Introduction: As prospective data on long-term patient-reported outcome measures (PROMs) to assess Health related Quality of Life (HRQoL) after stroke are still scarce, this study examined the long-term course of PROMs and investigated influential factors such as recanalization therapies.Materials and Methods: A total of 945  stroke patients were enrolled with a personal interview and chart review performed at index event. One hundred forty (15%) patients received thrombolysis (IVT) and 53 (5%) patients received endovascular therapy (ET) or both treatments as bridging therapy (BT). After 3 and 12 months, a follow-up was conducted using a postal questionnaire including subjective quality of life EQ-5D-5L . At all time-points, Modified Rankin Scale (mRS) was additionally used to quantify functional stroke severity. Differences between therapy groups were identified using post-hoc-tests. Linear and logistic regression analyses were used to identify predictors of outcomes.Results: Recanalization therapies were associated with significant improvements of NIHSS  and ET/BT 7.6; p = 0.001] and mRS   between admission and discharge compared to patients with stroke unit therapy only, with a trend toward improvement of EQ-5D after 12 months [regression coefficient 4.67 (p = 0.17)] with IVT. HRQoL was considerably impaired by stroke and increased steadily in 3- and 12-months follow-up in patients with (mean EQ-5D from 56 to 68) and without recanalization therapy (mean EQ-5D from 62 to 68). In severe strokes a major and significant improvement was only detected during period of 3 to 12 months .Conclusions: Despite significant and continuous improvements after stroke the HRQoL after 12 months remained below the age-matched general population, but was still unexpectedly high in view of the accumulation of permanent disabilities in up to 30% of the patients. Especially in severe strokes, it is important to evaluate HRQoL beyond a 3-months follow-up as improvements became significant only between 3 months and 1 year. Approximately 15 million people suffer a stroke every year. A high proportion of the cases is fatal, and one-third of stroke patients is affected by a serious, permanent disability . Nearly In the vast majority of stroke-related outcome studies, so-called clinician-reported outcome parameters like the modified Rankin Scale (mRS) quantify the patients' functional status. Although commonly used, this scale does not cover the patient's cognitive and social functions , nor essPatient-reported outcome measures (PROMs) specifically address the patient's view without interpretation by clinicians or anyone else . Health-Intravenous thrombolysis therapy (IVT) and the recent implementation of endovascular thrombectomy (ET) as well as their combination termed “bridging therapy” (BT) led to a significant improvement in the short-term functional outcome of these severely affected subgroups of ischemic strokes with large vessel occlusions of the anterior circulation –14.Yet, prospective data regarding the long-term impact on PROMs are almost entirely lacking in this patient population.Therefore, we focused on the analysis of PROMs and disabilities in the long-term outcome of stroke patients in a large prospective cohort study with and without acute recanalization therapies.2 = 0.3, the inclusion of 997 patients would be sufficient to detect a significant difference with a statistical power of 80% at a significance level of 5%.Every year, ~1,700 patients with acute strokes are treated at the University Hospital Augsburg. It was estimated that about 60–70% of the patients would take part in the study . Thus, wBetween September 2018 and November 2019, all consecutive adult patients (18 years and older) with an incident as well as recurrent ischemic or hemorrhagic stroke, who were admitted to the University Hospital of Augsburg, were screened for enrollment. Proportions of baseline and follow-up assessment are shown in In summary, trained study nurses prospectively recorded all stroke cases and interviewed patients or legal caregivers after written informed consent. In the interview, demographic information, symptoms upon presentation, diagnosis, lifestyle factors and comorbidities  were gathered. Clinical data on comorbidities, risk factors, medication prescribed before hospital stay and at discharge, diagnostic procedures, clinical characteristics, disabilities, laboratory parameters, and treatment regimens during the hospital stay were additionally registered by a chart review.Three and 12 months after hospital discharge, all study participants received postal questionnaires or telephone interviews with questions on disease symptoms, disabilities, physical activity (German-PAQ-50+) , health-During inpatient stay, clinical outcomes were measured using the National Institute of Health Stroke Scale (NIHSS: score range 0–42) and mRS [score range 0  to 6 (deceased)] with higher scores indicating a greater neurological deficit or a higher degree of physical disability , 19. NIHPatient-reported health status was assessed by a visual analog scale (EQ VAS), which evaluates the patient's current overall subjective health from 0  to 100 . EQ-5D was assessed in the subacute stroke phase at the end of inpatient stay.Reliability and validity of the main measures NIHSS , 20, mRSAdditionally, information on care dependency  and use of medical aids  was collected.In the follow-up stage, mRS as a functional outcome and EQ-5D assessing the patients' subjective health status, were both evaluated by a postal questionnaire sent to the patients after 3 and 12 months.2-Tests were performed for categorical variables if each cell contained at least 5 expected values. If this was not the case, a Fisher's exact test was calculated. Continuous variables were tested for normal distribution using Shapiro-Wilk-Test and Q-Q plots. Non-parametric Mann-Whitney-U-Tests for non-normally distributed variables and t-tests for independent samples for normally distributed variables were used to compare patients with and without stroke-specific acute therapy. In a second step, differences between the four treatment groups  were examined using Chi2 or Fisher's exact test for categorical variables and non-parametric Kruskal-Wallis-Tests for continuous variables. If these were significant, treatment groups were compared pairwise using Bonferroni adjusted post-hoc-tests.Baseline characteristics are presented as mean ± standard deviation (SD) for normally distributed or median ± interquartile range (IQR) for non-normally distributed continuous variables and percentage for categorical variables . In a fin = 37; 5%) were excluded from statistical analyses on stroke severity and follow-up as well as in regression analyses.Patients with hemorrhagic stroke , physical activity [with IPAQ ] and the presence of at least one comorbidity. The treatment groups IVT and IAT/BT were compared to patients without acute therapy. All model assumptions were fulfilled.A subgroup analysis including severely affected patients (mRS 3-5) was performed using non-parametric Wilcoxon-Tests to identify relevant changes in patient-reported health between follow-up timepoints.During the study period, 945 consecutive patients were included. Baseline characteristics are shown in In most of the baseline characteristics, there were no significant differences between both patient groups. Still, the following significant difference in stroke etiology and severity was mentionable: In patients with recanalization therapy, cardiogenic causes were significantly more frequent compared to patients with stroke unit therapy only. Patients with stroke-specific acute therapy had significantly higher NIHSS and mRS values at admission and discharge and significantly lower EQ VAS values.p = 0.03, see The influence of stroke-specific acute therapies on clinical and patient-reported outcome measures is shown in A total of 587 (62%) patients took part in the 3-month follow-up and 534 (57%) in the 12-months-follow-up. The response rate of the two groups with and without stroke-specific acute therapy was similar. The results of the follow-up assessments are shown in Looking at EQ VAS change between baseline and 3 months follow-up, the patient's health status increased in both groups, with no significant changes between therapy or stroke unit therapy only. After 12 months, EQ VAS of treated patients was equal to the well-being of patients without recanalization therapy (mean EQ VAS 68 ± 19 in both groups). Altogether, 56% of patients with and 48% of patients without recanalization therapy reported increased overall health between the index event and 12 months on EQ VAS, as visualized in Because of the relatively low average mRS in the entire cohort, we added a subgroup analysis of patients with relevant functional deficits .The results are presented in p = 0.02), NIHSS on admission  and mRS at discharge  reported significantly lower EQ VAS scores after 3 months. After 12 months a history of at least one previous stroke  was associated with significantly worse patient's health. Stroke etiology had no significant effect on the patient's health well-being.Independent from the effect of therapy, patients with higher age  were permanently dependent on care, had a severely disabled pass or were dependent on medical aids such as walking sticks or wheelchairs. After 12 months of recovery from stroke, the numbers remained high, as shown in This is one of the first prospective cohort studies that has analyzed long-term outcomes in stroke patients with focus on HRQoL and effects of acute recanalization stroke therapies. We could show, that HRQoL continuously improved in all patient groups. However, the most pronounced effect occurred between 3 and 12 months after stroke, especially in patients with relevant functional deficits (mRS 3-5). This observation was valid independent from stroke-specific acute therapies.Acute recanalization therapies have a positive effect on functional deficits after stroke , 22. In For interpretation of EQ-5D values in stroke patients, it is necessary to compare these patients to healthy persons at the same age and to patients with comparable diseases. Patients in the present cohort rated their overall health status worse than a representative sample of the age-matched German population [mean EQ VAS = 75 in persons 60–79 years of age ]. IntereAltogether, the present results suggest that a relatively short follow-up time of 3 months - as recommended in a recent meta-analysis  and pracIndividual prognosis is essential for patients in the subacute period after stroke. In our data, younger age and better clinical outcome measures (NIHSS and mRS) positively influenced EQ VAS after 3 months. The chance for a good EQ VAS after 12 months was lower in patients with recurrent strokes. In the current literature, factors such as male sex, white race, social support and active coping strategies have also been identified as positive predictors for better HRQoL, whereas stroke severity and functional impairment were associated with a more unsatisfactory outcome in stroke survivors , 37.As PROMs reflect the patient-immanent strategies to cope with a disease, they do not necessarily correlate with objective outcome parameters such as need for professional care or medical aids. Interestingly, we observed a discrepancy between a high level of subjective health quality despite a significant proportion of our patients being in permanent need of care 12 months after the index event. These limitations based on objective criteria should be scrutinized in future observational outcome studies, as this information is especially relevant from a health care point of view a high economic burden for the health care system , 39. StaAs a result of our study and the current literature, PROMs are a valuable supplement, but no substitute to clinician-reported outcome measures. Despite a considerable proportion of objective impairments, the subjective health perception of stroke patients after 1 year is surprisingly high (mean EQ VAS 68 ± 19) and well above that of other chronic diseases such as cancer [mean EQ VAS 62 ] or hearTo guide individualized care concerning PROMs, clinicians need to know, which patients are at particular risk of long-term impairment of individual HRQoL. So far, we know that certain comorbidities as depression  and otheThe long follow-up period of prospectively analyzed stroke patients with focus on PROMs combined with the detailed information on acute stroke treatment and objective functional limitations represents a major strength of our study.The use of the EQ-5D enables a comparison with other diseases. However, the EQ-5D does not allow a detailed description of specific domains of HRQoL such as social, cognitive and emotional impairments. Thus, the results of this study should be confirmed using a more stroke-specific questionnaire. However, 47% of the consecutive stroke patients could not be included in the study e.g., due to refusal (5%) or inability (16%) to participate and 38% of the baseline assed patients were lost to follow-up. This may produce bias because more severely affected stroke patients may have been more likely to refuse participation. The patients in the different treatment groups are not matched and cannot be compared directly. This aspect was addressed by a subgroup analysis of severely affected patients (mRS 3-5) and by adjustment of confounders in regression models.n = 534) still participated after 12 months. Despite comparable recanalization therapy rates between our cohort and the Bavarian average  was financially supported by the Faculty of Medicine, University of Augsburg, Germany.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


It is important to gain insight into the burden of COVID-19 at city district level to develop targeted prevention strategies. We examined COVID-19 related hospitalisations by city district and migration background in the municipality of Amsterdam, the Netherlands.We used surveillance data on all PCR-confirmed SARS-CoV-2 hospitalisations in Amsterdam until 31 May 2020, matched to municipal registration data on migration background. We calculated directly standardised  rates (DSR) of hospitalisations, as a proxy of COVID-19 burden, per 100,000 population by city district and migration background. We calculated standardised rate differences (RD) and rate ratios (RR) to compare hospitalisations between city districts of varying socio-economic and health status and between migration backgrounds. We evaluated the effects of city district and migration background on hospitalisation after adjusting for age and sex using Poisson regression.Between 29 February and 31 May 2020, 2326 cases (median age 57 years [IQR = 37–74]) were notified in Amsterdam, of which 596 (25.6%) hospitalisations and 287 (12.3%) deaths. 526/596 (88.2%) hospitalisations could be matched to the registration database. DSR were higher in individuals living in peripheral (South-East/New-West/North) city districts with lower economic and health status, compared to central districts (Centre/West/South/East) , and among individuals with a non-Western migration background compared to ethnic-Dutch individuals . City district and migration background were independently associated with hospitalisation.City districts with lower economic and health status and those with a non-Western migration background had the highest burden of COVID-19 during the first wave of COVID-19 in Amsterdam.The online version contains supplementary material available at 10.1186/s12889-021-11782-w. The first cases of coronavirus disease 2019 (COVID-19) were reported at the end of 2019 in Wuhan, China. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing COVID-19, has since rapidly spread across the globe. The World Health Organization (WHO) consequently declared COVID-19 a global epidemic on 11 March 2020. By the end of June 2021, over 180 million cases and almost 4 million COVID-19 related deaths had been reported worldwide [In the Netherlands, COVID-19 was declared a Group A notifiable disease under the Public Health legal act on 28th January 2020  which weThe regional PHS of Amsterdam acts upon notifications of infectious diseases including COVID-19 for the wider Amsterdam-Amstelland area, consisting of 6 municipalities including Amsterdam, with a total regional population of about 1,06 million. Anecdotal reports from hospital staff in April 2020 suggested that a disproportionate number of patients of ethnic minority background had been admitted to hospitals and intensive care units (ICU) in Amsterdam. This echoed reports from the United Kingdom  (UK) andWe therefore aimed to examine differences in burden of COVID-19 hospitalisations between city districts and ethnic groups in the city of Amsterdam, using routinely collected surveillance data from 29 February to 31 May 2020.Up to and including 11th March 2020, SARS-CoV-2 testing in the Netherlands was conducted only in individuals who fulfilled a strict case definition: (i) having an epidemiological link to a confirmed case and/or returning from a high-risk region with widespread transmission within 14 days prior to the onset of symptoms, and (ii) the presence of fever with at least one of the following symptoms: coughing, shortness of breath (dyspnoea). Testing was mainly carried out by a home testing team of the PHS, by general practitioners and in hospitals.After restrictions were initiated between 12 and 15 March 2020, testing no longer required a confirmed epidemiological link or travel history, but instead focussed on mitigating the impact on frontline healthcare services and protecting vulnerable groups. Healthcare workers, residents of long-term care facilities and individuals at high risk of severe disease with COVID-like symptoms were prioritised. For patients, testing was carried out in the hospital setting (including purpose-built COVID-19 triage and testing tents), by family physicians, and by the PHS’s home testing team, who also performed testing in long-term care facilities. Healthcare workers could be tested at a special test location at the PHS site itself or at work  and were prioritised in situations where a staffing shortage was at stake.From 11 May 2020, testing at the PHS site was also made available to teachers and those working in other contact professions with COVID-like symptoms but remained inaccessible for the general public until 1 June 2020. Because of this restrictive test policy during the period analysed, we used hospitalisations as a marker of epidemic progression.Since 28th January 2020, all persons with a positive PCR test for SARS-CoV-2 are required to be notified to the regional PHS, which subsequently notifies the National Institute for Public Health and the Environment (RIVM). In the wider region of Amsterdam-Amstelland, all positive cases are notified to the regional PHS of Amsterdam. For this study, we retrieved secondary data collected between 29 February (date of first confirmed case) and 31 May 2020 from the Amsterdam-Amstelland COVID-19 notification database, the surveillance database by the PHS of Amsterdam on all notified cases, hospitalisations and deaths residing in the municipality of Amsterdam. These data included information on age and sex of the case, and whether the case had worked as a health care worker or was a resident in a long-term care facility. We matched surveillance data to registration data from the municipality records of the City of Amsterdam (BRP) to retrieve postal code and the country of birth of the case and their parents. Since this study made use of routine surveillance data, no human participants were involved. The database is not publicly available.We determined city district based on postal code of current residence . We asseWe evaluated the number of cases, hospitalisations and deaths, overall and over time (notification date and symptom onset). In the epidemiological curve by self-reported date of symptom onset, missing dates were imputed, assuming that all those who were tested had symptoms. First, we created a distribution of time between symptom onset and case notification for those with a known date of symptom onset. Second, we randomly sampled from this distribution to estimate the date of symptom onset if this was missing.We calculated crude and directly standardised rates (DSR) of hospitalisations per 100,000 population, overall and by city district and migration background. Rates were standardised for age  and sex . 95% confidence intervals (CI) were calculated using the gamma method , 18. We We evaluated the individual effects of city district , migration background, sex and age in a Poisson regression model, using the log of the population size per district/background/sex/age stratum as an offset. In this model, we sequentially added interaction terms between migration background and (1) city district, (2) age, and (3) sex which were tested for significance using likelihood ratio tests.P-value< 0·05. We used the dsr package in R [We assumed statistical significance at a age in R  to calcuBetween 29 February 2020 and 31 May 2020, 2326 COVID-19 cases were notified in Amsterdam, of which 596 (25.6%) hospitalisations and 287 (12.3%) deaths. The number of new cases peaked mid-March, shown by date of symptom onset in Fig. RR = 1.82, 95%CI = 1.65–1.99), with 36.87 additional hospitalisations per 100.000 population . The difference between peripheral and central city districts became increasingly apparent over time  could be matched to the registration database, including 526/596 hospitalisations (88.2%) and 235/287 (81.8%) deaths , with 57 additional hospitalisations per 100.000 population . No statistically significant difference was observed between individuals with a Western migration background and ethnic-Dutch individuals. Further stratification by specific large non-Western ethnic groups living in Amsterdam  is presented in Supplementary Table RR = 4.25, 95%CI = 3.31–5.19; RD = 136.75, 95%CI = -29.83–303.33) and Turkish ethnic origin . In our additional age-stratified analysis, we found that individuals < 60 years with a non-Western migration background had a three-fold higher DSR compared to ethnic-Dutch individuals < 60 years , while the DSR was reduced but remained almost two-fold higher in individuals ≥60 years    with a non-Western migration background had three-fold higher hospitalisation rates compared to ethnic-Dutch individuals living central, higher-income city districts .Previous research has demonstrated similar health disparities between city districts in Amsterdam . A quadrIn addition, our analysis demonstrated that individuals with a non-Western migration background, including groups with a Moroccan, Turkish, Surinamese and Ghanaian background, had a higher COVID-19 burden, even when stratifying by city district. This is in line with previous findings from the UK and USA and, more recently, other high-income countries such as Norway . In the Considering our findings substantiate reports of increased COVID-19 burden among ethnic minority groups in other countries, it is concerning that information on ethnicity is often not collected in routine surveillance systems in many countries . This reAn important limitation of our study is that the surveillance data paint an incomplete picture of the first wave of the outbreak, as cases were underreported due to selective testing and data collection was limited. We used the hospitalisation rate per 100,000 population as a marker of outbreak progression, but this limits the distinction that can be made between risk of infection and risk of severe disease requiring hospital admission. In addition, hospitalisations and deaths among already notified cases may also have been underreported, and we were unable to match all notifications to the municipal register. Furthermore, absence of key individual socio-demographic, socio-economic, and clinical characteristics limits the inferences that can be made about causal factors on an individual patient level. For example, we used city district as an imperfect proxy for SES, but SES at the community or individual level within each city district may have been different. By further stratifying groups by migration background and complementing this with qualitative research  more insight can be gained into which community-specific targeted prevention strategies may help minimise the disproportionate distribution of COVID-19 in Amsterdam.Our study is the first in the Netherlands to link surveillance data with registration data on migration background to demonstrate the unequal distribution of the burden of COVID-19 within the city of Amsterdam. We show that substantial differences in COVID-19 hospitalisation rates exist between city districts and ethnic groups in Amsterdam. Our findings corroborate reports from other high-income countries to suggest that public health efforts worldwide must be focussed on mitigating further impact of COVID-19 upon communities at highest risk of both infection and serious disease. Action must be taken to strengthen targeted prevention strategies which address the needs of affected communities.Additional file 1:. Supplementary materials contain Supplementary Figures 1 to 4 and Supplementary Tables 1 to 8.


Despite the significant reduction in pneumococcal disease due to pneumococcal vaccines, protection of vulnerable high-risk individuals, especially pediatric populations, remains a great challenge. In an effort to maximize the protection of high-risk children against pneumococcal disease, a combined schedule that includes both conjugate and polysaccharide vaccines is recommended by several countries in the developed world. On the other hand, middle- and low-income countries do not have in place established policies for pneumococcal immunization of children at risk. Pneumococcal conjugate vaccines, despite their benefits, have several limitations, mainly associated with serotype replacement and the wide range of serotype coverage worldwide. In addition, PPV23-impaired immunogenicity and the hyporesponsiveness effect among populations at risk have been well-documented. Therefore, the added value of continuing to include PPV23 in vaccination schedules for high-risk individuals in the years to come remains to be determined by monitoring whether the replacing/remaining serotypes causing IPD are covered by PPV23 to determine whether its benefits outweigh its limitations. In this review, we aim to describe serotype distribution and vaccine efficacy data on pneumococcal disease in the pre- and post-PCV implementation era among high-risk children in both developed and developing countries, assessing the optimization of current recommendations for their vaccination against pneumococcal disease. Streptococcus pneumoniae (S. pneumoniae) is a leading cause of mucosal diseases  as well as invasive infections  with considerable morbidity and mortality worldwide, comprising a major public health problem [ problem . Young c problem ,3. In ad problem ,5,6. Sim problem ,5. In En problem . Asthma  problem ,9.The number of patients at high risk requiring protection against IPD is persistently increasing owing to increasing numbers of people with underlying medical conditions and the elderly population worldwide. Pneumococcal infection is often more severe in such high-risk individuals than in immunocompetent subjects ,11,12. CCurrently, two types of pneumococcal vaccines, both targeting capsular polysaccharides, are licensed: the 23-valent pneumococcal polysaccharide-based vaccine (PPV23) and the 10- and 13-valent pneumococcal conjugate vaccines  . PPV23 pFollowing routine PCV administration in North America and Europe, a rapid and dramatic decline in vaccine-type (VT) invasive pneumococcal disease (IPD) and nasopharyngeal carriage was recorded not only among vaccinated children (direct effects) but also among unvaccinated children and adults through reduced transmission of vaccine serotypes (indirect effects) ,20. ReduS. pneumoniae. Combined PCV13/PPV23 immunization schedules are expected to combine the establishment of an immunological memory with maximum serotype coverage. Current guidelines from the U.S. Centers for Disease Control and Prevention (CDC) [For more than two decades, PPV23 has been recommended for the protection of immunocompromised individuals and the elderly against pneumococcal disease . Followion (CDC)  and the on (CDC) ,9. Amongon (CDC) ,25,26.The net benefits of pneumococcal vaccination are at least partially offset by several limitations. Both PPV23 and PCVs are serotype-based vaccines and therefore they elicit only serotype-specific protection. Emergence of replacement serotypes has repeatedly occurred after their introduction, even after the use of expanded-valency PCVs, albeit to a lesser extent ,10,11,12Decisions to fund and implement vaccination recommendations in both the developed and the developing world require assessing data on epidemiology in conjunction with vaccine efficacy data in each region. The added value of continuing to include PPV23 in vaccination schedules for high-risk individuals in the years to come remains to be determined by monitoring whether the replacing/remaining serotypes causing IPD are covered by PPV23 to determine whether its benefits outweigh its limitations. In this review, we aim to describe serotype distribution and vaccine efficacy data on pneumococcal disease in the pre- and post-PCV implementation era among the high-risk children in both developed and developing countries, assessing the optimization of current recommendations for the vaccination of the high-risk children against pneumococcal disease. To this aim, an extensive PUBMED literature search was conducted using the terms “pneumococcal vaccines”, “high-risk children”, “immunocompromised children”, “vaccine efficacy”, “vaccine effectiveness”, “polysaccharide conjugate vaccines”, “PCV7”, “PCV10”, “PCV13”, “23-valent vaccine”, “23-valent pneumococcal capsular polysaccharide vaccine”, “Pneumovax 23”, “PPSV23”, “PPV23”, “Pneumo23”, and “pneumococcal polysaccharide vaccine”.Universal childhood pneumococcal vaccination with PCVs+/-PPV23 has significantly reduced the pneumococcal disease burden in high-income countries among individuals at risk, although residual pneumococcal disease remains significantly high among such vulnerable populations due to limited vaccine efficacy or high rates of replacement disease ,48,49,50The net benefits of conjugate vaccines remain significant among high-risk children in high-income countries with substantial reductions in IPD incidence rates; however, a rise in the proportion of PPV23-only and NV-serotypes causing IPD in high-risk individuals occurred following PCV13 implementation in these settings. Thus, the current disease epidemiology, characterized by a significant proportion attributed to PPV23-only serotypes, could justify the use of a combined PCV13/PPV23 immunization schedule for the protection of immunocompromised pediatric populations in the developed world. The rationale behind this schedule is to benefit from the improved opsonophagocytic antibody activity and the immunological memory provided by PCV13 as well as the complimentary broader serotype coverage provided by PPV23. However, vaccine immunogenicity and effectiveness in this population, and PPV23-driven immunological hyporesponsiveness, should be taken into account when drafting or recommending anamnestic PPV23 immunization policies for the “high-risk” .In low- and middle-income countries of Africa, South-East Asia, and Latin America, the incidence of IPD as well as the associated mortality are higher compared with high-income countries. In addition, the pneumococcal epidemiology in these settings is characterized by higher rates of carriage and transmission than in high-income settings ,52,53,54South Africa was one of the first African countries to introduce PCV7 immunization in 2009 and transitioned to PCV13 in mid-2011. The incidence of IPD decreased substantially following PCV implementation among vaccinated young children, but also in non-vaccinated adults through herd protection . HoweverS. pneumoniae, which is an important precursor of pneumococcal disease, remains extremely common among children in many developing countries, such as India [Nasopharyngeal carriage of as India , Vietnamas India , Ethiopias India , even wias India . In Soutas India . In Ghanas India .The pneumococcal disease serotype epidemiology among high-risk children is summarized in PCVs have been universally used for pediatric populations since 2000 and their significant effectiveness among healthy children in high-income settings has been well documented. Early PCV7 studies had demonstrated 96% vaccine effectiveness against IPD among healthy children , while tData on PCV effectiveness among high-risk individuals in high-income countries are limited. Thus, the recommendation of PCVs for the protection of individuals at increased risk for pneumococcal infection has been made based upon immunogenicity studies that showed non-inferiority to the previously recommended PPV23 . An obseAmong healthy children in middle- and low-income countries, the introduction of PCV resulted in a significant reduction in deaths due to pneumococcal disease. Remarkably, Rwanda, Peru, and El Salvador, with the highest pneumococcal mortality rates in the pre-PCV era, had the greatest relative reductions ranging from 89% to 93% . A 7-yeaData on PCV effectiveness among high-risk children in developing counties are even more scarce. Nevertheless, there are some effectiveness and efficacy studies that collectively demonstrate that the PCV effectiveness for the prevention of IPD is higher than that of PPV23 in immunocompromised children, although inferior to that in the healthy aged-matched population ,71,83,84Thus, early surveillance data from low-income countries that have already incorporated PCV vaccination show indeed a high degree of vaccine effectiveness with a significant public health benefit through direct and herd protection . The benPPV23’s effectiveness against IPD among high-risk individuals remains debatable despite its extensive use for over 25 years. A number of randomized controlled trials and observational studies ,87,88, aThis is a time of change for pneumococcal vaccination policies in both the developed and the developing world. In Europe, there is a continuing effort to implement infant schedules with a reduced number of doses in order to minimize public expenses and facilitate the funding of other important vaccines . On the In the developed world, disease epidemiology and vaccine efficacy data support the recommendation of a combined PCV13/PPV23 immunization schedule for immunocompromised individuals . PCV13/PIn the low-income regions, the success of the early years of PCV implementation should be enhanced by maximizing coverage rates among infants. Regarding the use of PPV23 for the protection of high-risk individuals in low-income countries, there is currently no clear evidence of emerging PPV23-only serotype IPD in these settings, implying that the potential benefits of PPV23 implementation may not offset its limitations . As for HIV-infected individuals in developing countries, the WHO has concluded that currently available evidence does not support the routine use of PPV23 in HIV-infected patients and focus should be placed on the early HAART initiation  in orderAs in most low-income countries, high-risk older children and adults are not universally immunized with PCVs, so their protection largely depends upon the establishment of strong herd protection through the infant vaccination schedules. Therefore, the optimization of infant schedules in order to maximize the conferred herd protection is highly important. Recent data show that the lack of anamnestic immunization in the three-dose schedule has a significant effect on both direct and indirect vaccine protection. More specifically, the 3 + 0 PCV13 schedule implemented in Australia  resultedTherefore, a combined PCV/PPV23 schedule may be justified for use among high-risk individuals in developed countries. In these combined schedules, where recommended, PCV administration should precede PPV23 administration, in order for the PCV to establish immunological memory for the serotypes it includes and for PPV23 to induce antibody responses to the additional serotypes . HoweverOn the other hand, in the developing world emphasis should be placed on better compliance with PCV vaccination schedules. Nevertheless, all currently available immunization strategies for high-risk individuals have limitations due to reduced vaccine efficacy and the unique epidemiology of pneumococcal disease among patients at risk.To expand serotype coverage, a 20-valent PCV (PCV20) containing PCV13 components and seven additional serotypes  has been recently developed and already approved for use among adults > 18 years of age. These serotypes were selected due to their association with increased disease severity, invasive potential, antibiotic resistance, and increased prevalence as a cause of pediatric pneumococcal disease worldwide in the post-PCV era . SurveilIn the developed world, a combined PCV/PPV23 schedule may be justified for use among high-risk pediatric populations based on serotype-epidemiology. However, reassessment of the intervals between vaccinations is an important priority to maximize the potential of the immune response to future vaccination in terms of magnitude and longevity.In the developing world, special focus should be given on better compliance with PCV vaccination schedules. In these settings with higher prevalence of coexisting morbidities, such as human immunodeficiency virus (HIV) infection and sickle cell disease that predispose to IPD, current serotype epidemiology does not justify PPV23 administration, as its limitations will most likely outweigh its benefits.


Background: A range of neuropsychiatric diagnoses have been reported in association with coronavirus disease 2019 (COVID-19). However, only sporadic cases of mania or hypomania have been reported in patients with COVID-19. This study aimed to report clinical characteristics of 15 consecutive cases of COVID-19-associated mania or hypomania seen in three general hospitals in Qatar in the early months of the pandemic in 2020.Methods: This study is a retrospective case-note review of 15 cases of COVID-19-associated mania or hypomania (confirmed by polymerase chain reaction test), seen as inpatient consultations out of the first 100 consecutive patients managed by consultation-liaison psychiatric teams in Qatar between 2 March 2020 and 7 July 2020.Results: The mean age of the 15 patients was 40 years. Twelve patients had mania, and three had hypomania. Regarding the physical severity of COVID-19, 10 patients were asymptomatic, two had upper respiratory tract symptoms alone and three had pneumonia. None of the patients were intubated. Potential risk factors for mania/hypomania included pandemic-related psychosocial stress before admission (n = 9), past history of mania/bipolar disorder (n = 6) or psychosis (n = 2), raised inflammatory markers (n = 7) and steroid use (n = 3). None had a history of recent substance misuse. Other than one patient with advanced cancer, none had comorbidity regarded as likely to have caused mania or hypomania. Three patients had mild white matter ischaemic changes on brain imaging. Standard pharmacological treatment for mania (i.e. antipsychotic medication supplemented by prn benzodiazepines) was effective. Ten patients were discharged home from the COVID-19 facility where they presented, but five required transfer to Qatar's psychiatric hospital for further treatment of mania.Conclusion: The association of mania or hypomania with COVID-19 may be spurious  or causal. The reported cases illustrate a range of potential aetiological mechanisms by which COVID-19 could cause mania or hypomania. Cohort studies are necessary to determine the incidence, aetiology and prognosis of COVID-19-associated mania/hypomania. A health-record cohort study that investigated the incidence of neurological and psychiatric diagnoses of over 81 million patients, primarily across the USA found that nearly one-third of patients with COVID-19 received a neuropsychiatric diagnosis within 6 months of infection. These included intracranial haemorrhage, ischaemic stroke, encephalitis, dementia, psychosis, mood disorders, anxiety disorders, substance use disorder and insomnia. Although this study reported pooled incidence of all disorders and most individual disorders, which was higher than the control health conditions, it did not analyse cases of mania alone.Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 primarily affects the respiratory system, but multiple organs and systems can be involved, and increasing attention has focused on the psychiatric effects. This could represent a spurious association, or alternatively, mania could be caused by COVID-19 through psychosocial and/or organic mechanisms. As per the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), the patient must present with persistently elevated, expansive or irritable mood for at least 1 week or 4 consecutive days along with  ≥ 3 associated symptoms to qualify for the diagnosis of mania and hypomania, respectively. The associated symptoms include inflated self-esteem or grandiosity, decreased need for sleep, increased talkativeness, racing thoughts, distractibility, increased goal-directed activity or psychomotor agitation and engaging in risky activities. The International Classification of Diseases, 10th revision (ICD-10) similarly describes mania and hypomania as characterised by a persistent or mild elevation of mood with other associated symptoms leading to severe or mild disruption of work or social life, respectively. Mania can present with delusions  or hallucinations. DSM-5 and ICD-10 allow the diagnosis of a manic episode caused by a medical disorder and medication or substance use. Medical disorders have been reported to cause mania, including thyroid abnormalities, various neurological conditions, and systemic inflammatory disorders among several others. Medications associated with mania include corticosteroids and sympathomimetics.A few case reports have reported mania or hypomania in association with COVID-19. Herein, 15 consecutive cases of mania and hypomania associated with COVID-19 encountered in three general hospitals in Qatar from 2 March 2020 to 7 July 2020 are reported. During this period, Qatar recorded 100,936 confirmed COVID-19 cases.Qatar is a peninsula in the Arabian Gulf, with a population of approximately 2.9 million, of which approximately 75% were men, and foreign nationals in Qatar make up more than 85% of the population.Qatar operates a publicly funded healthcare system. All residents, irrespective of nationality, are entitled to free or highly subsidised healthcare, including inpatient treatment. Consultation-liaison (CL) psychiatry services have been operating across all major hospitals, including the country's main COVID-19-designated hospital. All psychiatric assessments within the CL service are conducted by consultant psychiatrists or psychiatry fellows under the supervision of a consultant psychiatrist. including the data extraction details from the clinical records. The inclusion criteria were patients aged  ≥ 18 years who had a positive antigen test  during the index hospitalisation. From each clinical record, patients’ sociodemographic and clinical data were retrieved using a standardised data abstraction form. Data were abstracted for the whole hospitalisation; in some cases, the CL team conducted several assessments during this period. Two research team members (Y.I. and S.A.) extracted the data with regular discussions to ensure consistency in data recording. Rating uncertainties were resolved by discussion with a third team member. Diagnoses reflected the psychiatric diagnosis made at discharge after the index admission . Diagnoses reflected clinical judgement and were not operationally defined. In this study, clinical details of all cases of mania and hypomania seen within an extended cohort of 100 patients were reported. Patients with mania and hypomania were referred to the CL team from 2 March to 7 July 2020. A diagnosis of mania, rather than hypomania, required the presence of psychotic symptoms and/or marked behavioural disturbance or functional impairment due to manic symptoms.The CL services conducted a retrospective case-note review of the first 100 consecutive referrals of patients who tested positive for SARS-CoV-2 since the start of the pandemic to offer a good representation of patients with various psychiatric presentations in this setting. The clinical characteristics of the first 50 of such referrals have been reported,The study was approved by the Hamad Medical Corporation Institutional Review Board (MRC-05–072).The consecutive series of 100 patients with COVID-19 included 15 cases of mania and hypomania. Steroids were prescribed to three patients. One patient had a pre-existing neuropsychiatric condition (well-controlled epilepsy). Only one patient had an organic disorder, other than COVID-19, that was regarded as a possible aetiological factor for the hypomanic or manic episode; this was a patient with brain metastases (primary lung cancer) and an existing diagnosis of bipolar disorder. The metastasis and/or recent cancer treatment might have been partly responsible for his manic relapse.All patients responded well to standard treatment for mania or hypomania. Upon discharge from COVID-19-designated hospitals, five patients were transferred to Doha's psychiatry hospital for the treatment of on-going manic symptoms, whilst the remaining 10 were discharged from the COVID-19-designated facilities to their homes.Follow-up data of up to 6 months was available for 11 patients; six remained psychiatrically well, three experienced a manic relapse requiring hospitalisation and one had a depressive episode treated as an outpatient. Two of the four patients who relapsed had an existing psychiatric diagnosis before the index admission, with one of them having a bipolar diagnosis.14• Psychosocial stress related to the pandemic, most commonly social isolation and financial difficulties, was documented in nine cases. Life events are recognised to precede mania, though it is difficult to determine whether life events are a cause or effect of mood symptoms. and COVID-19 is associated with an inflammatory state. Exactly how inflammation may cause mania is unclear, but potential mechanisms include disruption of the blood–brain barrier, glial cells and neuro-endocrine and neurotransmitter systems.• Raised peripheral inflammatory markers were reported in seven cases. Pro-inflammatory cytokines are elevated during mania,• A past history of bipolar affective disorder was present in six cases, of which there was evidence of poor medication adherence in three cases. There was insufficient information to know whether non-adherence reflected the pandemic causing disruption of these patients’ psychiatric care or medication supply. and have been implicated in some reports of COVID-19-associated mania.• Steroids were prescribed to three patients. Steroids can cause maniaThree patients had mild white matter ischaemic changes. This may be a coincidental finding that predated COVID-19. Alternatively, the lesions could be due to COVID-19, with possible mechanisms including hypoxia, inflammation and a hypercoagulable state. Inflammation appears the most plausible in our cases. SARS-CoV-2 may also cause neuropsychiatric disorders by a direct neurotropic effect. Cerebrospinal fluid analysis was not performed in our cases, making it impossible to comment further on this.To the best of our knowledge, this is the largest case series of mania and hypomania associated with COVID-19. The coexistence of mania or hypomania and COVID-19 makes it reasonable to consider COVID-19 as a potential aetiological factor. However, this cannot be proved, and the association may be coincidental. A cohort study of patients with acute COVID-19, compared with a control acute medical event, would be necessary to investigate causality. Nevertheless, our case series builds up on the existing literature by suggesting some potential mechanisms by which COVID-19 infection, and the pandemic more broadly, could be a risk factor for mania or hypomania:Sleep disturbance was the most common psychiatric symptom documented in our case series. This could be a symptom of mania or hypomania, a direct effect of COVID-19 illness and/or hospitalisation. Insomnia can trigger mania and hypomania. No other patients in our series had symptoms suggestive of delirium.In our series, one patient had concurrent delirium and mania. Manic delirium is a controversial diagnosis, but it is well documented in the literature. Improvement in the manic or hypomanic illness was documented in all cases upon hospital discharge.Treatment of several cases was challenging, as a disinhibited behaviour can disrupt infection control measures. The pharmacological treatment used was consistent with evidence-based mania guidelines and consisted of an antipsychotic with benzodiazepines to provide additional control of disturbed behaviour.One of the challenges of the CL team was a diverse ethnic population speaking different languages. Where possible, members of the CL team who spoke the patients’ native language were allocated to conduct assessments.Our case series is limited to patients with mania and hypomania during an index admission for COVID-19 at a COVID-19 facility or general hospital referred to the CL team. Given the behavioural disturbance associated with mania, it is reasonable to assume that all manic cases were referred. However, some hypomanic cases may have gone unreferred. This study also excluded manic and hypomanic cases that occurred soon after recovery from acute COVID-19; as these patients are not infectious, they would be assessed or treated at the main psychiatric hospital and not admitted to a COVID-19 facility or general hospital with subsequent referral to the CL team. Furthermore, as this was a retrospective case series, there may possibly be some elements of missing data; thus, further information about the socioeconomic status, education level and level of family support might have strengthened the paper.Mania or hypomania with COVID-19 may represent a spurious  or causal association. In this study, psychosocial stress, increased levels of inflammatory markers and past history of bipolar affective disorder were potential risk factors for mania or hypomania. Sleep disturbance was the most common symptom. Outcomes of COVID-19-associated mania and hypomania were favourable with standard pharmacological treatment. CL psychiatry services play an important role in undertaking comprehensive assessment, establishing diagnoses and collaborative work with the medical team in offering on-going holistic care whilst following strict infection control measures. CL services also assist with providing psychoeducation to patients and offering support and reassurance regarding COVID-19. Cohort studies, with larger sample sizes, are necessary to determine the incidence, aetiology and longer-term prognosis of COVID-19-associated mania and hypomania.The study was approved by the Institutional Review Board of Hamad Medical Corporation (MRC-05–072).Not applicableThe data that support the findings of this study are available from the corresponding author upon reasonable request and pending additional ethical approval.PMH reports personal fees from Janssen, Lundbeck, Otsuka, NewBridge Pharmaceuticals and Sunovion, outside the submitted work.This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.All authors contributed to the design of the study, interpretation of the data and drafting and revising the manuscript. M.A., Y.I. and P.M.H. conceptualised the study. Y.I. and S.A. collected and analysed the data. P.M.H. and Y.I. conducted data analysis.None


How is the COVID-19 pandemic associated with risks and benefits of standard cancer therapy?In this comparative effectiveness study reanalyzing data from 8 randomized trials across oncology, radiation fractionation was not associated with outcomes in low COVID-19–risk scenarios. In higher-risk scenarios, aggressive hypofractionation was associated with a survival benefit, whereas moderate hypofractionation was not.These findings suggest that the expected benefit of altering radiation therapy during the COVID-19 pandemic is associated with local pandemic factors and the specifics of treatment modification, and can be estimated using a quantitative framework based on completed randomized trials to support treatment decision-making. This comparative effectiveness study investigates how the COVID-19 pandemic is associated with the benefits and risks of standard radiation therapy in simulated patients. During the COVID-19 pandemic, cancer therapy may put patients at risk of SARS-CoV-2 infection and mortality. The impacts of proposed alternatives on reducing infection risk are unknown.To investigate how the COVID-19 pandemic is associated with the risks and benefits of standard radiation therapy (RT).This comparative effectiveness study used estimated individual patient–level data extracted from published Kaplan-Meier survival figures from 8 randomized clinical trials across oncology from 1993 to 2014 that evaluated the inclusion of RT or compared different RT fractionation regimens. Included trials were Dutch TME and TROG 01.04 examining rectal cancer; CALGB 9343, OCOG hypofractionation trial, FAST-Forward, and NSABP B-39 examining early stage breast cancer, and CHHiP and HYPO-RT-PC examining prostate cancer. Risk of SARS-CoV-2 infection and mortality associated with receipt of RT in the treatment arms were simulated and trials were reanalyzed. Data were analyzed between April 1, 2020, and June 30, 2020.COVID-19 risk associated with treatment was simulated across different pandemic scenarios, varying infection risk per fractions (IRFs) and case fatality rates (CFRs).Overall survival was evaluated using Cox proportional hazards modeling under different pandemic scenarios.Estimated IPLD from a total of 14 170 patients were included in the simulations. In scenarios with low COVID-19-associated risks , fractionation was not significantly associated with outcomes. In locally advanced rectal cancer, short-course RT was associated with better outcomes than long-course chemoradiation (TROG 01.04) and was associated with similar outcomes as RT omission (Dutch TME) in most settings . Moderate hypofractionation in early stage breast cancer  and prostate cancer (CHHiP) was not associated with survival benefits in the setting of COVID-19 . More aggressive hypofractionation  and accelerated partial breast irradiation (NSABP B-39) were associated with improved survival in higher risk scenarios .In this comparative effectiveness study of data from 8 clinical trials of patients receiving radiation therapy to simulate COVID-19 risk and mortality rates, treatment modification was not associated with altered risk from COVID-19 in lower-risk scenarios and was only associated with decreased mortality in very high COVID-19–risk scenarios. This model, which can be adapted to dynamic changes in COVID-19 risk, provides a flexible, quantitative approach to assess the potential impact of treatment modifications and supports the continued delivery of standard evidence-based care with appropriate precautions against COVID-19. To mitigate these risks, multiple groups have published treatment guidelines advocating shorter treatment courses or omission of treatments with risk of immunosuppression.5 Randomized clinical trials (RCTs) that evaluated these treatment regimens were performed in non-pandemic settings. The extent to which these alternative courses should be reconsidered in a pandemic setting is unclear. There is an urgent need to integrate COVID-19–associated risks with existing evidence to understand the tradeoff of risks associated with cancer therapy in the COVID-19 era.Cancer care remains essential during the COVID-19 pandemic but requires repeated contact with the health care system. People with cancer are at particularly high risk for COVID-19.6 This quantitative framework could help guide treatment decision-making and allow for characterization of infection risk associated with treatment. We applied this framework to several trials that have helped define the current standard of care in rectal, breast, and prostate cancer.In this comparative effectiveness study, we developed a simulation-based model to reanalyze published RCTs with incorporation of the risk of COVID-19 infection associated with receipt of radiation therapy.ISPOR) reporting guideline.This comparative effectiveness study used publicly available data from publications by using image analysis to reconstruct and estimate survival data from published figures. An estimated dataset of patient survival was generated based on a mathematical algorithm and did not use patient clinical trial data requiring informed consent. Given the methods, the project was determined to be exempt from review and informed consent by the Mass General Brigham institutional review board, as it did not meet criteria for human participant research. This study is reported in accordance with recommendations by the International Society for Pharmacoeconomics and Outcomes Research (7 and the Trans-Tasman Radiation Oncology Group (TROG) 01.04 trial (2001-2006) in rectal cancer8; the Cancer and Leukemia Group B (CALGB) 9343 trial (1994-1999),9 Ontario Clinical Oncology Group (OCOG) hypofractionation trial (NCT00156052) (1993-1996),10 UK FAST-Forward trial (ISRCTN19906132) (2011-2014),11 and the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-39 (NCT00103181) trial (2005-2013)12 in early stage breast cancer; and the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy in Prostate Cancer (CHHiP)  trial (2002-2011)13 and the Ultra-Hypofractionated vs Conventionally Fractionated Radiotherapy for Prostate Cancer (HYPO-RT-PC) (ISRCTN45905321) trial (2005-2015)14 in localized prostate cancer. Estimated individual patient–level data were extracted from published Kaplan-Meier survival curves as previously described.17 Outcome measures (hazard ratios [HRs] and OS estimates) and Kaplan-Meier figures from reconstructed data sets were compared with original publications for quality assurance  with at-risk tables and to report total numbers of death events. We included the Dutch TME trial (1996-1999)18 Two parameters were used to simulate mortality due to COVID-19: (1) the risk of SARS-CoV-2 infection per fraction of radiation received  and (2) the risk of death of COVID-19 for patients who are infected . IRF was assumed to be a constant, per-fraction risk, independent of prior fractions. Our model did not incorporate other possible infection risks  except for risk per radiation fraction.We simulated risk of SARS-CoV-2 infection using a binomial transmission model based on prior work.n). For the accelerated partial breast irradiation (APBI) arm in NSABP B-39, we conservatively simulated 10 fractions.12 We then simulated the number of deaths (dN) caused by COVID-19 using a binomial distribution with parameters n and death rate P = CFR, and selected dN individuals randomly from the pool of patients who were infected. These dN individuals had their survival time adjusted as follows: we assumed an approximately 4-week period between diagnosis and start of radiation and added the number of fractions on treatment until infection (based on the aforementioned simulations). We added a 5-day incubation period, and simulated time from symptom onset to death as a γ random variable with mean 18 days, based on published estimates.20 The risk of COVID-19–related death (simulated components) and the risk of non–COVID-19–related death  were distinct competing risks, and the occurrence of 1 of these 2 events became the censoring time point of the other.For each patient, we simulated the radiation fraction at which that patient was infected with a geometric random variable, with IRF representing the failure probability for each fraction. Patients for whom this value was less than the total number of fractions they received were considered to have been infected by SARS-CoV-2 during treatment . Data were analyzed from April 1, 2020, to June 30, 2020.Estimated individual patient-level data from 8 selected randomized clinical trials comprising 14 170 patients with breast, prostate or rectal cancer were analyzed.7 compared preoperative RT of 25 Gy in 5 fractions followed by total mesorectal excision (RT+TME) vs TME alone, and demonstrated a reduction in local recurrence rates of more than 50% with RT, without a difference in OS. In our reconstructed data set, prior to simulation of COVID-19 deaths, we obtained an HR of 0.99  for OS, very close to the published trial. We reanalyzed the Dutch TME trial with simulation of COVID-19 risk under different pandemic scenarios . The CHHiP trial demonstrated noninferiority of 20 fractions vs 37 fractions in treatment of localized, primarily low- and intermediate-risk, prostate cancer.13 The trial included a 19-fraction arm that did not reach noninferiority, and we did not include it in our analysis. In simulations with varying COVID-19 risk, the 20-fraction regimen was not associated with changes in HR for OS  at baseline to a median HR of 0.99  in the lowest-risk scenario (scenario A) in favor of the hypofractionated arm  and the resulting risk of death from infection (CFR). While we specifically examined 3 possible risk scenarios for illustration, the model can be extended to varying scenarios. To our knowledge, our study is the first to attempt to quantify these risks in a model incorporating RCT data and varying COVID-19 risk. With such a design, we are able to appreciate the differential benefits of radiation hypofractionation in different settings.4 While expert opinions and consensus guidelines are valuable, real-time clinical decisions can also be aided by quantitative tools that can provide estimates of outcomes based on varying risk, tailored to a specific setting and patient. Such quantitative models can facilitate an adaptive approach to weigh risks and benefits of treatment regimens relative to the dynamic risk of COVID-19, and serve an important complementary role to expert-derived guidelines.The COVID-19 pandemic has created unprecedented challenges in delivery of cancer therapy. Oncologists face a difficult risk-benefit calculus in weighing risk of infection against risk of cancer progression. To help provide guidance to clinicians, several groups have released guidelines on cancer therapy in the COVID-19 era.29 the lower-risk scenario may be applicable to most clinical settings. Thus, our results support the continuation of necessary clinical care for patients receiving cancer care in these settings, despite a general trend during COVID-19 toward deescalating or postponing care and a sharp decline in cancer screening.30 These findings are supported by an initial study by Xie et al31 on RT delivery during the COVID-19 pandemic that reported a very low infection rate of 0.5% but in which more than 50% of patients experienced disruption of RT.In a setting with lower risks, there were minimal changes to treatment effect estimates. As risk mitigation strategies have been implemented,32 In higher-risk scenarios, more abbreviated courses with 5-fraction RT or APBI were associated with better survival outcomes. Furthermore, in scenarios in which treatment may be omitted, such as in patients older than 70 years with T1N0 estrogen receptor–positive breast cancer, our results support omission of treatment and the associated exposure risk.In higher risk settings, the use of hypofractionated RT courses was associated with decreased COVID-19 mortality risk, and the degree of hypofractionation was associated with magnitude of benefit. Breast and prostate cancer trials provide illustrative examples. Even in higher-risk pandemic scenarios, moderate hypofractionation in breast cancer was not associated with improvement in survival, likely since the small relative reduction in number of fractions was not sufficient to substantially affect survival. Regardless, moderate hypofractionation represents the appropriate standard of care vs conventional fractionation for eligible patients.34 While delaying RT may be reasonable, clinicians must weigh the uncertainty of evolving COVID-19 risks, as short-term delays may not be beneficial if local COVID-19 risks persist.We observed a similar pattern in localized prostate cancer, in which moderate hypofractionation was not associated with a survival advantage in the CHHiP trial, but more aggressive hypofractionation in the HYPO-RT-PC trial was associated with a benefit in higher-risk scenarios. While shorter regimens should be considered, concerns remain about the potential long-term toxic effects of ultra-hypofractionated regimens. Delay of treatment with use of androgen deprivation therapy is another consideration and is supported by RCT data in some settings.35 In our reanalysis of the Dutch TME trial, the addition of short-course preoperative RT was not associated with a substantial change in survival in all but the highest-risk scenarios. Our findings thus support continued use of RT in most pandemic settings, given the known benefits with 50% reduction in local recurrence and an overall survival benefit for patients with stage III disease on subgroup analysis.7In rectal cancer, some published expert guidelines have recommended omission of preoperative RT in patients with cT3a/b and cN1-2 disease in the setting of COVID-19.37 In addition, infection risk from community spread, independent of health care system contact, would be a competing risk for survival outcomes. We did not examine the strategy of delaying patients, which is difficult to study given the paucity of RCTs evaluating treatment delay. We focused on survival outcomes, but there are other clinical end points, such as quality of life and local control, that are also relevant. Our analyses were based on reconstructed data, which are thought to be representative of published data but do not allow for incorporation of other covariates and risk factors for COVID-19, such as comorbidities, race/ethnicity, and body mass index.Our study has several limitations. We did not model infection risks associated with other treatment modalities, such as surgery, chemotherapy, or immunotherapy. Our model could be extended to analyze these modalities by similarly incorporating infection and mortality risk associated with surgical or chemotherapy encounters into published RCTs. Further data on the association of specific therapies with COVID-19–related risks would allow for better modeling of these risks.In this comparative effectiveness study, we developed a quantitative approach for assessing COVID-19–associated risk using RCTs. Our results suggest minimal mortality risk with standard treatment regimens when infection control measures can keep daily infection risk at or below 0.5% and support the delivery of standard evidence-based cancer care in most settings when appropriate precautions are taken. We demonstrate that the benefits of treatment modification vary based on the local pandemic scenario and degree of treatment shortening. Our model provides a framework to help guide clinical decision-making for cancer patients during the COVID-19 pandemic.


Outcome measures were clinician-assessed and self-reported PTSD symptoms. Predictors were identified in the exposure therapies (PE and iPE) and STAIR+PE separately using random forests and subsequent bootstrap procedures. Next, these predictors were used to calculate PAI and to retrospectively determine optimal and suboptimal treatment in a leave-one-out cross-validation approach. Results: More depressive symptoms, less social support, more axis-1 diagnoses, and higher severity of childhood sexual abuse were predictors of worse treatment outcomes in PE and iPE. More emotion regulation difficulties, lower general health status, and higher baseline PTSD symptoms were predictors of worse treatment outcomes in STAIR+PE. Randomization to optimal treatment based on these predictors resulted in more improvement than suboptimal treatment in clinician assessed (Cohens’ d = 0.55) and self-reported PTSD symptoms (Cohens’ d = 0.47). Conclusion: Personalization based on PAI is a promising tool to improve therapy outcomes in patients with CA-PTSD. Further studies are needed to replicate findings in prospective studies.Background: Differences in effectiveness among treatments for posttraumatic stress disorder (PTSD) are typically small. Given the variation between patients in treatment response, personalization offers a new way to improve treatment outcomes. The aim of this study was to identify predictors of psychotherapy outcome in PTSD and to combine these into a personalized advantage index (PAI). Methods: We used data from a recent randomized controlled trial comparing prolonged exposure (PE;  After exposure to a traumatic event such as sexual or physical violence, some people develop posttraumatic stress disorder PTSD . These pDespite the well-established effectiveness of psychotherapy for PTSD such as TF-CBT , meta-anTreatment personalization of PTSD has received little attention, compared to other fields . There have been three studies that investigated treatment personalization in patients with PTSD. Two studies used a personalized advantage index (PAI), which indicates a relative preference for one treatment, compared to another, based on a combination of predictors or moderators of treatment outcomes ,24. BothTo summarize, personalization offers a promising approach for PTSD treatment, but so far, no study evaluated its relevance for treatment recommendations using PTSD symptoms as the outcome, while this is the primary focus of treatment. Furthermore, most studies only assessed a limited number of potential predictors, which does not capture the heterogeneous symptom representation of patients with PTSD. In the current study, we aimed to develop and evaluate treatment personalization in patients with CA-PTSD using PAI based on a broad range of patient characteristics including both self-reported and clinician assessed characteristics. We used a sample of 149 patients randomized to an exposure-only condition (PE and intensified PE (iPE)) or STAIR+PE. We measured patients repeatedly during treatment and therefore calculated their treatment outcome using all available measurements .Our first aim was to identify which patient characteristics were predictors of treatment outcome in the exposure-only conditions (PE and iPE) and STAIR+PE separately. Our second aim was to calculate the PAI based on these predictors and evaluate retrospectively whether optimal treatment according to the PAI resulted in better treatment outcomes, compared to suboptimal treatment.n = 48), intensified PE (n = 51) or STAIR+PE (n = 50).This study used the data of a randomized controlled trial investigating three psychotherapies of CA-PTSD ,27. A tohttps://clinicaltrials.gov/ct2/show/NCT03194113, accessed on 26 February 2021.Inclusion criteria of the original study sample included: age between 18 and 65 years; PTSD diagnosis according to the DSM-5 established with the clinician-administered PTSD scale for DSM-5 (CAPS-5)  at leastWritten informed consent was obtained from all participants before the baseline assessment when patients received all relevant information and decided to participate. Patients were randomized in a 1:1:1 ratio to PE, iPE, and STAIR+PE. Predictors were assessed during the baseline assessment (T0). PTSD symptoms were assessed at baseline (T0), after four weeks (T1), eight weeks (T2), and posttreatment after 16 weeks (T3). Clinical interviews were carried out by independent interviewers who were blind to the treatment condition of patients. The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008.PE included 16 weekly sessions of 90 min and consisted of a combination of imaginal exposure and exposure in vivo . iPE incPTSD symptom severity measured with the CAPS-5  was the Self-reported PTSD symptom severity measured with the PTSD checklist for DSM-5 PCL-5  was the Patients’ expectancies of the treatments were indicated by two predictors: total score of the expectancy of burden (Cronbach’s α current study = 0.91) and credibility questionnaire (Cronbach’s α current study = 0.90), as used in previous studies e.g., . See TabDemographic predictors included age, gender, cultural background education, and employment.Social support was indicated by the total score of the social support survey from the Medical Outcome Study.   We included four subscale scores of the Childhood Trauma Questionnaire (CTQ)  as indicGeneral health status was measured with the visual analog scale of the EuroQoL 5 Dimensions 5 Levels (EQ-5D-5L) ,36.Depressive symptoms were indicated by the Beck’s Depression Inventory  . PosttraMeeting criteria for at least one personality disorder was assessed with the Clinical Interview for DSM-IV Personality Disorders (SCID-2) . A numben = 99) and STAIR+PE (n = 50) were outcome variables in all analyses , with higher scores indicating larger symptom decrease. They were separately calculated by subtracting the predicted posttreatment score from the baseline score per individual using all available measurements per outcome from baseline to posttreatment  using the R package Boruta [Predictors of treatment outcome for the exposure conditions (PE and iPE) and STAIR+PE were selected separately out of the total number of potential predictors . The predicted treatment outcome that patients did not receive was based on the patients of the other condition; therefore, every patient had two predictions in total: one for exposure therapies and one for STAIR+PE. PAI was calculated by subtracting the predicted outcome in the STAIR+PE condition from the predicted outcome in exposure conditions and indicated the relative advantage of exposure conditions over STAIR+PE. When patients had been randomized to their recommended treatment, we defined them as having received optimal treatment versus suboptimal, when they had been randomized to their non-recommended treatment. Finally, the benefit of randomization to optimal treatment (based on the PAI predictions) was determined using the calculated change in CAPS-5 and PCL-5 scores.M = 21.38; SD = 7.90), compared to STAIR+PE , while calculated change in PCL-5 scores from baseline to posttreatment was significantly larger in the exposure conditions , compared to STAIR+PE .The average calculated change in CAPS-5 scores from baseline to posttreatment was not different in the exposure conditions  in the exposure conditions and 4.06 (SD = 7.25) in the STAIR+PE conditions. Half of the patients  were randomized to their optimal treatment, while n = 74 (50%) were not. Patients randomized to their optimal treatment improved more on the CAPS-5 from baseline to posttreatment , compared to patients randomized to their suboptimal treatment  = 11.36, p < 0.001). The standardized mean difference between optimal and suboptimal treatments corresponded to a medium effect size . For the PCL-5, the average error of the predictions was 7.09 (SD = 6.16) in the exposure conditions and 7.24 (SD = 4.74) in the STAIR+PE condition. Based on the PCL data, a little more than over half of the patients  were randomized to their optimal treatment, while n = 55 (37%) were not. Patients randomized to their optimal treatment improved more on the PCL-5 , compared to patients randomized to their suboptimal treatment  = 7.67, p = 0.006). The standardized mean difference between optimal and suboptimal treatments corresponded to a medium effect size . The PAI was calculated based on the final models using leave-one-out cross-validation. For the CAPS-5, the average error of the predictions  was 5.09 (This study aimed to identify characteristics of patients with CA-PTSD, which predicted treatment outcome in exposure conditions and STAIR+PE, and to evaluate the relevance of the PAI for differential treatment outcomes based on the combination of these predictors. Predictors were different in the two conditions, which implies that personalized treatment recommendations have clinical potential. We found that more severe depressive symptoms and less social support were related to worse treatment outcomes in the exposure conditions for both clinician-assessed and self-reported PTSD symptoms. For clinician-assessed PTSD symptoms, we also found that more axis-1 diagnoses and more severe childhood sexual abuse were related to worse treatment outcomes. For the STAIR+PE condition, we found that more severe emotion regulation difficulties and lower general health status were related to worse treatment outcomes for clinician-assessed and self-reported PTSD symptoms. For clinician-assessed PTSD symptoms, we also found that more severe baseline PTSD symptoms were related to worse treatment outcomes. Patients randomized to their optimal treatment based on the PAI improved significantly more with medium effect sizes in clinician-assessed and self-reported PTSD symptoms compared to patients randomized to their suboptimal treatment. About half of the patients were randomized to their suboptimal treatment, implying that these patients could have benefitted from treatment selection based on baseline predictors.worse outcomes in STAIR+PE specifically. Furthermore, many predictors often indicated as relevant for PTSD treatment outcomes such as dissociation and personality disorders did not predict worse treatment outcomes for exposure conditions and STAIR+PE. This suggests that only a few predictors might have to be taken into account for relevant personalization recommendations. Note that up to now, personalization studies for PTSD focused on psychotherapy only, while other treatment options such as pharmacotherapy exist and also merit further investigation [Clinical predictors identified in the current study correspond well to the type of predictors found in previous personalization studies in patients with PTSD. Symptom burden, emotion regulation, and social support are consistent indicators for personalization ,24,26. Itigation .Strengths of the current study include the repeated measures of clinician-assessed and self-reported PTSD symptoms, the broad range of predictor candidates including patient expectancies, and the robust predictor selection process and use of cross-validation techniques . NotablyAn important limitation of the current study is the sample size, which did not allow for evaluation of the model using a 5–10-fold cross-validation or a holdout sample—a statistically independent validation sample; see, for example, . A recenThe current study identified predictors of exposure therapies and STAIR+PE and showed that a combination of these predictors is relevant for differential treatment outcomes of patients with CA-PTSD. Future studies could evaluate previously found prediction models in independent samples and perform prospective studies in which patients are randomized based on personalized predictions or routine care . Especia


Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy that is almost always fatal and lacks effective systemic treatment options. Current treatments of ATC include surgery, radiation, and chemotherapy, used in combination when possible. In the aspect of immunotherapy, the biomarker of TMB-H and MSI-H may suggest that patients benefit from pembrolizumab. Programmed cell death-ligand 1 (PD-L1) is highly expressed in ATC but has not been written into the guidelines or approved by the FDA as a biomarker for thyroid cancer immunotherapy.A 55-year-old woman was admitted to our hospital because of a slight right-sided neck enlargement in November 2019.The clinical diagnosis was ATC, pT3bN0M0, and stage IVB.Oral administration of apatinib (250 mg 3 times daily) was initiated after surgery, but some unpleasant side effects emerged after 1 month of treatment. Next-generation sequencing revealed that the tumor harbored 2 mutations, HRAS p.Q61R and TP53 p.P278S, and PD-L1 staining was positive with a high expression. Thus, camrelizumab (programmed cell death protein 1 inhibitor) was combined with apatinib, and apatinib was changed to 250 mg once a day from March 2020.No adverse reactions were observed after the treatment immunotherapy combined with antiangiogenic drugs. Currently, the survival time of patients is more than 11 months, and the quality of life is not affected.This case suggests that immunotherapy in patients with ATC based upon PD-L1 evaluation provides a therapeutic option. Targeting programmed cell death protein 1/PD-L1 may provide a much-needed treatment option for patients with advanced ATC. Current treatments of ATC include surgery, radiation, and chemotherapy, used in combination when possible.,4 However, the overall response rates are typically short, and the various therapies probably do not affect overall survival at the population level. Given the poor prognosis and paucity of current therapies, molecular profiling of tumors may provide additional opportunities for therapeutic targets. However, a critical unmet need remains for effective therapy for patients with BRAF wild-type, RET wild-type, and NTRK wild-type disease.,7 In the aspect of immunotherapy, the biomarker of TMB-H and MSI-H may suggest that patients benefit from pembrolizumab. Programmed cell death-ligand 1 (PD-L1) is highly expressed in ATC but has not been written into the guidelines or approved by the FDA as the biomarker for thyroid cancer immunotherapy. Here, we describe a patient who benefited from programmed cell death 1 (PD-1) inhibitor camrelizumab combined with antiangiogenic targeting drugs apatinib after operation.Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignant thyroid tumor representing 1% to 2% of all thyroid cancers. The prognosis is poor, with a mortality rate of >90% and a mean survival of 6 months after diagnosis.2 It was combined with apatinib, and apatinib was changed to 250 mg once a day from March 2020. The medication was well tolerated, with no adverse events, and CT revealed slight local recurrence in June  was initiated after surgery, and axial view of computed tomography (CT) scans of the neck showed that the primary lesion was stable (Fig. 3,12 In most cases, however, the diagnosis of ATC is in the advanced stage. Patients with ATC are considered inoperable and show an adverse reaction rate to systemic chemotherapy, so the overall treatment effect is very poor. Our patient was not amenable to the above conventional treatment options considering her personal reasons after surgery. New therapeutic strategies were urgently needed.In all thyroid cancer types, the management of ATC remains most challenging. Previous analyses have reported that the extent of traditional therapeutics, such as surgery, radiotherapy, and chemotherapy, may be associated with the length of survival. agents targeting VEGFR can block the effects of vascular endothelial growth factors and play antiangiogenic and antitumor roles in solid tumors. Apatinib, a novel tyrosine kinase inhibitor that has highly selective competition in the ATP binding site of VEGFR-2, blocks down pathways and inhibits tumor angiogenesis.,15 Moreover, overwhelming efficacy has been achieved in radioiodine-refractory differentiated thyroid cancer. All the above evidence favored apatinib as an ideal choice for our patient. As a result, gratifying outcomes were achieved regarding a durable response, but she reduced apatinib dosage because of some unpleasant side effects.Given that increased VEGFR expression has been found in the microvascular endothelial cells of ATC tumor specimens, In 2018, the FDA approved dabrafenib in combination with trametinib for the adjuvant treatment of patients with BRAF V600 mutation-positive ATC who could not be treated by resection or whose cancer cells had spread to other parts of the body. This therapy has greatly improved the survival of such patients. Additionally, the value of gene examinations needs to be thoroughly examined in decision-making using an appropriate sample size of patients with ATC because of their success in methodology. The above evidence demonstrated that the patients underwent NGS molecular detection for targeted therapy or immunotherapy, and NGS revealed that PD-L1 staining was positive with a high expression.The era of incurable ATC is gradually being replaced by molecular-based personalized therapies, which integrate multidisciplinary therapies including surgery, immunotherapy, radiation therapy, and targeted therapy. the potential of combining targeted therapies with immunotherapy agents such as pembrolizumab and atezolizumab is being studied in completed and/or ongoing clinical trials, with significant results to date. In addition, a clinical trial reported that spartalizumab promises clinical activity and a good safety profile in a patient population with an aggressive incurable disease and short life expectancy targeting PD-L1-positive advanced ATC. In our case, overexpression of PD-L1 may be a potential reason for the patient to benefit from immunotherapy.Currently, PD-1 blockades are widely used in multiple tumor types, and effective responses have been obtained. In recent years, the use of immunotherapy has increased significantly in the current ATC treatment research, although the improvements in survival cannot be directly attributed to immunotherapy alone due to a variety of confounding factors, especially the use of synchronous targeted therapy. Even though single-agent immunotherapy has not shown broad prospects in the treatment of ATC,Given the poor prognosis of ATC, patients with ATC should discuss care goals with a multidisciplinary team. Multimodal therapy is associated with longer overall survival in patients with ATC. In the past few years, the treatment of ATC has evolved from palliative care and hospice care to effective highly specialized molecular-based personalized therapies and surgery when appropriate, regardless of the disease stage. Immunotherapy may delay and/or prevent the emergence of drug-resistant mutations, and it can maintain targeted therapies so that disease control can be sustained. This case suggests that immunotherapy in patients with ATC based upon PD-L1 evaluation provides a therapeutic option. Targeting PD-1/PD-L1 may provide a much-needed treatment option for patients with advanced ATC. Additional investigations will be necessary to characterize the mechanism for the efficacy observed with immune checkpoint inhibition. Further research on immunotherapy will be carried out in ATC in the future, and the practicability and efficacy of the treatment of these patients need to be further studied.We would like to thank Yinfeng Gene Technology Co., Ltd. for the help in organizing the data and revising this article.Conceptualization: Luming Zheng.Data curation: Qingqing He, Ling Li.Investigation: Meng Wang, Yunhan Ma.Supervision: Yunhan Ma.Validation: Jian Zhu, Yanchen Li, Xiaokang Fu.Writing – original draft: Ling Li, Qingqing He.Writing – review & editing: Yaxuan Zhang.