Evaluation of efficacy and safety of Qiangzhu-qinggan formula as an adjunctive therapy in adult patients with severe influenza: study protocol for a randomized parallel placebo-controlled double-blind multicenter trial.

BACKGROUND: Influenza can fall into three categories according to severity: mild influenza, severe influenza, and critical influenza. Severe influenza can result in critical illness and sometimes death particularly in patients with comorbidities, advanced age, or pregnancy. Neuraminidase inhibitors (NAIs) are the only antiviral drugs in widespread use for influenza. However, the effectiveness of NAIs against severe influenza is uncertain. New effective drugs or regimens are therefore urgently needed. Qiangzhu-qinggan (QZQG) formula has been found to be effective against influenza virus infection during long-term application in China, which lacks support of evidence-based clinical trial till now. This study is designed to assess the efficacy and safety of QZQG formula as an adjuvant therapy in adult patients with severe influenza. METHODS: This protocol is drawn up in accordance with the SPIRIT guidelines and CONSORT Extension for Chinese herbal medicine formulas. This is a randomized, placebo-controlled, double-blind, multicenter trial. Two hundred twenty-eight adults with severe influenza are randomly assigned in a 1:1 ratio to QZQG or placebo for 7 days. All participants need to receive 1 day of screening before randomization, 7 days of intervention, and 21 days of observation after randomization. The primary outcome is the proportion of clinical improvement, defined as the proportion of patients who met the criteria of 3 points or less in the seven-category ordinal scale or 2 points or less in National Early Warning Score 2 within 7 days after randomization. DISCUSSION: This is the first randomized, controlled, parallel, double-blind clinical trial to evaluate the efficacy and safety of traditional Chinese herbal formula granules as an adjuvant therapy in adult patients with severe influenza. This study aims to redefine the value of traditional Chinese herbal medicines in the treatment of virus-related respiratory infectious diseases and serves as an example of evidence-based clinical trials of other Chinese herbal medicines.

Small molecules in the treatment of COVID-19.

The outbreak of COVID-19 has become a global crisis, and brought severe disruptions to societies and economies. Until now, effective therapeutics against COVID-19 are in high demand. Along with our improved understanding of the structure, function, and pathogenic process of SARS-CoV-2, many small molecules with potential anti-COVID-19 effects have been developed. So far, several antiviral strategies were explored. Besides directly inhibition of viral proteins such as RdRp and Mpro, interference of host enzymes including ACE2 and proteases, and blocking relevant immunoregulatory pathways represented by JAK/STAT, BTK, NF-κB, and NLRP3 pathways, are regarded feasible in drug development. The development of small molecules to treat COVID-19 has been achieved by several strategies, including computer-aided lead compound design and screening, natural product discovery, drug repurposing, and combination therapy. Several small molecules representative by remdesivir and paxlovid have been proved or authorized emergency use in many countries. And many candidates have entered clinical-trial stage. Nevertheless, due to the epidemiological features and variability issues of SARS-CoV-2, it is necessary to continue exploring novel strategies against COVID-19. This review discusses the current findings in the development of small molecules for COVID-19 treatment. Moreover, their detailed mechanism of action, chemical structures, and preclinical and clinical efficacies are discussed.

Traditional Chinese medicine as an adjunctive therapy for mild and common COVID-19: A systematic review and network meta-analysis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) in many countries is still very serious. At present, there is no specific and effective drug for this disease. Traditional Chinese medicine (TCM) has played a great role in fighting against COVID-19. However, their effectiveness and safety are still obscure and deserve further investigation. The aim of the study was to evaluate the efficacy and safety of TCM assisted in conventional treatment in the treatment of mild and common COVID-19. METHODS: PubMed, EMbase, MEDLINE, China National Knowledge Infrastructure Database, WANFANG DATA, and VIP Chinese Science and Technology Periodical Database were searched for randomized controlled trials (RCTs) and non-randomized controlled trials of TCM assisted in conventional treatment. The RCT research quality was evaluated by Cochrane 5.1.0 bias risk scale and the non-randomized controlled trial research quality was evaluated by Newcastle Ottawa scale, and the statistical analysis was conducted by Revman 5.3 and R software. The bias and sensitivity of the statistical results were analyzed by STATA 14.0. Registration number: CRD42020210619. RESULTS: Fifteen studies were included with 7 RCT studies and 8 retrospective cohort studies, involving a total of 1623 patients. Compared with the control group, TCM can improve the main index clinical effective rate (odds ratio [OR] = 2.64, 95% Confidence interval (CI) [1.94,3.59], P < .00001). The results of Begg test (Pr > z = 0.266) and sensitivity analysis showed that the results were relatively stable. Toujie Quwen (OR = 4.9, 95%CI [1.9,14.0]), Shufeng Jiedu (OR = 2.9, 95%CI [1.5,5.7]), and Lianhua Qingwen (OR = 2.4, 95%CI [1.6,3.6]) were with the best. It can also improve the main clinical symptoms (fever, cough, fatigue, and the regression time of the 3 symptoms), severe conversion rate, and computed tomography improvement rate. Its safety was not significantly compared with conventional treatment. However, in terms of safety of a single TCM, Shufeng Jiedu (OR = -0.86, 95%CI [-1.89,0.09]) and Lianhua Qingwen (OR = -0.49, 95%CI[-0.94,-0.05]) were lower than those of conventional treatment. CONCLUSION: TCM as an adjuvant therapy combined with conventional treatment has good curative effect on mild and common type of COVID-19 patients. Its advantages lie in clinical efficacy and improvement of symptom group, and can prevent patients from transforming to severe disease. In terms of clinical efficacy and safety, Shufeng Jiedu and Lianhua Qingwen have obvious advantages, which are worthy of clinical promotion.

Primary therapy of early breast cancer: Egyptian view of 2021 St. Gallen consensus.

PURPOSE: The theme of the St. Gallen International Breast Cancer Conference 2021 held virtually for the first time, due to the COVID-19 pandemic, was on tailoring therapies for patients with early breast cancer. A monkey survey that included an Egyptian Panel voted on most of the questions of the original St. Gallen consensus, and some added new questions most relevant to oncology practice in the country, to be able to compare voting results that reflect differences in breast cancer management and decision making. METHODS: The panel included 74 Egyptian scientists from different oncology specialties. Management issues including controversial diagnostic and therapeutic interventions were prepared by a small committee and then projected using the online monkey survey website: https://www.surveymonkey.com . The survey included 130 questions. Results were then analyzed, tabulated, and compared to the voting results of the original St. Gallen consensus. RESULTS AND CONCLUSIONS: Voting questions and resulting percentages of answers from the Egyptian panel were summarized. There was no consensus between the Egyptian and the original St. Gallen panels on 28/130 statements. They mostly included genetic and pathologic aspects, specifically the routine use of gene signature assays and a few queries involving surgical, radiotherapeutic, and systemic interventions. Probably, available resources and healthcare system differences in Egypt compared to European and the USA were the cause of these differences. This would also be applicable to other low- and low-middle-income healthcare scenarios present in many countries, especially with the present constraints of the COVID-19 pandemic.

The Impact of COVID-19 on the Diagnosis and Treatment of Lung Cancer over a 2-Year Period at a Canadian Academic Center.

BACKGROUND: We have recently reported a 35% drop in new lung cancer diagnoses and a 64% drop in lung cancer surgeries during the first year of the pandemic. METHODS: The target population was divided into three cohorts: pre-COVID-19 (2019), first year of COVID-19 (2020), and second year of COVID-19 (2021). RESULTS: The number of new lung cancer diagnoses during the second year of the pandemic increased by 75%, with more than 50% being in the advanced/metastatic stage. There was a significant increase in cases with multiple extrathoracic sites of metastases during the pandemic. During the first year of the pandemic, significantly more patients were treated with radiosurgery compared to the pre-COVID-19 year. During the second year, the number of radiosurgery and surgical cases returned to pre-COVID-19 levels. No significant changes were observed in systemic chemotherapy and targeted therapy. No statistical difference was identified in the mean wait time for diagnosis and treatment during the three years of observation. However, the wait time for surgery was prolonged compared to the pre-COVID-19 cohort. CONCLUSIONS: The significant drop in new diagnoses of lung cancer during the first year of the pandemic was followed by an almost two-fold increase in the second year, with the increased rate of metastatic disease with multiple extra-thoracic site metastases. Limited access to surgery resulted in the more frequent use of radiosurgery.

Child sexual abuse survivors: Differential complex multimodal treatment outcomes for pre-COVID and COVID era cohorts.

BACKGROUND: Child sexual abuse (CSA) is a form of early-life trauma that affects youth worldwide. In the midst of the current COVID-19 pandemic, it is imperative to investigate the potential impact of added stress on already vulnerable populations. OBJECTIVE: The aim of this study was to evaluate the effectiveness of a multimodal treatment program on mental health outcomes for youth CSA survivors aged 8-17. Secondary to this, we explored the potential impact of the COVID-19 on treatment outcomes. PARTICIPANTS AND SETTING: Participants of this study were children and youth aged 8-17 who were engaged in a complex multimodal treatment program specifically designed for youth CSA survivors. METHODS: Participants were asked to complete self-report surveys at baseline and at the end of two subsequent treatment rounds. Surveys consisted of measures pertaining to: (1) PTSD, (2) depression, (3) anxiety, (4) quality of life, and (5) self-esteem. RESULTS: Median scores improved for all groups at all timepoints for all five domains. For the pre-Covid participants, the largest improvements in the child program were reported in depression (36.6 %, p = 0.05); in the adolescent program anxiety showed the largest improvement (-35.7 %, p = 0.006). Improvements were generally maintained or increased at the end of round two. In almost every domain, the improvements of the pre-COVID group were greater than those of the COVID-I group. CONCLUSIONS: A complex multimodal treatment program specifically designed for youth CSA survivors has the capacity to improve a number of relevant determinants of mental health and well-being. The COVID-19 pandemic may have retraumatized participants, resulting in treatment resistance.

Feasibility of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for advanced peritoneal surface tumors during the COVID-19 pandemic: A single-institution experience.

BACKGROUND AND OBJECTIVES: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a complex treatment used in selected patients with peritoneal surface malignancies. HIPEC procedures are time and resource intensive. The primary aim of this analysis was to compare the experience of treating advanced abdominal tumors with CRS-HIPEC before and during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: Patients included in this analysis received CRS-HIPEC at a single center during either a prepandemic (March 18, 2019-March 17, 2020) or pandemic (March 18, 2020-February 5, 2021) interval. A retrospective chart review was performed. RESULTS: Our analysis included 67 patients: 30 (45%) treated prepandemic and 37 (55%) treated during the pandemic. Median age at the time of operation was 58 years (interquartile range: [49-65]); 53% of patients were women. Patients treated during the pandemic presented with higher peritoneal cancer index (PCI) scores with 32% (n = 12) having a PCI > 20 at the time of surgery (p = 0.01). Five patients had delays in surgery due to the pandemic. Rates of overall postoperative morbidity, reoperation, and readmission were not different between the cohorts. CONCLUSIONS: Despite presenting with more extensive disease, patients treated with CRS-HIPEC during the height of the COVID-19 pandemic had comparable perioperative outcomes to patients treated prepandemic.

Sleep Problems Prior to Radio-chemotherapy in Patients With Locally Advanced Cancer of the Esophagus or the Esophagogastric Junction.

BACKGROUND/AIM: Many patients with locally advanced cancer of the esophagus or esophagogastric junction receive definitive or neoadjuvant radiochemotherapy. Patient anticipation of this treatment can cause or aggravate distress and sleep disorders. This study aimed to identify the prevalence of sleep disorders and risk factors. PATIENTS AND METHODS: Thirty-eight patients assigned to radio-chemotherapy were retrospectively evaluated for pre-treatment sleep disorders. Investigated characteristics included age; sex; performance score; comorbidity index; previous malignancies; family history; distress score; emotional, physical or practical problems; tumor site; histology and grading; tumor stage; planned treatment; and relation to 2019 Coronavirus pandemic. RESULTS: Sleep problems were reported by 15 patients (39.5%). Significant associations were found for higher distress scores (p=0.016) and greater numbers of emotional problems (p<0.0001). A trend was observed for greater numbers of physical problems (p=0.176). CONCLUSION: The prevalence of sleep problems was high. Risk factors were found that can help identify patients requiring psychological support already prior to radio-chemotherapy.

Prophylactic surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC CO2) versus standard surgery in colorectal carcinoma at high risk of peritoneal carcinomatosis: short-term and long-term outcomes from the CHECK study - protocol for a randomised, multicentre, phase 3 trial.

INTRODUCTION: Up to one-fifth of patients with colorectal cancer will develop peritoneal metastases, frequently without other districts' involvement. Despite the recent unsuccesses of hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer peritoneal metastases treatment, the rationale in the prophylactic setting remains strong. Several clinical and pharmacokinetic data suggest that the efficacy of intraperitoneal chemotherapy is highest when the disease is microscopic. However, robust evidence demonstrating whether the addition of HIPEC for high-risk colorectal cancers offers better control of local recurrence is lacking. METHODS AND ANALYSIS: This is a multicentre randomised phase 3 trial comparing prophylactic surgery plus HIPEC CO2 with mitomycin, over standard surgical excision in patients with colorectal cancer at high risk of peritoneal carcinomatosis; 388 patients will be included in this study. The primary objective is to compare the efficacy of prophylactic surgery (radical colorectal resection, omentectomy, appendectomy, round ligament of the liver resection and bilateral adnexectomy) plus HIPEC CO2 with mitomycin and standard surgery in terms of local recurrence-free survival. The main secondary endpoints are disease-free survival (DFS), overall survival (OS) and safety. The primary endpoint will be described with a cumulative incidence function and will be analysed with Grey test to take account of the competing risks. DFS and OS will be described with the Kaplan-Meier method. ETHICS AND DISSEMINATION: This trial has been evaluated by the Italian Medicines Agency, local ethics committees and will be submitted to the Ministry of Health to notify the start of the trial according to the regulation of trials on devices with CE mark/certification.The results will be submitted for presentation at academic meetings and for publication in a peer-reviewed journal, whatever the findings. TRIAL REGISTRATION NUMBER: NCT03914820.

Severe myopericarditis following the third dose of an mRNA COVID-19 vaccine: utility of a multimodal treatment approach.

We report a rare case of severe myopericarditis in a healthy man in his 20s after the third dose of an mRNA COVID-19 vaccine. His symptoms and troponinemia resolved with a beta-blocker in addition to standard anti-inflammatory therapy, highlighting the utility of multimodal therapy.

[Acupuncture as adjuvant therapy for 32 cases of coronavirus disease 2019].

OBJECTIVE: To observe the clinical effect of acupuncture on coronavirus disease 2019 (COVID-19) based on the conventional treatment. METHODS: A total of 35 patients with COVID-19 of mild or ordinary type were involved (3 cases dropped off). Acupuncture was applied on the basis of western medicine and Chinese materia medica treatment. Dazhui (GV 14), Fengchi (GB 20), Kongzui (LU 6), Hegu (LI 4), etc. were selected as the main acupoints, the supplementary acupoints and the reinforcing and reducing manipulations were selected according to syndrome differentiation. Acupuncture treatment was given once a day, 5 times a week. On day 3 and day 7 of acupuncture, relief condition of the main symptoms was observed. Before acupuncture and on day 3 and day 7 of acupuncture, efficacy evaluation scale of TCM on COVID-19 (efficacy evaluation scale) score was recorded. The effects of different intervention time of acupuncture on patients' hospitalization time were compared, the understanding of acupuncture treatment of patients discharged from hospital was recorded, the clinical efficacy and safety of acupuncture treatment were evaluated. RESULTS: On day 3 and day 7 of acupuncture, the symptoms of lung system and non lung system were both relieved; the scores of efficacy evaluation scale were both decreased compared before acupuncture (P<0.05), and the efficacy evaluation scale score of day 7 of acupuncture were lower than day 3 of acupuncture (P<0.05). The average hospitalization time of patients received early acupuncture was shorter than late acupuncture (P<0.05). The total effective rate was 84.4% (27/32) on day 7 of acupuncture, which was higher than 34.4% (11/32) on day 3 of acupuncture (P<0.05). During the acupuncture treatment, there were neither adverse reactions in patients nor occupational exposures in doctors. The patients generally believed that acupuncture could promote the recovery of COVID-19 and recommended acupuncture treatment. CONCLUSION: On the basis of the conventional treatment, acupuncture can effectively relieve the clinical symptoms in patients with COVID-19, early intervention of acupuncture can accelerate the recovery process. Acupuncture has good safety, clinical compliance and recognition of patients.

Diagnosis and Management of Myocarditis in Children: A Scientific Statement From the American Heart Association.

Myocarditis remains a clinical challenge in pediatrics. Originally, it was recognized at autopsy before the application of endomyocardial biopsy, which led to a histopathology-based diagnosis such as in the Dallas criteria. Given the invasive and low-sensitivity nature of endomyocardial biopsy, its diagnostic focus shifted to a reliance on clinical suspicion. With the advances of cardiac magnetic resonance, an examination of the whole heart in vivo has gained acceptance in the pursuit of a diagnosis of myocarditis. The presentation may vary from minimal symptoms to heart failure, life-threatening arrhythmias, or cardiogenic shock. Outcomes span full resolution to chronic heart failure and the need for heart transplantation with inadequate clues to predict the disease trajectory. The American Heart Association commissioned this writing group to explore the current knowledge and management within the field of pediatric myocarditis. This statement highlights advances in our understanding of the immunopathogenesis, new and shifting dominant pathogeneses, modern laboratory testing, and use of mechanical circulatory support, with a special emphasis on innovations in cardiac magnetic resonance imaging. Despite these strides forward, we struggle without a universally accepted definition of myocarditis, which impedes progress in disease-targeted therapy.

[An Overview and Interpretation of Important Clinical Studies 
on Non-small Cell Lung Cancer in 2021].

Though the coronavirus disease is still raging in 2021, clinical research on non-small cell lung cancer (NSCLC) did not stop. However, benefiting from advances in lung cancer treatment modality, NSCLC patients have experienced significant improvements in overall survival and quality of life. Currently, research advances on targeted therapy and immunotherapy have together transformed the status of postoperative adjuvant therapy and established a new standard treatment modality for resectable NSCLC. There are equally important research advances in locally advanced and advanced NSCLC, including new treatment modalities, new therapeutic agents, etc., all of which bringing more options for clinical treatment. These therapies will bring changes to NSCLC and will gradually lead to the chronicity of lung cancer in the foreseeable future. Therefore, this paper reviews important studies that will change clinical practice in NSCLC treatment and noteworthy research advances in 2021.
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Coagulopathy and Fibrinolytic Pathophysiology in COVID-19 and SARS-CoV-2 Vaccination.

Coronavirus Disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is frequently complicated by thrombosis. In some cases of severe COVID-19, fibrinolysis may be markedly enhanced within a few days, resulting in fatal bleeding. In the treatment of COVID-19, attention should be paid to both coagulation activation and fibrinolytic activation. Various thromboses are known to occur after vaccination with SARS-CoV-2 vaccines. Vaccine-induced immune thrombotic thrombocytopenia (VITT) can occur after adenovirus-vectored vaccination, and is characterized by the detection of anti-platelet factor 4 antibodies by enzyme-linked immunosorbent assay and thrombosis in unusual locations such as cerebral venous sinuses and visceral veins. Treatment comprises high-dose immunoglobulin, argatroban, and fondaparinux. Some VITT cases show marked decreases in fibrinogen and platelets and marked increases in D-dimer, suggesting the presence of enhanced-fibrinolytic-type disseminated intravascular coagulation with a high risk of bleeding. In the treatment of VITT, evaluation of both coagulation activation and fibrinolytic activation is important, adjusting treatments accordingly to improve outcomes.

Effect of Intra-arterial Alteplase vs Placebo Following Successful Thrombectomy on Functional Outcomes in Patients With Large Vessel Occlusion Acute Ischemic Stroke: The CHOICE Randomized Clinical Trial.

Importance: It is estimated that only 27% of patients with acute ischemic stroke and large vessel occlusion who undergo successful reperfusion after mechanical thrombectomy are disability free at 90 days. An incomplete microcirculatory reperfusion might contribute to these suboptimal clinical benefits. Objective: To investigate whether treatment with adjunct intra-arterial alteplase after thrombectomy improves outcomes following reperfusion. Design, Setting, and Participants: Phase 2b randomized, double-blind, placebo-controlled trial performed from December 2018 through May 2021 in 7 stroke centers in Catalonia, Spain. The study included 121 patients with large vessel occlusion acute ischemic stroke treated with thrombectomy within 24 hours after stroke onset and with an expanded Treatment in Cerebral Ischemia angiographic score of 2b50 to 3. Interventions: Participants were randomized to receive intra-arterial alteplase (0.225 mg/kg; maximum dose, 22.5 mg) infused over 15 to 30 minutes (n = 61) or placebo (n = 52). Main Outcomes and Measures: The primary outcome was the difference in proportion of patients achieving a score of 0 or 1 on the 90-day modified Rankin Scale (range, 0 [no symptoms] to 6 [death]) in all patients treated as randomized. Safety outcomes included rate of symptomatic intracranial hemorrhage and death. Results: The study was terminated early for inability to maintain placebo availability and enrollment rate because of the COVID-19 pandemic. Of 1825 patients with acute ischemic stroke treated with thrombectomy at the 7 study sites, 748 (41%) patients fulfilled the angiographic criteria, 121 (7%) patients were randomized (mean age, 70.6 [SD, 13.7] years; 57 women [47%]), and 113 (6%) were treated as randomized. The proportion of participants with a modified Rankin Scale score of 0 or 1 at 90 days was 59.0% (36/61) with alteplase and 40.4% (21/52) with placebo (adjusted risk difference, 18.4%; 95% CI, 0.3%-36.4%; P = .047). The proportion of patients with symptomatic intracranial hemorrhage within 24 hours was 0% with alteplase and 3.8% with placebo (risk difference, -3.8%; 95% CI, -13.2% to 2.5%). Ninety-day mortality was 8% with alteplase and 15% with placebo (risk difference, -7.2%; 95% CI, -19.2% to 4.8%). Conclusions and Relevance: Among patients with large vessel occlusion acute ischemic stroke and successful reperfusion following thrombectomy, the use of adjunct intra-arterial alteplase compared with placebo resulted in a greater likelihood of excellent neurological outcome at 90 days. However, because of study limitations, these findings should be interpreted as preliminary and require replication. Trial Registration: ClinicalTrials.gov Identifier: NCT03876119; EudraCT Number: 2018-002195-40.