Proposal to apply a "Positive Emotion, Engagement, Relationships, Meaning, and Accomplishment (PERMA)" based approach to manage the COVID-19-related mental health problems in the era of long COVID.

Long COVID (LC)-related health problems are highly concerned. Many patients seem to have "recovered" from an acute SARS-CoV-2 infection, however, they might experience various symptoms, almost involving all organs and systems. Of those, neuropsychiatric symptoms like depression, anxiety, and post-traumatic stress disorder (PTSD) are not rare. These problems significantly impact the quality of life (QOL) of patients, family, and caregivers, even lead a tragic suicide outcome. Other than the conventional psychological and medical approaches, here, we proposal a positive emotion, engagement, relationships, meaning, and accomplishment (PERMA)-based approach to fight against these COVID-19-related mental health problems (CRMHPs). This approach is characterized by positive psychological interventions and self-achievements, which has been proved to be a powerful tool against mood disorders in common people. Nowadays, abolishment of certain prophylactic measures (such as isolation, lockdown, compulsorily wearing a mask and maintaining social distance, measures to avoid crowding) enables us to have more opportunities to contact patients and implement the PERMA-based approach to the patients with CRMHPs. We believe that application of PERMA-based approach is conducive to alleviate the influence of the CRMHPs and improve their QOL.

Anatomical approach to suppression of para-Hisian ventricular arrhythmias with changes in QRS morphology following ablation at the earliest activation site.

BACKGROUND: The anatomical approach for the management of para-Hisian ventricular arrhythmias (VAs) with QRS morphological changes following catheter ablation (CA) has not been well investigated. OBJECTIVES: We aimed to evaluate the electrocardiographic and electrophysiological findings and ablation outcomes of para-Hisian VAs with QRS morphological changes following CA. METHODS: Among 30 patients who underwent CA for para-Hisian VAs at four institutions, 10 (33%) had QRS morphological changes following ablation. All 10 patients underwent an anatomical approach, targeting the site anatomically opposite to the site where the QRS morphology had been changed by ablation. We investigated the safety and efficacy of the anatomical approach. RESULTS: Among the 10 patients evaluated, the approach was switched from the right ventricular septum to the left ventricular septum/aortic root in seven (RL group), whereas three underwent left-to-right switches (LR group). Following CA, the precordial transition zone tended to be earlier in the RL group and later in the LR group. In the RL group, successful VA suppression was achieved despite suboptimal pace map concordance from the left side or a relatively delayed earliest activation time. Of the 10 patients who underwent an anatomical approach, eight had procedural success, and ablation was discontinued in one due to the risk of atrioventricular block. CONCLUSIONS: The anatomical approach showed promising results regarding safety and efficacy. Therefore, it should be considered when QRS morphological changes are observed during or after CA of para-Hisian VAs.

Evaluation of appropriateness of alerts overrides and physicians' responses of the medication-related clinical decision support system in China, a hospital-based study.

This study was designed to investigate the state quo of the appropriateness of alerts overrides of the medication-related clinical decision support system (MRCDSS) in China. The medication-related alerts in one hospital from Jan 2022 to Dec 2022 were acquired and sampled. Rates of alert overrides, appropriateness of alert generation and physicians' responses were observed. Total 14,612 medication-related alerts (≤ level 3) were recorded, of those, 12,659 (86.6%) alerts were overridden. The top 3 alert types were: drug and diagnosis contraindications (23.8%), drug and test value contraindications (23.3%), and compatibility issues (17.7%). Of all sampled 1,501 alerts, 80.2% of them were appropriately overridden by the physicians. The appropriate rate of alert generation was 57.9% and the inappropriate rate was 42.1%. The inappropriate rate of physicians' responses was 17.8%, and 2.0% physicians' responses were undetermined. A few medications accounted for over 10% of overrides, 88.3% of "overridden reasons" inputted by the physicians were meaningless characters or values, indicating an obvious "alert fatigue" in these physicians. Our results indicated that the overridden rate of MRCDSS in China was still high, and appropriateness of generation of alert was quite low. These data indicated that the MRCDSS currently using in China still needs constantly optimization and timely maintenance. Proper sensitivity to reduce triggering of useless alerts and generation of alert fatigue might play a vital role. We believed that these findings are helpful for better understanding the state quo of MRCDSS in China and providing useful insights for future developing and improving MRCDSS.

α-synuclein regulates Cyclin D1 to promote abnormal initiation of the cell cycle and induce apoptosis in dopamine neurons.

The etiology of Parkinson's disease (PD) is characterized by the death of dopamine neurons in the substantia nigra pars compacta, while misfolding and abnormal aggregation of α-synuclein (α-syn) are core pathological features. Previous studies have suggested that damage to dopamine neurons may be related to cell cycle dysregulation, but the specific mechanisms remain unclear. In this study, a PD mouse model was induced by stereotactic injection of α-syn into the nucleus, and treated with the cell cycle inhibitor, roscovitine (Rosc). The results demonstrated that Rosc improved behavioral disorders caused by α-syn, increased TH protein expression, inhibited α-syn and p-α-syn protein expression, and reduced the expression levels of G1/S phase cell cycle genes Cyclin D1, Cyclin E, CDK2, CDK4, E2F and pRB. Additionally, Rosc decreased Bax and Caspase-3 expression caused by α-syn, while increasing Bcl-2 protein expression. Meanwhile, we observed that α-syn can influence neuronal cell autophagy by decreasing the expression level of Beclin 1 and increasing the expression level of P62. However, Rosc can improve this phenomenon. In a cell model induced by α-syn in dopamine neuron injury cells, knockdown of Cyclin D1 led to similar results as those observed in animal experiments: Knocking down Cyclin D1 improved the abnormal initiation of the cell cycle caused by α-syn and regulated cellular autophagy, resulting in a reduction of apoptosis in dopamine neurons. In summary, exogenous α-syn can lead to the accumulation of α-syn and phosphorylated α-syn in dopamine neurons, increase key factors of the G1/S phase cell cycle such as Cyclin D1, and regulate downstream related indicators, causing the cell cycle to restart and leading to apoptosis of dopamine neurons. This exacerbates PD symptoms. However, knockdown of Cyclin D1 inhibits the progression of the cell cycle and can reverse this situation. These findings suggest that a Cyclin D inhibitor may be a novel therapeutic target for treating PD.

Roadmap for ending TB in China by 2035: The challenges and strategies.

Tuberculosis (TB) is one of the top ten causes of death worldwide, taking the lives of over a million people annually. In addition to being a serious health issue, TB is also closely linked to eradicating poverty according to the Sustainable Development Goals (SDGs) of the United Nations (UN). All UN members have committed to ending the TB epidemic by 2030. China has one of the highest TB loads worldwide, ranking third in the world on many TB burden indices. The national strategy for TB control is aimed at creating a collaborative network and integrating TB treatment into the medical system. According to the WHO's global TB report, China is expected to have 748,000 new cases of TB in 2022 and an incidence of 52 cases per 100,000 people. Ending TB remains a huge challenge and requires comprehensive control strategies in China. In this work, we have discussed the challenges of TB prevention and control in China and proposed specific measures to end TB.

Multidisciplinary treatment of advanced cervical esophageal adenocarcinoma derived from a gastric inlet patch: A case report.

A gastric inlet patch (GIP) is an ectopic gastric mucosal lesion usually arising at the cervical esophagus that may rarely cause esophageal adenocarcinoma (EAC). To the best of our knowledge, this is the first case of a GIP-derived EAC that was successfully treated using a multidisciplinary treatment approach. A 64-year-old man was referred to the Department of Gastrointestinal Surgery, Kanazawa University Hospital (Kanazawa, Japan) for surgical treatment of refractory recurrent cervical EAC derived from GIP who had previously been treated with induction chemotherapy, definitive chemoradiotherapy and photodynamic therapy (PDT). Esophagogastroduodenoscopy revealed a stenotic tumor at the GIP site in the cervical esophagus and submucosal tumors with suspected multiple intramural metastases in the anal side of the thoracic esophagus. The patient underwent robot-assisted thoracoscopic esophagectomy with laryngopharyngectomy and cervical lymphadenectomy as radical salvage surgery 4 months after the last PDT procedure. After postoperative adjuvant chemotherapy using oral administration of tegafur/gimeracil/oteracil (oral 5-fluorouracil prodrug) for 1 year; at present, the patient is alive without recurrence 3 years after the operation.

Validation of dual atrioventricular nodal physiology in dual atrioventricular nodal non-reentrant tachycardia via adenosine triphosphate injection during atrial pacing: A novel insight into the role of leftward inferior extension.

INTRODUCTION: Dual atrioventricular nodal non-reentrant tachycardia (DAVNNT) is a rare and challenging-to-diagnose arrhythmia, without previous reports associating it with a leftward inferior extension (LIE). METHODS: Diagnosis was made using adenosine triphosphate (ATP) injection during atrial pacing in a suspected DAVNNT patient. RESULTS: Ablation of the rightward inferior extension was unsuccessful in eliminating DAVNNT; however, subsequent ablation of the LIE successfully eradicated the arrhythmia. CONCLUSION: This unique case, marked by the first instance of DAVNNT caused by LIE, diagnosed through ATP injection, underscores the utility of this diagnostic approach and broadens the spectrum of our understanding and management of this condition.

Stumbling Blocks in the Investigation of the Relationship Between Age-Related Hearing Loss and Cognitive Impairment.

The relationship between age-related hearing loss (ARHL) and cognitive impairment (CI) remains intricate. However, there is no robust evidence from experimental or clinical studies to elucidate their relationship. The key unaddressed questions are (a) whether there is a causal effect of ARHL on CI and (b) whether efficacious treatment of ARHL (such as hearing-aid use) ameliorates CI and dementia-related behavioral symptoms. Because of several methodological and systematic flaws/challenges, rigorous verification has not been conducted. Addressing these stumbling blocks is essential to unraveling the relationship between ARHL and CI, which motivated us to undertake this review. Here, we discuss the methodological problems from the perspectives of potential confounding bias, assessments of CI and ARHL, hearing-aid use, functional-imaging studies, and animal models based on the latest information and our experiences. We also identify potential solutions for each problem from the viewpoints of clinical epidemiology. We believe that "objectivity," specifically the use of more objective behavioral assessments and new computerized technologies, may be the key to improving experimental designs for studying the relationship between ARHL and CI.

Development of a novel cholesterol tag-based system for trans-membrane transport of protein drugs.

The main technological difficulties of developing an intracellular (transmembrane) transport system for protein drugs lie in two points: i) overcoming the barriers in the cellular membrane, and ii) loading enough protein drugs, and particularly high-dose proteins, into particles. To address these two technological problems, we recently developed a novel cholesterol tag (C-Tag)-based transmembrane transport system. This pilot study found that the C-Tag dramatically improved the cellular uptake of Fab (902-fold, vs. Fab alone) into living cells, indicating that it successfully achieved transmembrane transport. Moreover, C-Tag-mediated membrane transport was verified using micron-scale large unilamellar vesicles (LUVs, approximately 1.5 µm)-based particles. The C-Tagged Fab was able to permeate the liposomal bilayer and it greatly enhanced (a 10.1-fold increase vs. Fab alone) internalization of proteins into the LUV-based particles, indicating that the C-Tag loaded enough proteins into particles for use of high-dose proteins. Accordingly, we established a novel C-Tag-based transport system that has overcome the known technological difficulties of protein transmembrane delivery, and this might be a useful technology for drug development in the future.

Impact of atherothrombotic risk stratification in patients with heavily calcified lesions following rotational atherectomy.

BACKGROUND: Patients who undergo percutaneous coronary intervention (PCI) with rotational atherectomy (RA) are at high risk of adverse clinical outcomes, and there are few clinical risk stratification tools for these patients. METHODS: We conducted a study with 196 patients who underwent PCI with RA out of 7391 patients who underwent PCI using a multicenter, prospective cohort registry. Patients were divided into three groups according to the tertiles of the Thrombolysis in Myocardial Infarction (TIMI) Risk Score for Secondary Prevention (TRS 2°P): 65 patients in the T1 group (TRS 2°P < 3), 66 patients in the T2 group (TRS 2°P = 3), and 65 patients in the T3 group (TRS 2°P > 3). The primary endpoint was the cumulative 2-year incidence of major adverse cardiovascular and cerebrovascular events (MACCE), defined as a composite of cardiac death, acute coronary syndrome, and ischemic stroke. RESULTS: Cumulative 2-year MACCE occurred in 41 patients (24 %) during the follow-up period. The cumulative incidence of MACCE was significantly higher in the T3 group than in the T1 group (log-rank test, p = 0.02). Multivariate Cox analyses revealed that the T3 group was associated with an increased risk of MACCE compared to that of the T1 group (adjusted hazard ratio, 2.66; 95 % confidence interval, 1.04-6.77; p = 0.04). The addition of TRS 2°P to conventional risk factors, including male sex, number of diseased vessels, and low-density lipoprotein cholesterol levels, improved the net reclassification improvement (NRI) and integrated discrimination improvement (IDI) (NRI 0.39, p = 0.027; IDI 0.072, p < 0.001). CONCLUSIONS: Atherothrombotic risk stratification using TRS 2°P was useful in identifying high-risk patients with heavily calcified lesions following RA.

Management of refractory intramural left ventricular summit ventricular arrhythmia: Acute success using bipolar radiofrequency catheter ablation with recurrence.

Bipolar radiofrequency catheter ablation (RFCA) is a novel strategy for refractory or recurrent ventricular arrhythmias (VAs) resistant to conventional ablation methods. Lesions created during bipolar RFCA are larger than those created during sequential unipolar ablation. We present a case of refractory LV summit VAs, which identified the origin using a 2.7-F over-the-wire microelectrodes catheter, and it was successfully treated with bipolar RFCA in the acute phase.

Predictive Value of CHADS2, CHA2DS2-VASc and R2-CHADS2 Scores for Short- and Long-Term Major Adverse Cardiac Events in Non-ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Non-ST-elevation myocardial infarction (NSTEMI) carries a poor prognosis, and accurately prognostication has significant clinical importance. In this study, we analyzed the predictive value of the CHADS2, CHA2DS2-VASc, and R2-CHADS2scores for major adverse cardiac events (MACE) following percutaneous coronary intervention (PCI) in patients with NSTEMI using data from a prospective multicenter registry.Methods and Results: The registry included 440 consecutive patients with NSTEMI and coronary artery disease who underwent successful PCI. Patients were clinically followed for up to 3 years or until the occurrence of MACE. MACE was defined as a composite of all-cause death and nonfatal MI. During the follow-up period, 55 patients (12.5%) experienced MACE. Risk analysis of MACE occurrence, adjusted for the multivariable model, demonstrated a significant increase in risk with higher CHADS2, CHA2DS2-VASc, and R2-CHADS2scores. Kaplan-Meier analysis showed a higher incidence of MACE in patients with higher CHADS2, CHA2DS2-VASc, and R2-CHADS2scores, both in the short- and long-term periods. CONCLUSIONS: Patients with NSTEMI and higher CHADS2, CHA2DS2-VASc, and R2-CHADS2scores displayed a greater incidence of MACE.

Symptomatic periesophageal vagal nerve injury by different energy sources during atrial fibrillation ablation.

Background: Symptomatic gastric hypomotility (SGH) is a rare but major complication of atrial fibrillation (AF) ablation, but data on this are scarce. Objective: We compared the clinical course of SGH occurring with different energy sources. Methods: This multicenter study retrospectively collected the characteristics and clinical outcomes of patients with SGH after AF ablation. Results: The data of 93 patients (67.0 ± 11.2 years, 68 men, 52 paroxysmal AF) with SGH after AF ablation were collected from 23 cardiovascular centers. Left atrial (LA) ablation sets included pulmonary vein isolation (PVI) alone, a PVI plus a roof-line, and an LA posterior wall isolation in 42 (45.2%), 11 (11.8%), and 40 (43.0%) patients, respectively. LA ablation was performed by radiofrequency ablation, cryoballoon ablation, or both in 38 (40.8%), 38 (40.8%), and 17 (18.3%) patients, respectively. SGH diagnoses were confirmed at 2 (1-4) days post-procedure, and 28 (30.1%) patients required re-hospitalizations. Fasting was required in 81 (92.0%) patients for 4 (2.5-5) days; the total hospitalization duration was 11 [7-19.8] days. After conservative treatment, symptoms disappeared in 22.3% of patients at 1 month, 48.9% at 2 months, 57.6% at 3 months, 84.6% at 6 months, and 89.7% at 12 months, however, one patient required surgery after radiofrequency ablation. Symptoms persisted for >1-year post-procedure in 7 patients. The outcomes were similar regardless of the energy source and LA lesion set. Conclusions: The clinical course of SGH was similar regardless of the energy source. The diagnosis was often delayed, and most recovered within 6 months, yet could persist for over 1 year in 10%.

A pilot study comparing the disinfecting effects of commercialized stable ClO2 solution (free of activation) with conventional H2O2 on dental unit waterlines in the dental practice setting.

Disinfection of dental unit waterlines (DUWLs) plays a key role in control and prevention of nosocomial infection in a dental clinic. The most conventional disinfectant is hydrogen peroxide (H2O2), while chlorine dioxide (ClO2) has been considered however was limited by the "activation" procedures. With the availability of commercialized stable ClO2 solution (free of activation), direct application of ClO2 in the dental practice became possible. This study was designed to compare the disinfecting effects of stable 5 ppm of ClO2 solution with conventional 0.24% of H2O2 on DUWLs in dental practice. Studies of colony-forming units (CFUs), confocal laser scanning microscopy (CLSM) and scanning electron microscope (SEM) were employed for evaluation. In CFUs studies, we found that the efficiency of ClO2 was no less than those of H2O2. In the morphological studies, the stronger disinfecting effects of ClO2 was verified by both CLSM and SEM studies for removal and prevention of biofilm. Importantly, ClO2 solution achieved a better disinfecting efficiency not only at the surface of bacterial biofilm, but also, it has penetrating effects, presented disinfecting effects from the surface to the bottom of the biofilm. This pilot study provided evidence regarding the efficiency of stable ClO2 solution on disinfection of DUWLs in the dental practice setting. Application of stable ClO2 solution in dental practice is therefore become possible.

Call for special attention to the caregiver burden of patients with drug-resistant tuberculosis in low- and middle-income countries.

The tuberculosis (TB)-related caregiver burden (CB), and particularly the multidrug and extensively drug-resistant tuberculosis (M/XDR-TB)-related CB, is not rare in caregivers caring for TB patients, especially when a family member is the caregiver. However, the existing studies on this topic are insufficient. This study briefly summarized the risk factors for the imposition of a TB-related CB and reasons why caregivers for patients with M/XDR-TB are more susceptible to a CB. We propose that special measures should be implemented to alleviate the TB-related CB based on our clinical experience and insights from China. This may improve the situation of caregivers for TB patients and ultimately improve the quality of life of TB patients.

Effectiveness of an artificial intelligence-based training and monitoring system in prevention of nosocomial infections: A pilot study of hospital-based data.

This work describes a novel artificial intelligence-based training and monitoring system (AITMS) that was used to control and prevent nosocomial infections (NIs) by improving the skills of donning/removing personal protective equipment (PPE). The AITMS has two working modes, namely an AI-based protective equipment surveillance mode and an AI-based training mode, that were used for routine surveillance and training, respectively. Data revealed that the accuracy rate of donning/removing PPE improved as a result of the AITMS. Interestingly, the frequency of NIs decreased with the use of the AITMS. This study suggested the key role of using PPE in controlling and preventing NIs. Data preliminarily proved that appropriate donning/removing PPE may help to reduce the risk of NIs. In addition, the newest computerized technologies, such as AI, have proven to be useful in controlling and preventing NIs. These findings should helpful to formulate a better strategy against NIs in the future.

Benefit of Nasal Douche in COVID-19 Patients with Recurrence of Positive SARS-CoV-2 Viral RNA.

Purpose: The purpose was to review relevant clinical data and formulate recommendations supporting the use of saline as a simple rinse for an early reassuring intervention to reduce the occurrence of re-positive COVID-19 patients. Methods: We conducted a single-centre retrospective cohort study, which enrolled patients with confirmed re-testing positive COVID-19 during 7-60 days after discharge from Third People's Hospital of Shenzhen. By one-to-two propensity score matching for age and sex, the control group of those not re-testing positive during the same period served as matched control. Results: A total of 223 patients were included in our study, 94 in re-positive group and 129 in non-re-positive group. The result shows that the rates of nasal douche treatment in the non-re-positive group were considerably higher than that of the re-positive group. And the Ct value of nasal douche group increased faster than that of non-nasal douche group after the Ct value reaching ≥35. Further analysis revealed that the higher the Ct value at the time of readmission, the shorter the time of average Ct values to reach ≥35. Conclusion: These findings suggest that nasal douche is beneficial to shorten the time of virus nucleic acid turning negative, thereby reducing the incidence of re-positive. The prevention and control of epidemics focuses on re-positive patients with Ct values <35.

Facing frailty: Are you ready?

By far, there is no general consensus concerning the definition of frailty even though it may be a global public health concern with aging of the population. It is regarded as a pathophysiological state before development of a severe illness that is associated with many adverse outcomes. Although previous studies attempted to verify its clinical value to prevent the development of serious illness, robust evidence is lacking. Based on previous studies of frailty, the current study analyzed the problems with existing investigations of frailty and it puts forward future strategies to improve those investigations. Finalizing the definition of frailty is the first step. Next, development of objective tools to identify/measure frailty based on the newest biological and computerized technologies is indispensable. Finally, well-designed clinical trials also need to be conducted to yield compelling evidence regarding the clinical value of medical interventions in frailty.

Efficacy and safety of SIM0417 (SSD8432) plus ritonavir for COVID-19 treatment: a randomised, double-blind, placebo-controlled, phase 1b trial.

Background: SIM0417 (SSD8432) is an orally administered coronavirus main proteinase (3CLpro) inhibitor with potential anti-SARS-CoV-2 activity. This study aimed to evaluate the efficacy and safety of SIM0417 plus ritonavir (a pharmacokinetic enhancer) in adults with COVID-19. Methods: This was a randomised, double-blind, placebo-controlled, phase 1b study in China. Adults with asymptomatic infection, mild or moderate COVID-19 were randomly assigned (3:3:2) to receive either 750 mg SIM0417 plus 100 mg ritonavir, 300 mg SIM0417 plus 100 mg ritonavir or placebo every 12 h for 10 doses. The main efficacy endpoints included SARS-CoV-2 viral load, proportion of participants with positive SARS-CoV-2 nucleic acid test and time to alleviation of COVID-19 symptoms. This trial is registered with ClinicalTrials.gov, NCT05369676. Findings: Between May 12 and August 29, 2022, 32 participants were enrolled and randomised to high dose group (n = 12), low dose group (n = 12) or placebo (n = 8). The viral load change from baseline in high dose group was statistically lower compared with placebo, with a maximum mean difference of -2.16 ± 0.761 log10 copies/mL (p = 0.0124) on Day 4. The proportion of positive SARS-CoV-2 in both active groups were lower than the placebo. The median time to sustained alleviation of COVID-19 symptoms was 2.0 days in high dose group versus 6.0 days in the placebo group (HR = 3.08, 95% CI 0.968-9.818). SIM0417 plus ritonavir were well tolerated with all adverse events in grade 1. Interpretation: SIM0417 plus ritonavir was generally well tolerated. The efficacy of SIM0417 showed a monotonic dose-response relationship, and the 750 mg SIM0417 plus 100 mg ritonavir was selected as the recommended clinical dose. Funding: The study was funded by Jiangsu Simcere Pharmaceutical Co., Ltd.

Devising novel near-infrared aggregation-induced-emission luminogen labeling for point-of-care diagnosis of Mycobacterium tuberculosis.

Detecting and appropriately diagnosing a Mycobacterium tuberculosis infection remains technologically difficult because the pathogen commonly hides in macrophages in a dormant state. Described here is novel near-infrared aggregation-induced-emission luminogen (AIEgen) labeling developed by the current authors' laboratory for point-of-care (POC) diagnosis of an M. tuberculosis infection. The selectivity of AIEgen labeling, the labeling of intracellular M. tuberculosis by AIEgen, and the labeling of M. tuberculosis in sputum samples by AIEgen, along with its accuracy, sensitivity, and specificity, were preliminarily evaluated. Results indicated that this near-infrared AIEgen labeling had satisfactory selectivity and it labeled intracellular M. tuberculosis and M. tuberculosis in sputum samples. It had a satisfactory accuracy (95.7%), sensitivity (95.5%), and specificity (100%) for diagnosis of an M. tuberculosis infection in sputum samples. The current results indicated that near-infrared AIEgen labeling might be a promising novel diagnostic tool for POC diagnosis of M. tuberculosis infection, though further rigorous verification of these findings is required.