Combined physical and cognitive training for older adults with and without cognitive impairment: A systematic review and network meta-analysis of randomized controlled trials.

Combining physical exercise with cognitive training is a popular intervention in dementia prevention trials and guidelines. However, it remains unclear what combination strategies are most beneficial for cognitive and physical outcomes. We aimed to compare the efficacy of the three main types of combination strategies (simultaneous, sequential or exergaming) to either intervention alone or control in older adults. Randomized controlled trials of combined cognitive and physical training were included in multivariate and network meta-analyses. In cognitively healthy older adults and mild cognitive impairment, the effect of any combined intervention relative to control was small and statistically significant for overall cognitive (k = 41, Hedges' g = 0.22, 95 % CI 0.14 to 0.30) and physical function (k = 32, g = 0.25, 95 % CI 0.13 to 0.37). Simultaneous training was the most efficacious approach for cognition, followed by sequential combinations and cognitive training alone, and significantly better than physical exercise. For physical outcomes, simultaneous and sequential training showed comparable efficacy as exercise alone and significantly exceeded all other control conditions. Exergaming ranked low for both outcomes. Our findings suggest that simultaneously and sequentially combined interventions are efficacious for promoting cognitive alongside physical health in older adults, and therefore should be preferred over implementation of single-domain training.

Cytokine Signature Induced by SARS-CoV-2 Spike Protein in a Mouse Model.

Although COVID-19 has become a major challenge to global health, there are currently no efficacious agents for effective treatment. Cytokine storm syndrome (CSS) can lead to acute respiratory distress syndrome (ARDS), which contributes to most COVID-19 mortalities. Research points to interleukin 6 (IL-6) as a crucial signature of the cytokine storm, and the clinical use of the IL-6 inhibitor tocilizumab shows potential for treatment of COVID-19 patient. In this study, we challenged wild-type and adenovirus-5/human angiotensin-converting enzyme 2-expressing BALB/c mice with a combination of polyinosinic-polycytidylic acid and recombinant SARS-CoV-2 spike-extracellular domain protein. High levels of TNF-α and nearly 100 times increased IL-6 were detected at 6 h, but disappeared by 24 h in bronchoalveolar lavage fluid (BALF) following immunostimulant challenge. Lung injury observed by histopathologic changes and magnetic resonance imaging at 24 h indicated that increased TNF-α and IL-6 may initiate CSS in the lung, resulting in the continual production of inflammatory cytokines. We hypothesize that TNF-α and IL-6 may contribute to the occurrence of CSS in COVID-19. We also investigated multiple monoclonal antibodies (mAbs) and inhibitors for neutralizing the pro-inflammatory phenotype of COVID-19: mAbs against IL-1α, IL-6, TNF-α, and granulocyte-macrophage colony-stimulating factor (GM-CSF), and inhibitors of p38 and JAK partially relieved CSS; mAbs against IL-6, TNF-α, and GM-CSF, and inhibitors of p38, extracellular signal-regulated kinase, and myeloperoxidase somewhat reduced neutrophilic alveolitis in the lung. This novel murine model opens a biologically safe, time-saving avenue for clarifying the mechanism of CSS/ARDS in COVID-19 and developing new therapeutic drugs.

Ornithine decarboxylase inhibition downregulates multiple pathways involved in the formation of precancerous lesions of esophageal squamous cell cancer.

The high incidence and mortality of esophageal squamous cell cancer (ESCC) is a major health problem worldwide. Precancerous lesions of ESCC may either progress to cancer or revert to normal epithelium with appropriate interventions; the bidirectional instability of the precancerous lesions of ESCC provides opportunities for intervention. Reports suggest that the upregulation of ornithine decarboxylase (ODC) is closely related to carcinogenesis. In this study, we investigated whether ODC may act as a target for chemoprevention in ESCC. Immunohistochemistry (IHC) assays indicate that ODC expression is higher in esophageal precancerous lesions compared with normal tissue controls. Its overexpression promotes cell proliferation and transformation of normal esophageal epithelial cells, and its activity is increased after N-nitrosomethylbenzylamine (NMBA) induction in Shantou human embryonic esophageal cell line (SHEE) and human immortalized cells (Het1A) cells. In addition, p38 α, extracellular regulated kinase (ERK1/2) in the mitogen-activated protein kinase pathway and protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase (p70S6K) pathways are activated in response to NMBA treatment. Difluoromethylornithine (DFMO) is an ODC inhibitor, which inhibits NMBA-induced activation of p38 α, ERK1/2 and AKT/mTOR/p70S6K pathways; this has been verified by Western blotting. DFMO was also found to suppress the development of esophageal precancerous lesions in an NMBA-induced rat model; IHC demonstrated p38 α, ERK1/2, and AKT/mTOR/p70S6K pathways to be downregulated in these rats. These findings indicate the mechanisms by which ODC inhibition suppresses the development of esophageal precancerous lesions by downregulating p38 α, ERK1/2, and AKT/mTOR/p70S6k signaling pathways, ODC may be a potential target for chemoprevention in ESCC.

Proteome and phosphoproteome reveal mechanisms of action of atorvastatin against esophageal squamous cell carcinoma.

Statins comprise a class of prescription drugs used for reducing cholesterol. Evidence has also showed that statins could reduce cancer incidence. However, the anti-tumor mechanism of statins has not been fully defined. Here, we found that atorvastatin inhibited proliferation of esophageal squamous cell carcinoma (ESCC) cells. The underlying mechanisms were explored by mass spectrometry. The proteome data revealed that atorvastatin inhibited the cAMP and Rap1 signal pathways, except for Ras signal pathway. Interestingly, phosphoproteome profiles suggested that ERKT185/Y187, CDK1T14, and BRAC1S1189 phosphorylation-mediated Th17 cell differentiation, Gap junction and the Platinum drug resistance pathway were down-regulated after atorvastatin treatment. The phosphorylation levels of ERKT185/Y187, CDK1T14 and BRAC1S1189 were confirmed by western blotting in KYSE150 cells. More importantly, atorvastatin suppresses ESCC tumor growth in PDX models. The molecular changes in tumor tissues were confirmed by immunohistochemistry. In conclusion, deep-proteome and phosphoproteome analysis reveal a comprehensive mechanism that contributes to atorvastatin's anti-tumor effect.

Emergency Department Septic Screening in Respiratory Syncytial Virus (RSV) and Non-RSV Bronchiolitis.

OBJECTIVE: To identify factors associated with culture-proven serious bacterial infection (SBI) and positive emergency department septic screening (EDSS) tests in children with bronchiolitis and to identify factors associated with the performance of EDSS. METHODS: We reviewed an existing study database of patients with bronchiolitis. We defined a positive EDSS as urine with >/=10 WBC per high power field or cerebrospinal fluid (CSF) with >/=10 WBC per high power field (>25 WBC in neonates), or if organisms were identified on gram stain. We defined SBI as significant growth of an accepted pathogen in blood, urine or CSF. Our composite endpoint was positive if either of these was positive. The decision to perform testing was modeled using modified Poisson regression; the presence of the combined outcome was modeled using logistic regression modified for rare events. RESULTS: We studied 640 children. Testing was performed in 199/640 (31.1%). These tended to be younger than two months RR 2.69 (95% CI 2.11, 3.44), febrile RR 2.01 (95% CI 1.58, 2.55), more dehydrated RR 1.50 (95% CI 1.28, 1.75) and had more severe chest wall retractions RR 1.54 (95% CI 1.22, 1.94). Only 11/640(1.7%) had a positive EDSS or SBI. Younger age (OR 0.67 per month; 95% CI 0.45, 0.99) and a negative RSV antigen test (OR 6.22; 95% CI 1.30, 29.85) were associated with the composite endpoint. CONCLUSION: Testing was more likely to be performed in children younger than two months of age, and in those who were febrile, dehydrated, and had more severe chest wall retractions. A positive EDSS or SBI was rare occurring in younger infants with non-RSV bronchiolitis.

Chlorobenzylidenemalonitrile gas exposure from a novelty personal-protection gun.

We present an unusual case of chlorobenzylidenemalonitrile (CS) tear-gas exposure from the unwitting discharge of a personal-protection handgun loaded with CS gas. The gun was in a bag of toys purchased from a local thrift store and was discharged by a child. The responding paramedic presumptively identified the substance as CS based solely on personal experience. This recognition led to suboptimal field management of the incident with the paramedic failing to follow the standard operating procedures for an unknown chemical exposure. As this was a benign agent, there were no serious consequences. This case highlights the pre-hospital and emergency department challenges associated with the management of an unknown chemical exposure and the potential consequences if the chemical is a toxic substance. A methodical approach following established protocols can reduce the potential for negative outcomes. Review of the literature found no other report of CS gas exposure from such a personal-protection weapon.