Immunogenic Comparison of Nucleic Acid-Based Vaccines Administered by Pyro-Drive Jet Injector.

mRNA vaccines were successfully developed and approved for emergency use to fight coronavirus disease 2019. However, the effect of DNA vaccines against SARS-CoV-2 is considerably lower than that of mRNA vaccines. A pyro-drive jet injector (PJI) efficiently delivers plasmid DNA intradermally into animal models. Here, we compared the immunogenic potential of DNA and mRNA vaccines in mice using the same platform. PJI was used to deliver naked mRNA and pDNA and their efficacy in inducing antigen expression and immune responses was assessed. Our results showed that PJI efficiently delivered mRNA into the skin, and a smaller effective dose than that of pDNA injection was required to achieve similar levels of antigen expression. The PJI-delivered CpG-free pDNA vaccine efficiently induced antigen-specific antibody production and a cell-mediated IFN-γ response compared to the mRNA vaccine, as well as the upregulation of inflammatory cytokines (IL-6, IFN-γ, and IL-1ß) in the skin and lymph nodes. However, the intradermal mRNA vaccine was significantly less immunogenic than the standard intramuscular mRNA-lipid nanoparticle vaccine, despite equivalent mRNA dosages. Improvements in lipid nanoparticle and mRNA technology have revolutionized mRNA vaccines, and DNA vaccines can be similarly modified for higher clinical efficacy.

Vaccine Therapy for Heart Failure Targeting the Inflammatory Cytokine Igfbp7.

BACKGROUND: The heart comprises many types of cells such as cardiomyocytes, endothelial cells (ECs), fibroblasts, smooth muscle cells, pericytes, and blood cells. Every cell type responds to various stressors (eg, hemodynamic overload and ischemia) and changes its properties and interrelationships among cells. To date, heart failure research has focused mainly on cardiomyocytes; however, other types of cells and their cell-to-cell interactions might also be important in the pathogenesis of heart failure. METHODS: Pressure overload was imposed on mice by transverse aortic constriction and the vascular structure of the heart was examined using a tissue transparency technique. Functional and molecular analyses including single-cell RNA sequencing were performed on the hearts of wild-type mice and EC-specific gene knockout mice. Metabolites in heart tissue were measured by capillary electrophoresis-time of flight-mass spectrometry system. The vaccine was prepared by conjugating the synthesized epitope peptides with keyhole limpet hemocyanin and administered to mice with aluminum hydroxide as an adjuvant. Tissue samples from heart failure patients were used for single-nucleus RNA sequencing to examine gene expression in ECs and perform pathway analysis in cardiomyocytes. RESULTS: Pressure overload induced the development of intricately entwined blood vessels in murine hearts, leading to the accumulation of replication stress and DNA damage in cardiac ECs. Inhibition of cell proliferation by a cyclin-dependent kinase inhibitor reduced DNA damage in ECs and ameliorated transverse aortic constriction-induced cardiac dysfunction. Single-cell RNA sequencing analysis revealed upregulation of Igfbp7 (insulin-like growth factor-binding protein 7) expression in the senescent ECs and downregulation of insulin signaling and oxidative phosphorylation in cardiomyocytes of murine and human failing hearts. Overexpression of Igfbp7 in the murine heart using AAV9 (adeno-associated virus serotype 9) exacerbated cardiac dysfunction, while EC-specific deletion of Igfbp7 and the vaccine targeting Igfbp7 ameliorated cardiac dysfunction with increased oxidative phosphorylation in cardiomyocytes under pressure overload. CONCLUSIONS: Igfbp7 produced by senescent ECs causes cardiac dysfunction and vaccine therapy targeting Igfbp7 may be useful to prevent the development of heart failure.

Early acquisition of S-specific Tfh clonotypes after SARS-CoV-2 vaccination is associated with the longevity of anti-S antibodies.

SARS-CoV-2 vaccines have been used worldwide to combat COVID-19 pandemic. To elucidate the factors that determine the longevity of spike (S)-specific antibodies, we traced the characteristics of S-specific T cell clonotypes together with their epitopes and anti-S antibody titers before and after BNT162b2 vaccination over time. T cell receptor (TCR) αß sequences and mRNA expression of the S-responded T cells were investigated using single-cell TCR- and RNA-sequencing. Highly expanded 199 TCR clonotypes upon stimulation with S peptide pools were reconstituted into a reporter T cell line for the determination of epitopes and restricting HLAs. Among them, we could determine 78 S epitopes, most of which were conserved in variants of concern (VOCs). After the 2nd vaccination, T cell clonotypes highly responsive to recall S stimulation were polarized to follicular helper T (Tfh)-like cells in donors exhibiting sustained anti-S antibody titers (designated as 'sustainers'), but not in 'decliners'. Even before vaccination, S-reactive CD4+ T cell clonotypes did exist, most of which cross-reacted with environmental or symbiotic microbes. However, these clonotypes contracted after vaccination. Conversely, S-reactive clonotypes dominated after vaccination were undetectable in pre-vaccinated T cell pool, suggesting that highly responding S-reactive T cells were established by vaccination from rare clonotypes. These results suggest that de novo acquisition of memory Tfh-like cells upon vaccination may contribute to the longevity of anti-S antibody titers.

Preventive effects of vasohibin-2-targeting peptide vaccine for diabetic nephropathy.

Diabetic nephropathy remains the leading cause of end-stage kidney disease in many countries, and additional therapeutic targets are needed to prevent its development and progression. Some angiogenic factors are involved in the pathogenesis of diabetic nephropathy. Vasohibin-2 (VASH2) is a novel proangiogenic factor, and our previous study showed that glomerular damage is inhibited in diabetic Vash2 homozygous knockout mice. Therefore, we established a VASH2-targeting peptide vaccine as a tool for anti-VASH2 therapy in diabetic nephropathy. In this study, the preventive effects of the VASH2-targeting peptide vaccine against glomerular injury were examined in a streptozotocin (STZ)-induced diabetic mouse model. The mice were subcutaneously injected with the vaccine at two doses 2 wk apart and then intraperitoneally injected with 50 mg/kg STZ for 5 consecutive days. Glomerular injury was evaluated 20 wk after the first vaccination. Treatment with the VASH2-targeting peptide vaccine successfully induced circulating anti-VASH2 antibody without inflammation in major organs. Although the vaccination did not affect blood glucose levels, it significantly prevented hyperglycemia-induced increases in urinary albumin excretion and glomerular volume. The vaccination did not affect increased VASH2 expression but significantly inhibited renal angiopoietin-2 (Angpt2) expression in the diabetic mice. Furthermore, it significantly prevented glomerular macrophage infiltration. The preventive effects of vaccination on glomerular injury were also confirmed in db/db mice. Taken together, the results of this study suggest that the VASH2-targeting peptide vaccine may prevent diabetic glomerular injury in mice by inhibiting Angpt2-mediated microinflammation.NEW & NOTEWORTHY This study demonstrated preventive effects of VASH2-targeting peptide vaccine therapy on albuminuria and glomerular microinflammation in STZ-induced diabetic mouse model by inhibiting renal Angpt2 expression. The vaccination was also effective in db/db mice. The results highlight the importance of VASH2 in the pathogenesis of early-stage diabetic nephropathy and the practicability of anti-VASH2 strategy as a vaccine therapy.

Efficacy and safety in mice of repeated, lifelong administration of an ANGPTL3 vaccine.

Previously, we reported that an ANGPTL3 vaccine is a hopeful therapeutic option against dyslipidemia. In our current study, we assess durability and booster effects of that vaccine over a period representing a mouse's lifespan. The vaccine remained effective for over one year, and booster vaccination maintained suppression of circulating triglyceride levels thereafter without major adverse effects on lungs, kidneys, or liver, suggesting vaccine efficacy and safety.

Long Term Follow-Up Study of a Randomized, Open-Label, Uncontrolled, Phase I/II Study to Assess the Safety and Immunogenicity of Intramuscular and Intradermal Doses of COVID-19 DNA Vaccine (AG0302-COVID19).

Pharmacological studies have demonstrated antibody production and infection prevention with an intradermal coronavirus disease 2019 (COVID-19) DNA vaccine (AG0302-COVID-19). This clinical trial aimed to investigate the safety and immunogenicity of high doses of AG0302-COVID19 when injected intramuscularly and intradermally. Healthy adults were randomly divided into three intramuscular vaccination groups (2 mg, three times at 2-week intervals; 4 mg, twice at 4-week intervals; and 8 mg, twice at 4-week intervals) and two intradermal groups (1 mg, three times at 2-week intervals or twice at 4-week intervals). After a one-year follow-up, no serious adverse events were related to AG0302-COVID-19. At Week 52, the changes in the geometric mean titer (GMT) ratios of the anti-S antibodies were 2.5, 2.4, and 3.2 in the 2, 4, and 8 mg intramuscular groups, respectively, and 3.2 and 5.1 in the three times and twice injected intradermal groups, respectively. The number of INF-γ-producing cells responsive to S protein increased after the first dose and was sustained for several months. AG0302-COVID-19 showed an acceptable safety profile, but the induction of a humoral immune response was insufficient to justify progressing to a Phase 3 program.

Development of a Novel and Simple Anti-Metastatic Cancer Treatment Targeting Vasohibin-2.

Vasohibin-2 (VASH2), a homologue of vasohibin-1 (VASH1), is overexpressed in various cancer cells and promotes tumor progression. We therefore regard VASH2 as a molecular target for cancer treatment. Here we applied vaccine technology to develop a therapy against VASH2. We selected two amino acid sequences of VASH2 protein; the MTG and RRR peptides, which contain possible B cell epitopes. These sequences are identical between the human and murine VASH2 proteins and distinct from those of the VASH1 protein. We conjugated these peptides with the carrier protein keyhole limpet hemocyanin, mixed with an adjuvant, and injected subcutaneously twice at a 2-week interval in mice. Both vaccines increased antibodies against the antigen peptide; however, only the MTG peptide vaccine increased antibodies that recognized the recombinant VASH2 protein. When Lewis lung cancer (LLC) cells were subcutaneously inoculated, tumors isolated from mice immunized with the MTG peptide vaccine showed a significant decrease in the expression of epithelial-to-mesenchymal transition (EMT) markers. EMT is responsible for cancer cell invasion and metastasis. When the LLC cells were injected into the tail vein, the MTG peptide vaccine inhibited lung metastasis. Moreover, the MTG peptide vaccine inhibited the metastasis of pancreatic cancer cells to the liver in an orthotopic mouse model, and there was a significant inverse correlation between the ELISA titer and metastasis inhibition. Therefore, we propose that the MTG peptide vaccine is a novel anti-metastatic cancer treatment that targets VASH2 and can be applied even in the most malignant and highly metastatic pancreatic cancer.

Acquisition of Humoral Immune Responses in Convalescent Japanese People with SARS-CoV-2 (COVID-19) Infection in 2021.

We investigated humoral immune responses in 222 unvaccinated Japanese people after recovery from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in 2021. Anti-spike-protein IgG antibody levels and neutralizing antibody titers were measured in serum samples obtained within 20-180 days after diagnosis. The geometric mean of antibody titers was 1555 ELU/mL (95% confidence interval (CI) = 1257-1923), and the neutralizing activity (50% inhibitory dilution) was 253 (95% CI = 204-313). The antibody titer and neutralizing activity both increased with increasing disease severity, and both values were approximately fourfold higher for hospitalized patients than for non-hospitalized patients. However, these differences were smaller in older patients. The humoral immune response, which increased with increasing disease severity, gradually decreased over time after SARS-CoV-2 infection. Most patients with mild or moderate symptoms sustained neutralizing activity for up to 180 days after the infection; the decay of the neutralizing activity in the asymptomatic patients was rather faster than in the other groups. Around 11.7% (26/222) of patients had very low neutralizing activity, and half of these were aged in their 20s. Our study's results show the importance of measuring the neutralizing activity to confirm the immune status and to estimate the timing of vaccines.

Intradermal administration of DNA vaccine targeting Omicron SARS-CoV-2 via pyro-drive jet injector provides the prolonged neutralizing antibody production via germinal center reaction.

Emerging SARS-CoV-2 Omicron variants are highly contagious with enhanced immune escape mechanisms against the initially approved COVID-19 vaccines. Therefore, we require stable alternative-platform vaccines that confer protection against newer variants of SARS-CoV-2. We designed an Omicron B.1.1.529 specific DNA vaccine using our DNA vaccine platform and evaluated the humoral and cellular immune responses. SD rats intradermally administered with Omicron-specific DNA vaccine via pyro-drive jet injector (PJI) thrice at 2-week intervals elicited high antibody titers against the Omicron subvariants as well as the ancestral strain. Indeed, the Omicron B.1.1.529-specific antibody titer and neutralizing antibody were higher than that of other strains. Longitudinal monitoring indicated that anti-spike (ancestral and Omicron) antibody titers decreased toward 30 weeks after the first vaccination dose. However, neutralization activity remained unaltered. Germinal center formation was histologically detected in lymph nodes in rats immunized with Omicron DNA vaccine. Ancestral spike-specific immune cell response was slightly weaker than Omicron spike-specific response in splenocytes with Omicron-adapted DNA vaccine, evaluated by ELISpot assay. Collectively, our findings suggest that Omicron targeting DNA vaccines via PJI can elicit robust durable antibody production mediated by germinal center reaction against this new variant as well as partially against the spike protein of other SARS-CoV-2 variants.

Impact of insufficient recovery of cerebral blood flow due to partial reperfusion on the pathophysiology of ischemic stroke in mice.

Recent advances in endovascular treatment (EVT) dramatically changed the outcome of ischemic stroke, but partial reperfusion does not improve the outcome as well as no reperfusion. Although partial reperfusion is estimated to be more potential for therapeutic intervention than permanent occlusion due to some blood supply, their pathophysiological difference is still unknown. To answer the question, we analyzed the difference in mice, which were exposed to distal middle cerebral artery occlusion with 14-min common carotid artery (CCA) occlusion (partial reperfusion) or permanent CCA occlusion (no reperfusion). Although the final infarct volume was same between permanent and partial reperfusion, Fluoro-jade C staining showed that neurodegeneration was inhibited both in the severe and moderate ischemic region 3 h after partial reperfusion. Also, partial reperfusion increased the number of TUNEL-positive cells only in the severe ischemic region. IgG extravasation was suppressed at 24 h only in the moderate ischemic region in partial reperfusion. Injected FITC-dextran was observed in the brain parenchyma with BBB leakage at 24 h in partial reperfusion, but not in permanent occlusion. The expression of il1ß and il6 mRNA was inhibited in the severe ischemic region. Thus, partial reperfusion showed region-dependent favorable pathophysiology, such as delayed neurodegeneration, suppressed BBB destruction and inflammation, and potential for drug delivery, when compared to permanent occlusion. Further studies on the molecular differences and effectiveness of drugs will shed light on the development of novel treatments for partial reperfusion in ischemic stroke.

Renal dysfunction, malignant neoplasms, atherosclerotic cardiovascular diseases, and sarcopenia as key outcomes observed in a three-year follow-up study using the Werner Syndrome Registry.

Werner syndrome is an adult-onset progeria syndrome that results in various complications. This study aimed to clarify the profile and secular variation of the disease. Fifty-one patients were enrolled and registered in the Werner Syndrome Registry. Their data were collected annually following registration. A cross-sectional analysis at registration and a longitudinal analysis between the baseline and each subsequent year was performed. Pearson's chi-squared and Wilcoxon signed-rank tests were used. Malignant neoplasms were observed from the fifth decade of life (mean onset: 49.7 years) and were observed in approximately 30% of patients during the 3-year survey period. Regarding renal function, the mean estimated glomerular filtration rate calculated from serum creatinine (eGFRcre) and eGFRcys, which were calculated from cystatin C in the first year, were 98.3 and 83.2 mL/min/1.73 m2, respectively, and differed depending on the index used. In longitudinal analysis, the average eGFRcre for the first and fourth years was 74.8 and 63.4 mL/min/1.73 m2, showing a rapid decline. Secular changes in Werner syndrome in multiple patients were identified. The prevalence of malignant neoplasms is high, and renal function may decline rapidly. It is, therefore, necessary to carry out active and detailed examinations and pay attention to the type and dose of the drugs used.

R-spondin 3/LGR4 (Leucine-Rich Repeat-Containing G Protein-Coupled Receptor 4) Axis Is a Novel Inflammatory and Neurite Outgrowth Signaling System in the Ischemic Brain in Mice.

BACKGROUND: Although stimulation of Wnt/ß-catenin signaling is an important strategy to treat ischemic stroke, its signaling pathway has not been fully clarified yet. Recently, RSPO3 (R-spondin 3)/LGR4 (leucine-rich repeat-containing G protein-coupled receptor 4) signaling has resolved TLR4 (toll-like receptor 4)-induced inflammation in lung injury; however, whether this signal is critical in the ischemic brain remains unknown. Therefore, we investigated the role of RSPO3/LGR4 signaling in the ischemic brain. METHODS: BALB/c mice were exposed to permanent distal middle cerebral artery and common carotid artery occlusion. Temporal RSPO3 and LGR4 expressions were examined, and the mice were randomly assigned to receive vehicle or recombinant RSPO3. The underlying mechanisms were investigated using microglial cell lines and primary mixed glia-endothelia-neuron and primary neuronal cultures. RESULTS: In the ischemic brain, RSPO3 and LGR4 were expressed in endothelial cells and microglia/macrophages and neurons, respectively. Stimulation of RSPO3/LGR4 signaling by recombinant RSPO3 recovered neurological deficits with decreased Il1ß and iNOS mRNA on day 3 and increased Gap43 on day 9. In cultured cells, LGR4 was expressed in neuron and microglia, whereas RSPO3 promoted nuclear translocation of ß-catenin. Neuroprotective effects with reduced expression of inflammatory cytokines were observed in lipopolysaccharide-stimulated glia-endothelium-neuron cultures but not in glutamate-, CoCl2-, H2O2-, or oxygen glucose deprivation-stimulated neuronal cultures, indicating that RSPO3/LGR4 can protect neurons by regulating inflammatory cytokines. LGR4-Fc chimera, which was used to block endogenous RSPO3/LGR4 signaling, increased LPS-induced production of inflammatory cytokines, suggesting that endogenous RSPO3 suppresses inflammation. RSPO3 decreased TLR4-related inflammatory cytokine expression by decreasing TLR4 expression without affecting the M1/M2 phenotype. RSPO3 also inhibited TLR2- and TLR9-induced inflammation but not TLR7-induced inflammation, and promoted neurite outgrowth. CONCLUSIONS: RSPO3/LGR4 signaling plays a critical role in regulating TLR-induced inflammation and neurite outgrowth in the ischemic brain. Enhancing this signal will be a promising approach for treating ischemic stroke.

Monitoring with wearable devices will clarify the association between indoor temperature and blood pressure.

The association of blood pressure and temperature is well known in seasonal observation, and low temperature in the winter season is often considered a cause of high blood pressure. The current evidence for short-term studies of temperature and blood pressure is based on the daily observation, however continuous monitoring with wearable devices will allow us to evaluate the rapid effect of cold temperature exposure on blood pressure. In a Japanese, prospective intervention study from 2014 to 2019 (the Smart Wellness Housing survey), approximately 90% of Japanese lived in cold houses (indoor temperature less than 18 °C). Importantly, the indoor temperature was associated with the increase of morning systolic blood pressure. We recently addressed the sympathetic nervous activation of individuals in both their houses and a highly insulated and airtight model house in the winter season using portable electrocardiography equipment. A few subjects showed a morning surge in sympathetic activity, which was more intense at their cold houses, which suggests the importance of the indoor environment in the management of early morning hypertension. In near future, real-time monitoring with wearable devices will provide important information for a better life-environment, leading to risk reduction of morning surge and cardiovascular events.

Peptide-based vaccine targeting IL17A attenuates experimental spondyloarthritis in HLA-B27 transgenic rats.

OBJECTIVES: Spondyloarthritis (SpA) is known as series of immune-mediated inflammatory disease of the axial and peripheral joints. Human leucocyte antigen (HLA)-B27 is a genetic risk factor for SpA. Recent evidence suggests that the interleukin -17 (IL17) axis strongly contributes to SpA. This study aimed to assess the efficacy of an IL17A peptide-based vaccine on SpA manifestations in model rats. METHODS: HLA-B27/human ß2-microglobulin (hß2M) transgenic rats were immunised with heat-inactivated Mycobacterium tuberculosis (MT) to develop spondylitis and arthritis as an experimental SpA model after immunisation with a keyhole limpet hemocyanin-conjugated IL17A peptide-based vaccine with an alum adjuvant three times. The IL17A antibody titre was assessed using ELISA, and arthritis score and joint thickness were monitored two times a week. Enzyme-linked immunospot (ELISpot) assays for IL4- and interferon-γ-secreting splenocytes were conducted to evaluate IL17A-specific T cell activation. We also evaluated the effect of IL17A vaccine in SpA therapeutic model. RESULTS: The IL17A peptide-based vaccine with alum adjuvant successfully induced antibody production and suppressed the arthritis score and joint thickness. X-ray and histological analyses showed that enthesitis, bone destruction and new bone formation were inhibited by the IL17A vaccine. The ELISpot assay showed that the IL17A peptide-based vaccine did not elicit any IL17A-reactive T cell responses. IL17A vaccine tends to mitigate, but not significant, in SpA treatment model. These data showed that the peptide-based vaccine targeting IL17A alleviated the SpA phenotype in a heat-inactivated MT-induced SpA model in HLA-B27/hß2M transgenic rats. CONCLUSIONS: IL17A peptide-based vaccine may be a therapeutic option for SpA treatment.

Effects of nicotinamide mononucleotide on older patients with diabetes and impaired physical performance: A prospective, placebo-controlled, double-blind study.

OBJECTIVE: Nicotinamide adenine dinucleotide regulates various biological processes. Nicotinamide mononucleotide (NMN) increases its intracellular levels and counteracts age-associated changes in animal models. We investigated the safety and efficacy of oral nicotinamide mononucleotide supplementation in older patients with diabetes and impaired physical performance. METHOD: We carried out a 24-week placebo-controlled, double-blinded study of male patients with diabetes aged ≥65 years with reduced grip strength (<26 kg) or walking speed (<1.0 m/s). The primary end-points were to determine the safety of NMN oral administration (250 mg/day), and changes in grip strength and walking speed. The secondary end-points were to determine the changes in various exploratory indicators. RESULTS: We studied 14 participants aged 81.1 ± 6.4 years. NMN was tolerable without any severe adverse events. The changes in grip strength and walking speed showed no difference between the two groups: 1.25 kg (95% confidence interval -2.31 to 4.81) and 0.033 m/s (-0.021 to 0.087) in the NMN group, and -0.44 kg (-4.15 to 3.26) and 0.014 m/s (-0.16 to -0.13) in the placebo group, respectively. There were no significant differences in any exploratory indicators between the two groups. However, improved prevalence of frailty in the NMN group (P = 0.066) and different changes in central retinal thickness between the two groups (P = 0.051) was observed. CONCLUSION: In older male patients with diabetes and impaired physical performance, NMN supplementation for 24 weeks was safe, but did not improve grip strength and walking speed. Geriatr Gerontol Int 2023; 23: 38-43.

COVID-19 pandemic and hypertension: an updated report from the Japanese Society of Hypertension project team on COVID-19.

The number of reported cases with coronavirus disease 2019 (COVID-19) has exceeded 620 million worldwide, still having a profound impact on people's health and daily lives since its occurrence and outbreak in December 2019. From the early phase of the COVID-19 pandemic, there has been a concern that the rapid spread of this communicable disease can negatively influence non-communicable diseases. Accumulating data indicate that the restriction on the access to medical care, psychological distress, and life-style changes triggered by the pandemic have indeed affected blood pressure control in hypertensive patients. Since our previous report in 2020 that summarized the findings of the literature related to COVID-19 and hypertension, there has been a considerable progress in our understanding of the association between these two disorders; nonetheless, there are remaining challenges and emerging questions in the field. In this article, we aim to summarize the latest information on the impact of the pandemic on blood pressure control, the use of the renin-angiotensin system inhibitors in patients with COVID-19, and the blood pressure changes as one of the possible post-acute sequelae of COVID-19 (also known as long COVID). We also summarize the evidence of telemedicine and COVID-19 vaccination in hypertensive subjects, based on data available as of June 2022.

Long COVID and hypertension-related disorders: a report from the Japanese Society of Hypertension Project Team on COVID-19.

The coronavirus disease 2019 (COVID-19) affects infected patients even after the acute phase and impairs their health and quality of life by causing a wide variety of symptoms, referred to as long COVID. Although the evidence is still insufficient, hypertension is suspected to be a potential risk factor for long COVID, and the occurrence of cardiovascular diseases seems to be a key facet of multiple conditions observed in long COVID. Nonetheless, there are few reports that comprehensively review the impacts of long COVID on hypertension and related disorders. As a sequel to our previous report in 2020 which reviewed the association of COVID-19 and hypertension, we summarize the possible influences of long COVID on hypertension-related organs, including the cardiovascular system, kidney, and endocrine system, as well as the pathophysiological mechanisms associated with the disorders in this review. Given that the clinical course of COVID-19 is highly affected by age and sex, we also review the impacts of these factors on long COVID. Lastly, we discuss areas of uncertainty and future directions, which may lead to better understanding and improved prognosis of clinical problems associated with COVID-19.

Morning surge in sympathetic nervous activity in the indoor environment during the cold winter season.

We addressed to the sympathetic nervous activation of the same people in both their houses and a highly insulated and airtight model house (model house) during the cold winter season. Eight subjects (4 males and 4 females) stayed two nights at each house and were continuously monitored for sympathetic nerve system by calculating LF (low frequency)/HF (high frequency) in the analysis of heart rate variability using a wearable electrocardiography equipment. The room temperatures were kept constant at 20 °C or more in model house, but much lower in their houses. In all subjects, the sleeping duration is longer in model house compared with that in the participants' houses. Four subjects showed a morning surge in sympathetic activity that were more intense at their houses. This morning surge in sympathetic activity in a residential setting suggests the importance of the indoor environment in the management of early morning hypertension.