Journal of Investigative Medicine

Academic centers and industry partners have had love–hate relationships for more than a century. Despite many examples of socially beneficial collaborations between academia and industry, it has become increasingly difficult to find an arrangement where neither clinicians/researchers working with industry nor industry itself is demonized. Regardless, we must incentivize innovation. Preclinical research is primarily funded by the government, whereas 70% of clinical research is supported by industry. Due to external political pressure and industry's concern about lack of control over content, industry's support of continuing medical education (CME) has shrunk to 10% from 40% and has led to diversion of funding to non-CME events. Despite scrutiny of clinical faculty members’ interactions with industry, corporate philanthropy is much sought after by academic institutions. Developing new therapeutics requires both academia and industry to transparently and ethically partner with creation of innovative start-ups, sharing of non-proprietary clinical trial data, and in postmarketing surveillance. The search continues for truly symbiotic relationships between academia and industry.

Although cannabinoid hyperemesis syndrome (CHS) was first reported more than 15 years ago, it still remains an unfamiliar clinical entity among physicians worldwide. CHS is categorized by Rome IV classification as a functional gastroduodenal disorder. It is characterized by stereotypical episodic vomiting in the setting of chronic, daily cannabis use, with cycles decreasing by the cessation of cannabis. CHS is also associated with abdominal pain reduced by hot baths and showers with comparative well-being between attacks. Thus, its clinical presentation resembles ‘classic’ cyclic vomiting syndrome, but eliciting a cannabis history is crucial in diagnosing this entity. In acute attacks, parenteral benzodiazepines are very effective. For prevention and long-term management, tricyclic antidepressants such as amitriptyline are the mainstay of therapy requiring doses in the range of 50–200 mg/d to achieve symptom control. In addition, counseling to achieve marijuana cessation, accompanied by antianxiety medications, is necessary for sustaining clinical outcomes. Once the patient is in remission and off marijuana for a period of 6–12 months, then tapering the dose of amitriptyline can be implemented, with the goal of no therapy being achieved in the majority of patients over time. With the legalization of marijuana in many states, CHS will become an increasingly prevalent clinical entity, so educating about CHS is an important goal, particularly for emergency department physicians who generally first encounter these patients.

Atrial fibrillation (AFIB) is the most common heart rhythm abnormality and is associated with significant morbidity and mortality. While the treatment of AFIB involves strategies of rate with or without rhythm control, it is also essential to strategize appropriate therapies to prevent thromboembolic complications arising from AFIB. Previously, anticoagulation was the main treatment option which exposed patients to higher than usual risk of bleeding. However, with the advent of new technology, novel therapeutic options aimed at surgical or percutaneous exclusion or occlusion of the left atrial appendage in preventing thromboembolic complications from AFIB have evolved. This review evaluates recent advances and therapeutic options in treating AFIB with a special focus on both surgical and percutaneous interventions which can reduce and/or eliminate thromboembolic complications of AFIB.

COVID-19 has posed an extraordinary burden on health and the economy worldwide. Patients with cardiovascular diseases are more likely to have severe illness due to COVID-19 and are at increased risk for complications and mortality. We performed a narrative literature review to assess the burden of COVID-19 and cardiovascular morbidity and mortality. Myocardial injury has been reported in 20%–30% of patients hospitalized due to COVID-19 and is associated with a worse prognosis and high mortality (~50%–60%). Proposed mechanisms of myocardial injury include inflammation within the myocardium (due to direct viral infection or cytokine storm), endotheliitis, coronary vasculitis, myocarditis, demand ischemia, plaque destabilization and right ventricular failure. The right ventricle is particularly vulnerable to injury and failure in COVID-19-infected patients, given the hypoxic pulmonary vasoconstriction, pulmonary microthrombi or pulmonary embolism. Echocardiography is an effective and accessible tool to evaluate left and right ventricular functions and risk stratify patients with COVID-19 infection. Cardiac MRI has detected and characterized myocardial injury, with changes compatible with other inflammatory cardiomyopathies. The long-term consequences of these inflammatory changes are unknown, but accumulating data will provide insight regarding the longitudinal impact of COVID-19 infection on cardiovascular morbidity and mortality.

The prevalence of randomized controlled trials (RCTs) performed without fully informed prospective consent from subjects is unknown. We performed this study to estimate the prevalence of high-impact RCTs performed without informed consent from all subjects and examine whether such trials are becoming more prevalent. We performed a systematic review of English-language RCTs published from 2014 through 2018 identified in Scopus and sorted to identify the top 100 most highly cited RCTs each year. Text search of title and abstract included terms randomized controlled or clinical trial and spelling variants thereof, and excluded metaanalyses and systematic reviews. We independently identified the most highly cited RCTs based on predefined criteria and negotiated to agreement, then independently performed keyword searches, read, abstracted and coded information regarding informed consent from each paper and again negotiated to agreement. No quality indicators were assessed. We planned descriptive qualitative analysis and appropriate quantitative analysis to examine the prevalence and characteristics of trials enrolling subjects with other than fully informed prospective consent. We find that 44 (8.8%, binomial exact 95% CI 6.5% to 11.6%) of 500 high-impact RCTs did not secure informed consent from at least some subjects. The prevalence of such trials did not change over the 5 years (OR=1.09, z=0.78, p=0.44). A majority (66%) of the trials involved emergency situations, and 40 of 44 (90.9%) of the trials involved emergency interventions, pragmatic designs, were cluster randomized, or a combination of these factors. A qualitative analysis explores the methods of and justifications for waiving informed consent in our sample of RCTs.

It is reported that lncRNA KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) is oncogenic in many cancers. This work aimed at probing into its expression and biological functions in retinoblastoma (RB) as well as its regulatory effects on miR-153-3p and hypoxia-inducible factor-1α (HIF-1α). In our study, RB samples in pair were collected, and quantitative real-time PCR (qRT-PCR) was employed for examining the expression levels of KCNQ1OT1, miR-153-3p and HIF-1α. KCNQ1OT1 short hairpin RNAs were transfected into SO-Rb50 and HXO-RB44 cell to inhibit the expression of KCNQ1OT1. The proliferative activity, colony formation ability and apoptosis were examined through cell counting kit-8 assay, colony formation assays, Transwell assay and flow cytometry, respectively. qRT-PCR and western blot analysis were used for analyzing the changes of miR-153-3p and HIF-1α induced by KCNQ1OT1. The regulatory relationships between miR-153-3p and KCNQ1OT1, miR-153-3p and HIF-1α were examined by dual luciferase reporter gene assay and RNA-binding protein immunoprecipitation assay. The results of our study showed that KCNQ1OT1 expression was markedly enhanced in RB tissue samples, and KCNQ1OT1 knockdown had an inhibitory effect on the proliferation, migration, invasion and viability of RB cells. There were two validated binding sties between KCNQ1OT1 and miR-153-3p, and KCNQ1OT1 negatively regulated the expression of miR-153-3p in RB cells. HIF-1α was a target gene of miR-153-3p, and could be positively regulated by KCNQ1OT1. In conclusion, our study indicates that KCNQ1OT1 can increase the malignancy of RB cells via regulating miR-153-3p/HIF-1α axis.

Accumulating studies have shown that the dysregulation of microRNAs is related to the carcinogenesis and development of gastric cancer (GC), and the role of miR-635 in GC remains largely unknown. miR-635 and Kinesin Family Member C1 (KIFC1) mRNA expression in GC tissues and paracancerous tissues and cells were detected by quantitative real-time PCR. KIFC1 protein expression in GC tissues and paracancerous normal tissues and cells was detected by immunohistochemistry and western blot. Cell proliferation was monitored by Cell Counting Kit-8 assay and 5-bromo-2′-deoxyuridine assay. Transwell assay was employed to detect the migration and invasion of GC cells. The dual-luciferase reporter gene assay was adopted to detect the targeting relationship between miR-635 and KIFC1. Compared with paracancerous tissues, miR-635 expression was remarkably decreased in GC tissues; conversely, KIFC1 expression was significantly increased. Compared with human normal gastric epithelial cell GSE-1, miR-635 expression was markedly decreased in GC cell lines. Meanwhile, KIFC1 expression was significantly increased, and the Kaplan-Meier Plotter database showed that its high expression was remarkably associated with poor prognosis. Additionally, miR-635 can negatively regulate KIFC1. miR-635 can target KIFC1 to inhibit proliferation, migration and invasion of GC cells. Collectively, miR-635 is lowly expressed in GC, and it inhibits proliferation, migration and invasion of GC cells via regulating KIFC1.

Cardiac damage from chemotherapy is a known phenomenon leading to significant morbidity and mortality in the cancer surviving population, and identifying high-risk pediatric patients early is challenging. The purpose of this pilot study was to evaluate whether echo strain, cardiac MRI (CMR), and serum biomarkers are more sensitive methods for detecting cardiac toxicity than standard echo and to examine the relationship between biomarkers in patients without decreased systolic function as determined by standard echo. In this pilot study, we prospectively enrolled pediatric subjects after completion of anthracycline inclusive chemotherapy. Each subject underwent a post-treatment echocardiogram (standard with strain), serum biomarkers (N-terminal brain natriuretic peptide (NT-pro-BNP) and interleukin 1 receptor-like 1 protein (ST2)), and CMR (standard and extracellular volumes (ECVs)). We correlated the markers using Pearson correlation. We enrolled 30 subjects, 11F/19M, aged 8–21 years. Cumulative anthracycline dose (CAD) correlated with BNP (p=0.06), CMR ECV 4-chamber (p=0.05) and sagittal (p=0.01), and mitral valve E/A (p=0.02). BNP correlated with CMR ECV 4-chamber (p=0.001) and sagittal (p=0.001) and with echo average longitudinal strain (ALS) (p=0.05). This study demonstrated a significant correlation of CAD with BNP and CMR ECV. There was also a significant correlation of NT-pro-BNP with CMR ECV and ALS. Combining these parameters with standard echo has the potential to identify high-risk patients early. Further studies are needed for long-term follow-up and management in this vulnerable population.

Outside sleep laboratory settings, peripheral arterial tonometry (PAT, eg, WatchPat) represents a validated modality for diagnosing obstructive sleep apnea (OSA). We have shown before that the accuracy of home sleep apnea testing by WatchPat 200 devices in diagnosing OSA is suboptimal (50%–70%). In order to improve its diagnostic performance, we built several models that predict the main functional parameter of polysomnography (PSG), Apnea Hypopnea Index (AHI). Participants were recruited in our Sleep Center and underwent concurrent in-laboratory PSG and PAT recordings. Statistical models were then developed to predict AHI by using robust functional parameters from PAT-based testing, in concert with available demographic and anthropometric data, and their performance was confirmed in a random validation subgroup of the cohort. Five hundred synchronous PSG and WatchPat sets were analyzed. Mean diagnostic accuracy of PAT was improved to 67%, 81% and 85% in mild, moderate-severe or no OSA, respectively, by several models that included participants’ age, gender, neck circumference, body mass index and the number of 4% desaturations/hour. WatchPat had an overall accuracy of 85.7% and a positive predictive value of 87.3% in diagnosing OSA (by predicted AHI above 5). In this large cohort of patients with high pretest probability of OSA, we built several models based on 4% oxygen desaturations, neck circumference, body mass index and several other variables. These simple models can be used at the point-of-care, in order to improve the diagnostic accuracy of the PAT-based testing, thus ameliorating the high rates of misclassification for OSA presence or disease severity.

Glial fibrillar acidic protein (GFAP) in serum has been evaluated as a promising biomarker to differentiate between intracerebral hemorrhage (ICH) and acute ischemic stroke (AIS). We assessed its value as diagnostic and prognostic tool for ICH through a literature systematic review and individual patient data (IPD) meta-analysis.

We performed a systematic search in PubMed database until November 2018 for publications that evaluated GFAP to differentiate AIS and ICH within 4.5 hours after symptoms onset. Thereafter, we invited authors of selected studies to participate in this work by providing IPD from their cohorts. We used standardized individual subject's data to evaluate the association of GFAP concentrations with stroke subtype, demographics, stroke characteristics and factors related with GFAP measurement.

From 4 selected studies, we collected data of 340 patients (236 AIS and 104 ICH). Standardized GFAP blood levels were significantly elevated in ICH compared with those with AIS (median and IQR: 0.84 (0.781–1.24), 0.79 (0.74–0.81); p<0.0001). In both stroke types, GFAP concentrations correlated with baseline stroke severity (r=0.27, p<0.0001; r=0.36, p<0.001; for AIS and ICH, respectively) but no correlation was found regarding time to sampling. Limited data precluded the evaluation of GFAP levels and functional outcome.

These findings demonstrate substantially different levels of GFAP in the blood of patients with ICH compared with patients with AIS soon after the event, while no association was found with outcome. In summary, GFAP could be a valuable diagnostic tool to assist in medical decision-making and to optimize management of stroke in the acute setting.

We examined the status and role of autophagy, a process of lysosomal recycling of cellular material, in clear cell renal cell carcinoma (ccRCC). Paired samples of tumor and adjacent non-malignant tissue were collected from 20 patients with ccRCC after radical nephrectomy. The mRNA levels of apoptosis (BAD, BAX, BCL2, BCLXL, BIM) and autophagy (ATG4, BECN1, GABARAP, p62, UVRAG) regulators were measured by RT-qPCR. The protein levels of autophagosome-associated LC3-II, autophagy receptor p62, apoptotic marker PARP, as well as phosphorylation of autophagy initiator Unc 51-like kinase 1 (ULK1), its activator AMP-activated protein kinase (AMPK) and 4EBP1, the substrate of ULK1 inhibitor mechanistic target of rapamycin (mTOR), were analyzed by immunoblotting. The mRNA levels of pro-apoptotic BAX, anti-apoptotic BCLXL and pro-autophagic ATG4, p62 and UVRAG were higher in ccRCC tumors. Autophagy induction was confirmed by an increase in phospho-ULK1 and degradation of the autophagic target p62, while apoptotic PARP cleavage was unaltered. AMPK phosphorylation was reduced and 4EBP1 phosphorylation was increased in ccRCC tissue. The expression of apoptosis regulators did not correlate with clinicopathological features of ccRCC. Conversely, high mRNA levels of ATG4, GABARAP and p62 were associated with lower tumor stage, as well as with smaller tumor size and better disease-specific 5-year survival (ATG4 and p62). Accordingly, low p62 protein levels, corresponding to increased autophagic flux, were associated with lower tumor stage, reduced metastasis and improved 5-year survival. These data demonstrate that transcriptional induction of autophagy in ccRCC is accompanied by AMPK/mTOR-independent increase in ULK1 activation and autophagic flux, which might slow tumor progression and metastasis independently of apoptosis.

Due to the rapid spread of the COVID-19 pandemic, a lockdown including limitation of activity and restrictions of non-essential travel was imposed on March 21, 2020 in the State of Bavaria, Germany. The implementation of activity restrictions not only strongly affects the economy but will possibly also impact the mental and physical health status of the general population. Therefore, the present study aimed to explore psychological effects of the COVID-19 crisis on a sample of Bavarian students. In this cross-sectional study, we enrolled 1943 voluntary subjects from Bavarian universities. All subjects completed an online questionnaire asking for mental health stress, as well as potential factors, influencing the state of mental stress during pandemic lockdown. In our study cohort, 17.3% (n=336) of the students indicated that they experienced less mental stress through COVID-19 pandemic, while 39.6% (n=770) stated that they had an increased psychological burden. The bivariate analysis identified sex and the level of physical activity as potential risk factors for the level of mental stress during the COVID-19 pandemic. Further research is necessary to investigate specific symptoms of mental stress and the overall long-term impact on mental health.

Believed to have originated from a local Huanan Seafood Wholesale Market in Wuhan, Hubei Province in China, the COVID-19 has had an unprecedented and catastrophic impact on humanity, with the WHO declaring it a global pandemic. Although the first case of COVID-19 was reported in December 2019, the primary source and intermediate host have not been confirmed, but human-to-human transmission has been universally accepted. The main mode of transmission of the virus is through respiratory droplets along with prominent respiratory system involvement. However, fecal-oral transmission due to the shedding of the virus in the gastrointestinal (GI) tract may continue for up to 10 weeks after respiratory clearance and is fast becoming important. SARS-CoV-2 shows a high affinity to ACE2 receptors, making sites of high ACE2 receptor expression, such as lungs, GI tract, brain, kidneys, heart, liver and immune system, a prime target for infection. Through this literature review, we aim to summarize the current knowledge of immunological pathways that contribute to the disease with a focus specifically on the GI tract involvement. We direct attention to the pathophysiological mechanism of involvement of the GI tract leading to symptomatic manifestations, track GI organ-specific viral loads to compare and contrast with other organ systems. We briefly detail specific treatment strategies from a GI disease standpoint and mention special considerations when there is involvement of the GI tract.

Growth differentiation factor 15 (GDF-15) has been suggested as a prognostic biomarker for bleeding and mortality in atrial fibrillation (AF). To date, serum and EDTA matrices are standardized for the GDF-15 assay but it is unclear if it can be measured also in citrate. In this study, we aim to investigate if the Elecsys GDF-15 assay (Roche Diagnostics, Mannheim, Germany) can be determined accurately in citrate samples in a cohort of 10 patients with AF and 10 healthy controls. From January 2018 to March 2018, we included healthy controls and patients with AF under vitamin K antagonists in a tertiary hospital. Blood samples were drawn in both groups. We included 10 controls (50% males, mean age 36.4±8.9 years) and 10 patients with AF (80% males, mean age 76.5±16.6 years). The mean GDF-15 levels were increased in patients with AF in comparison to healthy controls, as expected by the presence of a heart-related condition and the higher age of this population. In healthy controls, GDF-15 levels showed an optimal correlation between EDTA-serum (r=0.975; p<0.001), EDTA-citrate (r=0.972; p<0.001), and serum-citrate (r=0.997; p<0.001) samples. This was also observed in patients with AF: EDTA-serum (r=0.975; p<0.001), serum-citrate (r=0.835; p=0.003), and EDTA-citrate (r=0.768; p=0.009). Our results demonstrate that citrate samples may be used for the determination of GDF-15 in AF given the positive and good correlation with EDTA and serum matrices. Further studies should validate these observations.