Although COVID-19 has had dire consequences on diagnosis of cancer, little data assessing its impact on the whole range of diagnostic activity relevant to cancer are available. We examined trends in the provision of full diagnostic tests for consecutive patients with suspected cancer referred to an academic hospital-based Quick Diagnosis Unit from January 2019 to December 2020. As weekly volumes declined, waiting times for endoscopic, imaging and biopsy/cytology procedures increased steeply during the COVID-impacted period (26 February–28 April 2020). The average weekly increase compared with the same period in 2019 was substantial for invasive procedures requiring admission (200.70%), CT scans (171.20%), GI endoscopy (161.50%), PET/CT scans (152.50%), ultrasonography (148.40%), and ambulatory biopsy/cytology procedures (111.20%). Volumes and waiting times to other procedures showed similar trends. There was a remarkable downward trend in cancer diagnosis during the COVID-impacted period, with a 54.07% reduction compared with the same weeks in 2019. Despite a modest recovery in the following months, the decline in weekly activity and cancer rates persisted until 30 December. Providing insight into how COVID-19 changed the full spectrum of diagnostic activity for suspected cancer informs resilience-building interventions to guarantee access to fast and efficient diagnostics ahead of new threats. Patients with cancer are commonly diagnosed after seeking care for associated symptoms at primary care (PC) centers. Based on suspected symptoms, physical examination findings, and perhaps some initial tests, these patients may be referred to specialized healthcare to make a diagnosis and, if cancer is confirmed, consider treatment options. Alternatively, diagnosis of cancer sometimes occurs after patient presentation to the emergency department (ED), in which case a more advanced stage with poorer outcomes is expected ,2.People with suspected cancer in several countries are managed through specific pathways. Rolled out as alternatives to hospital admission, Quick Diagnosis Units (QDUs) were conceived in Spain around the middle of 2000s for timely diagnosis of potentially serious diseases including symptomatic organic diseases and cancers with both narrow and broad symptom signatures . This moStudies evaluating nonspecific symptom pathways have shown diagnostic yield estimates for cancer ranging from 8% in the UK to 11% and 22% in Denmark and Sweden ,10,11. TWith nearly 2 million cases and 51,000 deaths by 30 December 2020, the responses to the pandemic in Spain were much the same as in other countries and included reductions in the number of patients seeking healthcare and in hospital admissions, virtual interruption of PC services with a massive shift from face-to-face to telehealth visits, and major shortfalls in medical services for non-COVID-19 patients ,17. A reThe purpose of this study was to investigate the effects of COVID-19 on the full provision of key diagnostic tests in patients with symptoms suggestive of cancer referred from PC to QDU in a public academic hospital in Spain including the periods before the first outbreak, the spike and lockdown, through to the end of 2020.This was a retrospective observational study of all consecutive adult patients referred to the QDU of our Institution  between 1 January 2019, and 30 December 2020. This Institution is the first point of contact with health services for many individual patients within the hospital and the community and provides complex clinical care to patients referred from 16 PC centers and secondary-level hospitals from the Barcelona area. Collectively, Hospital Clínic and its associated centers provide healthcare for a population of 700,000. The city was the epicenter of the COVID-19 pandemic in Catalonia. The unit is located at an ambulatory daycare center and is staffed with Internal Medicine consultants and residents, Family Medicine residents, registered nurses, and administrative workers. As a fundamental principle governing referral and evaluation, patients’ performance status is expected to be well enough to let them go to hospital for appointments and examinations, then returning home [Eligible patients were those aged >18 years who were newly referred from PC centers for investigation of suspected cancer during 2019 and 2020. Patients had to meet predefined criteria for referral ,9, outliInformation was extracted from the e-medical database of the hospital. To investigate changes over time in reported healthcare quality indicators of QDUs ,19, dataTo describe the characteristics of the overall cohort, data collected included demographics , smoking history , alcohol intake , comorbidity score ) , clinicaTrends in weekly volumes and waiting times in 2019 and 2020 were first noticed by scatterplot visualization of data. We identified time cut points associated with changes in volumes in 2020. Four periods were defined: (1) stable pre-COVID, from 1–7 January to 19–25 February; (2) COVID-impacted, from 26 February–3 March to 22–28 April, around the time of maximum transmission rate of SARS-CoV-2 and first lockdown on March 14 ; (3) de-Percent differences in 2020 metrics, stratified by procedure types, were calculated by week for pre-COVID, COVID-impacted, de-escalation and second wave periods, and compared with 2019 figures. Differences in the 2020 calendar year were compared with the same weeks in 2019 to assess the degree of change accounting for monthly or seasonal variation within the same calendar year. Changes are shown with 95% confidence intervals (CI) based on the ratio of two rates (assuming a Poisson distribution).t-tests were performed comparing the mean weekly values in years 2020 and 2019 for each period. Threshold for statistical significance was established a priori at p < 0.05. Data that were not present in the e-health database were excluded from analysis and no imputation was performed. Statistical analyses were performed using GraphPad Prism v8 .Quantitative variables are expressed as means (standard deviation) in case of normal distribution or medians (interquartile range) otherwise. Categorical variables are expressed as numbers (percentage). Normality of continuous data was assessed using histograms and confirmed with the Shapiro–Wilk test. For all relevant metrics, mean weekly values were calculated for pre-COVID, COVID-impacted, de-escalation, and second wave periods, stratified by procedure types. Independent-samples Among 1427 initially eligible patients in 2019, 107 (7.50%) were excluded, leaving 1320 who were referred from 1 January to 30 December with symptoms suggestive of cancer. After excluding 85 of 1060 (8.02%) eligible patients in 2020, there were 975 who were referred from 1 January to 30 December including 176 patients in pre-COVID, 126 in COVID-impacted, 169 in de-escalation, and 504 in second wave periods .After increasing during January 2020 and 2019 (a characteristic trend following the Christmas period), referrals declined sharply during the COVID-impacted period in 2020, then increasing during de-escalation and second wave periods . Comparep = 0.0092). Nonmalignant organic disorders in patients from 2020 most included gastrointestinal (22.62%), hepatobiliary/pancreatic (11.90%), and rheumatic/autoimmune/granulomatous diseases (5.95%) without relevant differences vs. 2019 patients (patients .p = 0.0058), representing an average reduction of 42.04% (CI 95%: 22.66–61.42). Despite a gradual recovery through de-escalation and second wave, volumes did not return to 2019 levels. In the second wave period, the total volume of GI endoscopy/USE procedures decreased by 14.24% compared with the same weeks in 2019. As shown in The mean number of referrals, appointments per case and ratio of successive/first visits in each period of the study in 2020 are shown in Mean times to appointments, procedures, and diagnosis in each study period are presented in p < 0.0001), which represented an increase of 200.70% (95% CI: 144.20–257.20) (p = 0.9258). However, a sharply increasing trend was observed during the COVID-impacted period, with a 97.04% (95% CI: 65.15–128.90) rise compared with the same 9-week period in 2019 .Waiting times to QDU appointments and procedures increased steeply during the COVID-impacted period. Compared with the same periods in 2019, times to GI endoscopy/USE increased by 161.50% (95% CI: 111.60–211.40) during the COVID-impacted period and remained above non-pandemic values during the second wave. Among all procedures, the greatest increase was seen for invasive procedures requiring admission. From 5.17 ± 0.31 days in the previous year, the waiting time increased to 15.53 ± 3.81 days in the COVID-impacted period (–257.20) . Despite–257.20) . BecauseTrends in numbers of cancer across each study period in 2020 are displayed in This is the first study to characterize the impact of COVID-19 on all diagnostic activity relevant to suspected cancer in patients referred from PC to a public hospital in Spain. We used data from prior pre-pandemic periods of 2020 and 2019 for comparison to address potential biases from seasonal and monthly variation. The study revealed huge changes through the diagnostic pathway. The number of people referred with concerning symptoms and the number subsequently diagnosed with cancer dropped sharply during the lockdown period and a decline persisted up until the end of 2020. COVID-19 had a deleterious impact on the access to key tests with significant delays through all pandemic periods. Delays in diagnosis and missing cancers because of such a gridlock imply longer times to enter treatment pathways, leaving disease progression unaffected.The impact of changes on cancer brought about by the pandemic has been investigated throughout the full pathway from referral for suspected symptoms, diagnostic procedures, and number of people with new cancers referred for treatment ,26,27. TThe investigative management of symptomatic-but-as-yet-undiagnosed cancer can shape the interval between symptom onset and diagnosis. COVID-19 has had dire consequences on diagnostic service provision for cancer, as revealed in studies analyzing radiology and endoscopic practices. Data from a large healthcare system in the USA showed an average reduction in the weekly imaging volume of 28% during 1 March–18 April, 2020, compared with the same period in 2019. Volume reduction differed according to procedure types . SimilaChanges in endoscopic activity due to COVID-19 have also implied marked reductions in procedure volumes. Analyzing GI endoscopy reports from a UK national database, one study showed a substantial decline in the average weekly number of endoscopic procedures during 23 March–31 May, compared with a pre-pandemic period in 2020, with a 90% reduction for colonoscopy/flexible sigmoidoscopy, 86% for esophagogastroduodenoscopy, and 44% for ERCP . SimilarThis concerning decrease in the number of cancers is consistent across cancer sites. A cross-sectional study of patients across USA showed a 46% decline in the weekly number of six cancers combined  during 1 March–18 April, with a partial recovery starting 29 March . AdditioSlow and incomplete restoration trends in cancer and procedure volumes following the COVID-19 acme are consistent across published studies. In our institution, most of the original reasons for decreased activity including issues of people’s reluctance to present to PC doctors or attend hospital appointments and issues of staff relocation and readjustment of diagnostic services persisted all through the second wave period.Direct comparisons of our findings with existing literature are challenging because previous reports are based on population-based data. We focus on a population from an academic medical institution at the pandemic nucleus and national data or aggregation data from several QDUs were not used. From the start of lockdown to 30 December, the highest rates of cases and deaths in Spain were reported in Madrid  and Catalonia  communities . TherefoThe international survey of nuclear medicine departments provided an overall picture of the factors heading up changes in diagnostic practices. The reduction in procedure volumes was attributed to a combination of incidents including shortages of personal protective equipment (50% of sites), SARS-CoV-2 infections ), reduction of working hours (up to 26% of sites), staff redeployment to other departments (34%), and demand and supply disruptions . ExpertiThis investigation has provided insight into the impact of COVID-19 on the diagnostic pathway of symptomatic-but-as-yet-undiagnosed cancer in Spain, from referral initiated by PC clinicians to a complete panel of investigative tests and procedures. Examining weekly trends from the start of lockdown throughout successive months and varying levels of restrictions, we have shown how time-critical access to cancer diagnostic services in patients with suspected symptoms collapsed. A multilevel failure effectively translated into substantial increases in waiting times for weekly procedures and reductions in procedure volumes and cancer diagnoses. Changes were more marked between March and April when Spanish hospitals experienced a massive surge in COVID-19 admissions. Even though a recovery started in the week commencing 30 April, when some restrictions were lifted, diagnostic activity and cancer rates did not return to baseline levels.Exposing the burden of COVID-19 on diagnosis of suspected cancer can inform short-term and long-term practice decisions to protect healthcare cancer services and provide fast and efficient diagnostics ahead of new challenging periods.


China has the highest prevalence of hepatitis B virus (HBV) infection worldwide. Universal HBV screening might enable China to reach the WHO 2030 target of 90% diagnostics, 80% treatment, and 65% HBV-related death reduction, and eventually elimination of viral hepatitis. We evaluated the cost-effectiveness of implementing universal HBV screening in China and identified optimal screening strategies.We used a Markov cohort model, inputting parameters based on data from previous studies and public databases, to assess the cost-effectiveness of four HBV serological screening strategies in China in different screening scenarios. We simulated universal screening scenarios in 15 adult age groups between 18 and 70 years, with different years of screening implementation  and compared to the status quo ; in total, we investigated 180 different screening scenarios. We calculated the incremental cost-effectiveness ratio (ICER) between the different screening strategies and the status quo (current screening strategy). We performed probabilistic and one-way deterministic sensitivity analyses to assess the robustness of our findings.With a willingness-to-pay level of three times the Chinese gross domestic product (GDP) per capita (US$30 828), all universal screening scenarios in 2021 were cost-effective compared with the status quo. The serum HBsAg/HBsAb/HBeAg/HBeAb/HBcAb (five-test) screening strategy in people aged 18–70 years was the most cost-effective strategy in 2021 . This strategy remained the most cost-effective, when the willingness-to-pay threshold was reduced to 2 times GDP per capita. The two-test strategy for people aged 18–70 years became more cost-effective at lower willingness-to-pay levels. The five-test strategy could prevent 3·46 million liver-related deaths in China over the lifetime of the cohort. It remained the most cost-effective strategy when implementation was delayed until 2026 (ICER $20 183/QALY) and 2031 (ICER $23 123/QALY). Screening young people (18–30 years) will no longer be cost-effective in delayed scenarios.The five-test universal screening strategy in people aged 18–70 years, implemented within the next 10 years, is the optimal HBV screening strategy for China. Other screening strategies could be cost-effective alternatives, if budget is limited in rural areas. Delaying strategy implementation reduces overall cost-effectiveness. Early screening initiation will aid global efforts in achieving viral hepatitis elimination.National Natural Science Foundation of China. Hepatitis B virus (HBV) infection is a major global health issue, with 257 million chronically infected individuals and 887 000 HBV-related deaths in 2015.The wide availability of birth-dose HBV vaccination to both urban and rural communities has drastically reduced HBsAg prevalence in children aged 5 years in China to 0·2% in 2016.Universal screening has not been proposed or implemented for chronic HBV infection. Previously, the high cost of antiviral drugs was a major barrier for HBV screening because HBV treatment and care were not affordable after diagnosis.Evidence before this studyHepatitis B virus (HBV) screening is recommended for people born in regions with a disease prevalence of 2% or higher, but it has yet to be universally implemented in many HBV-endemic countries. China accounts for one-third of the world's HBV-infected population but has diagnostic and treatment coverages below the WHO 2030 goals. Improvements in health-care infrastructure and the introduction of low-cost generics could allow for universal HBV screening in China to be cost-effective. We searched PubMed, Embase, and Web of Science between Jan 1, 2000, and Feb 28, 2021, with no language restrictions, using the terms “China” or “Chinese”, “Hepatitis B”, “HBV”, “screening”, “test”, “diagnosis”, and “cost-effectiveness” to identify published economic evaluations on universal HBV screening strategies. We found no previous studies describing the costs or cost-effectiveness of universal screening for HBV infection in mainland China. We also searched for studies on the cost-effectiveness of HBV screening in other countries using the same search terms, without “China” or ”Chinese”. Only three previous studies evaluated the cost-effectiveness of one type of HBV screening in high-income countries and focused on high-risk or immigrant populations. One study evaluated the cost-effectiveness of community-based screening in a low-income country, but it only considered the HBsAg rapid test for HBV screening.Added value of this studyBased on our cost-effectiveness analysis of 180 screening scenarios, universal HBV screening is cost-effective and can be applied to every screening strategy if implemented early. The most cost-effective strategy was the serum HBsAg/HBsAb/HBeAg/HBeAb/HBcAb (five-test) screening strategy in people aged 18–70 years. This strategy remained robustly cost-effective even after reductions in willingness-to-pay levels. Different screening strategies were suitable for different willingness-to-pay thresholds, allowing for generalisation to the whole of China or individual application to different Chinese regions. Early initiation of universal HBV screening could potentially identify 86·8% of infected individuals by the end of the cohort's lifetime, and could potentially save 3·46 million Chinese individuals from HBV-related mortality. Although a delay in screening implementation by 5–10 years did not alter our conclusions, overall cost-effectiveness was reduced, with the exclusive screening of the younger age groups (18–30 years and 18–40 years) no longer being cost-effective.Implications of all the available evidenceUniversal HBV screening is cost-effective in China, especially when implemented early. Delay in screening implementation reduces cost-effectiveness. It is now prime time for the initiation of universal HBV screening, which will improve the current suboptimal diagnostic and treatment rates for HBV infection in China, and will help China to achieve the WHO 2030 objectives of eliminating HBV as a public health threat.This study evaluates the effectiveness and cost-effectiveness of various universal HBV screening strategies for all Chinese adults compared with the current practice. We also conducted the simulation at different years of initiation at 2021, 2026, and 2031 to understand the effect of early or delayed implementation.We conducted an economic evaluation based on a decision-analytic model to assess the cost-effectiveness of various HBV universal screening strategies in China. The model was constructed using TreeAge Pro 2020 and the analysis was reported according to the Consolidated Health Economic Evaluation Reporting Standards statement.We collected data from a literature search and Chinese and English public databases to parameterise prevalence data, screening, cost, and other model parameters . Costs wMathematical models have been widely used to evaluate prevention programs for sexually transmitted infections.We assumed that health state transition rates differed between participants on treatment and those who remained untreated. We defined treatment-eligible individuals as HBsAg-positive individuals (diagnosed and undiagnosed) with a high viral load (≥2000 IU/mL), cirrhosis or hepatocellular carcinoma, or who have undergone liver transplantation according to the international and local guidelines.Chinese age-specific natural death rates were applied to the cohorts.We defined the current practice of HBV screening in China as the status quo. Since 2017, only couples undergoing premarital testing, pregnant women, and individuals who developed clinical symptoms were eligible to receive screening.We simulated universal HBV screening to target age subgroups between 18–70 years in the Chinese population  born before the HBV vaccine was integrated into the expanded Chinese national programme on immunisation and was made free in 2002.We calculated an incremental cost-effectiveness ratio  between current practice (status quo) and the different screening strategies to determine the screening strategy's cost-effectiveness. We adopted the WHO definition of cost-effectiveness of fewer than three times Chinese gross domestic product (GDP) per capita.32We conducted probabilistic sensitivity analyses to characterise all model parameters’ combined uncertainty based on 1000 Monte Carlo simulations. We conducted one-way deterministic sensitivity analyses to determine the effects of parameter uncertainties and model robustness (tornado plots). We evaluated the impact of varying treatment coverage (10–80%) on the ICER, based on an about 30% coverage rate as in other east Asian countriesThe funder of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.If the status quo continued and no further scale-up of screening strategies was implemented, only 19·0% of the study population would be screened by the end of the cohort's lifetime. An estimated 6·4% (6440/100 000) would be living with HBV infection over their lifetime; 18·9% (1217/6440) of infected individuals would be diagnosed; and 12·6% (310/2460) of eligible HBV-infected individuals would receive treatment. 23·0% (1479/6440) of infected individuals would eventually die of HBV-related diseases. The overall screening cost would be $267 000 and treatment cost would be $13·6 million for the status quo over the lifetime of the 100 000-person cohort .TableEffThe incremental costs and QALYs for the 60 universal HBV screening scenarios  compared with the status quo is shown in the We identified six screening strategies on the cost-effectiveness frontier A. The fiIf the five-test strategy was initiated among the population aged 18–70 years in 2021, 86·8% of infected individuals would be diagnosed by the end of the cohort's lifetime, and 38·4% of treatment-eligible HBV-infected individuals would receive treatment . We projIf universal screening was initiated in 2026, screening strategies involving an upper age range of 40 years or older remained cost-effective but to a lesser extent B. The fiIf universal screening was to be initiated in 2031, the cost-effectiveness would be further reduced C. The fiThe probability of a strategy being cost-effective varied depending on the willingness-to-pay threshold  did we find that low-cost rapid tests for all age groups would be the most cost-effective option. Furthermore, we recommend prioritising screening to the youngest age group (18–30 years) before extending the programme to the older age groups, if additional resources become available. To our knowledge, this is the first economic evaluation study of universal screening and treatment strategy for HBV in China.International guidelines recommend HBV screening for people born in regions with 2% or higher disease prevalence.Our study has several important findings. First, universal HBV screening in China is cost-effective regardless of screening strategies if implemented in 2021. The five-test strategy is generally the most cost-effective option. Our sensitivity analysis  illustraSecond, our study findings are robust and can be generalised to China as a nation or applied individually to smaller regions and provinces. A health-care intervention is deemed cost-effective if the ICER is below the willingness-to-pay threshold.Third, our analysis suggests that a delay of 5–10 years in screening implementation will reduce its cost-effectiveness , with exEven with universal screening involving adults aged up to 70 years, the decline in HBV-related mortality is only relatively modest at 16·8% compared with the status quo in 2021. The study findings are similar to those of a previous modelling study using a case-finding approach,Although our study findings demonstrate the clinical and economic benefits and the urgency of universal HBV screening in China, it does have limitations. It does not consider the real-world practicality of mass screening using China's current health-care infrastructure. The Chinese Government should make use of the extensive primary care infrastructure introduced since health-care reform in 2009. Our nationally representative survey among 149 community health centres and 3580 frontline primary care practitioners from 20 cities, found 80% of community health centres had the facility to offer HBV testing, and 85% of doctors saw the benefits of providing HBV testing, yet only 19% had diagnosed HBV and 15% managed HBV in the previous month.In conclusion, universal screening for HBV among adults aged 18–70 years is cost-effective in China, with various strategies suitable for various willingness-to-pay thresholds. A universal screening programme will still be cost-effective even with a 5–10 year delay, although reduced. Initiating universal HBV screening as soon as possible is recommendable for HBV prevention in China. It might improve the current suboptimal rates of diagnostic and treatment coverage and help China achieve the WHO objective of eliminating HBV as a public health threat.All data relevant to the study are included in the Article or in the online PC is a staff member of WHO; PC alone is responsible for the views expressed in this publication, and they do not necessarily represent the decisions or policies of WHO. M-FY is an advisory board member or has received research funding from AbbVie, Arbutus Biopharma, Assembly Biosciences, Bristol Myers Squibb, Dicerna Pharmaceuticals, GlaxoSmithKline, Gilead Sciences, Janssen, Merck Sharp and Dohme, ClearB Therapeutics, and Springbank Pharmaceuticals; and has received research funding from Arrowhead Pharmaceuticals, Fujirebio Incorporation, and Sysmex Corporation. W-KS received speaker's fees from AstraZeneca and Mylan, is an advisory board member of CSL Behring, is an advisory board member and received speaker's fees from AbbVie, and is an advisory board member and received speaker's fees and researching funding from Gilead Sciences. FJ received speaker's fees from Gilead Sciences, Merck Sharp and Dohme, and Bristol Myer Squibb, and is an advisory board member of Gilead Sciences and Merck Sharp and Dohme. All remaining authors declare no competing interests.


Antibodies against the 65-kDa isoform of glutamic acid decarboxylase (GAD65) are biomarkers of autoimmune disorders and are more common in non-neurological autoimmune diseases than in neurological disorders. As for the central nervous system (CNS), it is well known that GAD65 is primarily associated with stiff-person syndrome, cerebellar ataxia, epilepsy, and paraneoplastic neurological syndrome. However, GAD65 antibodies have not been reported in patients with brain tumors.This study presents the case of a 62-year-old man who manifested rapidly progressive dizziness with gradually worsening physical disturbance and unstable gait in the 2 months prior to consultation. Antibodies against GAD65 were detected in his serum. Brain magnetic resonance imaging (MRI) showed abnormal signals in the corpus callosum, the semi-oval center in both hemispheres, and the area below the frontal cortex, along with enhanced intracranial lesions in the same regions. Positron emission tomography–computed tomography (PET–CT) showed high metabolism in the corpus callosum, which protruded into both ventricles. Due to signs of malignancy, the patient was diagnosed with a malignant glioma.This case raises awareness on the fact that anti-GAD65 antibodies may be associated with CNS neoplastic lesions. Early recognition of anti-GAD antibodies could be of great importance for the early diagnosis and targeted treatment of neoplastic lesions, and could lead to better prognosis. Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the central nervous system (CNS), and glutamic acid decarboxylase (GAD) is the rate-limiting enzyme that mediates its synthesis. GAD is a pyridoxal 5’-phosphate-dependent enzyme that is selectively expressed in GABAergic neurons and pancreatic β-cells. Two isoforms with different molecular weights exist, GAD65 and GAD67, which are each encoded by two different genes , 2. GAD6A 62-year-old man was admitted to our hospital with complaints of rapidly progressive dizziness and unstable gait, which had been present for the previous 2 months. He deviated to the left when walking. The patient had a 10-year history of hypertension and a 1-year history of gout without systematic diagnosis and treatment; he denied having any history of diabetes, autoimmune diseases, blood transfusions, or other familial conditions. Neurological examinations showed no abnormalities, except for spastic paralysis of the left lower limb. It showed decreased muscle strength of the left lower limb (level 4) with hyperactive tendon reflexes. And the Babinski and Chaddock signs were positive on the left side.The level of serum glycosylated hemoglobin was 6.20% . MRI of the head showed abnormal lesions in the corpus callosum, the semi-oval center in both hemispheres, and the area below the frontal cortex with contrast medium enhancement  or CSF are associated with various autoimmune neurological diseases, including autoimmune epilepsy, SPS, cerebellar ataxia, limbic encephalitis, progressive encephalomyelitis with rigidity and myoclonus, and PNS . RepreseIn this study, we performed chest CT scans and whole-body PET–CT scans to diagnose GAD65-related tumors and exclude the possibility of brain metastasis. The PET–CT results in the lungs, extremities, and abdomen were negative, brain PET–CT showed high metabolism in the genu of the corpus callosum and both ventricles, implying the presence of a malignant glioma.The differential diagnosis for a brain lesion relies on a patient’s age, risk factors for infection, the presence of other tumors, and imaging characteristics. Primary differential diagnoses include metastases, infections, inflammatory disorders, and vascular lesions. A well-defined lesion with a normal overlying cortex tends to metastasize in a single ring-enhanced lesion. Lesions with ill-defined contours and adjacent cortical enlargement tend to be high-grade gliomas, while lesions with reduced central diffusion are more likely to be abscesses . The finAs the most common primary brain tumor, gliomas are all the tumors that originate from glial cells. Gliomas constitute approximately 27% of all primary CNS tumors and 80% of malignant tumors . Like maBased on the diagnosis of malignant glioma, we believe that another possible reason for the increase in serum anti-GAD65 antibody levels observed in our patient could be the overexpression of the abovementioned proto-oncogenes, which can lead to increased GLUT expression. The responsive rise in blood glucose further promotes the function of pancreatic islet β-cells, which consequently heightens blood GAD65 antibody levels.Researches have shown that high GAD65-ab serum levels are associated with neurological disorders and cancers in lung or breast, but no studies have reported a potential correlation between GAD65 and neoplastic CNS diseases. This case raises awareness on the fact that anti-GAD65 antibodies may be associated with CNS neoplastic lesions. Further research is needed to confirm this conclusion. However, we emphasize the importance of clinical screening for patients with progressive dizziness and gait ataxia. Specifically, anti-GAD antibody levels should be tested, and, if present, should raise suspicion of an underlying tumor in the CNS.


Recent research investigating changes in gambling behaviors during periods of COVID-19 social restrictions, such as enforced lockdowns, are somewhat limited by methodology, being generally cross-sectional in nature and with participant samples recruited via online panels. The present study overcame these limitations via a secondary analysis of data collected in 2012 and 2015 from a New Zealand (NZ) longitudinal gambling study, with questions related to gambling behaviors due to COVID-19 lockdown periods included in an additional data collection, of participants who had previously scored as a risky gambler, during 2020/21. Almost one-quarter of online gamblers increased their gambling during lockdown with this most likely to be on overseas gambling sites, instant scratch card gambling and Lotto. The only sociodemographic risk factor for increased online gambling was higher education. Behavioral risk factors included being a current low risk/moderate risk/problem gambler, a previously hazardous alcohol drinker or past participation in free-to-play gambling-type games. These past behaviors could act as trigger points for health services or family and friends to monitor a person’s gambling behaviors during lockdown, or future stressful periods when usual terrestrial gambling opportunities are curtailed or unavailable, and to support safer gambling practices. New Zealand (NZ) is a small geographically isolated country located in the Pacific Ocean, with a population of approximately 5 million people . The firThe NZ gambling environment, although highly regulated, is relatively liberal, allowing many land-based opportunities for gambling, such as table games and electronic gaming machines (EGMs) in casinos, EGMs in community pubs and clubs, track and sports betting via the Totalisator Agency Board (TAB), lottery-based products , bingo, and more informal activities, such as charitable raffles . ProvisiDuring Alert Levels 3 and 4 in NZ, access to land-based gambling was denied with the only available gambling opportunities being online. These included NZ lottery-based products, gambling via the TAB and overseas online gambling sites. Preliminary gambling expenditure data collated by the NZ Department of Internal Affairs (the government department responsible for regulating gambling) indicated that during the 2019/20 financial year, all gambling expenditure decreased because of the pandemic, apart from lottery-based gambling, which increased by 13% due to increased online gambling . DespiteSeveral research articles investigating gambling behavior changes during COVID-19 restrictions worldwide have recently been published. These have mainly been cross-sectional online survey studies. A recent review of published studies relating to gambling participation during the COVID-19 pandemic identified that, as was to be expected with restricted land-based gambling opportunities, gambling engagement was reduced overall. However, risk factors for increased online gambling, although varying between studies, generally included a higher gambling risk categorization related to being a young adult, and being male . Whilst The present study aimed to extend current knowledge of gambling behaviors during COVID-19 restrictions by examining NZ data. This was achieved via a new partial wave of data collection in 2020/21 from an existing population representative cohort for which annual gambling-related data had been collected over a four-year period, from 2012 to 2015; the NZ National Gambling Study. There were two aims to the present study: (1) to describe changes in NZ gamblers’ online gambling participation during a year in which there were COVID-19 lockdowns (Alert Levels 3 and 4), and (2) to use existing longitudinal data to identify risk factors associated with increased online gambling, because of COVID-19 lockdowns and the associated unavailability of land-based gambling opportunities.This study utilized data collected from the first and last years of the population representative NZ National Gambling Study (NGS). In 2012, NGS baseline data were collected from 6251 participants, including gamblers and non-gamblers. The design and methods of the original NGS are published separately ; the finNGS participants who scored as an at-risk gambler in 2012 or any of the subsequent data collection years (2013 to 2015) on either the Problem Gambling Severity Index  ,17, who The original NGS data were collected via face-to-face structured interviews; however, the 2020/21 data collection was via telephone structured interviews due to the various social isolation and restriction procedures in place at periods during the year. The 2020/21 questionnaire was modelled on the baseline NGS questionnaire to enable comparison and analyses of changes over time. However, the questionnaire was updated to take into consideration the changed gambling environment since 2012, including more detailed questions on online gambling and new questions relating to online gambling behavior change during periods of COVID-19 lockdown. The Short Gambling Harm screen was also added. Interviews were conducted from 2 October 2020 to 9 March 2021. Participants received a NZ $50 gift voucher after completion of the interview as an appreciation of the time they gave to the interview.The 2020/21 questionnaire included the following measures.Gambling participation. Participants were asked about their involvement in gambling activities in the past 12 months. For each reported activity, participants were asked about frequency and, if the activity was available online, these questions were repeated specifically for the online behavior. Participants were then asked if their online behavior increased, decreased or stayed the same during COVID-19 lockdown (Alert Levels 3 and 4). Participants were also asked about their involvement (participation and frequency) in free-to-play online gambling type activities .Gambling risk level. The nine-item Problem Gambling Severity Index [ty Index  was usedty Index  and beenGambling harm. The 10-item Short Gambling Harm Screen (SGHS) [n (SGHS)  was usedn (SGHS)  measuresMajor life events. Participants were asked about 15 major life events  and whether they had experienced these in the prior five years . An ‘other’ category was also included.Mental health. General psychological distress in the prior four weeks was measured with the 10-item Kessler-10 [ssler-10 . Scores Quality of life. The eight-item EUROHIS-QOL 8 measured quality of life in the prior two weeks. This short form is psychometrically robust, and overall performance is strongly correlated with scores from the original WHOQoL instrument [strument . Scores Substance use. Hazardous alcohol consumption was measured using the three-item AUDIT-C, which was developed from the 10-item Alcohol Use Disorders Identification Test [ion Test . The AUDion Test . IndividGeneral health. Individual questions were asked about overall general health and disability in the prior 12 months.Deprivation. To measure current (past 12 month) individual level of deprivation, the eight-item NZ Index of Socio-economic Deprivation for Individuals was used [was used . It has Sociodemographic data. Sociodemographic data that could vary since the baseline survey were collected in the 2020/21 questionnaire . Sociodemographic data collected at baseline and used in the present study included gender, age, ethnicity and country of birth.n) and percentages (%). Inferential statistics, utilizing Pearson’s chi-square and Fisher’s exact tests, where relevant, were undertaken to examine changes over time.Descriptive statistics were produced for the variables of interest, presenting counts  was undertaken to investigate associations with increased online gambling during lockdown. Potential explanatory covariates were considered for possible inclusion in the model. For age, gender and ethnicity, baseline (2012) measures were used. For other covariates that varied over time, both 2015 and 2020/21 measures were utilized.p-value ≤ 0.2. Models were then developed for each of the major data domains  using the candidate variables, in order to identify the best subset of variables from that data domain. All of the results from the separate domains were then considered for an overall model. Each of the model building procedures followed a stepwise selection method tempered by consideration of the information criteria. Parsimonious models were favored and competing models with a similar fit but markedly different compositions have all been reported.Model selection generally proceeded through several steps. The first step identified candidate variables in bivariate analyses with the outcome variables that had a p-value for the covariate.The base odds and odds ratio of potential explanatory covariates are reported as point estimates and 95% confidence intervals, accompanied by a The study sample comprised 301 participants. There were slightly more females than males  and about two-thirds were born in NZ (69.8%). Half of the sample were of NZ European/other ethnicity (50.2%), one-quarter (24.6%) were of Māori ethnicity (NZ’s indigenous population), 14.3% were of Pacific ethnicity and 11% were of Asian ethnicity. At baseline (in 2012), two-thirds of participants were aged between 25 years and 54 years (64.1%). p ˂ 0.0001). However, a majority of participants earned below or about the NZ national median income in 2020/21 and this remained similar to the percentage in 2012  [in 2012) .p ˂ 0.0001) and disability (p = 0.005). Whilst an increase in hazardous alcohol consumption was also noted in 2020/21 (p = 0.05), a lower proportion of participants reported using cannabis (p = 0.002).There were increases in the percentages of people experiencing five or more major life events in 2020/21 (p ˂ 0.0001), visual inspection indicated that the significance was likely due to the increase in participants who gained a university or ‘other’ qualification.Although statistical significance was attained for change in the highest educational level .Participants moved between the different risk levels over time. At baseline in 2012, more than one-third (36.2%) had gambled in a risky manner ; this increased to more than two-fifths (43.5%) in 2015. However, in 2020/21, there was a decrease in the proportion of risky gamblers with only one-quarter (25.6%) remaining classified as such . This diInferential analyses, adjusting for confounding factors, identified four covariates that were statistically associated with increased online gambling during COVID-19 lockdown periods (Alert Levels 3 and 4) in NZ. There were two socio-demographic factors associated with increased online gambling. One was educational level, with participants with the highest educational level (university degree or higher) in 2020/21 having 8.07 times (adjusted) odds of increased online gambling, compared with participants without any formal qualifications. Almost one-quarter (22.8%) of participants with a university degree or higher increased their online gambling during lockdown. The other socio-demographic factor was hazardous alcohol consumption in 2015 but not 2020/21. Participants who drank alcohol in a hazardous manner in 2015 had 2.80 times (adjusted) odds of increased online gambling in lockdown, compared with participants who did not drink alcohol hazardously. Almost one-fifth of participants (18.8%) of participants who drank alcohol in a hazardous manner in 2015 increased their online gambling behavior during lockdown.Being a risky gambler  in 2020/21 was associated with 4.09 times (adjusted) odds of increased online gambling compared with non-gamblers/non-problem gamblers. This association was not found with being a risky gambler in 2015.Participants who engaged in free-to-play gambling-type activities in 2015 had 3.38 times (adjusted) odds of increased online gambling, compared with participants who did not participate in free-to-play gambling-type activities. This association was not found with engaging in free-to-play gambling-type activities in 2020/21. Almost one-quarter of participants (23.7%) of participants who engaged in free-to-play gambling-type activities in 2015 increased their online gambling behavior during lockdown.No other covariates were associated with increased online gambling during lockdown, when confounding variables were taken into consideration, although some associations were noted in bivariate logistic regression analyses for age, employment status, cannabis use, experiencing two or more indicators of gambling harm and taking up gambling for money from a free-to-play site.The NZ population was relatively fortunate in that they were able to live much more of 2020/21 ‘normally’ compared with people in other countries who experienced longer lockdown restrictions due to COVID-19. Nonetheless, NZ experienced its fair share of strict lockdown periods during 2020/21 and this provided an opportunity to study gambling behavior changes during those times. A strength of the present study is that data from an existing population-representative gambling study  were available and could be used in analyses of COVID-19 related behavior change, with the opportunity taken to collect new data from the cohort in 2020/21. We were specifically interested in understanding changes in online gambling behavior during lockdown periods as land-based gambling was not possible at those times, and to understand current and past risk factors for increased online gambling during lockdown.In 2020/21, online gambling participation was relatively high, ranging from 19% of scratch card gamblers to 70% of keno gamblers. In general, Lotto gamblers were the most common with half buying tickets online. Relatively few participants gambled on overseas online gambling sites with only 5% reporting doing so. Overall, 56% of participants reported gambling online. During periods of lockdown, two-thirds of the online gamblers reported that their online gambling stayed the same, and just over one-quarter reported a decrease in online gambling. This finding was similar to that reported in a scoping review conducted in the first part of 2021 , wherebyHowever, almost one-quarter of online gamblers increased their gambling during lockdown, with the largest proportions being for Lotto, scratch card gambling and overseas online gambling. Initially, this profile appeared to be different from other studies. For example, in Australia and Sweden, the largest increase in online gambling during lockdown was noted for track betting ,29 and, Other studies of online gambling behaviors during COVID-19 lockdowns have generally found that being male, a young adult and having a higher gambling risk level categorization were risk factors . Our anaIn our study, in bivariate analyses, although age was a risk factor for increased online gambling during lockdown, male gender was not, and the statistical significance for age disappeared when confounding factors were accounted for. This finding was contrary to that reported in many other studies. The reason for this difference bears further investigation as in NZ, online gamblers are more likely to be male and aged between 18 and 54 years  and thisHowever, our study found that highly educated participants (university degree or higher) had greater odds for increased online gambling in lockdown than uneducated participants. This could simply be due to financial stability. More highly educated people tend to earn higher incomes and to be able to work from home during periods of lockdown, compared with less educated people who may be in lower paid manual labor jobs and unable to work during lockdown, thus reducing disposable income for activities such as gambling. They may also more easily access individual (rather than shared) devices making it easier to gambling online. However, this is speculation and requires further investigation. As noted by , who revAs previously mentioned, a strength of this study was the ability to draw upon previously collected data for the participants, thus reducing the likelihood of recall bias, which can occur when participants are asked to retrospectively reflect on behaviors. Our study found that participants who drank alcohol in a hazardous manner in 2015, or who engaged in free-to-play gambling type games in 2015 had higher odds for increasing their online gambling during lockdown in 2020/21. That current hazardous alcohol consumption was not associated with increased online gambling during lockdown is a similar finding to that noted by . This isWhilst little studied, there is preliminary evidence that about one-quarter of free-to-play online gamers migrate to online gambling six months later, with micro-transactions being the only unique predictor of the migration . In our A limitation of our study is that, due to budget and time constraints, it was not possible to collect data from the full NGS cohort in 2020/21, with only participants who had previously scored as a risky gambler recruited. This means that our study is not population representative. However, collecting data only from people who had, at some point, previously been gambling in a risky manner is justifiable as this study aimed to investigate online gambling behaviors. Prior research has indicated that online gambling is associated with problem gambling ,31 and eTo date, most studies of online gambling behaviors during periods of COVID-19 lockdown have been cross-sectional in nature. Whilst these have identified risk factors for increased gambling behaviors during periods of restriction and social isolation, colloquially known as lockdown, potential past behavior risk factors remained unknown. Yet knowing what such factors are could help in public health efforts to encourage safer online gambling behaviors during future periods of lockdown or other similarly stressful situations, especially as online gambling is known to be highly associated with risky and problematic gambling. This study identified that past hazardous alcohol consumption and past participation in free-to-play gambling-type games were both significantly associated with increased online gambling during lockdown. Being past behaviors, they are likely to be known to others and are potential trigger points for health providers and family or friends to check on a person’s gambling behaviors during lockdown and support safer gambling. The gambling activities in which the highest proportions of participants increased their gambling during lockdown were overseas online gambling and online scratch card gambling. Both types of activity are continuous in nature, and more likely to lead to harm than non-continuous activities such as Lotto gambling. Encouraging a person to stick to the recently released Lower Risk Gambling Guidelines  could he


The COVID-19 pandemic has had a profound effect on societies and citizens worldwide, raising concerns about potential mental health impacts. We aimed to describe trajectories of depression, anxiety and stress symptoms during the COVID-19 outbreak compared to before the outbreak, and to determine if trajectories were modified by pre-pandemic loneliness, poor sleep quality and mental health problems.We conducted a cohort study with 1836 Swedish university students entering the study before 13 March 2020, the onset of the pandemic, with follow-ups within three (FU1) and six months (FU2) of the outbreak. Generalized Estimating Equations were used to estimate mean differences in symptom levels over time-periods, and to estimate potential effect modifications.We found small differences in mean levels of the depression, anxiety and stress scale (DASS-21) over time. Compared to before the pandemic, depression increased by 0.25 points of 21 (95% CI: 0.04 to 0.45) at FU1 and decreased by 0.75/21 (95% CI:−0.97 to −0.53) at FU2. Anxiety decreased from baseline to FU1 by 0.09/21 (95% CI: −0.24 to 0.07) and by 0.77/21 (95% CI: −0.93 to −0.61) to FU2. Stress decreased from baseline to FU1 by 0.30/21 (95% CI: −0.52 to −0.09) and by 1.32/21 (95% CI: −1.55 to −1.09) to FU2. Students with pre-pandemic loneliness, poor sleep quality or pre-pandemic mental health problems did not have worse trajectories of mean mental health symptoms.Symptom levels were relatively stable during the first three months of the pandemic, while there was a slight decrease during the summer months, probably due to seasonality effects. The COVID-19 pandemic has had a profound impact globally on societies and the daily lives of citizens. In a call for action, Holmes et al. , 3; therA ‘living’ systematic review of the literature found that most studies reported small to negligible worsening of mental health symptoms during the pandemic . HoweverThe impact of physical distancing and loneliness on mental health during the COVID-19 pandemic has been expressed as a key concern  and is aIn Sweden, the spread of COVID-19 accelerated rapidly beginning in early March 2020. On 13 March 2020, the Public Health Agency of Sweden declared that the risk of community-acquired COVID-19 had reached a very high level and issued recommendations to stay at home when experiencing symptoms . Like inGiven Sweden’s unique strategy, and the initiation of the Sustainable University Life (SUN-study) in August 2019, there is a unique opportunity to conduct a longitudinal evaluation of the mental health impact of the COVID-19 pandemic among Swedish university students. University students, with generally higher levels of mental health problems than the general population , are a pWe aimed to describe the trajectories of depression, anxiety and stress symptoms in Stockholm university students before and during the first six months of the COVID-19 pandemic. Our secondary aim was to determine whether trajectories of depression, anxiety and stress symptoms were modified by pre-pandemic loneliness, poor sleep quality or mental health problems. We hypothesized that symptoms of depression, anxiety and stress would worsen during the COVID-19 pandemic, and that the worsening would be more severe for students with loneliness, poor sleep quality and pre-pandemic mental health problems.http://clinicaltrials.gov/ ID: NCT04465435), in which data collection began in August 2019 and will be ongoing until November 2021.We conducted a cohort study of university students in Stockholm, Sweden with recruitment beginning before the outbreak of COVID-19 in Sweden and follow-up surveys at three-month intervals continuing after the outbreak. This cohort study is nested within a larger dynamic cohort study of university students: the Sustainable University Life (SUN-study)  and at on-campus information sites. Participants were followed via web surveys every three months for one year and chose to fill out the survey either in Swedish or English. Participants not responding to follow-up surveys received reminders by email, text-message and one phone call. The study was approved by the Swedish Ethical Review Authority . Informed consent was provided by all participants electronically prior to completing the baseline survey.Figure 1, Supplemental eFigure 1). The date marking the start of the pandemic, 13 March, is the date that the Public Health Agency of Sweden declared that Sweden had entered a new phase in the pandemic with high risk of community acquired COVID-19 [eFigure 1).The collected data was divided into three time-periods: before the pandemic (19 August 2019 to 13 March 2020), follow-up period 1  and follow-up period 2    at each Pre-pandemic mental health problems were classified at baseline as scoring above the recommended DASS-21 cut-offs for moderate symptom levels on any of the three subscales  . These cr = 0.82) with the 20-item revised UCLA loneliness scale [Pre-pandemic loneliness was measured using the UCLA three-item loneliness scale (UCLA-3) , with itss scale .r = 0.82) over one month [We used the Pittsburgh sleep quality index (PSQI) to measure pre-pandemic sleep quality . The PSQne month .We used generalized estimating equations (GEE) to model mental health symptoms over three time periods. GEE models treat correlation between observations from the same individual as nuisance parameters and provide estimates of marginal population means of the outcome. Our data was not normally distributed, which was one reason for choosing GEE since these models do not rely on the assumption of normally distributed outcome measures or the normality of residuals. We built three separate models, one each for symptoms of depression, anxiety and stress, to assess overall mean differences in symptoms over the three time periods. These models included only time-period as the predictor in order to estimate mean differences in symptom levels from baseline across follow-up periods for the full group. All GEE models, including the models described below, were specified with exchangeable working correlation structures, robust sandwich variance estimators and Gaussian link functions.Subsequently nine separate models were fitted to assess differences in the trajectories over time by exposure levels. We dichotomized our exposures , into exposed and unexposed groups as described above. An interaction term between exposure and time-period was included, letting the mean symptom levels over time to vary between exposed and unexposed. This allows estimation of difference-in-differences between mean symptom levels among exposed/unexposed over time. These models were adjusted for age and gender, which were selected a priori based on previous literature.We conducted sensitivity analyses to examine potential attrition bias by performing complete case-analyses (using data from participants who provided complete follow-up). Furthermore, we conducted a sensitivity analysis in a sample of 496 participants with baseline assessment in August to September 2019 and first follow-up prior to the pandemic in November 2019 to January 2020 to compare the trajectories of exposed and unexposed groups during the pandemic to those of an earlier time-period. Graphs from these sensitivity analyses were compared to those from the main analysis by visual inspection.Cronbach’s α values for the scales used were constructed from the baseline data of the cohort to determine their internal consistency in our cohort.Mean imputation by the individual scale means was used to handle missing data for the PSQI that arose due to initial technical problems with the web survey. Three items of the scale were missing  for the first 512 respondents . No otheAll analyses were performed using RStudio ver-sion 1.2.5001, the packages ‘geepack’ ‘psych’ and ‘emmeans’ were used to perform GEE analyses and to derive estimated marginal means from the models.n = 1364) and 60% (n = 1095) provided follow-up data during the first and second follow-up periods respectively . At baseline, respondents had a mean age of 26.5 years (SD 6.8), 73% were female and 80% were born in Sweden (We invited 6681 students and 1836 (27%) agreed to participate. Of those, 74% .We compared symptom levels during FU1 and FU2 to baseline levels, for the three DASS-21 subscales . Mean deParticipants exposed to pre-pandemic loneliness, poor sleep quality or mental health problems all had higher mean levels of depression, anxiety and stress before the pandemic . At FU1 Supplemental eTable I).The difference-in-difference estimates from the complete-case sensitivity analyses comparing exposed and unexposed were all within 0.21 points of the original analyses and all in the same direction as in the main analyses  and during the following three summer months (16 June to 10 September 2020) when the rate of spread of the virus had declined but by no means stopped. Our hypothesis that symptoms of would worsen during the pandemic was not supported by our data. Symptom levels were relatively stable during the first three months of the pandemic compared to pre-pandemic levels, with only a slight increase in depressive symptoms. During the following three summer months symptoms levels decreased, which we believe may be related to seasonality effects and changes in everyday life brought about by the summer vacations. However, it may also be related to the decreased spread of COVID-19 in Sweden; it is not possible to separate out these two explanations with the current data and design. Nevertheless, all these group-level changes were small in relation to what would be considered clinically relevant change on an individual level .We hypothesized worse mental health trajectories for groups of students who were lonely, had poor sleep quality or pre-pandemic mental health problems. Our data did not support this hypothesis either. During the pandemic, the exposed groups showed relatively favourable trajectories of mental health symptoms compared to the unexposed groups, with larger decreases in mental health symptoms for the exposed groups as compared to the unexposed groups. These patterns are similar to those seen among students in the SUN cohort whose first follow-up occurred during the autumn of 2019 (before the pandemic). One possible explanation for this pattern of decreasing differences between exposed and unexposed is that loneliness and poor sleep may not be constant over time. Some participants who experienced loneliness and sleep problems at baseline may no longer have these problems at follow-up. Mental health symptoms over time dichotomized by pre-pandemic mental health problems were most likely subject to ‘regression towards the mean’. Our interpretation is that the groups exposed to pre-pandemic loneliness, poor sleep quality or mental health problems did not show unfavourable mental health trajectories during the first months of the COVID-19 pandemic compared to the unexposed groups.Our results contrast with previous studies which reported that mental health problems worsened during the COVID-19 pandemic , 12. HowThe strengths of our study include the conduct of a natural experiment to investigate differences in mental health symptoms before and after the pandemic reached Sweden. Secondly, the instruments used for measurements of all variables have good psychometric properties, limiting the risk of misclassification. Finally, we included a large and diverse sample of university students from six universities.We recruited 27% of eligible students. Therefore, it is possible that selection bias influenced our results. However, the baseline pre-pandemic levels of mental health symptoms measured in our cohort were similar to those reported in previous studies of Swedish university students using the same instrument (DASS-21) . This suSymptoms of depression, anxiety and stress among Swedish university students were stable during the first three months of the pandemic, while there were decreased symptom levels during the summer months, probably due to seasonality effects. Pre-pandemic loneliness, poor sleep quality or mental health problems were not associated with trajectories of depression, anxiety and stress symptoms. Contrary to our hypothesis, our results do not support a worsening of mental health in Swedish university students during the first months of the COVID-19 pandemic. Neither did we find worse trajectories for students exposed to pre-pandemic loneliness, poor sleep quality or mental health problems.Click here for additional data file.Supplemental material, sj-docx-1-sjp-10.1177_14034948211015814 for Depression, anxiety and stress among Swedish university students before and during six months of the COVID-19 pandemic: A cohort study by Fred Johansson, Pierre Côté, Sheilah Hogg-Johnson, Ann Rudman, Lena w. Holm, Margreth Grotle, Irene Jensen, Tobias Sundberg, klara Edlund and Eva Skillgate in Scandinavian Journal of Public HealthClick here for additional data file.Supplemental material, sj-docx-2-sjp-10.1177_14034948211015814 for Depression, anxiety and stress among Swedish university students before and during six months of the COVID-19 pandemic: A cohort study by Fred Johansson, Pierre Côté, Sheilah Hogg-Johnson, Ann Rudman, Lena w. Holm, Margreth Grotle, Irene Jensen, Tobias Sundberg, klara Edlund and Eva Skillgate in Scandinavian Journal of Public HealthClick here for additional data file.Supplemental material, sj-jpg-1-sjp-10.1177_14034948211015814 for Depression, anxiety and stress among Swedish university students before and during six months of the COVID-19 pandemic: A cohort study by Fred Johansson, Pierre Côté, Sheilah Hogg-Johnson, Ann Rudman, Lena w. Holm, Margreth Grotle, Irene Jensen, Tobias Sundberg, klara Edlund and Eva Skillgate in Scandinavian Journal of Public HealthClick here for additional data file.Supplemental material, sj-pptx-1-sjp-10.1177_14034948211015814 for Depression, anxiety and stress among Swedish university students before and during six months of the COVID-19 pandemic: A cohort study by Fred Johansson, Pierre Côté, Sheilah Hogg-Johnson, Ann Rudman, Lena w. Holm, Margreth Grotle, Irene Jensen, Tobias Sundberg, klara Edlund and Eva Skillgate in Scandinavian Journal of Public Health


What are the profiles of cancer risk associated with immune-mediated diseases?In this cohort study of 478 753 participants, immune-mediated diseases were associated with an increased risk of total cancer. Organ-specific immune-mediated diseases had stronger associations with risk of local cancers than extralocal cancers, and many immune-mediated diseases were associated with increased risk of cancer in the involved organs and in the near and distant organs or different systems.The findings suggest that immune-mediated diseases are associated with risk of cancer at the local and systemic levels, supporting the role of local and systemic immunoregulation in carcinogenesis. Immune regulation is important for carcinogenesis; however, the cancer risk profiles associated with immune-mediated diseases need further characterization.To assess the prospective association of 48 immune-mediated diseases with the risk of total and individual cancers and the prospective association of organ-specific immune-mediated diseases with the risk of local and extralocal cancers.This prospective cohort study used data from the UK Biobank cohort study on adults aged 37 to 73 years who were recruited at 22 assessment centers throughout the UK between January 1, 2006, and December 31, 2010, with follow-up through February 28, 2019.Immune-mediated diseases.The association of immune-mediated diseases with risk of cancer was assessed with multivariable hazard ratios (HRs) and 95% CIs after adjusting for various potential confounders using time-varying Cox proportional hazards regression. Heterogeneity in the associations of organ-specific immune-mediated diseases with local and extralocal cancers was assessed using the contrast test method.P < .002 for heterogeneity). Nine immune-mediated diseases were associated with an increased risk of cancers in the involved organs ; 13 immune-mediated diseases were associated with an increased risk of cancer in the near organs  or distant organs  or in different systems .A total of 478 753 participants  were included in the study. During 4 600 460 person-years of follow-up, a total of 2834 cases of cancer were documented in 61 496 patients with immune-mediated diseases and 26 817 cases of cancer in 417 257 patients without any immune-mediated diseases . Five of the organ-specific immune-mediated diseases were significantly associated with higher risk of local but not extralocal cancers: asthma , celiac disease , idiopathic thrombocytopenic purpura , primary biliary cholangitis , and autoimmune hepatitis  (In this cohort study, immune-mediated diseases were associated with an increased risk of total cancer. Organ-specific immune-mediated diseases had stronger associations with risk of local cancers than extralocal cancers. The associations for individual immune-mediated diseases were largely organ specific but were also observed for some cancers in the near and distant organs or different systems. Our findings support the role of local and systemic immunoregulation in cancer development. This cohort study uses data from the UK Biobank to assess the associations of immune-mediated diseases with risk of total and individual cancers and of organ-specific immune-mediated diseases with risk of local and extralocal cancers. H17 and regulatory T-cell (Treg)–mediated suppression of immune surveillance, inhibition of TH1 immunity, and local and distant tumorigenesis regulated by microbiota via alterations in the inflammatory and metabolic circuitry.1Inflammation plays a pivotal role in carcinogenesis. Recent breakthroughs in cancer immunotherapy have markedly advanced our understanding about the importance of immunoregulation in cancer development. Specific mechanisms of immunoregulation in tumorigenesis have been elucidated, such as tumor-promoting inflammation, T3 Several of the aforementioned immune mechanisms for cancer are also implicated in immune-mediated diseases, such as inflammation-promoting TH17 dominance, dysfunctional Treg surveillance, and microbiota cross talk between colonized and distant organs.5 Several immune-mediated diseases have been associated with increased risk of cancer in the involved organs, such as inflammatory bowel diseases and colorectal cancer,6 primary sclerosing cholangitis and hepatobiliary cancer,7 and celiac disease and small intestine cancer.8 These findings suggest a local carcinogenic effect of immune dysregulation. However, a recent study9 found an association of certain immune-mediated diseases with higher risk of cancer in the distant organs, such as Crohn disease with extracolonic cancer and ulcerative colitis with hepatobiliary cancer. Rheumatoid arthritis as a systemic disease has been associated with a higher risk of lymphoma and lung cancer and a lower risk of breast, colorectal, and prostate cancers.11 These findings suggest that some immune-mediated diseases may be associated with cancer risk in the distant organs or systemically beyond local organs.Immune-mediated diseases constitute a clinically heterogeneous group of disorders, affecting up to 10% of the population worldwide.12 most prior studies13 did not adjust for the lifestyle risk factors that may confound the associations. In addition, previous studies13 did not assess the less common immune-mediated diseases associated with cancer risk.To our knowledge, no studies have examined the association of organ-specific immune-mediated diseases with the risk of local and extralocal cancers. The cancer risk profiles for individual immune-mediated diseases need further characterization. Moreover, although immune-mediated diseases and cancer share some similar environmental triggers,We comprehensively assessed the prospective association of 48 immune-mediated diseases with risk of total and individual cancers in the UK Biobank. We also tested the organ specificity of the associations by mapping each organ-specific immune-mediated disease with risk of local and extralocal cancers.14 Between January 1, 2006, and December 31, 2010, a total of 502 536 adults aged 37 to 73 years were recruited at 22 assessment centers throughout the UK. All participants were registered with the UK National Health Service. At the recruitment visit, participants completed a self-administered touchscreen questionnaire on sociodemographic characteristics, lifestyle exposures, medical history, and medication use and underwent physical measurements. The International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) was used to record disease diagnoses. For the current study, we excluded participants who withdrew informed consent (n = 30) and those who had prevalent cancer at recruitment (n = 23 753). A total of 478 753 participants were included. All participants provided written informed consent. All data were deidentified. The UK Biobank received ethical approval from the UK National Health Service, National Research Ethics Service North West, the National Information Governance Board for Health and Social Care in England and Wales, and the Community Health Index Advisory Group in Scotland. In addition, an independent ethics and governance council was formed to oversee its continued adherence to the ethics and governance framework. The current study was approved by the UK Biobank. Additional ethical approval and other details are provided in the eMethods in the STROBE) reporting guideline.This cohort study was a post hoc analysis of the UK Biobank study, a prospective cohort study that aimed to investigate the genetic, lifestyle, and environmental causes of a range of diseases.ICD-10 code was first recorded in participants’ inpatient records. We required the immune-mediated disease diagnosis to be present at least 12 months before the cancer diagnosis.We identified a total of 48 immune-mediated diseases and compared cancer risk between individuals with and without any of these diseases. For analyses of individual immune-mediated diseases, we focused on the 27 diseases with at least 100 affected individuals and at least 10 cancer cases among the affected individuals . Total cancers included all cancers except nonmelanoma skin cancer (C44). For analysis of individual cancers, we restricted to those with at least 100 events , whichever occurred first. A total of 1253 participants were lost to follow-up, and thus, 99.7% completed the study. Individuals with either prevalent immune-mediated diseases reported at baseline enrollment or incident diseases reported during follow-up were classified as the exposure group. For incident cases, patients were considered to have no immune-mediated disease until the date of the first reported diagnosis during follow-up.We calculated hazard ratios (HRs) and 95% CIs of total and individual cancers using time-varying Cox proportional hazards regression with age as the time scale. Model 1 was adjusted for age at recruitment, sex, and ethnicity. Model 2 was further adjusted for a set of a priori determined cancer risk factors that may be associated with immune-mediated diseases, including socioeconomic status (Townsend deprivation score), educational level, total physical activity, body mass index (BMI), waist-to-hip ratio, height, smoking status and intensity, alcohol use, consumption of processed meat and oily fish, family history of cancer, and regular use of aspirin and vitamin supplements. Sensitivity analysis of medications for immune-mediated diseases and histologic finding–specific analysis are described in the eMethods in the P value for heterogeneity in the associations of immune-mediated diseases with local and extralocal cancers using the contrast test method based on a fully unconstrained approach developed in the competing risks framework using a cause-specific proportional hazards model.15 To account for multiple testing, we performed Bonferroni correction for the primary analysis on the associations of the 27 individual immune-mediated diseases with total cancer risk and considered α = .05/27 = .002 as statistically significant. We did not conduct the correction for secondary analyses on individual cancers, which were considered exploratory, and interpreted the results with caution. SAS software, version 9.4 (SAS Institute Inc) was used for all analyses. All statistical tests were 2-sided.For the organ-specific immune-mediated diseases, we calculated the A total of 478 753 participants  were assessed in this cohort study. Most participants were White (95%), and 61 496 (13%) had at least 1 immune-mediated disease . CompareDuring a total of 4 600 460 person-years and a median of 10.0  years of follow-up, we documented 2834 cases of cancer in participants with immune-mediated diseases and 26 817 cases in those without immune-mediated diseases. Overall, immune-mediated diseases were associated with total cancer risk after multivariable adjustment  . FurtherUlcerative colitis was significantly associated with an increased risk of total cancer, with a multivariable-adjusted HR of 1.33 . Asthma  and primary biliary cholangitis  were associated with an increased risk of total cancer .For individual cancers, participants with any immune-mediated disease were at higher risk of developing lung cancer , lymphoma , and liver cancer  . We furtP < .001 for all comparisons; P < .002 for heterogeneity). In contrast, ulcerative colitis was significantly associated with higher risk of colorectal cancer and extracolorectal cancer, with a stronger association for colorectal  than extracolorectal cancer  , celiac disease with small intestine cancer , idiopathic thrombocytopenic purpura with hematologic cancer , primary biliary cholangitis with hepatobiliary cancer , and autoimmune hepatitis with hepatobiliary cancer  (13-1.49) .P < .002). In addition, 2 associations with cancers in the involved organs were found for sicca syndrome with small intestine  and mouth cancers  and Guillain-Barré syndrome with soft tissue cancer .Thirteen immune-mediated diseases were associated with an increased risk of cancer in the near or distant organs or different systems. Among them, 2 were associated with increased risk of cancer in the near organs ; 2 were associated with cancer in the distant organs . Twelve immune-mediated diseases were associated with cancers in different systems, such as idiopathic thrombocytopenic purpura with liver cancer , bullous disorders with laryngeal cancer , Graves disease or autoimmune thyroiditis with soft tissue cancer , and ulcerative colitis with prostate cancer .Among all cancers, lymphoma demonstrated an extensive association with immune-mediated diseases. The HR ranged from 2.01  for rheumatoid arthritis to 7.72  for idiopathic thrombocytopenic purpura. Rheumatoid arthritis was associated with an increased risk of lung cancer  and lymphoma  but a decreased risk of prostate  and breast  cancers. Necrotizing vasculopathies as a systemic disease was significantly associated with an increased risk of multiple myeloma . Type 1 diabetes was associated with an increased risk of liver , esophageal , and tonsil  cancers but a decreased risk of prostate cancer .In this large prospective cohort study, we found that any immune-mediated disease was associated with a modestly increased risk of total cancer after adjusting for common cancer risk factors. Although organ-specific immune-mediated diseases had stronger positive associations with risk of local cancers than extralocal cancers, several immune-mediated diseases were associated with an increased risk of cancers in the near or distant organs or different systems. Some systemic immune-mediated diseases had a positive association with risk of some cancers but a negative association with risk of other cancers. These findings may provide insight into the local and systemic effect of immune-mediated disease in the development of cancer.18 For example, a national cohort study16 in Sweden found an association of asthma with a 19% increased risk of total cancer. Ulcerative colitis was associated with a 40% higher risk of total cancer, mainly colorectal and hepatobiliary cancers.17 Patients with primary biliary cholangitis had double the risk of total cancer and approximately 40 times higher risk of hepatobiliary cancer.18To our knowledge, the current study represents the first comprehensive effort to dissect various individual immune-mediated diseases associated with cancer risk. We found that ulcerative colitis, asthma, and primary biliary cholangitis were associated with an increased risk of total cancer. These findings are consistent with prior studies.19 ulcerative colitis,6 primary biliary cholangitis,7 celiac disease,8 autoimmune hepatitis,20 idiopathic thrombocytopenic purpura,21 and lichen planus.22 In addition, we found that Sicca syndrome was associated with an increased risk of small intestine and mouth cancers and Guillain-Barré syndrome with soft tissue cancer. Regarding the mechanisms of these findings, overactivation of interleukin (IL)–12 and IL-23 signaling in immune-mediated diseases drives aberrant TH1 and TH17 immune responses, leading to chronic inflammation.4 The IL-23/TH17/IL-17 axis may reduce barrier function in the skin and local mucosa of the gut and lung and suppress cytotoxic T-cell–mediated antitumor immune surveillance in the involved organs.25 Immunopathology-mediated cell and organ damage, such as that induced by TH17 activation in inflammation, may also explain our observed associations.27Furthermore, we reported, for the first time to our knowledge, that organ-specific immune-mediated diseases were more strongly associated with higher risk of local cancers than extralocal cancers. We identified 7 immune-mediated diseases that were significantly associated with increased risk of cancer in the involved organs. These findings suggest an important role of a local carcinogenic effect of immune dysregulation. Similar associations with local cancer risk have been reported in previous studies of asthma,28 have found an association of Crohn disease and ulcerative colitis with hepatobiliary cancer. Despite the increasing evidence for the gut-liver axis30 and gut-oral axis,33 the observed associations of autoimmune hepatitis with tongue and esophageal cancers and ulcerative colitis with tongue cancer have not been reported elsewhere to our knowledge. We also observed an association between immune-mediated disease and risk of cancers in the different systems, such as ulcerative colitis with increased risk of prostate cancer and bullous disorders with laryngeal cancer. Consistent with our findings, 2 nationwide studies in Korea34 and Denmark35 reported an increased risk of prostate cancer in patients with ulcerative colitis but not Crohn disease. The association of aberrant fecal microbiome with ulcerative colitis36 and risk of prostate cancer37 as well as the anatomical proximity may explain the association. Although case series have reported that patients with mucous membrane pemphigoid may be susceptible to laryngeal cancer,38 the association of bullous disorders with laryngeal cancer risk has not been reported to our knowledge. Other positive associations of immune-mediated disease with cancers in the different systems, such as idiopathic thrombocytopenic purpura with liver cancer, Graves disease or autoimmune thyroiditis with soft tissue cancer, and psoriasis with lung and laryngeal cancer, have not been reported and need further research. The potential mechanisms include shared triggers such as hepatitis virus,39 herpesvirus,41 and skin, lung, and oral dysbiosis.44Of interest, we found that autoimmune hepatitis, Crohn disease, and ulcerative colitis were associated with increased risk of cancers in the near or distant organs within the gastrointestinal system. This finding could explain why inflammatory bowel disease and ulcerative colitis were associated with extracolorectal cancer risk in our study. Previous studies49 The mechanisms may involve chronic antigenic stimulation, inflammation, and shared genetic susceptibility. Of note, compared with solid tumors, lymphoma shares more common genetic components with immune-mediated diseases.50In our study, lymphoma was among the cancers most extensively associated with immune-mediated diseases, such as idiopathic thrombocytopenic purpura, systemic lupus erythematosus, rheumatoid arthritis, and allergic rhinitis. Some of these findings have been reported in prior studies.51 Patients with rheumatoid arthritis manifest oral and lung dysbiosis and pulmonary involvement, which could increase the risk of lung cancer.53 Previous studies56 suggest that the inverse associations with prostate and breast cancers are unlikely caused by the use of anti-inflammatory drugs, consistent with our sensitivity findings. We also found a bidirectional association of type 1 diabetes with cancer risks. Similar observations have been reported previously.57 The mechanisms for the bidirectional associations of type 1 diabetes and inverse associations of rheumatoid arthritis with risk of certain cancers remain unclear. Although increasing data indicate the diverse role of some immune components  and the gut microbiome in the development of different types of cancers,59 more studies are needed to characterize these immune and microbial changes in patients with immune-mediated diseases and elucidate the potential association of these changes with cancer risk.Rheumatoid arthritis, as a systemic disease, had a bidirectional association in our study, with a positive association with lung cancer and lymphoma and a negative association with prostate cancer and breast cancer. These findings are in line with previous reports.The major strengths of this study include the prospective cohort design, large sample size, and comprehensive organ-specific assessment. In addition, we adjusted for a variety of lifestyle risk factors that may have confounded the association of immune-mediated disease and cancer risk.62 and thus are unlikely to have had a substantial confounding effect on our results. Second, the number of cancer cases was small for some rare immune-mediated diseases. Third, despite our use of Bonferroni correction for multiple testing, chance findings could not be ruled out. Fourth, the ascertainment of immune-mediated diseases was based on inpatient records only. We may have missed some diagnoses made in the outpatient setting. However, our reported prevalence of immune-mediated disease appeared to be consistent with those in other studies in Western countries.3 In addition, given the prospective design, any misclassification in the exposure status is likely to have biased the associations toward the null. Fifth, the cohort was relatively young, with a limited number of cases of rare cancers, thus reducing the power to identify associations, particularly for metastatic cancers. Sixth, the cohort participants are predominantly White, and the findings may not be generalizable to other racial and ethnic groups.This study also has some limitations. First, the medications for treatment of immune-mediated diseases were self-reported by participants at recruitment only. No detailed data on dose or duration information were collected, thus precluding a detailed analysis of these medications. However, in line with our sensitivity analysis results, medications for immune-mediated diseases have not been associated with cancer riskIn this cohort study, overall immune-mediated diseases were associated with an increased risk of total cancer. Organ-specific immune-mediated diseases had stronger associations with risk of local cancer than extralocal cancer. Many immune-mediated diseases were associated with increased risk of cancers in the involved organs and in the near and distant organs or different systems. These findings support the importance of local and systemic immunoregulation in carcinogenesis and may inform future research elucidating the role of immunoregulation and microbiota in cancer development.