rate . Respiratory rate during the 7 days before testing significantly predicted a positive vs negative COVID-19 test, adjusting for age, sex, race, and device type .Significant differences existed between the cohorts by race, ethnicity, CIED device type, and medical admissions. Several sensors changed earlier for COVID-positive vs COVID-negative patients: HeartLogic index (mean 16.4 vs 9.2 days [Physiologic data from CIEDs could signal early signs of infection that precede clinical symptoms, which may be used to support early detection of infection to prevent decompensation in this at-risk population.  Respiratory rate during the 7 days before testing significantly predicted a positive vs negative COVID-19 test, adjusting for age, sex, race, and device type, suggesting sensors may have future predictive potential.•A higher proportion of COVID-positive patients had an implantable cardioverter-defibrillator vs other device type, indicating more severe heart failure, and on average their HeartLogic index was elevated above baseline 2 weeks prior to symptom onset and testing, which precedes the viral incubation period for COVID-19. It is possible that early sensor changes may have represented worsening heart failure status, which created a greater susceptibility to a COVID-19 infection.•Distinct cardiac implantable electronic device sensor changes were also observed during the testing period and for several days following testing among COVID-positive compared to COVID-negative patients. Specifically, for COVID-positive patients, respiratory rate, activity, thoracic impedance, and HeartLogic index also remained significantly changed from baseline for several days or weeks after COVID-19 testing.,,,Patients with cardiovascular disease, especially heart failure, are at increased risk for contracting and suffering worse outcomes from severe acute respiratory syndrome coronavirus 2 or COVID-19.This study seeks to characterize early physiologic changes associated with an acute COVID-19 infection among patients with CIEDs during the COVID-19 pandemic in New York City. The primary hypothesis was that significant differences in CIED sensor data would be observed during the immediate time period before COVID-19 testing for patients who tested positive compared to those who tested negative. Additionally, we aimed to characterize differences in sensor changes at the time of COVID-19 testing between patients who tested positive, tested negative, and did not receive a COVID-19 test. Finally, we aimed to compare the resolution of sensor changes after COVID-19 testing among patients who tested positive compared to those who tested negative.In this cohort study, CIED sensor data were evaluated from March 2020 through February 2021 among patients at 2 large, urban, academic medical centers that are part of the NewYork-Presbyterian (NYP) Hospital network: NYP-Cornell and NYP-Columbia. Data originated from 3 sources: CIEDs, institutional COVID-19 repositories, and institutional electronic health record (EHR) data warehouses.CIED data were retrieved from Boston Scientific, where data from remotely monitored permanent pacemakers, implantable cardiac defibrillators (ICDs), and cardiac resynchronization therapy (CRT) devices are stored. Boston Scientific captures and stores all sensor data from its devices, creating a longitudinal dataset for each patient over time. Ten CIED sensors were examined: respiratory rate, activity, heart rate, night heart rate, temperature, rapid shallow breathing index, thoracic impedance, heart sounds , and HeartLogic index.HeartLogic is a proprietary algorithm that uses multiple sensors to track physiological trends and combines them into 1 composite index to send as a proactive alert of potential worsening heart failure.Some sensors  are measured in all patients with devices while others are only available in a subset of patients. For example, HeartLogic and its component sensors, including heart sounds and thoracic impedance, is only available for ICDs and certain types of CRT devices, and therefore only measured in patients with indications for those devices (predominantly patients with heart failure with reduced ejection fraction).Pulse generator temperature is monitored as an internal feature of these devices at the location of the implant. It is used within the devices for component monitoring purposes, such as battery status, and is not intended to provide a measure of core body temperature. Deviations in core body temperature could be reflected in the device’s temperature measurements, but the use of this feature in this setting is investigational.Institutional COVID-19 repositories consist of COVID-19-related data from the EHRs of all patients who have received a COVID-19 polymerase chain reaction test documented at NYP-Cornell or NYP-Columbia. COVID-19 test date and test status were obtained from institutional COVID-19 repositories.Demographics , clinical characteristics , and events at the time of COVID-19 testing  were obtained from institutional EHR warehouses. We conducted a chart review of COVID-positive patients’ EHRs to determine the timing of symptom onset and types of symptoms reported as documented by clinicians in the emergency department or inpatient admission notes.This study was approved by the Weill Cornell Medicine and Columbia University Irving Medical Center Institutional Review Boards.All patients who had an actively transmitting Boston Scientific CIED during the study period at NewYork-Presbyterian Hospital network, including Cornell and Columbia, and were aged 18 years or older were eligible for inclusion. Initially a total of 2210 patients meeting inclusion criteria were successfully linked to Boston Scientific and institutional EHR data. In the setting of limited available COVID-19 polymerase chain reaction tests during the first few months of the study period, institutional testing protocols were designed to prioritize testing for patients with a probable COVID-19 infection based on presenting signs and symptoms. Therefore, during part of the study period, COVID-negative patients were acutely ill enough to warrant a test. The timeline of when the COVID-19 tests were administered to patients in the study by test result (positive vs negative) is shown in To account for this testing bias in the first few months of the study period, we created a cohort of 100 randomly selected untested “true” control patients. Thus, 3 cohorts of patients were created using COVID-19 test date and status documented in the institutional COVID-19 repositories: (1) patients with a positive COVID-19 test (“COVID-positive”), (2) patients with a temporally concordant negative COVID-19 test (“COVID-negative”), and (3) patients who had a Boston Scientific CIED but did not have a COVID-19 test (“control”).Characteristics of each cohort were described using frequencies and percentages or means and standard deviations for categorical and continuous variables, respectively. Ten CIED sensors were examined in each analysis. Baseline parameters were computed using average sensor data from 60 to 30 days before COVID-19 testing for each patient. Pretest parameters were computed as the average sensor data during the 7 days preceding COVID-19 testing for all sensors except temperature, for which we selected the maximum value instead of the average. Event parameters were computed using maximum temperature and average of other sensors during the 15-day window surrounding COVID-19 testing.a priori that a sensor value is considered significantly different from baseline if it increased or decreased 1 standard error above or below that patient’s baseline and continued to remain different until the COVID-19 test date. This ensures that all days following the first significant day are also significantly different. The number of days after COVID-19 testing until sensors returned to baseline values was identified for each sensor was also identified using 1 standard error difference.The number of days before COVID-19 testing that the sensors considerably differed from baseline was identified for each sensor. We determined The primary comparison was between COVID-positive and COVID-negative patients. This comparison allowed changes that were specific to COVID-19 infection, and not other causes of acute decompensation, to be identified. As a sensitivity analysis to account for testing bias, COVID-positive patients were also compared to 100 randomly selected untested control patients. In the absence of a COVID-19 test to anchor the analytic window for control patients, a 15-day window between March 1 and July 1, 2020, was randomly selected to serve as a simulated event. This time frame was selected because it includes the first COVID-19 shutdown period in New York City, allowing possible changes in activity, breathing, heart rate, and other sensors that may be due to either stay-at-home orders, change in activity levels, or overall stress and anxiety owing to the pandemic.P < .5) and adjusting for age, sex, race, and device type. Wilcoxon signed rank tests were used to compare sensor changes from baseline to event within cohorts (paired test). Mann-Whitney U tests were used to compare the magnitude of mean change in each sensor between cohorts.The number of days before COVID-19 testing that the sensors significantly differed from baseline and the number of days that elapsed after a test before sensors returned to baseline were compared between COVID-positive and COVID-negative patients. Logistic regression models were used to identify whether the presence of sensor changes greater than 1 standard deviation in the 7 days before a test were associated with test status (positive vs negative). Multivariable model selection included screening univariate sensor associations . A data engineer from Boston Scientific (R.A.) conducted all statistical analyses because of his knowledge and prior experience analyzing and interpreting the volume and variety of data collected from CIED sensors. The data engineer met weekly with 2 researchers not employed by the company  to discuss the ongoing study, identify appropriate statistical analyses, and interpret findings. All raw data and analytic files were shared with the 2 researchers for transparency purposes. Furthermore, all coauthors met regularly to discuss the ongoing analysis and contribute insights from their clinical expertise and experience caring for cardiac patients with COVID-19. Therefore, we made a concerted, conscientious effort to ensure research findings were interpreted in the context of clinical relevance only.Of the 2210 patients meeting eligibility criteria, 433 had a COVID-19 test result in the institutional repositories during the study period and 1777 did not . Of the P = .04]) and ethnicity (Hispanic/Latino: 45% vs 19% vs 11% [P = .004]). Age, sex, and body mass index did not significantly differ between the 3 cohorts.Demographic characteristics of the 3 cohorts are reported in P < .001), but there was no difference in intensive care unit admissions or deaths.There were also significant differences by device type. Comparing COVID-positive vs COVID-negative vs control, more COVID-positive patients had an ICD (65% vs 29% vs 47%) and fewer COVID-positive patients had a pacemaker (20% vs 50% vs 25%). There was no difference in the proportion of patients diagnosed with heart failure between the cohorts. A higher proportion of COVID-positive patients had a medical admission at the time of COVID-19 testing compared to COVID-negative , respiratory rate , activity , and temperature .The illustrated unique sensor changes associated with COVID-positive patients and not COVID-negative patients were confirmed in statistical tests. In unadjusted multivariable logistic regression models, respiratory rate, activity, and temperature significantly predicted a positive COVID-19 test . After aAmong COVID-positive patients, we observed statistically significant changes in respiratory rate (15% increase), temperature (1% increase), HeartLogic index (227% increase), and activity (44% decrease) from baseline to event . Among CP = .08), activity , and respiratory rate .Multiple sensors returned to baseline later for COVID-positive compared to COVID-negative patients: HeartLogic index . It is possible that we may have detected significant differences in other sensors if we had been able to examine more devices that measured a wider range of sensors. Specifically, there were no significant differences on a number of sensors between COVID-positive and COVID-negative patients that we may have been able to detect with greater statistical power. Future work determining differences in sensors changes between larger cohorts of COVID-positive and COVID-negative patients, including those with devices that measure a range of sensors, are needed. Larger cohorts could also be used to build and validate a predictive classifier of COVID status using sensor data, which we were unable to do because of the small number of positive cases. An additional limitation is classification bias owing to rapid changes in institutional testing protocols and accuracy of COVID-19 tests during the study period, together with a lack of access to COVID-19 tests performed outside our institutions. Therefore, patients in the COVID-negative or control cohorts may have actually been infected with COVID-19. Finally, the data analyst was unable to remain blinded to the study question or COVID test status because of the data science needed to create the 3 cohorts, which may have introduced bias into the analysis.In conclusion, physiologic data from remotely monitored CIEDs provide a unique opportunity to detect physiologic changes that may be associated with COVID-19 infection early in the course of illness. Sensor changes in COVID-positive patients signal early signs of infection that precede clinical symptoms, which may be used to support early detection of infection to prevent decompensation in this at-risk population.Given his role as Section Editor, David Slotwiner had no involvement in the peer review of this article and has no access to information regarding its peer review.10.13039/100008497Boston Scientific Corporation. M.R.T. is funded through NIH/10.13039/100000056NINR (K99NR019124).This project was funded through a research grant from


Chronic diseases are putting huge pressure on health care systems. Nurses are widely recognized as one of the competent health care providers who offer comprehensive care to patients during rehabilitation after hospitalization. In recent years, telerehabilitation has opened a new pathway for nurses to manage chronic diseases at a distance; however, it remains unclear which chronic disease patients benefit the most from this innovative delivery mode.This study aims to summarize current components of community-based, nurse-led telerehabilitation programs using the chronic care model; evaluate the effectiveness of nurse-led telerehabilitation programs compared with traditional face-to-face rehabilitation programs; and compare the effects of telerehabilitation on patients with different chronic diseases.A systematic review and meta-analysis were performed using 6 databases for articles published from 2015 to 2021. Studies comparing the effectiveness of telehealth rehabilitation with face-to-face rehabilitation for people with hypertension, cardiac diseases, chronic respiratory diseases, diabetes, cancer, or stroke were included. Quality of life was the primary outcome. Secondary outcomes included physical indicators, self-care, psychological impacts, and health-resource use. The revised Cochrane risk of bias tool for randomized trials was employed to assess the methodological quality of the included studies. A meta-analysis was conducted using a random-effects model and illustrated with forest plots.P=.01; heterogeneity: X21=1.9; I2=48%; P=.16; chronic respiratory diseases: SMD 0.18; 95% CI 0.05 to 0.31; P=.007; heterogeneity: X22=1.7; I2=0%; P=.43) and self-care  were observed in the groups that used telerehabilitation. For patients with any of the 6 targeted chronic diseases, those with hypertension and diabetes experienced significant improvements in their blood pressure , and hemoglobin A1c  levels. Despite these positive findings, telerehabilitation was found to have no statistically significant effect on improving patients’ anxiety level, depression level, or hospital admission rate.A total of 26 studies were included in the meta-analysis. Telephone follow-ups were the most commonly used telerehabilitation delivery approach. Chronic care model components, such as nurses-patient communication, self-management support, and regular follow-up, were involved in all telerehabilitation programs. Compared with traditional face-to-face rehabilitation groups, statistically significant improvements in quality of life (cardiac diseases: standard mean difference [SMD] 0.45; 95% CI 0.09 to 0.81; This review showed that telerehabilitation programs could be beneficial to patients with chronic disease in the community. However, better designed nurse-led telerehabilitation programs are needed, such as those involving the transfer of nurse-patient clinical data. The heterogeneity between studies was moderate to high. Future research could integrate the chronic care model with telerehabilitation to maximize its benefits for community-dwelling patients with chronic diseases.International Prospective Register of Systematic Reviews CRD42022324676; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=324676 One of Many systematic reviews have been published in recent years on the effectiveness of telerehabilitation programs for those with one specific chronic disease . A previous systematic review suggested that there is controversy over the effectiveness of telerehabilitation and that its impacts could differ depending on which chronic disease a person has . HoweverThe objectives of the review are to identify the intervention components of current nurse-led telerehabilitation programs for community-dwelling people with chronic diseases, to evaluate the effectiveness of nurse-led telerehabilitation programs compared with traditional face-to-face rehabilitation programs, and to compare the effects of telerehabilitation on patients with different chronic diseases.A systematic review and meta-analysis was conducted following the PRISMA  2020 statement . This stThe literature search was performed by 2 independent reviewers (AYLL and AKCW) without the involvement of librarians. PubMed, MEDLINE, CINAHL, Embase, PsycInfo, and the Cochrane Central Register of Controlled Trials were searched for articles published from 2015 to 2021, with the aim of capturing the most updated telerehabilitation approaches under rapid technological development. Handsearching was performed using Google Scholar and the reference lists of included papers. Gray literature, such as abstracts and editorials, were excluded as most of these articles are not peer-reviewed and their inclusion would have lowered the quality of evidence. Search strategies for all databases were constructed based on the key search terms, which included “telerehabilitation,” “chronic disease,” “nursing,” “multi-disciplinary,” and “randomized controlled trial.” The search was further expanded by the inclusion of different chronic diseases and medical subject headings mesh terms .Studies that included people with hypertension, cardiac diseases , chronic respiratory diseases , diabetes, cancer, or stroke were the target of this review because these are common diseases among people in the community that require the provision of long-term nursing rehabilitation care. Articles were screened using the following eligibility criteria constructed using the patient, intervention, comparison, and outcome (PICO) strategy.The inclusion criteria for articles were the following: participants aged 18 years or above, diagnosed with one of the targeted chronic diseases, and living independently in the community outside health care facilities; telerehabilitation employed as the intervention delivery channel in 1 arm of the intervention , with nurses providing of at least 50% of the program in terms of the frequency or duration of the provision of care; comparison to conventional face-to-face center-based consultations or a waitlist control; outcomes of quality of life, disease-specific physical indicators, self-care ability, psychological outcomes , and health-resource use; and a randomized controlled trial study design.The exclusion criteria for articles were the following: participants were patients living in assisted residential care facilities  and interventions were telerehabilitation programs conducted in hospital settings where the purpose of the program was to provide education or training only to health care professionals.The literature screening process is reported using the PRISMA flowchart . The seaThe following variables were extracted and are listed in The interventions of all included studies were extracted according to the chronic care model. The six components of the model are as follows: (1) active, two-way interactions between an informed patient and proactive health care providers; (2) effective self-management support during communication; (3) an intact delivery system design with regular follow-ups for evaluation; (4) proper decision support from expertise, protocols, or training; (5) a clinical information system between patients and health care providers for managing the patients’ clinical data; and (6) community resources .The Cochrane risk of bias tool was used to identify the potential risk of bias in the included studies . Two revI2 statistics, and a P value (<.05). The value of I2 could be interpreted as indicating unimportant (0%-40%), moderate (30%-60%), substantial (50%-90%), or considerable (75%-100%) heterogeneity [A meta-analysis was conducted using Review Manager version 5.4.1 (The Cochrane Collaboration) and illustrated using a forest plot when at least 2 studies were measured for the same outcomes for a chronic disease at the longest follow-up timepoint . Under table 75%-0% heteroable 75%-0% heteroThe screening process is reported in A total of 9677 participants with a mean age of 63.75 years were included in the 38 studies. Of these, 5105 received telerehabilitation and 4572 received conventional face-to-face consultations; 6 studies were 3-armed randomized controlled trials -16, and The programs were performed by registered nurses (n=20), specialty nurses (n=8), advanced practice nurses (n=3), community nurses (n=1), a nurse case manager (n=1), or people involved in more than one health-related discipline (n=5). The study periods ranged from 4 weeks to 36 months, with 8 weeks (n=8), 12 weeks (n=7), and 24 weeks (n=7) being the most common durations.The technologies used in telerehabilitation programs are summarized in A total of 32 studies conducted telerehabilitation programs through telephone (n=26) -43,46-48There were 2 studies framed by problem-solving theory, which supported chronic disease rehabilitation by developing behavioral plans and providing positive reinforcement during nurse-led phone counseling ,28. AnotNine studies integrated telemonitoring in their telerehabilitation program for patients with heart failure, asthma, COPD, or diabetes -32,34,35Apart from nurse follow-ups and telemonitoring, there were 4 studies that used smartphone apps to support chronic disease rehabilitation in the community ,35,44,45The overall chronic care model elements among all included studies are illustrated in Forest plots for all outcomes are shown in One study reported that telerehabilitation programs had a positive effect on the quality of life of people with hypertension .P=.01), with moderate heterogeneity .A significant improvement in the quality of life of cardiac disease patients who had received telerehabilitation was observed when compared with those who had received a nontechnological intervention .Pooled analyses of 3 studies showed that patients with COPD who received telerehabilitation had a significantly higher quality of life than did those who received conventional face-to-face rehabilitation .From a meta-analysis of 2 studies, it was revealed that there was no significant difference in quality of life between the intervention and control groups of patients with cancer , with moderate heterogeneity . However, no significant difference was observed in their diastolic blood pressure .Pooled intervention effects from 2 studies showed a significant improvement in the systolic blood pressure of patients through telerehabilitation . However, the above result might have been affected by an outlier since the findings showed substantial heterogeneity .A meta-analysis of 5 studies found that telerehabilitation had no significant effect on improving the hemoglobin A1c levels of patients , with mild heterogeneity . A subgroup analysis showed that participation in telerehabilitation led to a significant improvement in the participants’ self-care management  and self-care confidence  but not in their self-care maintenance .A pooled analysis indicated that telerehabilitation could have a beneficial effect on the self-care ability of patients with cardiac diseases .The pooled SMD indicated that telerehabilitation had a significant positive effect on enhancing the self-care behavior of patients with diabetes when compared with conventional face-to-face nursing consultations .A meta-analysis showed that telerehabilitation had no significant effect on reducing the depression levels of patients who experience heart failure  and depression levels  in patients with COPD.Pooled analyses in 3 studies found there to be a significant reduction in anxiety .The pooled MD showed no significant effect between groups on relieving anxiety .A pooled intervention effect of 3 studies showed that telerehabilitation had no significant effect on reducing hospitalizations of patients with heart failure , with no heterogeneity observed .Telerehabilitation had no significant effect on reducing respiratory-related hospitalizations  . DiffereIn addition to decision support systems, clinical information systems are another important component in the chronic care model that need to be considered in nurse-led telerehabilitation programs. The lack of a shared clinical information system among health care professionals has shown to increase the risk of medical errors . With thChronic diseases are usually associated with functional impairment, which can reduce the ability of patients to adapt telerehabilitation. The evidence shows that patients with greater physical disabilities are less likely than their counterparts to comply with a telerehabilitation program ,27,78. TMost older adults not only suffer from a single chronic disease, but also face the problem of multimorbidity. The prevalence of multimorbidity in China and the United States has been reported to be 49.4% and 59.6%, respectively ,82. RehaThis review has several limitations. First, it only included papers written in English, so relevant studies reported in different languages were missed. Second, this review only included nurse-led telerehabilitation programs for the 6 most common chronic diseases. There was no coverage of telerehabilitation programs for those with other chronic diseases resulting in high functional disability, such as arthritis and neurological diseases. Third, the heterogeneity between studies was from moderate to high due to the differences in intervention characteristics, such as study duration, sample size, and technological devices used. Fourth, not all studies were included in the meta-analysis due to data incompleteness despite reviewers’ attempts to contact corresponding authors for relevant data.Although the meta-analysis showed that the programs led to a significant improvement in the quality of life and self-care ability of patients with various chronic diseases, it did not have an advantage over traditional face-to-face consultations with regard to anxiety, depression, or the number of hospital admissions. Guided by the chronic care model, the review showed that the usage of decision support and clinical information systems may facilitate the work of nurses in telerehabilitation programs. In addition, despite the commonality of multimorbidity, limited studies regarding the effectiveness of telerehabilitation programs targeting patients with multiple chronic diseases are available. Future research could focus on the use of telerehabilitation among these patients.


In the GLM, endometriosis (p = 0.026) and maternal age (p = 0.007) were associated with increased third trimester UtA-PI Z-scores, whereas conception by in-vitro fertilization with frozen-thawed embryo transfer significantly decreased UtA-PI measures (p = 0.011). According to these results, r-AFS stage III–IV endometriosis is associated with a clinically measurable impaired late placental perfusion. Closer follow-up may be recommended in pregnant patients affected by moderate-severe endometriosis in order to attempt prediction and prevention of adverse pregnancy and perinatal outcomes due to a defective late placental perfusion.The aim of this study was to evaluate if moderate-severe endometriosis impairs uterine arteries pulsatility index (UtA-PI) during pregnancy when compared to unaffected controls. In this prospective cohort study, pregnant women with stage III–IV endometriosis according to the revised American Fertility Society (r-AFS) classification were matched for body mass index and parity in a 1:2 ratio with unaffected controls. UtA-PIs were assessed at 11–14, 19–22 and 26–34 weeks of gestation following major reference guidelines. A General Linear Model (GLM) was implemented to evaluate the association between endometriosis and UtA-PI Z-scores. Significantly higher third trimester UtA-PI Z-scores were observed in patients with r-AFS stage III–IV endometriosis when compared to controls ( Endometriosis is a chronic hormone-dependent, inflammatory, fibrotic condition in which endometrial stroma and epithelium can be identified outside the uterine cavity, predominantly but not exclusively in the pelvic cavity ,2. It isMajor evidence from two decades of research showed that the combined screening test promoted by the Fetal Medicine Foundation (FMF) achieves the highest detection rate for some of these outcomes compared to any other available test . As a coPrevious researchers failed to show significant differences in measurements of UtA-PI, pregnancy associated plasma protein-A (PAPPA-A) as well as rates of SGA and PE between pregnant women with and without adenomyosis, except for cases with diffuse disease . HoweverThe aim of the current study was to evaluate whether the presence of stage III–IV endometriosis according to the revised American Fertility Society classification (r-AFS)  could imThis is an observational, monocentric, prospective cohort study carried out from January 2016 to January 2021 at IRCSS San Raffaele Scientific Institute in Milan, Italy. The study was conducted and reported according to the Strengthening the reporting of observational studies in epidemiology (STROBE) guidelines . Singleton pregnancies with moderate or severe endometriosis (stage III or IV following r-AFS classification) assessed either surgically and histologically or confirmed by ultrasound (US) were selected as cases. Endometriotic lesions were phenotypically classified according to their localization, as ovarian endometrioma (OMA), deep endometriosis (DE), or both ,25. No cPregnant women with no evidence of the disease  were randomly enrolled as controls in a 1:2 match. Matching of cases to controls was achieved by enrolling the first two pregnancies with no evidence of endometriosis, with identical parity and body mass index (BMI) similarity (±1 unit), observed within 5 days from recruitment of each case with endometriosis. The patient selection process is shown in Women with multiple gestations, fetal structural abnormality or fetal aneuploidy, uterine malformation, significant uterine fibroids, previous uterine surgery and significant pre-gestational maternal diseases, such as cardiovascular, liver or renal disease, diabetes mellitus, coagulation and autoimmune disorders were excluded. Data collection followed the principles outlined in the Declaration of Helsinki . PregnanPatients’ data were prospectively recorded in a database including the following: (i) baseline maternal characteristics, such as age, BMI, parity, method of conception, smoking status; (ii) first, second and third trimester US measurements including CRL, serum levels of free-beta human chorionic gonadotropin (beta-hCG) and PAPP-A, estimated fetal weight (EFW); (iii) maternal and perinatal outcomes, including GA at delivery , birthweight , the proportion of SGA and large for gestational age (LGA) fetuses, preterm birth (PTB), gestational hypertension/PE and oligohydramnios. Estimated fetal weight (EFW) centiles were defined according to FMF fetal and neonatal population weight charts . AccordiThe outcome of this study was UtA-PI Z-scores in the 1st, 2nd and 3rd trimester of pregnancy calculated from reference equations of previously published normal ranges .t-test or Wilcoxon signed-ranks test with an exact test for quantitative variables and Pearson’s Chi square test or Fisher’s exact test for qualitative variables were performed to compare data of cases and controls, as appropriate.The Shapiro–Wilk test was used to ascertain whether continuous variables had a normal distribution. Continuous and normally distributed variables were presented as mean ± standard deviation (SD), whereas continuous not normally distributed variables were expressed as the median and interquartile range (IQR) and categorical variables were presented as absolute values and percentages (%). The Student p-values < 0.05 were considered statistically significant.A General Linear Model (GLM) was performed to determine the association between endometriosis and UtA-PI Z-scores. Analysis of minimal deviance was used to define optimal link and variance functions. Conventional goodness-of-fit tests were performed to select the best multivariable model. Average marginal effects with 95% Confidence Intervals (CIs) for all the variables included in the model were additionally plotted. STATA version 17 software  was used for statical analysis. All tests were two-sided and Power analysis for the comparison of two independent means was conducted before the enrollment started, setting the sample allocation ratio to 1:2. The sample size calculation analysis indicated that a total of 32 cases and 64 controls, with a UtA-PI coefficient of variation equal to SD/mean ≤0.35 as calculated by published data , were reOf the 47 endometriosis patients enrolled in the study, 36 (76.6%) had an OMA phenotype, 1 (2.1%) had a DE phenotype and 10 (21.3%) had simultaneously an OMA and a DE localization. In four out of 46 cases with an ovarian localization of the disease (8.7%), bilateral endometriomas were reported. Additionally, 27/47 (57.4%) of endometriosis cases underwent a previous laparoscopic and histologic confirmation of the disease, whereas, in 20/47 (42.6%) of cases, DE or OMA were assessed before conception by US. All the included cases had a stage III–IV  endometriosis disease according to r-AFS classification. The study group consisted of 47 (33.6%) cases of endometriosis and 93 (66.4%) controls with no evidence of the disease, matched by parity and BMI. Baseline characteristics of endometriosis cases and controls are shown in p = 0.024). No statistically significant differences were observed either in the 1st trimester levels of serum biomarkers (MoM PAPP-A and MoM free β-hCG) or in CRL standardized measures. A higher yet not significant rate of SGA fetuses and SGA neonates were observed in cases; on the other hand, a lower still not significant proportion of LGA fetuses and LGA neonates was observed in cases. Remarkably, no significant differences in GA at US examinations  were observed. First, second and third trimester US variables assessment in cases and controls are summarized in p = 0.03), despite no difference in overall GA at delivery between the two groups. Pregnancy and perinatal outcomes in cases and controls are presented in To further investigate the observed significant differences of third trimester UtA-PI Z-scores in endometriosis and controls, we performed a GLM . p = 0.021). In the univariate model, the presence of endometriosis was associated with a significant increase by 0.111 units (95% CI: 0.016–0.206) in third trimester UtA-PI Z-scores . Similarly, a significant increase in the response variable was observed with increasing maternal age (p = 0.007). Conversely, conception by IVF significantly decreased third trimester UtA-PI Z-scores (p = 0.011). Neither nulliparity nor BMI significantly affected third trimester UtA-PI Z-scores. A 35.797 log likelihood was computed for the proposed model. Post-estimation goodness of fit analysis for the multivariate model showed an Akaike’s information criterion (AIC) of −59.595 and a Bayesian information criterion (BIC) based on the number of observations was equal to −47.232. The association between third trimester UtA-PI Z-scores (response variable) and endometriosis was further assessed with a multivariable model adjusted for several explanatory variables including nulliparity, conception by IVF, maternal age and BMI. Average marginal effects with 95% CIs for all the independent variables included in the model are shown in Box plots of third trimester UtA-PI Z-scores in endometriosis patients and controls weighted for the predictors included in the multivariable model are shown in This prospective cohort study showed significantly higher third trimester UtA-PI Z-scores in patients with r-AFS stage III–IV endometriosis when compared to unaffected controls and no differences in first or in second trimesters UtA-PI Z-scores. The extent of UtA-PI increase in endometriosis was about 13% with additional effects of maternal aging (positive by 1.5%) and IVF conception (negative by 11%). We would like to speculate on the underlying mechanisms on the basis of our findings. In normal pregnancies, UtA-PI progressively declines with advancing gestation, reflecting the underlying process of placentation and so the conversion of spiral arteries into uteroplacental arteries . Such a Endometriosis-related fibrosis may interfere with the regulation of peripheral vessels physiology altering endothelial function and vascular stiffness ,37. The The physiological progressive decrease of UtA-PIs throughout gestation is thought to be also due to a progressive increase in estrogen levels during pregnancy, which tend to have a vasodilatory effect . We can Remarkably, a recent review emphasized the possibility of defective deep placentation in endometriosis due to several structural and functional abnormalities of eutopic endometrium and myometrium . As a maThe results of the present study suggest that, in line with the higher risk of adverse maternal/perinatal outcomes observed in large population-based studies, the higher uterine artery impedance in the third trimester of pregnancies with documented r-AFS stage III–IV endometriosis may be a clinically measurable indicator of impaired placentation in those patients . The finEndometriosis was found to be associated with several adverse obstetric/perinatal outcomes . Two recAccording to previous evidence, our data also support the additional effect of increasing maternal age on UtA-PIs in the third trimester of pregnancy . AdvanceThis study presents some limitations. Firstly, the diagnosis of deep and ovarian endometriosis was in some cases assessed by the US alone before conception, even if in the majority of cases a diagnostic laparoscopy was performed. However, US assessment for deep and/or ovarian endometriosis has been validated worldwide as a reliable diagnostic tool , especiaHowever, this study presents several strengths, as well. Firstly, the case-control matching for parity and BMI , with no differences in the type of conception between the two groups, allowed us to control for potential sources of biases. Secondly, data were collected with quality and homogeneity of ultrasound methodology . Thirdly, the robustness of the statistical analysis performed within a model providing a high power contributed to strengthening our conclusions. Finally, restricting the analysis to the moderate and severe forms of endometriosis (r-AFS stage III–IV) contributed on the other hand to reduce the clinical heterogeneity of the study group.The presence of stage III–IV endometriosis according to r-AFS is associated with a clinically measurable impaired placental perfusion during the third trimester of pregnancy, as showed by the 13% higher UtA-PI Z-scores as compared to unaffected controls. Endometriosis-related fibrosis altered vascular response to estrogens/progesterone and the inflammatory microenvironment may be the pathophysiological mechanisms justifying our findings. Thus, we feel appropriate to recommend closer follow-up with serial well-being and growth scans in the third trimester (28 to 36 weeks) of patients with advanced stages of endometriosis, in order to diagnose or prevent potential consequences of defective placentation. Further studies will be needed to elucidate the potential link between impaired placental perfusion and endometriosis in relation to obstetric/perinatal complications, with the final aim to improve the final pregnancy outcome.


COVID-1As of December 2022, among 194 countries, 154 (79%) had reported both overall and older adult COVID-19 vaccination coverage at least once to WHO; ≥78% of countries in all income groups reported coverage during the last three months of 2022.The impact of COVID-19 during the last 3 years has been substantial, and COVID-19 mortality is an important outcome indicator for monitoring the pandemic. These COVID-19 deaths and excess mortality estimates showing that persons aged ≥60 years accounted for more than 80% of total COVID-19 deaths even when controlling for income levels are consistent with the initial SARS-CoV-2–related mortality patterns described in China and subsequently by other countries . This is particularly important because most countries have ended most mandated public health and behavioral measures to mitigate the spread of SARS-CoV-2.COVID-19 vaccines, which have received WHO Emergency Use Listing,The findings in this report are subject to at least two limitations. First, age-disaggregated mortality and vaccination data were self-reported by countries with different reporting frequencies, limited data verification processes, and varying capacity for reporting up-to-date information. As a result, reported vaccination coverage rates included in the analysis might be lower than the countries’ published figures because of nonreporting to WHO. Second, the WHO-modeled excess mortality data included all countries and age groups available for 2020 and 2021, but not yet for 2022. Thus, direct association between COVID-19 mortality and vaccination coverage among older adults was not examined in this analysis. Future analyses could be conducted with more regular reports and more availability of detailed data, including vaccination status for reported deaths.With both timely and reliable data necessary for accurate monitoring of global targets, countries need to be able to strengthen COVID-19 surveillance and vaccination reporting systems to provide better and more detailed data to guide public policies. The collection of accurate disaggregated data by age, and by vaccination dose , will be critical to monitoring progress in achieving coverage targets among older adults at highest risk for COVID-19–associated death. Because vaccination rates among older adult populations remain below the recommended global vaccination target of 100%, efforts are needed to understand and address the reasons that target populations are not reached by current vaccination programs, while integrating COVID-19 vaccination into primary care systems to facilitate completion of a primary COVID-19 vaccination series and receipt of booster doses recommended by WHO and national health authorities for all older adults.COVID-19 vaccines are safe and reduce COVID-19 mortality. The World Health Organization (WHO) recommends that countries prioritize populations at increased risk, e.g., older adults, for COVID-19 vaccination with a goal of 100% coverage with a completed primary series for populations at-risk.COVID-19–associated mortality among persons aged ≥60 years exceeded 80% of total COVID-19 mortality in 2020 and 2021 across all income groups; however, the median reported completed primary series coverage among older adults in 2022 was 76%, substantially below the WHO goal, especially in middle- and low-income countries.Efforts are needed to increase COVID-19 primary series and periodic booster dose coverage among older adults as recommended by WHO and national health authorities.


Several studies have reported that the coronavirus disease (COVID-19) pandemic has increased sedentary behaviour and obesity; however, these analyses used self-reported data, and the association between sedentary behaviour and visceral fat and adipocytokines during the COVID-19 pandemic remains unclear. We aimed to investigate the association of the COVID-19 pandemic with objectively measured sedentary behaviour and these obesity-related factors.Longitudinal analysis was conducted on 257 Japanese participants who underwent health check-ups in 2018 before and in 2020 during the COVID-19 pandemic. For both time points, sedentary behaviour was measured using an accelerometer for at least 7 days, visceral fat area (VFA) was measured using abdominal bioelectrical impedance analysis, and blood adiponectin level was measured using latex agglutination turbidimetric immunoassay. Multiple linear regression was performed to determine the association between sedentary behaviour and these outcomes.P < 0.001, P = 0.006) whereas adiponectin level was significantly decreased (P < 0.001) in 2020. Increased sedentary behaviour was significantly associated with an increase in VFA  and a decrease in adiponectin level . However, the association of sedentary behaviour with adiponectin level was not significant after considering the effects of VFA.Compared with data in 2018, sedentary behaviour and VFA were significantly increased (The COVID-19 pandemic was associated with objectively measured sedentary behaviour and obesity-related factors in Japanese adults. Additionally, an increase in sedentary behaviour was associated with an increase in VFA, whereas the association of sedentary behaviour with adiponectin was partly mediated by VFA. These results suggest that avoiding increasing sedentary time is important to prevent visceral adiposity thereby ameliorating adiponectin, especially during behavioural limitations such as the COVID-19 pandemic. The incidence of obesity has increased over the recent decades . The corObesity is caused by an imbalance between energy intake and expenditure, and sedentarism causes obesity by decreasing energy expenditure . PreviouDue to the nature of behavioural measures, sedentary behaviour may have been much more affected by the COVID-19 pandemic compared to other health behaviours , therebyThe Iwaki Health Promotion Project was launched in 2005. As part of the project, an annual health check-up was conducted for adults living in the Iwaki region of Hirosaki City, Aomori Prefecture, located in northern Japan . Aomori In 2018, 1,056 individuals participated in a health check-up from May 27 to June 5. In 2020, 524 individuals participated in a health check-up from September 17 to September 25. The number of participants in the 2020 check-up was approximately half that in a typical annual check-up because of the COVID-19 pandemic. Of these, 410 individuals who participated in both the 2018 and 2020 health check-ups were enroled in the study. We excluded 153 participants due to incomplete clinical assessments, dietary data, or accelerometer data. Ultimately, 257 participants were included in the analysis. Supplementary Figure https://www.umin.ac.jp) prior to the analyses (UMIN ID: UMIN000036741).The study was approved by the Ethics Committee of Hirosaki University School of Medicine  and was conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all participants before the study. This study was registered in the University Hospital Medical Information Network , in 2018 and HW-200R  in 2020. The HW-100 and HW-200R are similar, with the HW-200R being more compact than the HW-100. The epoch length of the accelerometer was 4 s with a sampling frequency of 64 Hz. Activity intensity was measured as previously described , 29, 30.The participants were instructed to wear the accelerometer on the waist throughout their awake period, except during swimming or bathing, and to maintain their usual activities. Additionally, the participants were instructed to begin wearing the accelerometer promptly after completing their health check-up and to return it after 10 days. The criterion for analysis was wearing the accelerometer for a total duration of ≥7 days (≥10 h/day) during the first 10 days.Obesity-related factors were assessed in both 2018 and 2020. VFA was measured using a bio-impedance-type visceral fat metre , which is an authorised medical device in Japan (No. 22500BZX00522000) for non-invasive VFA measurement . The meaData on smoking habits (never/former/current) were obtained through questionnaires prepared for the health check-up. Daily alcohol intake and total energy intake were calculated using the brief-type self-administrated diet history questionnaire (BDHQ) , 34. Ther = 0.80) and the differences in accelerometer wear time, we standardised the sedentary time to 16 h per day of accelerometer wear time using residuals obtained when regressing sedentary time on accelerometer wear time, as previously described [Given the strong correlation between accelerometer wear time and sedentary time  or percentage. Owing to their skewed distribution, adiponectin level was log-transformed. Comparisons before and during the COVID-19 pandemic were performed using paired t-tests. The correlation between the two variables was determined using Pearson’s correlation coefficient and partial correlation coefficient. A partial correlation between changes in sedentary time and changes in adiponectin was adjusted by changes in VFA.Linear regression analysis was used to assess the association of changes in sedentary time or changes in the number of steps with obesity-related factors, which was reported as a regression coefficient (β) and 95% confidence interval (CI) per hour or 1000 steps. In addition to excessive energy intake, VFA is associated with smoking  and alcoP < 0.05. As interactions by age and sex with changes in sedentary time and number of steps were not statistically significant, pooled analyses were conducted. All analyses were performed using SPSS version 25 software .Statistical tests were two-tailed, and statistical significance was set at We performed sensitivity analyses using longitudinal data obtained from the health check-up, including in 2019, to confirm that the change in obesity-related factors was due to the COVID-19 pandemic, not due to ageing see . For potP < 0.05). Supplementary Fig. Table r = 0.132, P = 0.035) and changes in adiponectin , whereas changes in sedentary time were not significantly associated with changes in BMI . A significant correlation was found between changes in VFA and adiponectin . After adjusting for changes in VFA, the association between changes in sedentary time and changes in adiponectin was not significant .Figure P = 0.004) and decreased adiponectin , whereas an increase in sedentary time was not significantly associated with increased BMI . However, the associations between changes in sedentary time and adiponectin levels did not remain significant after adjusting for changes in VFA (Model 2). Supplementary Table Table P = 0.006), however, the direct effect was not significant .Supplementary Fig. Figure Supplementary Table Results of sensitivity analyses showed that VFA was significantly increased and adiponectin was significantly decreased between 2019 and 2020; however, these were not significantly different between 2018 and 2019  in this study show that analysing variables assessed as changes Table  providedThe strengths of this study include the analysis of objectively measured data, including sedentary behaviour, VFA, and adipocytokines before and during the COVID-19 pandemic. In addition, activity was measured for ≥7 days (≥10 h/day) with 4 s epochs, which allowed the reflection of actual daily activity . PreviouRegardless of the low SARS-CoV-2 infection rate and not having mandatory lockdowns, the COVID-19 pandemic altered sedentary behaviour and obesity-related factors in Japan. In addition, an increase in sedentary behaviour was associated with an increase in VFA, whereas the association of sedentary behaviour with adipocytokines was partly mediated by VFA. Monitoring and managing sedentary behaviour may prevent visceral fat accumulation and thereby improve adipocytokine abnormalities, which contribute to the prevention of COVID-19 severity. Further large-scale longitudinal or interventional studies are required to confirm the effectiveness of reducing sedentary time.Supplementary informations


Patients who are HIV-positive and have breast cancer have worse overall survival (OS) compared with patients who are HIV-negative. Pathologic complete response (pCR) and relative dose intensity (RDI) of chemotherapy are associated with survival. We assessed whether pCR and RDI rates were lower for patients who are HIV-positive and received neoadjuvant chemotherapy (NACT).This was a prospective cohort analysis of patients initiating NACT in Botswana (February 2017 to September 2019). Primary outcomes were pCR and RDI; secondary outcomes were OS and toxicity. HIV status and zidovudine (ZDV) treatment were stratification factors. Multivariable analysis was used to control for confounding.P = .048) and RDI < 0.85  were associated with pCR. In multivariable analysis, the magnitude of association decreased for HIV-positive , but RDI < 0.85 remained independently associated with pCR . Patients who are HIV-positive had significantly lower mean RDI, and those on ZDV had significantly lower RDI. Ninety-one (83%) were stage III with 2-year OS significantly worse for patients who are HIV-positive (58% v 74%). Hazard ratio for all-cause mortality was 2.68  in patients who are HIV-positive compared with patients who are HIV-negative. Toxicity rates were similar despite patients who are HIV-positive receiving significantly lower dose intensity chemotherapy.In total, 26 of 110 enrolled individuals were HIV-positive. In univariable analysis, HIV-positive (odds ratio [OR] = 0.2; Patients who are HIV-positive and have breast cancer in Botswana have lower pCR rates and also receive lower dose intensity therapy, which may contribute to worse OS. Patients who are HIV-positive on ZDV-containing regimens received even lower dose intensity of NACT. Administering optimal dose intensity in patients who are HIV-positive remains a challenge, and targeted interventions that address modifiable risk factors are needed to improve therapy delivery and outcomes. There are also limited data on association of treatment toxicity and adequacy of cancer therapy delivery with HIV viremia or ART regimen. Botswana is a middle-income country in SSA with the fourth highest prevalence of HIV in the world.7 Breast cancer represents 18% of all cancers diagnosed and 12.5% of cancer-associated deaths with an age-standardized mortality rate of 7.0 per 100,000.8 Additionally, 25%-30% of patients with breast cancer are WLWH.9 Recent data from the region suggest worse survival in WLWH with breast cancer compared with patients who are HIV-negative,5 which represents a huge public health burden.Antiretroviral therapy (ART) has led a drop in overall incidence of AIDS-defining cancers and an upsurge in age-related non–AIDS-defining cancers, as the HIV population ages.Key ObjectiveTo evaluate survival outcomes in patients living with HIV and patients who are HIV-negative and have breast cancer in Botswana and furthermore to assess whether patients who are HIV-positive receive lower relative dose intensity (RDI) of neoadjuvant chemotherapy and have lower pathologic complete response rates.Knowledge GeneratedPatients who are HIV-positive received significantly lower RDI of chemotherapy, with lowest RDI in patients on zidovudine-based antiretroviral regimens. Furthermore, patients who are HIV-positive had lower pathologic complete response rates. These observed differences in our prospective cohort may partly account for survival disparities between patients who are HIV-positive and HIV-negative and who are diagnosed with breast cancer.RelevanceAdministering optimal dose intensity chemotherapy in patients with HIV and who have breast cancer remains a challenge and adversely affects survival. Care integration with HIV specialists and pharmacists should be considered to address modifiable risk factors.12 Relative dose intensity (RDI) is a composite measure that includes actual cumulative dose of chemotherapy received and duration of treatment received, expressed as a proportion of the intended standard dose and duration of therapy. RDI < 0.85 has been associated with worse survival in patients with nonmetastatic breast cancer.15 We hypothesized that patients who are HIV-positive in Botswana might receive lower RDI that may have an adverse impact on pCR rates and subsequent survival. Therefore, our aim was to assess whether pCR rates were lower for patients who are HIV-positive and received NACT compared with patients who are HIV-negative and whether lower chemotherapy RDI was different between WLWH and patients who are HIV-negative diagnosed with breast cancer. We also evaluated overall survival (OS) and toxicity in patients who were HIV-positive versus HIV-negative receiving NACT as secondary outcomes.Response to neoadjuvant chemotherapy (NACT), as measured by the pathologic complete response (pCR), is a strong predictor of event-free survival (EFS) within specific molecular subtypes.This was a prospective cohort study of patients who are HIV-positive or HIV-negative with newly diagnosed breast cancer, age ≥ 18 years, and with stage I-III disease who initiated NACT at Princess Marina Hospital, the largest cancer care referral center in Botswana. Patients who were pregnant, had previously undergone excisional biopsy, received prior chemotherapy, or unable to consent were excluded. Informed consent was obtained before enrollment. This study was approved by the Institutional Review Boards at the University of Pennsylvania, the Botswana Human Research Development Committee, Ministry of Health, and Princess Marina Hospital.16 which consists of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 once a day, every 21 days for four cycles, followed by paclitaxel 175 mg/m2 once a day, every 21 days for four cycles ; plus trastuzumab 6 mg/kg once a day every 21 days, with a loading dose of 8 mg/kg for patients with human epidermal growth factor receptor 2 (HER2)—positive tumors (AC-TH). Primary prophylaxis with granulocyte colony-stimulating factor is not administered in patients receiving AC-T. If operable, patients are recommended to undergo modified radical mastectomy (approximately 4-6 weeks after the last cycle of chemotherapy) with pathology evaluation of response of surgical specimen. Breast conservation surgery is rarely offered because of lack of surgical expertise and image-guided resources. All pathology assessments were performed using standardized criteria at the Botswana National Health Laboratory. Patients with hormone receptor-positive disease and HER2-positive disease were prescribed endocrine therapy and trastuzumab, respectively.Guidelines for breast cancer NACT treatment in Botswana is aligned with the National Comprehensive Cancer Network harmonized guidelines for enhanced resource countries,17 Toxicities were assessed at each chemotherapy cycle visit, at their surgery appointment, and every three-months follow-up conducted after treatment via phone or at clinic visit to assess vital status until March 2, 2021.Baseline patient and clinical variables collected included demographics, cancer stage, molecular subtype, HIV status, and CD4 count at the initiation of breast cancer therapy and ART for patients who are HIV-positive. Chemotherapy dosing and date, laboratory data, and toxicity were assessed at each cycle visit. Toxicity, including laboratory assessment of complete blood count and creatinine and total bilirubin level, and febrile neutropenia, peripheral neuropathy, and pain were assessed using common toxicity criteria 4.03, the most recent version at the start of the study.14 we used this as a cutoff for suboptimal therapy receipt. We also assessed RDI as a continuous variable and compared means of the RDI stratified by HIV status and treatment. pCR was defined as no residual invasive cancer in the breast and lymph nodes, with noninvasive residual disease in breast allowed,12 and was analyzed overall for the group and by receptor status—classified as triple-negative, HER2-positive, or hormone receptor-positive/HER2-negative. Secondary outcomes were toxicity and OS by HIV status. OS was defined as time from initiation of treatment until death from any cause.Our primary outcomes were RDI and pCR. Since RDI < 0.85 for adjuvant chemotherapy regimens has been associated with inferior disease-free survival and OS in patients with breast cancer,2) or Fisher's exact tests (when expected cell size was < 5) were used to compare proportions of categorical patient baseline, tumor, and treatment characteristics in patients who are HIV-positive and HIV-negative. Student's t-tests were used to compare means of normally distributed continuous variables, and Wilcoxon rank-sum tests were used to compare medians of continuous variables with nonparametric distributions. The OS analyses were performed using the Kaplan‐Meier estimator and limited to stage III patients who were the majority of patients, given the wide variation in breast cancer survival by stage.18 Comparisons of OS between patients who were HIV-positive and HIV-negative were analyzed using log‐rank tests and crude hazard ratios (HRs) and corresponding 95% CIs, computed using Cox proportional hazards regression. Within the population who are HIV-positive, two further subcohorts were created on the basis of whether the ART regimen was zidovudine (ZDV)-containing versus non–ZDV-containing, since ZDV is known to cause myelosuppression.19 RDI analyses were repeated by using the ZDV regimen. Grade ≥ 3 toxicity rates were compared by HIV status and ZDV regimen. Multivariable linear and logistic regressions were used to control for potential confounding variables for RDI and pCR, respectively. Covariates significantly associated with exposure and outcome with P < .2 in the univariable or bivariable analyses were included in the multivariable model. For pCR analysis, hormone receptor status was forced in the model given the known association with pCR in the literature.10 Analyses were carried out in STATA version 16 . P values for pCR analyses were a priori one-sided given the aim to test only if rates were lower for HIV-positive than HIV-negative; all other P values were two-sided.Chi-squared  with HIV in this analysis . As expected, pCR rates by receptor status were highest overall in HER2-positive disease, followed by triple-negative disease and hormone receptor-positive/HER2-negative disease (Table P = .03), but age at diagnosis, hormone receptor status, and BMI were not associated with pCR with P < .2 threshold. In the multivariable analysis, including RDI and hormone receptor status forced into the model, HIV-positive  was not significantly associated with pCR, but RDI < 0.85  was significantly associated with pCR. In the adjusted model, hormone receptor‐positive status was associated with a lower likelihood of pCR, although the association was not significant in our cohort .Of the patients who underwent surgery and had adequate surgical pathology data (n = 86), the pCR rate was significantly lower among patients who are HIV-positive compared with patients who are HIV-negative . Additionally, 78% (7 of 9) of patients on ZDV-containing regimen had RDI < 0.85 compared with 67% (10 of 15) of patients on non–ZDV-containing regimen (P = .669).Patients who are HIV-positive received a significantly lower mean RDI of NACT compared with patients who are HIV-negative  significantly predicted RDI. Being underweight was associated with RDI  and was included in the multiple linear regression model. In the adjusted model, HIV remained significantly associated with RDI .In the simple linear regression model, HIV status ; however, this difference was not statistically significant, and overall, treatment discontinuation was high in both cohorts (Table P = .359): 25% (4 of 16) for the non-ZDV group and 22% (2 of 9) for the ZDV group (P = 1.00). The proportion of patients with any dose reduction during treatment was 21% (18 of 84) for the HIV-negative group, compared with 32% (8 of 26) for the HIV-positive group (P = .184): 31% (5 of 16) for the non-ZDV group and 33% (3 of 9) for the ZDV group (P = .626). The mean duration of a cycle for patients who are HIV-negative was 27 days  and it was 31 days for those who are HIV-positive : 28 days for the non-ZDV group  and 35 days for the ZDV group .Despite lower RDI in patients who are HIV-positive, rates of grade ≥ 3 toxicity were similar in both groups, most commonly because of neutropenia or febrile neutropenia. The summary of other grade ≥ 3 toxicity assessed by Common Terminology Criteria for Adverse Events criteria is provided in Table v 74%, respectively; Fig P = .028) for HIV-positive compared with HIV-negative. A similar trend of worse OS in the patient group who are HIV-positive and have breast cancer was observed for the combined cohort and subset of patients with hormone receptor-positive/HER2-negative disease only.After a median follow-up of approximately 20 months, the estimated 2-year OS for stage III patients was significantly lower in patients who are HIV-positive and have breast cancer compared with patients who are HIV-negative and have breast cancer  patients who are HIV-positive were on endocrine therapy compared with 73% (33 of 45) of patients who are HIV-negative; 1 of 45 (2%) in the HIV-negative group declined endocrine therapy and 1 of 45 (2%) was lost to follow-up. The remaining patients were deceased.Although there is robust literature on survival outcomes in patients who are HIV-positive and have breast cancer, this prospective cohort analysis provides novel evidence showing that patients who are HIV-positive in Botswana received less dose-intense NACT and also have lower pCR rates. These lower pCR rates would be expected to lead to reduced EFS and OS, and we report lower OS for patients who are HIV-positive compared with patients who are HIV-negative.20 Subsequently, most patients who are HIV-positive have CD4 > 250 and are virally suppressed.21This prospective study has several limitations. Because of the small sample size, this study was not powered to detect significant differences in subgroup analyses; therefore, clinically meaningful differences may not be statistically significant. An important limitation is that we could not assess the relationship between RDI and pCR rates within breast cancer subtypes. Patients with hormone receptor-positive disease have lower pCR rates than other subtypes, and we could not assess the attribution of low RDI on that rate specifically. Additionally, approximately 19% (5 of 26) of patients who are HIV-positive were missing receptor status for HER2 compared with 2.4% (2 of 84) in the HIV-negative group. The differential level of missingness of HER2 data has the potential to bias our results away from the null if there were more patients with HER2 disease who did not receive targeted anti-HER2 therapy, which would have improved response. However, within patients with known HER2-positive status, pCR rates were lower for HIV-negative compared with patients living with HIV. We could not determine whether the lower pCR rates led to reduced EFS and subsequent OS. In addition, other treatment factors, including differences in adherence to adjuvant endocrine therapy and adjuvant anti-HER2 therapy, could have contributed to lower OS. However, in the multivariable analysis where hormone receptor-positive status was forced into the model, the magnitude of the association between HIV-positive and pCR was decreased suggesting that hormone receptor status may contribute partially to the lower pCR in our HIV-positive cohort. Our regression analysis within the limitations outlined suggests that RDI may be a contributor to lower pCR rates in the HIV-positive group in our cohort. Finally, among patients who are HIV-positive, CD4 and viral load data were missing for a substantial proportion of the patients. However, current Botswana treatment guidelines for HIV recommend the treat-all strategy, which aims to start anyone with a positive HIV diagnosis on treatment immediately, regardless of the CD4 count level.22Despite these limitations, our study has several strengths. We analyzed detailed surgical pathology data and granular chemotherapy administration data and toxicity grading which informed our analyses. Our study showed lower RDI for patients who are HIV-positive and have breast cancer, especially those on ZDV ART, which is a novel finding and an important consideration for improving outcomes in patients who are HIV-positive receiving cytotoxic chemotherapy. Although ZDV-containing therapy is no longer first-line ART in Botswana, the median duration of ART for our population was 9.8 years, suggesting that at least half of the patients started therapy before updated guidelines which recommend dolutegravir as first-line therapy. Additionally, current guidelines do recommend certain ZDV-based therapies  in the list of second-line therapies to be considered in patients living with HIV who develop specific resistant mutations on first-line therapy.3 Similar studies from SSA have shown lower OS in patients who are HIV-positive and have breast cancer compared with patients who are HIV-negative and have breast cancer.5 Notably, even among patients who are HIV-negative, although the 2-year OS for stage III patients was similar to rates in SSA,23 it was lower than 5-year OS for North American cohorts, which is 75%.24 The difference is likely related to lower rates of optimal therapy delivery, differences in general health care infrastructure between Botswana and North America, differences in disease biology and younger age at presentation. In addition, of note, 83% of our patient population had stage III disease, which is also higher than the proportion of patients with de novo breast cancer in a North American cohort (27% on the basis of 2012-2016 SEER data). This is likely reflective of lack of screening, breast cancer awareness, and early detection programs in Botswana, which is similar to most African countries.27The OS disparity documented in our study is similar to those in large retrospective cohort analysis in the United States of patients who are HIV-positive and have breast cancer with increased all-cause mortality .28 A potential mechanism may be disparities in dose intensity between the two groups, which was significantly associated with pCR in the multivariable analyses. The small sample size and the differences in proportion of missing molecular status data do not allow us to conclusively account for the contributions of molecular status and RDI on pCR. Importantly, we noted that the proportion of patients receiving optimal dose intensity was low in patients who are HIV-positive and HIV-negative, which is concerning and an indicator of suboptimal therapy delivery at baseline for all patients with breast cancer regardless of HIV status. HIV-positive is further associated with even lower dose intensity of therapy represented by a larger proportion of patients receiving low dose intensity therapy and a significantly lower mean RDI. Assessment of RDI in patients with locally advanced diseased in Rwanda showed that 61.9% of those with locally advanced disease receiving NACT had RDI ≥ 0.85,29 compared with 44% in our cohort. These data are robust and important for assessing optimal therapy delivery and explaining disparities in outcomes; however, few countries in SSA have these data because of lack of electronic medical record systems, paper-based record keeping, and other logistical challenges.We confirmed our hypothesis that pCR rates will be lower in patients who are HIV-positive. Nietz et al showed similar findings in a South African cohort with patients who are HIV-positive less likely to achieve pCR .30 The combined effects of higher premature discontinuation, dose reductions, and increased median duration of treatment cycle may contribute to lower RDI in patients living with HIV and in particular patients on ZDV. Since the design of the study, new National Comprehensive Cancer Network guidelines states that ZDV is contraindicated in patients who are HIV-positive initiating cytotoxic chemotherapy because of risk of causing or exacerbating myelosuppression.31We report a significant difference in RDI between patients who are HIV-positive and have breast cancer and patients who are HIV-negative and have breast cancer, which may contribute to lower rates of pCR and worse OS. We hypothesize that this could be partly due to toxicity in patients who are HIV-positive. In fact, although patients who are HIV-positive received significantly less dose intense therapy, toxicity rates were similar between the two groups, which suggests that patients who are HIV-positive were dose reduced in an attempt to prevent greater toxicity, although we do not have data on decision making by the providers to support that. Lower RDI may also be due to intolerance of the complete regimen among patients who are HIV-positive, evidenced by the higher but nonsignificant rate of premature treatment discontinuation in that group. Furthermore, our analysis suggests that differences in RDI may have been due to longer cycle lengths and time to treatment completion among patients who are HIV-positive compared with patients who are HIV-negative, which may also have been related to slower recovery after each cycle by patients who are HIV-positive. Furthermore, patients who are HIV-positive had more cycles with dose reductions compared with patients who are HIV-negative, which may be appropriate but also reflect a provider bias to recommend dose reduction or premature discontinuation of therapy in patients who are HIV-positive and experience toxicity compared with patients who are HIV-negative.In conclusion, patients who are HIV-positive and have breast cancer have lower pCR rates, which may be due in part due to reduced RDI and may subsequently lead to worse OS. The frequency and magnitude of low dose intensity therapy among patients who are HIV-positive and have breast cancer highlight the challenges clinicians face in delivering optimal dose intensity treatment to this population. Although some risk factors are not modifiable, it is critical to examine implementation strategies that can specifically target modifiable risk factors associated with suboptimal therapy delivery for patients who are HIV-positive. Our next steps are to implement strategies for deimplementation of ZDV, whereby it is replaced with a safer alternative ART before initiation of cytotoxic chemotherapy. Additional considerations are the implementation of granulocyte colony-stimulating factor prophylaxis in patients living with HIV initiating AC-T or other cytotoxic chemotherapy regimens with high (≥ 20%) risk of myelosuppression. Our results highlight that these implementation strategies should be performed within a broader context of optimizing care delivery for all patients, including HIV-negative. These will include efforts to decentralize cancer care and increase breast cancer treatment access in Botswana and to improve standardization of chemotherapy administration and delivery of optimal dose intensity.