Russia’s invasion of Ukraine (February 24, 2022) has begun and there are concerns about the impact on health care supply and mental health. This study analyzed tweets in the Ukrainian language to capture the medical needs and mental health conditions in wartime Ukraine by focusing on ostensibly relevant words. The number of tweets containing the keywords and their overall proportion was compared before and after the Russian invasion of Ukraine. The survey period was divided into four phases—the pre-2022 Russian invasion, acute phase (4 weeks), subacute phase (12 weeks), and the chronic phase (8 weeks) up to August 10, 2022. The analysis targeted tweets sent in Ukrainian. The tweets were screened using a set of six classes with 75 key groups and 303 Ukrainian (204 original Japanese) keywords. Overall, 98,526,440 tweets were analyzed, with a pre-invasion and post-onset average of 1,096,976 and 3,328,243 tweets/week (a 3.0-fold increase), respectively. Of these, 3,197,443 tweets contained the keywords, with a pre-invasion and invasion average of 26,241 and 114,640 tweets/week (a 4.4-fold increase), respectively. The post-onset phase witnessed a considerable increase in all classes—medical services, treatment, medical resources, medical situations, and special situations—but not in the symptom class. Keywords related to psychological distress and anxiety immediately increased during the acute phase; those related to depression and post-traumatic stress reactions continued increasing as the invasion persisted, which may have reflected the mental state of those impacted. Analyzing tweets is useful for predicting people’s real-time physical and mental health needs during wartime.

Antithrombin deficiency is a high-risk factor for venous thromboembolism during pregnancy, whereas cerebral venous thrombosis is rare. Cerebral venous thrombosis related to coronavirus disease 2019 (COVID-19) vaccines has been reported; however, there are a few reports of cerebral venous thrombosis after a messenger RNA (mRNA) vaccination. A 25-year-old female in her sixth week of pregnancy presented with headache 24 days after BNT162b2 mRNA COVID-19 vaccination. The following day, she presented with altered sensorium and was diagnosed with severe cerebral venous thrombosis. She demonstrated heparin resistance and was found to have an inherited antithrombin deficiency. A heterozygous missense variant in SERPINC1 (c.379T>C, p.Cys127Arg, ‘AT Morioka’) was detected by DNA analysis. Despite intensive care with unfractionated heparin, antithrombin concentrate, and repeated endovascular treatments, she died on the sixth day of hospitalization. Cerebral venous thrombosis in pregnant women with an antithrombin deficiency can follow a rapid and fatal course. Treatment with unfractionated heparin and antithrombin concentrate may be ineffective in severe cerebral venous thrombosis cases with antithrombin deficiency. Early recognition of antithrombin deficiency and an immediate switch to other anticoagulants may be required. Although the association between cerebral venous thrombosis and the vaccine is uncertain, COVID-19 vaccinations may require careful evaluation for patients with prothrombic factors.

The prevalence of Alzheimer’s disease (AD) has been rapidly increasing worldwide. We have developed a novel angiogenic therapy with low-intensity pulsed ultrasound (LIPUS), which is effective and safe in animal models of AD and vascular dementia. We performed two trials of LIPUS therapy for AD (mild cognitive impairment due to AD and mild AD); a roll-in open trial for safety, and a randomized, double-blind, placebo-controlled (RCT) trial for efficacy and safety. The LIPUS therapy was performed for whole brain through the bilateral temporal bones for one hour 3 times a week as one session under the special conditions (1.3 MPa, 32 cycles, 5% duty cycle) we identified. The LIPUS therapy was performed for one session in the roll-in trial, and 6 sessions in the RCT trial with 3-month intervals for 1.5 years. The primary endpoint was ADAS-J cog scores. The RCT trial was terminated prematurely due to the COVID-19 pandemic. In the roll-in trial (N = 5), no adverse effects were noted. In the RCT trial (N = 22), the worsening of ADAS-J cog scores tended to be suppressed in the LIPUS group compared with the placebo group at week 72 (P = 0.257). When responders were defined as those with no worsening of ADAS-J cog scores at week 72, the prevalence was 50% (5/10) and 0% (0/5) in the LIPUS and placebo groups, respectively (P = 0.053). No adverse effects were noted. These results suggest that the LIPUS therapy is safe and tends to suppress cognitive impairment although a next pivotal trial with a large number of subjects is warranted.

A myeloid immune checkpoint, leukocyte immunoglobulin-like receptor (LILR) B4 (B4, also known as ILT3/CD85k in humans and gp49B in mice) is expressed on dendritic cells (DCs). However, a mode of regulation of DCs by B4/gp49B is not identified yet in relation to the ligand(s) as well as to the counteracting, activation-type receptor. Our recent identification of the physiological/pathological ligand for B4/gp49B as the fibronectin (FN) N-terminal 30-kDa domain poses the question of the relationship between B4/gp49B and a classical FN receptor/cellular activator, integrin, on DCs. Here we showed that FN is not constitutively tethered on the surface of bone marrow-derived cultured DCs (BMDCs) or splenic DCs, even though the FN receptor integrin and gp49B are co-expressed on these cells. Confocal laser scanning microscopic analysis, however, revealed weak correlation of fluorescent signals between gp49B and integrin β₁, suggesting their partial co-localization on the BMDC surface even in the absence of FN. We found that the plating of BMDCs onto immobilized FN induced tyrosine phosphorylation of focal adhesion kinase (FAK) and spleen tyrosine kinase (Syk). In the absence of gp49B, while the FAK phosphorylation level was virtually unchanged, that of phosphorylation of Syk was markedly augmented. These results suggested that the immobilized FN induced a crosstalk between gp49B and integrin in terms of the intracellular signaling of BMDCs, in which gp49B suppressed the integrin-mediated pro-inflammatory cascade. Our observations may provide a clue for elucidating the mechanism of the therapeutic efficacy of B4/gp49B blocking in autoimmune disease and cancer.

Disruption of cancer screening programs and diagnoses of gastrointestinal cancers by the COVID-19 pandemic has been reported; however, little attention has been paid to the situation in depopulated areas with low infection rates. Akita Prefecture is one of the most depopulated areas of Japan and has the lowest COVID-19 infection rate per capita; at the same time, the prefecture has been top-ranked for mortality due to gastrointestinal cancer for years. In this population-based study in Akita Prefecture, we investigated the occurrence of gastrointestinal cancers and the number of cancer screening procedures over the five-year period of 2016-2020, employing a database from the collaborative Akita Prefecture hospital-based registration system of cancers. The occurrence of gastrointestinal cancers, especially esophago-gastric cancers, declined by 11.0% in 2020, when the COVID-19 pandemic affected the overall healthcare system, compared with the average of 2016-2019. Nonetheless, the occurrence of advanced-stage (stage IV) esophago-gastric cancers increased by 7.2% in 2020. The decrease in the gastrointestinal cancer diagnosis rate in 2020 coincided with a 30% decline in the total number of regular population-based screening programs. Under the ongoing COVID-19 pandemic, cancer screening was uniformly suspended throughout Japan. Accordingly, the COVID-19 pandemic has substantially disrupted the cancer screening system, leading to delays in diagnoses of gastrointestinal cancer, even in depopulated areas (Akita Prefecture) of Japan with a low prevalence of infection. Suspension of cancer screening procedures during an infectious disease pandemic should be thoroughly considered for each region based on the cancer incidence and infection status in that area.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remained a major global health concern in 2021. To suppress the spread of infection, mass vaccinations have been performed across countries worldwide. In Japan, vaccinations of the first and second doses for most of the nation were performed during the nationwide outbreak of the B.1.617.2 (Delta) variant with the L452R spike protein mutation, and the effectiveness of the vaccinations to suppress the spread of COVID-19 among the people in Japan remains uncertain. In this study, adults aged ≥18 years, who were in contact with patients with COVID-19 and underwent nasopharyngeal swab reverse transcription-polymerase chain reaction (RT-PCR) tests during August and September 2021 at a mass screening test center in Japan, were enrolled. In this period, more than 95% of the COVID-19 infections were reportedly caused by the Delta variant. As a result, a total of 784 adults with recent contact history, including 231 (29.5%) RT-PCR test-positive cases, were enrolled. The test positivity rate was lower in individuals who had been vaccinated twice than in unvaccinated individuals (12.5% vs. 39.0%, p < 0.0001), with the risk ratio of 0.32 (95% confidence interval 0.23-0.46). The vaccine effectiveness was the highest between 7-90 days after the second vaccine dose. In conclusion, two doses of mRNA COVID-19 vaccines effectively suppressed transmission in Japan during the nationwide pandemic of the Delta variant, estimated to have prevented 50-80% of the infection.

Recent advances in dysphagia treatment have given us many methods of stimulating swallowing function, but no attempt has been made to systematically classify them all. In this review, we provide an exhaustive description of all the techniques and stimulatory substances that stimulate swallowing that have so far been reported in the scientific literature, irrespective of their level of evidence, and we have tried to classify them with the objective of encouraging the future development of research in this direction. The Preferred Reporting Items for Systematic Reviews and Meta-analysis were followed for retrieval of relevant research. A total of 237 records were screened for this literature review. One record was excluded for being published in a language other than English, and 59 articles were excluded for having no original data. Of the 177 records that were assessed for eligibility in this review, 31 were excluded for reasons related to other inclusion and exclusion criteria. Finally, 146 records were classified. We found stimuli related to swallowing published in the literature could be divided into physical and chemical stimuli. Each stimulus had both peripheral and central stimuli when we assessed the main site of action. Physical stimuli included electric, magnetic and thermal stimulations and acupuncture. Chemical stimuli included spices activating transient receptor potential channels, several categories of medications, taste and flavor, and olfactory stimulants. Medications modifying substance P and the dopaminergic system are thought to be peripheral and central stimuli, respectively. This classification may pave the way to discover means to improve swallowing.

Coronavirus disease 2019 (COVID-19) is associated with various symptoms and changes in hematological and biochemical variables. However, clinical features, which can differentiate COVID-19 from non-COVID-19, are not clear. We therefore examined the key clinical features of COVID-19 and non-COVID-19 patients. This study included 60 COVID-19 patients and 100 non-COVID-19 patients, diagnosed by PCR, and no significant differences in the age and sex were seen between the two groups. The frequencies of fatigue, loose stool, diarrhea, nasal obstruction, olfactory dysfunction, taste dysfunction, underlying hyperlipidemia, and the prescription of angiotensin II receptor blocker (ARB) were significantly higher in COVID-19 patients than those in non-COVID-19 patients. The counts of leucocytes, neutrophils, lymphocytes, eosinophils, monocytes, and basophils and the levels of chloride and calcium in blood of COVID-19 patients were significantly lower than those of non-COVID-19 patients. The frequencies of atypical lymphocytes and the levels of lactate dehydrogenase (LDH) and potassium were significantly higher in COVID-19 than those in non-COVID-19. The C-reactive protein (CRP) level in COVID-19 patients was significantly lower than that in non-COVID-19 patients, when we compared CRP levels among patients with elevated CRP. This study is the first to indicate that electrolyte levels and the frequency of atypical lymphocytes in COVID-19 are significantly different from those in non-COVID-19. Fatigue, loose stool, diarrhea, nasal obstruction, olfactory dysfunction, and taste dysfunction were the key symptoms of COVID-19. Furthermore, hyperlipidemia and ARB may be risk factors of COVID-19. In conclusion, leucocytes, leucocyte fractions, CRP, LDH, and electrolytes are useful indicators for COVID-19 diagnosis.

The Coronavirus Disease 2019 (COVID-19) pandemic has killed many people worldwide since December 2019, and Iran has been among the most affected countries. In this retrospective study, we aimed to determine the prognostic factors associated with mortality in COVID-19 patients by analyzing 396 survived and 63 non-survived patients in Shahid Modarres Hospital, Tehran, Iran, from January 30^th until April 5^th, 2020. As the results, the BMI > 35 (p = 0.0003), lung cancer (p = 0.007), chronic kidney disease (p = 0.002), Immunocompromised condition (p = 0.003), and diabetes (p = 0.018) were more frequently observed in the expired group. The history of statins use was more common in the discharged group (p = 0.002), while there was no significant difference in the drug history of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, nonsteroidal anti-inflammatory drugs, aspirin, and/or steroids, and in the past-year influenza vaccination. Multivariable regression demonstrated rising odds of in-hospital death related with age (odds ratio (OR) = 1.055, p = 0.002), levels of C-reactive protein (CRP) (OR = 2.915, p < 0.001), creatinine (OR = 1.740, p = 0.023), lymphocyte count (OR = 0.999, p = 0.008), and magnesium level (OR = 0.032, p < 0.001) on admission. In conclusion, the patients with older age and higher BMI with lymphopenia, hypomagnesemia, elevated CRP and/or raised creatinine on admission are at higher risk of mortality due to the COVID-19 infection, which requires the physicians to use timely and strong therapeutic measures for such patients.

The present study provides an overview of the coronavirus disease 2019 (COVID-19) outbreak which has rapidly extended globally within a short period. COVID-19 is a highly infectious respiratory disease caused by a new coronavirus known as SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2). SARS-CoV-2 is different from usual coronaviruses responsible for mild sickness such as common cold among human beings. It is crucial to understand the impact and outcome of this pandemic. We therefore overview the changes in the curves of COVID-19 confirmed cases and fatality rate in China and outside of China from 31^st of December 2019 to 25^th of March 2020. We also aimed to assess the temporal developments and death rate of COVID-19 in China and worldwide. More than 414,179 confirmed cases of COVID-19 have been reported in 197 countries, including 81,848 cases in China and 332,331 outside of China. Furthermore, 18,440 infected patients died from COVID-19 infection; 3,287 cases were from China and 15,153 fatalities were reported worldwide. Among the worldwide infected cases, 113,802 patients have been recovered and discharged from different hospitals. Effective prevention and control measures should be taken to control the disease. The presented Chinese model (protocol) of disease prevention and control could be utilized in order to curb the pandemic situation.

The programmed cell death-1 (PD-1) pathway is a novel therapeutic target in immune checkpoint therapy for cancer. Nivolumab, an anti-PD-1 monoclonal antibody, blocks PD-1 and can restore anti-cancer immune responses by disrupting the signal that inhibits T-cell activation. Nivolumab may induce endocrine-related adverse events, including hypophysitis, autoimmune thyroiditis, and type 1 diabetes mellitus. Here we report a 68-year-old female patient with advanced renal cell carcinoma who was treated with nivolumab. She had positive anti-thyroglobulin antibodies and anti-thyroid peroxidase antibodies with slightly elevated thyroid-stimulating hormone (9.048 μU/mL), and was diagnosed as chronic thyroiditis with subclinical hypothyroidism before nivolumab therapy. She developed painless thyroiditis after the first cycle of the therapy (Day 14). At the 7th cycle of nivolumab therapy (Day 98), hyperglycemia (473 mg/dL) was noted, whereas glycated hemoglobin level was 6.9%. Islet-related autoantibodies were all negative. The glucagon tolerance test showed complete depletion of insulin. Human leukocyte antigen typing showed haplotype DRB1*09:01-DQB1*03:03, which was reported to be closely associated with type 1 diabetes mellitus in Japan. Fulminant type 1 diabetes mellitus was diagnosed, and she was immediately treated with multiple daily injections of insulin. Fulminant type 1 diabetes mellitus is characterized by rapid-onset diabetic ketoacidosis, and negative islet-related autoantibodies, and was proposed as a novel subtype of non-autoimmune diabetes. Preceding painless thyroiditis with positive thyroid autoantibodies observed in the present case, however, raises the possibility that autoimmune mechanisms are involved in the pathogenesis of nivolumab-induced fulminant type 1 diabetes mellitus.

Emerging studies suggest the significance of broadening the benefit of anti-programmed cell death 1 (PD-1) therapy for lung cancer. The anti-angiogenic agents have been reported to alter the tumor microenvironment and contributes to efficiency of anti-PD-1 therapy. This study aims to investigate whether the anti-angiogenic agent rhamnazin enhances the efficacy of anti-PD-1 therapy in lung cancer. In Lewis lung carcinoma (LLC) xenografts, the combination of rhamnazin and anti-PD-1 treatment suppressed tumor growth, elevated the infiltration of CD4⁺ T and CD8⁺ T cells in tumors and up-regulated interferon-gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and granzyme B. Furthermore, the combination reduced programmed cell death ligand 1 (PD-L1) expression in tumors more significant than anti-PD-1 treated group. In LLC cell experiments, rhamnazin inhibited vascular endothelial growth factor A (VEGFA)-stimulated vascular endothelial growth factor receptor 2 (VEGFR2) phosphorylation and PD-L1 expression, whereas VEGFR2 overexpression reversed these trends. T cell proliferation and cytotoxic factor production were evaluated after co-culturing with non-small cell lung cancer (NSCLC) H1975 cells. Rhamnazin promotes T cell proliferation and up-regulated IFN-γ, TNF-α and granzyme B in the co-culture system, while VEGFR2 overexpression abrogated these changes. These data suggest that rhamnazin enhances anti-tumor effect of anti-PD-1 therapy for lung cancer in mice via inhibition of PD-L1 expression.

Vitamin D attenuates inflammatory responses to viral respiratory infections. Hence, vitamin D deficiency may be a highly significant prognostic factor for severity and mortality in COVID-19 patients. To evaluate the complications and mortality in different vitamin D status groups in COVID-19 hospitalized patients, we conducted this retrospective study on 646 laboratory-confirmed COVID-19 patients who were hospitalized in Shahid Modarres Hospital, Tehran, Iran from 16th March 2020 until 25th February 2021. Overall, patients with vitamin D deficiency, insufficiency and sufficiency were 16.9%, 43.6% and 39.5%, respectively. The presence of comorbidity, length of hospitalization, ICU admission, and invasive mechanical ventilation requirement and overall complications were significantly more in patients with vitamin D deficiency (p-value < 0.001). 46.8% (51/109) of vitamin D deficient patients died due to the disease, whilst the mortality rate among insufficient and sufficient vitamin D groups was 29.4% (83/282) and 5.5% (14/255), respectively. In univariate analysis, age > 60 years (odds ratio (OR) = 6.1), presence of comorbidity (OR = 10.7), insufficient vitamin D status (OR = 7.2), and deficient vitamin D status (OR = 15.1) were associated with increase in COVID-19 mortality (p-value < 0.001). Finally, the multivariate analysis adjusted for age, sex, and comorbidities indicated vitamin D deficiency as an independent risk factor for mortality (OR = 3.3, p-value = 0.002). Vitamin D deficiency is a strong risk factor for mortality and severity of SARS-CoV-2 infection. Vitamin D supplementation may be able to prevent or improve the prognosis of COVID-19 during this pandemic.

Olfactory disorders are one of the characteristic symptoms of the coronavirus disease of 2019 (COVID-19), which causes infection and inflammation of the upper and lower respiratory tract. To our knowledge, there are no treatments for COVID-19-related olfactory disorder. Here, we report five olfactory disorder cases in COVID-19, treated using the Japanese traditional (Kampo) medicine, kakkontokasenkyushin’i. We treated five patients with mild COVID-19 at an isolation facility using Kampo medicine, depending on their symptoms. Patients with the olfactory disorder presented with a blocked nose, nasal discharge or taste impairment. Physical examination using Kampo medicine showed similar findings, such as a red tongue with red spots and sublingual vein congestion, which presented as blood stasis and inflammation; thus, we prescribed the Kampo medicine, kakkontokasenkyushin’i. After administration, the numeric rating scale scores of the smell impairment improved within 3 days from 9 to 3 in case 1, from 10 to 0 in case 2, from 9 to 0 in case 3, from 5 to 0 in case 4, and from 9 to 0 within 5 days in case 5. Following the treatment, other common cold symptoms were also alleviated. Kakkontokasenkyushin’i can be used for treating nasal congestion, rhinitis, and inflammation in the nasal mucosa. The olfactory disorder in COVID-19 has been reportedly associated with inflammation and congestion, especially in the olfactory bulb and olfactory cleft. Kakkontokasenkyushin’i may be one of the treatment alternatives for the olfactory disorder with rhinitis in patients with COVID-19.

Coronavirus disease 2019 (COVID-19) is causing disruptions in the global social system. Japanese children and adolescents have had their schools closed, government-mandated activity restrictions imposed, and interactions outside the home reduced. These restrictions can have a considerable psychological impact on children and adolescents. This review aims to describe the impacts of COVID-19 pandemic on physical activity and psychological status of this population. The review was conducted by searching PubMed for information on the impact of COVID-19−related activity restrictions on children and adolescents. The search identified 11 articles, three of which contained data on anxiety and psychological problems due to physical inactivity. Next, a PubMed search was conducted about physical activity and psychological status in children and adolescents under psychological stress. The search identified 368 articles, 28 of which were included in the review. For children, data that revealed a correlation between physical activity and psychological health and sedentary time leading to mood disorders were included. For adolescents, there were nine studies that reported a correlation between physical activity and psychological health and four studies that reported no correlation between physical activity and psychological health. Of the studies that reported a correlation, seven reported that physical activity improves psychological health. The impact of psychologically stressful situations such as COVID-19 on children and adolescents has been experienced worldwide. Physical activity has been correlated with psychological health, and it may improve psychological status; physical activity should be recommended to better support the psychological health of children and adolescents under the influence of COVID-19.

In response to the COVID-19 pandemic caused by SARS-CoV-2 in 2020, we conducted drive-through nasopharyngeal swab testing for COVID-19 in Sendai city, Japan, since April 2020. All tested individuals were judged in advance by public health centers for the necessity of undergoing the test with possible contact history and/or symptoms suggestive of COVID-19. In this study, to identify the predictors of SARS-CoV-2 test positivity for more efficient and evidenced selection of suspected individuals, we enrolled 3,540 consecutive individuals, tested in the first 7 months of the testing program, with data regarding to the history of close contact with COVID-19 patients, including those involved in cluster outbreaks. This cohort included 284 foreign students (257 males and 27 females) from a vocational school involved in the largest cluster outbreak in the area. Close contact history was present in 952 (26.9%) of the participants. The reverse transcription-polymerase chain reaction (RT-PCR) test results showed that 164 participants (4.6%) were positive and 3,376 participants (95.4%) were negative for the SARS-CoV-2 nucleocapsid gene (N2). In the univariate and multivariate analyses, history of close contact with COVID-19 patients, higher age, cough symptoms, and non-native ethnicity were predictors for SARS-CoV-2 test positivity. However, the significance of age and foreign nationality disappeared or declined upon excluding the foreign students from the aforementioned largest cluster outbreak. In conclusion, a history of close contact with COVID-19 patients and the presence of cough symptoms are significant predictors of SARS-CoV-2 test positivity.