Patients with type 2 diabetes have a higher risk of colorectal cancer (CRC), but whether Chinese herbal medicines (CHMs) can reduce this risk is unknown. This study investigated the effect that CHMs have on CRC risk in patients with type 2 diabetes.This cohort study used the Taiwanese National Health Insurance Research Database to identify 54 744 patients, newly diagnosed with type 2 diabetes, aged 20–70 years, who were receiving treatment between 1998 and 2007. From this sample, we randomly selected 14 940 CHMs users and 14 940 non-CHMs users, using propensity scores matching. All were followed through 2012 to record CRC incidence. Cox proportional hazards regression was used to compute the hazard ratio (HR) of CRC by CHMs use.During follow-up, 235 CHMs users and 375 non-CHMs users developed CRC, incidence rates of 1.73% and 2.47% per 1000 person-years, respectively. CHM users had a significantly reduced risk of CRC compared with non-CHM users . The greatest effect was in those receiving CHMs for more than 1 year. Huang-Qin, Xue-Fu-Zhu-Yu-Tang, Shu-Jing-Huo-Xue-Tang, Liu-Wei-Di-Huang-Wan, Ji-Sheng-Shen-Qi-Wan, Gan-Lu-Yin, Shao-Yao-Gan-Cao-Tang and Ban-Xia-Xie-Xin-Tang were significantly associated with lower risk of CRC.Integrating CHMs into the clinical management of patients with type 2 diabetes may be beneficial in reducing the risk of CRC. Despite recent improvements in diabetes treatment, those with type 2 diabetes are still found to have higher risk of cancer, especially colorectal cancer (CRC).Recently, Chinese herbal medicines have become increasingly popular as an adjunctive treatment for patients with chronic diseases; nevertheless, association of Chinese herbal medicines and the risk of CRC among patients with type 2 diabetes is still unknown.This retrospective 15-year cohort study clarified the therapeutic effect of Chinese herbal medicines on the subsequent risk of CRC among patients with type 2 diabetes.The most prominent effect was observed among those receiving Chinese herbal medicines for more than 1 year.The reported findings serve an important role for healthcare providers in helping to guide more effective treatment strategies to improve clinical outcomes for patients with type 2 diabetes.The corresponding findings could serve as a reference for further pharmacological studies and clinical trials.Diabetes mellitus has become an increasingly prevalent chronic condition that affects more than 400 million people worldwide.3In Taiwan, CRC is commonly diagnosed and is the third leading cause of cancer-related death. Massive developments in specialized diagnostic and therapeutic methods have improved the survival of patients with type 2 diabetes. Some studies have indicated that the long-term use of insulin or sulfonylureas may predispose patients with type 2 diabetes to develop CRC.With few side effects, Chinese herbal medicines (CHMs) had been used for patients with chronic illnesses such as dementia,Given the possible beneficial effect of CHMs on subsequent CRC risk, and the limited information on whether CHMs could modify the relationship between type 2 diabetes and CRC risk, findings from a long-term population-based cohort study might be useful in allocating medical resources and in instituting fact-based policymaking for the treatment of CRC among patients with type 2 diabetes. Nevertheless, to date, no clinical observations or empirical data have documented this potential benefit for patients with type 2 diabetes. Therefore, in this study, we analyzed a nationwide population-based database to compare the risk of CRC among patients with type 2 diabetes who either did or did not receive CHMs.For this study, we used a publicly released cohort dataset, the Longitudinal Health Insurance Database (LHID), comprised of approximately 1 000 000 randomly sampled people and obtained all records from 1996 to 2012. The database has been confirmed by the National Health Research Institute to be representative of the Taiwanese population and its data have been used in many previously published scientific papers.Patients, 20–70 years of age, newly diagnosed with type 2 diabetes between 1998 and 2007 were identified . To be iIn Taiwan, only certified Chinese medicine physicians are entitled to prescribe CHMs. We used the frequency of visits to a Chinese medicine physician to verify the CHMs exposure of each subject with type 2 diabetes. Those receiving CHMs after their initial diagnosis of type 2 diabetes for more than 30 days were identified as CHMs users, whereas those treated for 30 days or less were considered non-CHMs users.Covariates comprised the baseline sociodemographic characteristics and comorbidities. Sociodemographic data included patient’s age, sex, income (for estimating insurance payments) and urbanization level of the residential area. Monthly income was stratified into New Taiwan Dollar (NTD) ≤17 880; NTD 17 881–NTD 43 900 and ≥NTD 43 901. Urbanization levels were divided into urban (levels 1–2), suburban (levels 3–4) and rural (levels 5–7). Level 1 refers to the “most urbanized” communities and level 7 refers to the “least urbanized”.2 test and t-test analyses to examine the differences in demographic characteristics and comorbidities between patients with type 2 diabetes with and without CHMs treatment. The incidence rate of CRC was calculated as the number of cases per 1000 person-years (PYs). Multivariate Cox proportional hazards regression analysis was then applied to compute the HR with 95% CI of CRC risk in association with CHMs use. To test the robustness of the relationship between CHMs use and subsequent CRC risk, we divided the CHMs users into two subgroups: those who used CHMs for 30–365 days and those who used CHMs for more than 365 days. Analysis stratified by age and sex using Cox proportional hazards regression was also conducted to assess the HR of CRC among those who did and did not receive CHMs. Assumptions of the proportional hazards model were verified by using plots of log ) function) versus log (time) and Schoenfeld residuals versus time. All analyses were conducted using SAS V.9.3 software , at a p<0.05 statistically significant level.We conducted χThe CHMs user and non-CHMs user cohorts provided, each, data for 14 940 subjects. After the matching procedure with propensity score, no significant differences were observed between the two groups on age, sex, monthly income, residential area and comorbidities, indicating that the two groups were comparable with regard to these variables .Among all eligible subjects, 610 first episodes of CRC occurred, 375 in non-CHMs users and 235 in CHMs users, during follow-up periods of 151 745.04 and 135,251.86 PYs, respectively. The incidence rate of CRC was significantly lower in CHMs users than in non-CHMs users , with an adjusted HR of 0.71 (95% CI 0.60 to 0.84) . Of noteThis is the first evidence-based cohort study addressing the association between CHMs use and CRC risk in patients with type 2 diabetes through a large nationwide claims-based data source. In this follow-up study of 15 years (1998–2012), we found that patients with type 2 diabetes who were receiving CHMs had a nearly 30% lower chance of CRC than those not using CHMs. Furthermore, those receiving CHMs for more than 365 days were found to have a lower risk of CRC by nearly 60%. The dose-response relationship may elucidate the causality between CHMs use and the decrease in the predisposition for developing CRC. No previous studies have been conducted to determine the long-tern impact of CHMs on CRC risk among patients with type 2 diabetes, thus rendering a comparison of results impossible. However, the findings obtained herein are consistent with earlier research findings and add to the growing body of knowledge on the beneficial effects of CHMs for the patients with chronic diseases.6–8The effect of CHMs was further analyzed with stratification by age and sex. Taken together, the use of CHMs was found to have a greater effect on CRC risk in younger patients irrespective of their sex, and th finding echod these of previous studies.An additional contribution of the present study is the list of Chinese herbal products that were found to be beneficial in reducing CRC risk. For example, Huang-Qin is one of the most common CHMs used to treat type 2 diabetes and it may help in lessening the subsequent risk for CRC. Wogonin, the main ingredient in Huang-Qin, was found to have antineoplastic and anti-inflammatory effects in both in vitro and in vivo studies. One study found that wogonin can induce activation of AMP-activated protein kinase (AMPK), to inhibit the proliferation and induce apoptosis in cancer cells.20 21Findings of the present study revealed that the other commonly-prescribed formulas targeting type 2 diabetes, such as Xue-Fu-Zhu-Yu-Tang and Shu-Jing-Huo-Xue-Tang, also significantly lowered CRC risk. Recently, both animal experiments and human studies showed that Xue-Fu-Zhu-Yu-Tang has anti-inflammatory and anti-tumor effects, primarily via inhibiting the activation of such intracellular signaling pathways as phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin (PI3K-AKT-mTOR).27Similar to a previous report,Gan-Lu-Yin was also found to decrease the risk of CRC. In one study, relative to untreated controls, Gan-Lu-Yin-fed rats had markedly reduced cell proliferation and migration, through the induced differentiation of WEHI-3 cells.34Use of Ban-Xia-Xie-Xin-Tang was found to lessen the risk of developing CRC in patients with type 2 diabetes. One possible mechanism may involve the anti-inflammatory properties of Ban-Xia-Xie-Xin-Tang,38While our study is the first to investigate CHMs effect on reducing CRC risk among patients with type 2 diabetes, there are important limitations to consider. First, a coding error may occur in the retrospective study design due to factors related to the availability and accuracy of the medical record. Therefore, we enrolled patients with type 2 diabetes and CRC only after these patients had at least three outpatient visits reporting consistent diagnoses, or after the patients had at least one inpatient admission. The CRC cases were further verified using the catastrophic illness registry. It should also be noted that the Taiwan NHI randomly audits hospital claims, interviews patients and reviews medical charts to verify the accuracy of medical records. Second, the LHID does not include detailed information on the risk factors associated with CRC, such as smoking, alcohol consumption, level of obesity or dietary habits. Future research, considering these untested variables, is needed to better assess whether the present findings are replicable across diverse groups of individuals. Third, prescriptions for medications issued before 1996 were not reflected in our data analysis. This omission may have resulted in underestimation of the cumulative frequency of prescriptions and therefore may have weakened the apparent effects of the specified herbal products. Although several commonly-prescribed CHMs for patients with type 2 diabetes were identified as influential in decreasing the risk of CRC, their therapeutic effect and safety concerns remain to be elucidated in future pharmacological investigations. Fourth, we conducted two sensitivity analysis to confirm the relationships of interest. First, we did not exclude those receiving metformin with an average dose of more than 250 mg per day (n=14 457). The reanalysis showed that the protective effect of CHMs was somewhat attenuated, but was still statistically significant . Second, all CRC cases were divided into two groups based on the location of CRC, namely, the occurrence of malignant neoplasm of colon and rectal cancer. Of the 610 CRC cases, 395 were of colon cancer and 215 cases were attributed to rectal cancer. After adjusting for the confounders, the reanalysis indicated that integrating CHMs into the conventional therapy decreased the risk of colon cancer and rectal cancer, with an adjusted HR of 0.77 (95% CI 0.64 to 0.95) and 0.60 (95% CI 0.45 to 0.79), respectively. Taken together, the results from the reanalysis of the two sensitivity analyses lent support to the earlier findings of this study. Fifth, although our study revealed a substantial benefit resulting from the use of CHMs among patients with type 2 diabetes, it must be recognized that in our study patients were not randomly categorized into users and nonusers of CHMs. Therefore, potential biases may still remain, and in particular when they stem from unmeasured or unknown confounders. Caution, therefore, must be exercised when interpreting these findings.These limitations notwithstanding, this study also offer several strengths. These include the immediate availability of data, the comprehensiveness of the database, and the statistical power derived from the large sample. In addition, a long observational period offers the opportunity to determine in detail the association between CHMs usage and CRC risk among patients with type 2 diabetes, and the available findings may serve as a useful reference for future studies focusing on additional clinical outcomes, such as colorectal neoplasm.In summary, this large-scale nationwide cohort study demonstrates that the integration of CHMs, during treatment for type 2 diabetes, appears to lower the subsequent risk of CRC by nearly 30%. We believe that these findings could serve as a reference for healthcare providers in helping to establish more effective therapeutic interventions to improve the prognosis of patients with type 2 diabetes.


Hypertension is the single largest global contributor to disability-adjusted life years lost . The majEarly small case series did not indicate an excess of hypertension in people admitted to hospital with COVID-19 . The NovI2 = 24%). The OR for death was similar and weak evidence from meta-regression suggested that hypertension might be a clinical predictor of COVID-19 severity in people aged over 60 [Several other small case series that examine hypertension prevalence with and without severe COVID-19 have appeared in the literature [ over 60 . Likewis over 60 .Similar findings were reported with previous coronavirus infections, such as severe acute respiratory syndrome and Middle East Respiratory Syndrome , 13. Theany anti-hypertensive medication  and increased likelihood of either a positive coronavirus test or an increased risk of severe COVID-19 illness [The viral structural spike (S) protein binds to the angiotensin-converting enzyme 2 (ACE2) receptor to gain entry to cells; this has led to suggestions that use of ACE inhibitors and angiotensin II type-I receptor blockers (ARBs) may be implicated in poorer outcomes with COVID-19 , 18. Whi illness , 26.N = 421 and 161, respectively) [https://bihsoc.org/bihs-statement-on-acei-arb-and-covid19/) [It is important to recognise that, to date, no randomised trial evidence exists to demonstrate either benefits or risks of continuing ACE inhibitors or ARBs on the incidence or outcomes of COVID-19. It must also be acknowledged that these observational data carry risks of residual confounding . One retctively) . These sctively) . Neverthovid19/) . Currentovid19/) . The uniThe evidence base remains incomplete, so strong recommendations are difficult. However, people with complications of hypertension, such as ischaemic heart disease, are already regarded as being at high risk from COVID-19. It seems reasonable to advise those with poorly controlled hypertension (i.e. blood pressure above guideline targets), particularly if prolonged, to also consider themselves to be at elevated risk, and, therefore, to follow appropriate social distancing advice . For youWe should support all our hypertensive patients in continuing to strive for, and maintain, good blood pressure control by continuing to take their medications as prescribed, and by endeavouring to follow and maintain sensible lifestyle choices, including regular exercise .Large numbers of people are being affected by COVID-19 with potentially profound consequences, however, their continued surveillance will also provide further data that will help us to understand the true risk from elevated blood pressure, its treatment and co-morbidities, on outcomes of the disease. Careful and continuous research is vital for an understanding of the mechanisms underlying any additional risk from hypertension with COVID-19, and to determine the best and safest ways to treat those with severe manifestations of disease. Our patients are best served when their treatment is based on available evidence rather than speculation, and the growing body of evidence suggests that continuation of ACE inhibitors and ARBs during the current COVID-19 pandemic is safe.


New York City was the international epicenter of the COVID-19 pandemic. Health care providers responded by rapidly transitioning from in-person to video consultations. Telemedicine  is a potentially disruptive innovation; however, little is known about patient satisfaction with this emerging alternative to the traditional clinical encounter.This study aimed to determine if patient satisfaction differs between video and in-person visits.In this retrospective observational cohort study, we analyzed 38,609 Press Ganey patient satisfaction survey outcomes from clinic encounters  at a single-institution, urban, quaternary academic medical center in New York City for patients aged 18 years, from April 1, 2019, to March 31, 2020. Time was categorized as pre–COVID-19 and COVID-19 . Wilcoxon-Mann-Whitney tests and multivariable linear regression were used for hypothesis testing and statistical modeling, respectively.P<.001). In adjusted analyses, video visits  and the COVID-19 period  were associated with higher patient satisfaction. Younger age , female gender , and new visit type  were associated with lower patient satisfaction.We experienced an 8729% increase in video visit utilization during the COVID-19 pandemic compared to the same period last year. Video visit Press Ganey scores were significantly higher than in-person visits (94.9% vs 92.5%; Patient satisfaction with video visits is high and is not a barrier toward a paradigm shift away from traditional in-person clinic visits. Future research comparing other clinic visit quality indicators is needed to guide and implement the widespread adoption of telemedicine. New York City was the world’s COVID-19 epicenter in early 2020 .Historically, telemedicine focused on rural medicine  and/or mWe examined patient acceptance of video visits by comparing Press Ganey patient satisfaction scores for video vs in-person visits at an urban, quaternary referral, academic medical center from April 1, 2019, to March 31, 2020. We hypothesized that there would be no difference in Press Ganey patient satisfaction scores between video and in-person visits. We captured one month of clinic visits during the COVID-19 pandemic and sought to determine the factors associated with patient satisfaction during this time frame.NewYork-Presbyterian/Weill Cornell Medical Center (NYP/WCM) is a large nonprofit academic medical center located in New York City. As of May 8, 2020, NYP/WCM has admitted a total of 1443 COVID-19 patients. At our institution, inpatient services are provided at NYP, while outpatient services are provided predominately at WCM facilities; both institutions share the same providers.We used a customized version of the Press Ganey Outpatient Medical Practice Survey to evaluate patient satisfaction following clinic encounters at WCM from April 1, 2019, to March 31, 2020. The Press Ganey survey is used by more than 26,000 health care organizations, including over 60% of all US hospitals. It is the most commonly used, validated tool for assessing patient satisfaction in the outpatient setting . The datThe WCM Press Ganey Medical Practice Survey contains 31 items assessed on a 5-point Likert scale  to evaluate seven domains of patient care: Background Questions (3 items), Access (8 items), Moving Through Your Visit (4 items), Nurse/Assistant (3 items), Care Provider (6 items), Personal Issues (4 items), and Overall Assessment (3 items). WCM surveyed patients with 19 items from the standardized Press Ganey Outpatient Medical Practice Survey; the remaining 12 were by WCM from the Press Ganey item bank. The same survey instrument was used across all specialties and providers without variation for video vs in-person visits. Press Ganey sent the survey instrument 2-3 days after completion of the outpatient visit or video visit. Press Ganey then reported deidentified satisfaction scores to WCM without linkage to the patient’s electronic health record to maintain confidentiality.COVID-19 period. This timing corresponds with a WCM mandate to shift the majority of outpatient care from in-person to video visits.We performed a retrospective study of patients aged 18 years and older. In order to adjust for the COVID-19 pandemic, we categorized visits after March 3, 2020, as the Our total data included 45,667 outpatient visits across 210 visit categories with 2670 (5.8%) outpatients visits during the COVID-19 period. We defined the study group as consisting of video visits, which were identified if the visit type contained the words “Video Visit.” A total of 7058 outpatient visits were excluded: 4030 outpatient visits involving procedures  or imaging, 2993 visits comprising pediatric patients <18 years of age, 33 visits that did not have Press Ganey scores, and 2 visits that did not include patient gender. The comparison group consisted of in-person outpatient visits. After applying our exclusion criteria, our final WCM Press Ganey data included 38,609 visits across 88 visit categories; of these, 620 (1.6%) video visits constituted the study population .t test and the chi-squared test. Hypothesis testing was conducted using the nonparametric Wilcoxon-Mann-Whitney test, comparing Press Ganey satisfaction scores between in-person and video visits across the study period. Additionally, we compared in-person and video visits in the pre–COVID-19 period to in-person and video visits during the COVID-19 period, respectively.Independent variables were compared by pre–COVID-19 vs COVID-19 period using the paired The dependent variable in our study was the Press Ganey patient satisfaction score. We fit a multivariable linear regression model with the following covariables: video visit (vs in-person), gender, age , COVID-19 period (yes vs no), and new vs established visit.P<.05. Statistical analysis was performed in R  and STATA 14.0 (StataCorp LLC). The study was approved by the WCM Institutional Review Board and patient consent was not required for this study.Significance was established at NYP/WCM experienced an 8729% increase in video visit use during the COVID-19 period compared to the pre–COVID-19 period.P=.03) . Patients were slightly older in the pre–COVID-19 period than COVID-19 period  . There wIn the pre–COVID-19 period, very few outpatient visits types were video visits (0.3%). During the COVID-19 period, video visits comprised 21.9% of outpatient visits. The proportion of all in-person visit types decreased except for postoperative visits. The visit type “follow-up” showed the greatest decline in share of outpatient visits, decreasing from 50.0% to 36.5% over the past year. Internal medicine outpatient visits constituted the greatest proportion of visits in both time periods.P<.001). Notably, across the study period, patient satisfaction with video was significantly higher than in-person visits  (P<.001) and COVID-19 periods . While Press Ganey scores with video visits did not change across time periods , the scores for in-person visits increased in the COVID-19 period .Press Ganey patient satisfaction scores were significantly higher in the COVID-19 period when compared to the pre–COVID-19 period  ; this asOverall, all of our covariables were statistically significant . In adjuTraditionally, health care encounters between a provider and a patient have occurred face to face in a physical location. Over the past 20 years, the internet and technology have made it possible for health care to be delivered digitally, providing new avenues for medicine to improve the value of care. Bridging gaps in time and distance, video visits have enabled providers to remotely care for patients with acute stroke , requiriTelemedicine is a new, and potentially disruptive, innovation and must be shown to be safe, effective, patient-centered, timely, efficient, and equitable . ClinicaUsing the most current Press Ganey satisfaction scores, we found that video visits were associated with greater patient satisfaction when compared to in-person visits, which was not what we initially hypothesized. However, our results do not justify the use of telemedicine in lieu of in-person visits if both were equally accessible given the limitations outlined below. Furthermore, we observed that overall patient satisfaction is higher in the COVID-19 period, and that younger age, female gender, and new visit type were associated with lower patient satisfaction. To our knowledge, this is the largest study of patient satisfaction comparing video to in-person visits. The results of our study have particular relevance due to the unprecedented public health crisis that has necessitated the widespread adoption of video visits for patient safety and practicality.Our study must be interpreted in the context of the study design. First, this is a retrospective study that prevents us from establishing causality between video visits and increased patient satisfaction. However, our data captures a rapid transition of outpatient care to video visits associated with the COVID-19 pandemic, and our analysis was adjusted for time. Second, our deidentified data did not capture patient-level variables that may influence Press Ganey scores, such as race, income, education, comorbidities, and other characteristics as they were not reported to WCM by Press Ganey to maintain patient confidentiality. Third, the same Press Ganey survey items were used for both video and in-person visits even though Press Ganey developed a new telemedicine version of the Medical Practice Survey in 2018 that may better characterize unique aspects pertinent to video visits . Fourth,In conclusion, we demonstrate that patient satisfaction with video visits compared favorably with in-person visits over the past year and during the COVID-19 pandemic. Our findings support the use of video visits as a viable alternative to traditional in-person visits. The New York City experience may offer insights into the future use of video visits as a new paradigm for health care delivery generally and in times of public health crisis.


Creutzfeld-Jakob disease (CJD) is a rare neurodegenerative condition characterized by rapid progression and fatal outcomes. Patients with progressive dementia and associated atypical features should be investigated, especially with the MRI brain for CJD. Cortical ribboning on diffusion-weighted MRI images is a very crucial diagnostic sign for CJD. Here we present a case of a 52-year-old woman admitted to the hospital after a seizure episode and two-month history of altered mental status. She presented with a 40-minute episode of status epilepticus, necessitating admission to the intensive care unit. Head CT showed no acute intracranial abnormalities, and MRI showed generalized brain atrophy. Electroencephalography (EEG) demonstrated an intermittent slowing of the left hemisphere. Two weeks after admission, she got discharged. Four days later, she presented to the hospital after being found disoriented in a park. MRI showed ventricular dilation and a questionable focus of restricted diffusion in the left thalamus posteriorly. CJD protein panel was collected. Three days after discharge, she was brought to the hospital, and CJD protein testing revealed the presence of 14-3-3 protein, elevated T-tau, and negative real-time quaking-induced conversion (RT-QuIC). The National Prion Disease Surveillance Center reviewed her case, and the CJD diagnosis was confirmed. Creutzfeldt-Jakob disease (CJD) is a rare, invariably fatal disorder characterized clinically by rapidly progressive neurological decline, myoclonus, and eventual descent into a state of akinetic mutism . The preA 52-year-old woman with a medical history of stable pulmonary sarcoidosis, hypothyroidism, chronic alcoholic abuse, and protein-calorie malnutrition presented to the hospital with bizarre behavior and altered mental state for two months. She had a normal level of neurological functioning before. She was initially brought to medical attention when she had an episode of a seizure at a rehabilitation facility for an alcohol detoxification program. After admission, she continued to have partial complex seizures with myoclonic extremity movements and one 40-minute episode of status epilepticus, which lead to sedation and intubation in the intensive care unit (ICU). After stepping down to the medical floor, she had a waxing and waning pattern of confusion with visual hallucinations, agitation, and paranoia. However, there were no abnormalities in her interictal neurologic exam. A head CT scan revealed no acute intracranial abnormalities and generalized brain atrophy Figure MRI of the brain was also unremarkable. Laboratory work was significant only for mild macrocytic anemia, intermittent hypernatremia, and elevated creatinine kinase of 304 U/L. Her thyroid profile was within normal limits. She was briefly transferred to an outside facility where long-term EEG monitoring showed an intermittent slowing of the left cerebral hemisphere without evidence of spike and wave activity. Levetiracetam was initiated for seizures, and she was discharged to home. Four days later, she was brought in by ambulance service to an outside hospital after being found wandering in a park, appearing confused with nonsensical speech. At this time, the physical exam showed a contracted left upper extremity with neglect of right upper limb and bilateral lower limbs. She again experienced profound respiratory distress and required intubation under sedation. A repeated MRI brain showed ventricular dilation with no other significant signal changes. The toxicology screen, antitreponemal antibodies, and HIV testing were negative. Cerebrospinal fluid (CSF) showed red blood cells 81%, neutrophils 56%, glucose 56 mg/dL glucose , lactic acid dehydrogenase 2.7 U/L , protein 28 mg/dL , and myelin basic protein of 6.5 mg/dL . CSF was negative for cryptococcus, cytomegalovirus, enterovirus, herpes simplex virus 1 and 2, and varicella-zoster virus. Creutzfeldt-Jakob disease (CJD) protein panel was collected at that time, though the results remained pending throughout admission. The differential diagnosis at that time included autoimmune or viral encephalitis, end-stage frontotemporal dementia, Wernicke's encephalopathy, and CJD. Her maintenance therapy in the hospital included levetiracetam, thiamine, and folate with minimal improvement in her mental status for three weeks. Then she was discharged again to the family's care.Three days after the discharge, she again presented to the hospital with myoclonus of the right upper extremity, aphasic, repeating stereotyped phrases, and disorientation. An additional MRI showed high signal intensity involving the left temporal, parietal, and occipital lobes with extension towards the left hippocampus with surrounding edema Figure During this admission, CJD protein testing returned and revealed the presence of 14-3-3 protein, elevated T-tau (>4000 pg/mL), and negative real-time quaking-induced conversion (RT-QuIC). National Prion Disease Surveillance Center reviewed and confirmed the diagnosis of Creutzfeldt-Jakob disease. As there is no curative treatment for Creutzfeldt-Jakob disease, comfort care and symptomatic treatment were considered and continued.Human prion disease occurs at a rate of 1 to 1.5 per 1 million in most developed countries. In the United States, the incidence is around 1.2 in 1 million, with a peak age of onset between 55 to 75 years . Prion dCJD's definitive diagnosis is performed through histopathological analysis, which usually shows spongiform brain degeneration, astrocytic gliosis, and neuronal loss due to the accumulation of abnormal prion protein (PrPSc). The spongiform changes refer to grey matter tiny vacuole formation that may combine and give the appearance of holes under the microscope . DetectiDue to CJD's rare incidence, its diagnosis is often not entertained at the time of presentation. Clinical features are usually non-specific and can be confounded with other diseases that present with cognitive impairment, mainly in its early stages. Diagnostic tools include EEG, laboratory findings, and MRI. Early diagnosis is vital to exclude other treatable causes of neurological signals and symptoms presented by patients with suspected sCJD. Professionals can employ different noninvasive modalities to have an accurate and fast diagnosis. EEG is an integral part of sCJD diagnosis and can vary depending on the disease's clinical stage. The most typical finding is periodic sharp wave complexes (PSWC), mainly in the late stages of the disease . HoweverLaboratory markers of the disease have been discussed widely and matter of controversies. One of the most common markers is protein 14-3-3. Despite previous descriptions of its high sensitivity and specificity, recent literature points towards 14-3-3 being non-specific, as it can be positive in different neurological diseases, including encephalitis and acute stroke -13. InstConsidering the inherent difficulties of performing pathological diagnosis and accessing the accuracy of lab markers, MRI became a vital modality for evaluating patients with suspected prion disease. The abnormal MRI findings have been included in diagnostic guidelines published by the Centers for Disease Control and Prevention (CDC) . Even thIn our patient, 14-3-3 was positive. RT-QuIC was negative; however, the Tau protein was elevated. In the presence of the extremely elevated Tau and the 14-3-3 proteins, her images were reviewed with the National Prion Disease Surveillance Center, who assisted in arriving at the diagnosis. A broad and multidisciplinary approach was required for the correct sCJD diagnosis of the patient.Creutzfeldt-Jakob disease (CJD) is one of the rare causes of a rapidly progressive neurological deficit with a short lifespan. This article highlights that patients with progressive dementia and associated atypical features should be investigated, especially with diffusion-weighted and fluid-attenuated inversion recovery (FLAIR) MRI for Creutzfeldt-Jakob disease. Cortical ribboning in the MRI brain is a very crucial diagnostic sign for CJD; however, the absence of it does not rule out CJD, and physicians should investigate the patients with other diagnostic modalities whenever there is a high index of suspicion. This case also redemonstrates that patients have a debilitated and shorter lifespan after the diagnosis, and the unavailability of any treatment warrants the need for further research.


Human immunodeficiency virus (HIV), Tuberculosis (TB) and coronavirus disease (COVID-19) infections independently possess the ability to trigger formation of venous thromboembolism (VTE) and pulmonary embolism (PE). To the authors’ knowledge, this is the first case report describing the presence of PE in a patient with all three aforementioned infectious co-morbidities.A patient living with HIV with virological failure secondary to defaulting antiretroviral therapy (ART) presented with hypoxia, clinical and radiological features suggestive of community-acquired pneumonia (CAP) with raised inflammatory markers and D-dimer levels.She was commenced on prophylactic anticoagulation, supplemental oxygen and empirical antibiotics targeting CAP and pneumocystis jiroveci pneumonia, swabbed for COVID-19 infection and had sputa sent for Gene Xpert® TB testing. A day later, COVID-19 results returned positive and the patient was transferred to isolation and added onto dexamethasone and therapeutic anticoagulation. Sputa returned positive for mycobacterium TB a day later, and anti-tuberculosis therapy was added. She remained persistently hypoxic, with a Well’s score of 3 placing her at moderate risk for PE, which prompted for a computed tomography pulmonary angiogram (CTPA) being ordered, which demonstrated left lower lobe subsegmental PE. Warfarin was added to her regimen. She was discharged on day 18 with a therapeutic international normalised ratio (INR) and not requiring oxygen therapy.This scenario is relevant in low to middle-income countries. The utilisation of a raised D-Dimer in the setting of all four coexisting conditions in arriving at a definite diagnosis remains uncertain. We noted that despite our index patient being on thrombo-prophylaxis, she developed PE highlighting the need for increased vigilance in all COVID-19 patients, even those on prophylactic anticoagulation. Hypercoagulability in COVID-19 infection occurs either because of altered haemostasis, severe inflammation, endothelial dysregulation or disseminated intravascular coagulation.1Coronavirus disease (COVID-19) infection is associated with increased prevalence of venous thromboembolism and pulmonary embolism (PE).6The risk of venous thromboembolism (VTE) in patients living with HIV (PLHIV) is increased in patients who are antiretroviral therapy (ART)-naïve, those with a low cluster of differentiation (CD4) counts and virally unsuppressed.7 Reports of PE in PWTB in Africa are scarce. Kwas et al. have described three cases of TB associated with PE in patients from Tunisia,8 whilst Ekukwe and colleagues described another case of bilateral PE in a PWTB.9Dentan and colleagues showed that tuberculosis is significantly associated with VTE. They, however, found no link between TB and PE but postulated that the occurrence of PE in patients with TB (PWTB) could be explained by hypercoagulability.10Clinical and therapeutic challenges exist in PLHIV presenting with community-acquired pneumonia (CAP). Depending on the patient’s ART compliance, viral load, certain differentials arise – especially if the patient is viral unsuppressed where in addition to COVID-19 pneumonia, one considers pneumocystis jiroveci pneumonia (PJP) and/or pulmonary TB as differentials. Empirical therapy is commenced with an antibiotic (containing a combination of trimethoprim and sulfamethoxazole) plus corticosteroid therapy for PJP with amoxicillin-clavulanic acid and azithromycin for CAP.We describe the following typical patient encountered in clinical practice to demonstrate the need for maintaining a high level of clinical vigilance for PE in patients with coexistent HIV, TB and COVID-19 infection. No data exists, describing the occurrence of PE in such a patient co-infected with all three infectious conditions.Miss B.N.S., a 44-year-old female living with HIV since 1997, had defaulted ART since 2012 and was virologically unsuppressed . She presented on 22/09/2020 with a 1-week history of constitutional symptoms  associated with a non-productive cough and shortness of breath. No symptoms of fever, sore throat, anosmia or dysgeusia were elicited. Clinical examination revealed a chronically ill-looking patient, tachycardia (133 beats/min), tachypnoea (22 breaths/min) and hypoxic at room air (oxygen saturation of 88%). Chest auscultation revealed crepitations in the mid and lower zones of her right lung. Chest radiograph  showed bBlood investigations revealed results as per 11 A CTPA was ordered and revealed bilateral GGO and left lower lobe subsegmental pulmonary emboli  putting her at moderate risk of developing a PE.y emboli .No evidence of deep vein thrombosis was found. Warfarin 5 mg daily was added to her existing anticoagulation regimen.The final diagnosis made in Miss B.N.S. was that of a PLHIV, virologically unsuppressed, who defaulted ART with a CD4 of 66 with confirmed:14Severe COVID-19:Pulmonary tuberculosisPulmonary embolismPneumocystis iirovecii pneumonia .She remained hypoxic needing prolonged oxygen supplementation until Day 17 post-admission. On Day 18, she was transferred to a step-down facility off oxygen to continue with her anticoagulation and TB treatment with a view to restarting ART in 6–8 weeks.Individually, HIV, TB and COVID-19 can predispose to thromboembolism. This case report describes the presence of PE in a patient with all aforementioned infectious diseases and the complexities associated with diagnosis in a developing country. No literature could be found on the combination of HIV, TB, COVID-19 and the development of PE in a single patient.Daily clinical patient re-evaluation is a necessity even in the times of COVID-19. This is often neglected as clinical staff are afraid of their well-being and resort to making notes without careful patient re-examination. Together with clinical examination, review of blood investigations and patient’s oxygen consumption needs, a management plan could be formulated.18 This limited its use in differentiating between the four coexistent medical conditions in our patient, all of which are known to cause elevations in D-dimer levels. This highlights the complexity of diagnosing PE in the context of HIV, TB and COVID-19 infection.The plasma D-dimer test has a low specificity and can be raised in a multitude of conditions including HIV-infection, TB, VTE, PE, COVID-19, pneumonia and increased age.21 Prophylactic anticoagulation has long been recommended for at-risk in-patients with medical conditions such as HIV and/or TB.23 Despite being on prophylactic enoxaparin, our patient still developed a PE. This is similar to what Klok et al. and Tang et al. showed in their studies.24The debate on the use of thromboprophylaxis in patients hospitalised with COVID-19 is ongoing with most studies currently advocating for its use.Pulmonary embolism remains a great masquerader and clinicians must maintain a level of vigilance for diagnosing this life-threatening medical condition, more especially during the COVID-19 infection era.


COVID-19 vaccines will become available in China soon. Understanding communities’ responses to the forthcoming COVID-19 vaccines is important. We applied the theory of planned behavior as the theoretical framework.This study investigates the prevalence of and factors associated with behavioral intention to receive self-financed or free COVID-19 vaccinations among Chinese factory workers who resumed work during the pandemic. We examined the effects of factors including sociodemographics, perceptions related to COVID-19 vaccination, exposure to information about COVID-19 vaccination through social media, and COVID-19 preventive measures implemented by individuals and factories.Participants were full-time employees 18 years or older who worked in factories in Shenzhen. Factory workers in Shenzhen are required to receive a physical examination annually. Eligible workers attending six physical examination sites were invited to complete a survey on September 1-7, 2020. Out of 2653 eligible factory workers, 2053 (77.4%) completed the online survey. Multivariate two-level logistic regression models and ordinal logistic regression models were fitted.The prevalence of behavioral intention to receive a COVID-19 vaccination was 66.6%  and 80.6% . After adjusting for significant background characteristics, positive attitudes toward COVID-19 vaccination , perceived support from significant others for getting a COVID-19 vaccination , and perceived behavioral control to get a COVID-19 vaccination  were positively associated with both dependent variables . Regarding social media influence, higher frequency of exposure to positive information related to COVID-19 vaccination was associated with a higher intention to receive a COVID-19 vaccination at market rate  or a free vaccination . Higher self-reported compliance with wearing a face mask in the workplace  and other public spaces , hand hygiene , and avoiding social gatherings  and crowded places  were also positively associated with both dependent variables. The number of COVID-19 preventive measures implemented by the factory was positively associated with the intention to receive a COVID-19 vaccination under both scenarios .Factory workers in China reported a high behavioral intention to receive a COVID-19 vaccination. The theory of planned behavior is a useful framework to guide the development of future campaigns promoting COVID-19 vaccination. The COVID-19 pandemic remains out of control worldwide. As of September 20, 2020, there were 30,675,675 confirmed cases and 954,417 deaths [Development of the COVID-19 vaccines is on the way. According to the World Health Organization, there are 34 and 142 candidate vaccines in clinical and preclinical evaluation, respectively, as of September 3, 2020; four Chinese candidate vaccines have entered phase III clinical trials . The ana0) was 2.5 and vaccination occurred when 5% of the population had been exposed to SARS-CoV-2, a vaccine efficacy of 80% with 75% coverage could reduce the total number of SARS-CoV-2 cases by 85% without any other measures such as social distancing [The effectiveness of pandemic vaccination campaigns is dependent on both the vaccines’ effectiveness and people’s willingness to be vaccinated. Simulation experiments have shown that, when the reproduction number , presence of comorbid conditions, and trust in government. Moreover, perceptions related to COVID-19  and COVID-19 vaccination  influenced their intention to receive a COVID-19 vaccination -24. We cAcross countries, it is common to encounter vaccination-related information on social media . PreviouTo the best of our knowledge, there have been no studies investigating behavioral intention to receive a COVID-19 vaccination and associated factors among factory workers who resumed work during the COVID-19 pandemic. To address these gaps, this study investigated behavioral intention to receive a self-financed or free COVID-19 vaccination among a sample of factory workers in Shenzhen, China. We examined the effects of factors including sociodemographics, perceptions related to COVID-19 vaccination based on the TPB, exposure to COVID-19 specific information through different media, and COVID-19 preventive measures implemented by individuals and factories.We conducted a cross-sectional closed online survey of 2053 factory workers in Shenzhen, China on September 1-7, 2020. Of the 13 million residents in Shenzhen in 2018, 65.1% were internal migrants and 34.3% were factory workers .This study was conducted in the Longhua district of Shenzhen. In Shenzhen, the majority of the factories are located in Longhua. As of 2018, there are over 2000 factories and about one million factory workers in Longhua. Participants were full-time employees of factories in Shenzhen that were 18 years or older. In Shenzhen, factory workers are required to receive a physical examination at designated hospitals or the Centre for Disease Control and Prevention (CDC) annually. All five designated hospitals (three public and two private) and the one district CDC providing physical examination services to factory workers in Longhua were our study sites for recruitment. To avoid selection bias, the fieldworkers approached all adults attending these sites for physical examination during the study period. They briefed prospective participants about the study details, confirmed their eligibility, and invited them to join the study. Participants were guaranteed that participation was voluntary, refusal would have no effect on them, the survey would not collect personal contacts or identification, and data would be kept strictly confidential and only be used for research purposes. Verbal consent was obtained instead of written consent to allow participants to maintain anonymity. We developed an online questionnaire using Questionnaire Star, a commonly used online survey platform in China. Quick Response (QR) codes were generated to access the online questionnaire. Prospective participants were asked to scan the QR code on site to complete the survey. Each mobile device was only allowed to access the online questionnaire once to avoid duplicate responses. The participants were asked not to disseminate the QR codes to access the survey to other people. The survey had 66 items (about 15 items per page for four pages), which took about 15 minutes to complete. The Questionnaire Star performed completeness checks before the questionnaire was submitted. Participants were able to review and change their responses through a “Back” button. An e-coupon of ¥10 (US $1.54) was sent to participants upon completion. In case participants did not have internet access or a smartphone, the research team prepared a tablet computer in each study site for them to complete the online survey. All data was stored in the online server of Questionnaire Star and protected by a password. Only the corresponding author had access to the database. Ethics approval was obtained from the Longhua District CDC (reference: 2020001).A panel consisting of one CDC staff, two public health researchers, a health psychologist, a senior factory manager, and a factory worker was formed to develop the questionnaire used in this study. The questionnaire was pilot-tested among 10 factory workers to assess clarity and readability. These 10 workers did not participate in the actual survey. Based on the workers’ comments, the panel revised and finalized the questionnaire.Participants were asked to report on sociodemographics such as age, gender, relationship status, whether they had a child, highest education level, monthly personal income, status as frontline workers or management, and type of factory they were working in. In addition, participants were also asked about history of seasonal influenza vaccination and whether they had a family member with a history of COVID-19.Participants were briefed with the following: “COVID-19 vaccines developed by China are likely to become available by the end of 2020.” We assessed behavioral intention to receive COVID-19 vaccination under four scenarios: (1) conditional on 50% vaccine efficacy and market rate (¥1000 or US $154), (2) conditional on 80% vaccine efficacy and market rate, (3) conditional on 50% vaccine efficacy and free vaccines, and (4) conditional on 80% vaccine efficacy and free vaccines. On June 2020, the US Food and Drug Administration released guidance for development and licensure of vaccines to prevent COVID-19, which stated that the primary efficacy end point estimate for a placebo-controlled efficacy trial for a COVID-19 vaccine should be at least 50% to ensure that a widely deployed vaccine is effective . Based oThe response categories were 1 (very unlikely), 2 (unlikely), 3 , 4 (likely), and 5 (very likely). Behavioral intention was defined as “likely” or “very likely.” This definition has been commonly used in previous studies -53. In tCOVID-19 vaccination is highly effective in protecting you from COVID-19), (2) the four-item Negative Attitude Scale , and (3) the two-item Perceived Subjective Norm Scale . The Cronbach α of these scales ranged from .67 to .85; single factors were identified by exploratory factor analysis, explaining for 50.7%-54.0% of total variance. In addition, perceived behavioral control to receive a COVID-19 vaccination was measured by a single item .Three scales were constructed to assess perceptions related to COVID-19 vaccination based on the TPB. They were (1) the five-item Positive Attitude Scale  in the past month . Such information included positive information related to COVID-19 vaccination , negative information related to COVID-19 vaccination , testimonials given by participants of the COVID-19 clinical trials, and negative information about vaccine incidents in China .Participants were asked to report frequency of wearing face masks when having close contact with others in a workplace and other public settings (public spaces or transportation) in the past month . Participants also reported frequency of sanitizing hands using soaps, liquid soaps, or alcohol-based hand rubs after returning from public spaces or touching public installations or equipment and whether they avoided social or meal gatherings with people who they do not live with and crowded places in the past month. The Shenzhen government advocated that eight preventive measures should be implemented in the factories, including (1) prohibiting nonemployees from entering workplaces, (2) taking body temperature and sanitizing hands for all employees before entering the workplace, (3) providing face masks to all employees, (4) keeping adequate distance  between workstations, (5) requiring employees to wear face masks when they have close contact with other people, (6) disinfecting the workplace frequently, (7) maintaining adequate ventilation in the workplace, and (8) setting up partitions in factory canteens ,55. PartThe target sample size was 2000. Given a statistical power of 0.80 and an alpha value of .05, and assuming the level of behavioral intention to receive a COVID-19 vaccination in the reference group (without a facilitating condition) to be 30%-70%, the sample size could detect a smallest odds ratio (OR) of 1.29 between those with and without such facilitating condition .P<.05 in univariate analysis were adjusted in the multivariate two-level logistic regression model.The binary variables on behavioral intention to receive a COVID-19 vaccination conditional on 80% vaccine efficacy and market rate and conditional on same efficacy and free vaccines were used as the dependent variables. Multilevel logistic regression models  were used to analyze factors associated with the dependent variables. Random intercept models were used to allow the intercept of the regression model to vary across study sites, which could account for intracorrelated nested data. Multilevel logistic regression models are commonly used in studies with similar sampling methods ,56. A unr) were obtained. SPSS version 26.0 (IBM Corp) was used for data analysis, with P<.05 considered statistically significant.In addition, using behavioral intention to receive a COVID-19 vaccination conditional on 80% vaccine efficacy and market rate and conditional on same efficacy and free vaccines were used as ordinal dependent variables (from 1 to 5), and background characteristics were used as independent variables; ORs were obtained using ordinal logistic regressions. Adjustment for significant background characteristics, associations between independent variables of interest  and the dependent variables were then assessed by adjusted odds ratios (AORs). A similar approach was used in previous studies . PrincipOut of 2653 eligible factory workers (between 60 and 1200 across study sites) that were approached, 2053 completed the online survey (between 40 and 968 across study sites). The overall response rate was 77.4% (ranging from 66.7% to 80.7% at different sites). Main reasons for nonresponse were lack of time and other logistic reasons. All participants that were approached had access to the internet or a smartphone, and none of them used the tablet computers prepared by the research team. Over half of the participants were younger than 40 years , were female , were married , had children , did not receive tertiary education , had a monthly income less than ¥5000 , were frontline workers , and were working for electronic device manufacturers . Among the participants, 20.3% (n=416) had received a seasonal influenza vaccination at least once, and 1.6% (n=32) had at least one family member with a history of COVID-19 .The prevalence of behavioral intention to receive a COVID-19 vaccination was 53.5% , 66.6% , 75.6% , and 80.6%  and 81.6% (n=1675) of participants reported wearing a face mask every time they had close contact with other people in the workplace and in other public settings, respectively. More than half of the participants self-reported sanitizing hands , avoiding social or meal gatherings , and avoiding crowded places , perceived support from significant others on COVID-19 vaccination uptake , and perceived behavioral control to get a COVID-19 vaccination  were positively associated with both dependent variables . Regarding social media influence, higher frequency of exposure to positive information related to a COVID-19 vaccination was associated with higher intention to receive a COVID-19 vaccination at market rate  or to receive a free vaccination . Higher self-reported compliance with wearing a face mask in the workplace  and other public spaces , hand hygiene , and avoiding social and meal gatherings  and crowded places  were also positively associated with one or both dependent variables . A higher number of COVID-19 preventive measures implemented by the factory were significantly associated with a higher intention to receive COVID-19 vaccination under both scenarios  and used as dependent variables, the same sets of associated factors were identified by univariate and multivariate ordinal logistic regression models. The results are presented in r=0.083; P<.001), perceived subjective norm , and perceived behavioral control  related to a COVID-19 vaccination. A negative correlation was found between social media exposure and negative attitudes toward a COVID-19 vaccination . Moreover, frequency of exposure to positive information related to COVID-19 vaccinations on social media was negatively correlated with positive attitudes , perceived subjective norm , and perceived behavioral control  related to a COVID-19 vaccination. Furthermore, frequency of exposure to testimonials given by COVID-19 vaccine clinical trial participants on social media was negatively correlated with positive attitudes  but was positively correlated with perceived behavioral control to get a COVID-19 vaccination . In addition, frequency of exposure to negative information about other vaccines in China on social media was negatively correlated with positive attitudes  and perceived subjective norm  related to a COVID-19 vaccination  when comparing behavioral intention conditional on 50% vaccine efficacy and those conditional on 80% vaccine efficacy. The prevalence of behavioral intention conditional on free vaccination was higher than that reported in the United States  and SaudOur findings provide empirical insights to inform health promotion development. Similar strategies can be used to promote COVID-19 vaccinations at market rate or free vaccinations, as the associated factors of these two dependent variables were similar. Older participants had a lower intention to receive a COVID-19 vaccination. This finding is consistent with a previous study targeting the general population in the United States . YoungerThe TPB is a potentially useful framework to guide the development of future programs, as three of the four TPB constructs used in this study were significantly associated with both dependent variables in expected directions. It would be useful to increase positive attitudes toward COVID-19 vaccination, as this was found to be a facilitator. In addition to the beneficial effect for oneself , health communication messages should also emphasize that COVID-19 vaccination uptake would result in herd immunization, which could contribute to COVID-19 control. Building up confidence related to the vaccine supply may also be a useful strategy. Over 60% of participants perceived that medical professionals, family, and friends would support them in taking the COVID-19 vaccination. This perception was also a facilitator. Future programs should consider involving the significant others of factory workers to create a subjective norm favoring COVID-19 vaccination uptake. It would also be useful to enhance perceived behavioral control, as this was another facilitator. There is more room for improvement. Outreach in the factories and providing vaccination on-site may be a useful strategy to improve perceived behavioral control among the workers. Relatively few participants had concerns related to cost, side effects, and duration of vaccine protection. The associations between these concerns and behavioral intention were not statistically significant. Addressing these concerns might not be a useful strategy in future promotion campaigns.Our findings suggest that COVID-19 vaccination triggered intensive responses on social media, as about 60% of the participants sometimes or always were exposed to information specific to COVID-19 vaccination on different social media platforms. Our results showed that exposure to positive information related to COVID-19 vaccination through social media was positively correlated with positive perceptions  related to COVID-19 vaccination. These positive perceptions were determinants of behavioral intention to get a COVID-19 vaccination in this study. It is possible that higher amounts of positive information exposure on social media would enhance these positive perceptions, which in turn increases behavioral intention to get a COVID-19 vaccination. Longitudinal studies are needed to test whether this pathway exists. Negative information about vaccines is uniquely attractive to social media. Studies have shown that a major vaccine incident (Changchun Changsheng) had significantly impaired the confidence of vaccines among Chinese people . HoweverFactory workers who reported higher compliance to personal preventive measures were more willing to receive a COVID-19 vaccination. These people may have stronger motivation and self-efficacy to protect themselves, and a COVID-19 vaccination is likely to be considered as a useful means for protection. Preventive measures implemented by the factories also played important roles. More measures implemented by the factories was associated with a higher intention to receive a COVID-19 vaccination. Through implementation of these measures, factories could cultivate widely shared organizational norms to facilitate behavioral changes among the workers ,62.This study has some limitations. First, a direct measure of perceived behavioral control should assess self-efficacy and perceived controllability . PreviouIn summary, factory workers in China reported a high behavioral intention to receive a COVID-19 vaccination. The behavioral intention was cost-sensitive, and the proposed market rate was accepted by the majority of the participants. The TPB is a useful framework to guide the development of future campaigns promoting COVID-19 vaccination in this group.


Bartholin gland carcinomas (BGCs) are rare tumor types, for which no molecular analyses including genomic sequencing have been reported to date. Adenoid cystic carcinomas (ACCs) of the Bartholin’s glands are an atypical histological type of BGC, and currently nothing is known regarding their genetic profiles or similarity to ACC carcinogenesis in other organs including the salivary glands, thereby limiting possible therapeutic options using precision medicine.KRAS and KDM6A mutations were detected in tumor samples collected from each patient. No KRAS mutations have been previously reported in salivary gland ACCs, indicating that the carcinogenesis of BG-ACC differs from that of the salivary gland ACCs. KDM6A mutations are often reported in salivary gland ACCs and facilitate novel gene-targeted therapy, including the use of BET and HDAC inhibitors.We used targeted gene sequencing to analyze the occurrence of 160 cancer-related genes in two patients with BG-ACC. A better understanding of the underlying genetic mechanisms will help to clarify the carcinogenesis of BG-ACC. In turn, this will enable treatment with novel targeting agents, as well as the initial exploration of gene-based precision oncological therapies, which aim to improve treatment outcomes for patients with this disease. Bartholin gland carcinomas (BGCs) are extremely rare tumors, comprising less than 1% of total malignancies in female genitals , 3. PatiThe pathogenesis and carcinogenesis of BGCs remains unclear. The histological classifications, including adenocarcinoma, squamous, and adenosquamous, are similar to those of cervical cancer. In previous studies, it has been shown that a proportion of the squamous type might be related to human papillomavirus (HPV) infection, particularly HPV type 16, as well as to cervical cancer , 3. HowePrecision medicine, such as that using comprehensive genome sequencing, is a possible treatment approach for a number of cancers. In particular, recent molecular and whole-exome sequencing is beginning to reveal the genetic basis of this uncommon disease –8.To date, genetic profiling for BG-ACCs has not been reported. In the present study, we analyzed 160 cancer-related genes from two patients with BG-ACCs as an attempt to bridge the current knowledge gap regarding the genetic characteristics of this disease. This information will help to clarify the carcinogenesis of BG-ACCs and will be useful to identify potential therapeutic targets for future precision medicine.Patient 1 was a 63-year-old woman undergoing excision of a vulvar lesion based on the diagnosis of a Bartholin gland cyst. The resected specimens were reviewed by a pathologist, who diagnosed it as a stage I adenoid cystic carcinoma in the Bartholin glands (BG-ACC). The patient was not provided with adjuvant therapy because there were no residual tumor tissues. However, metastasis to the lung was observed 4 years later. Although the patient had undergone video-assisted thoracoscopic surgery, recurrence at a site in the vulva was detected 5 years after this surgery. She subsequently underwent excision of the recurrent vulvar lesion, which was used for molecular analysis.Patient 2 was a 61-year-old woman undergoing biopsy for a vulvar lesion and was diagnosed as having stage IV BG-ACC. She subsequently underwent total pelvic exenteration with resection of the inferior ramus. The patient had no adjuvant therapy because there were no residual tumors. However, metastases to the lung and liver were observed 2 years later. A biopsy obtained from the recurrent lesion in the liver was used for molecular analysis to establish an appropriate treatment approach.Similar pathological findings were obtained for the tumor in case patient 1 and one of the tumors in the case patient 2. Low-power views showed tumor cells organized in nests, sheets, and trabeculae, with a cribriform pattern  gene located on chromosome 6 with the nuclear factor I/B (NFIB) gene located on chromosome 9 in 44% of ACC cases [MYB/NFIB fusion gene have been performed for ACC mainly in the salivary gland, it remains unclear whether this gene is associated with the carcinogenesis of BG-ACC. The degree of contribution to the disease by other genes, and thereby the utility of the genes as possible therapeutic targets, is uncertain. Further, the extent to which other genes contribute to this disease and might constitute additional targets for potential therapeutic exploitation has not been well established, as previous genetic investigations have focused on salivary gland ACCs [In these cases, we focused on the association between histological types and genetic events. The histological type of both cases was ACC, an uncommon malignancy that can arise in more than one organ site, despite being observed most often in the salivary glands . For saland TSC1 , 10, 11.CC cases , 11, 12.PIK3CA, ATM, CDKN2A, SF3B1, SUFU, TSC1, and CYLD. Togashi et al. detected MYB or MYBL1 locus rearrangements in nearly all ACCs examined, suggesting that these might constitute good diagnostic markers for ACCs [MYB-NFIB and MYBL1-NFIB and ordinary split FISH assays for MYB and MYBL1 were less sensitive [KRAS mutation, which, to the best of our knowledge, has not been previously detected in salivary gland ACCs; this suggests differences between the carcinogenesis of BG-ACC and salivary gland ACCs [In the report of Stephens et al., multiple mutations were identified in half of the examined cases, which collectively implicated chromatin deregulation . In addifor ACCs . Howeverensitive . In our and ACCs , 11.KDM6A, which is related to chromatin remodeling. Previous studies have found alterations in genes implicated in histone modification and chromatin remodeling in cancer development [ARID1A in clear-cell, renal, transitional-cell bladder, and gastric carcinomas [CREBBP and EP300 in non-Hodgkin lymphoma [KDM6A in renal and transitional cell bladder carcinomas [KDM6A triggers super-enhancers that cause sex-specific squamous-like pancreatic cancer with sensitivity to bromodomain and extra-terminal motif (BET) protein inhibitors [SMARCA2) as drug targets for BG-ACC might require further investigation and confirmation. Moreover, there is increasing evidence from human cancer genome sequencing that KDM6A participates in oncogenesis, suggesting it as a therapeutic target for BG-ACCs.In our BG-ACC patient 2, we identified a mutation in elopment . Studiesrcinomas –16, as wlymphoma  and in Krcinomas , 14. Howrcinomas . Furtherhibitors . Becausehibitors  with potKRAS, have been detected in salivary gland ACCs to date, the detection of a KRAS mutation in the tumor of one of our patients suggests that we might have discovered a novel pathway related to BG-ACC carcinogenesis, which could in turn provide a novel therapeutic target.The recent and growing interest in the unique genetic pathways involved in neoplasia is partially a consequence of the promising developments in targeted therapies, which contribute to the increasing potential of personalized-medicine strategies. Previous studies have discovered a number of genetic abnormalities associated with oncogenes and tumor suppressor genes in the tumorigenesis of multiple cancer types. Given that no alterations in the RAS/ERK signaling pathway, which includes MYB/NFIB, as well as by the limited number of patients with BG-ACC. Nonetheless, this is the first study reporting the genomic profiling of BG-ACC. Further genetic analyses of BGCs will undoubtedly elucidate the carcinogenesis of BGC and BG-ACC and will thereby provide a basis for novel gene-targeted therapy as a step toward developing precision medicine strategies.Our study is limited by both its retrospective nature, which lacked information on fusion genes including Additional file 1: Figure S1. Details of the KRAS point mutation. Figure S2. Details of the KDM6A alteration. Figure S3.  in case 1. The horizontal axis corresponds to each examined gene and the vertical axis corresponds to (A) copy number or (B) VAF. Figure S4. Copy-number alteration and variant allele frequency (VAF) in case 2. The horizontal axis corresponds to each examined gene and the vertical axis corresponds to the (A) copy number or (B) VAF.Additional file 2: Table S1. Genes (160) examined in the PleSSision test


Deaths among patients with coronavirus disease 2019 (COVID-19) are partially attributed to venous thromboembolism and arterial thromboses. Anticoagulants prevent thrombosis formation, possess anti-inflammatory and anti-viral properties, and may be particularly effective for treating patients with COVID-19.To evaluate whether initiation of prophylactic anticoagulation within 24 hours of admission is associated with decreased risk of death among patients hospitalized with COVID-19.Observational cohort study.Nationwide cohort of patients receiving care in the Department of Veterans Affairs, the largest integrated healthcare system in the United States.All patients hospitalized with laboratory-confirmed SARS-CoV-2 infection March 1 to July 31, 2020, without a history of therapeutic anticoagulation.Prophylactic doses of subcutaneous heparin, low-molecular-weight heparin, or direct oral anticoagulants.30-day mortality. Secondary outcomes: inpatient mortality and initiating therapeutic anticoagulation.Of 4,297 patients hospitalized with COVID-19, 3,627 (84.4%) received prophylactic anticoagulation within 24 hours of admission. More than 99%  received subcutaneous heparin or enoxaparin. We observed 622 deaths within 30 days of admission, 513 among those who received prophylactic anticoagulation. Most deaths  occurred during hospitalization. In inverse probability of treatment weighted analyses, cumulative adjusted incidence of mortality at 30 days was 14.3% (95% CI 13.1–15.5) among those receiving prophylactic anticoagulation and 18.7% (95% CI 15.1–22.9) among those who did not. Compared to patients who did not receive prophylactic anticoagulation, those who did had a 27% decreased risk for 30-day mortality . Similar associations were found for inpatient mortality and initiating therapeutic anticoagulation. Quantitative bias analysis demonstrated that results were robust to unmeasured confounding . Results persisted in a number of sensitivity analyses.Early initiation of prophylactic anticoagulation among patients hospitalized with COVID-19 was associated with a decreased risk of mortality. These findings provide strong real-world evidence to support guidelines recommending the use of prophylactic anticoagulation as initial therapy for COVID-19 patients upon hospital admission. Deaths among individuals with COVID-19 have been partially attributed to venous thromboembolism and arterial thromboses.8 heparin-based therapies may be particularly effective in treating patients with COVID-19.9 Evaluations of the efficacy of prophylactic anticoagulation in COVID-19 patients in randomized clinical trials are underway but yet to be reported.10 Previous observational cohort studies have shown evidence that use of anticoagulation in COVID-19 patients was associated with decreased risk of mortality;12 however, these studies were limited in sample size or relatively small healthcare systems. Our objective was to estimate the effect of early initiation of prophylactic anticoagulation on the risk of 30-day mortality among patients hospitalized with COVID-19 in the largest integrated healthcare system in the United States.The most commonly used anticoagulants in hospital settings are heparin-based. Given these drugs also possess anti-inflammatory properties,We conducted an observational cohort study using electronic health record (EHR) data from the US Department of Veterans Affairs (VA), which comprises over 1,200 points of care nationwide including hospitals, medical centers, and community outpatient clinics. All care is recorded in an EHR with daily uploads into the VA Corporate Data Warehouse. Available data include demographics, outpatient and inpatient encounters, diagnoses, procedures, smoking and alcohol health behaviors, pharmacy dispensing records, vital signs, laboratory measures, and death information.We included all patients hospitalized between March 1 and July 31, 2020 who had a laboratory-confirmed positive SARS-CoV-2 test result on or within 14 days prior to hospital admission. We excluded patients who had no history of care , received therapeutic anticoagulation in the 30 days prior to hospital admission , received a red blood cell transfusion with 24 hours of admission (as active bleeding or severe anemia may have been a contraindication for anticoagulation), or experienced any of the primary outcomes  within 24 hours of admission and therefore did not have equal chance to be classified as exposed in this study.We extracted inpatient pharmacy records for warfarin, intravenous heparin, low-molecular-weight heparin , and direct oral anticoagulants . Doses and routes considered prophylactic anticoagulation are listed in The exposure of interest was receipt of prophylactic anticoagulation in the first 24 hours of hospitalization compared to no receipt of prophylactic anticoagulation in the same time frame. Primary outcome was mortality within 30 days of hospital admission , which included in-hospital deaths as well as those that occurred after discharge. Secondary outcomes were inpatient mortality and initiation of therapeutic anticoagulation. Algorithms to identify thromboembolic events during hospitalizations of COVID-19 patients have yet to be validated; thus, we considered initiation of therapeutic levels of anticoagulation after the first 24 hours of admission a proxy for a thromboembolic event. For all outcomes, we followed patients from date of hospital admission until earliest of date of outcome or a maximum of 30 days.Some VA hospitals report observation periods and admissions separately, even when a patient has not moved beds or changed providers. We combined these periods and considered a full hospitalization to begin at first presentation in a VA hospital and end when there was not a subsequent “stay” that began within 24 hours. Study design is depicted in 13 measure within two years prior to admission. Smoking status was determined by the most frequent response in the five years prior to hospitalization.14Potential confounders in the relationship between receipt of anticoagulation and COVID-19 mortality or thromboembolic events were identified by reviewing existing literature and through discussions with clinicians. We extracted information on age, race/ethnicity, sex, urban/rural residence, US Census region, clinical comorbidities, Charlson Comorbidity Index, and substance use. Presence of clinical comorbidities was determined by one inpatient or two outpatient diagnoses using International Classification of Diseases - 9th or 10th edition (ICD-9/10) codes in the two years prior to hospitalization, except for cancer, which was considered present if diagnosed ever prior to hospitalization. Level of alcohol consumption was calculated using the most recent Alcohol Use Disorder Identification Test - Consumption (AUDIT-C)We ascertained medication history in the 15 to 90 days prior to hospitalization. We captured vital signs and laboratory measures to account for acute health status at hospital admission. Height and weight measurements closest to hospitalization within five and two years, respectively, prior to admission were used to calculate body mass index. All other vital signs and all laboratory measures utilized the value closest to hospitalization within 14 days prior to admission. Further details on covariate ascertainment windows are depicted in 15 at any dose or intravenous remdesivir16 at any dose within the first 24 hours of hospitalization as well as treatments received after the first 24 hours.To account for potential effects of co-medications with other COVID-19 treatments, we ascertained receipt of oral or intravenous dexamethasoneCovariates with the largest proportion of missing data included alanine aminotransferase (13.5%), aspartate aminotransferase (15.2%), lymphocyte count (15.0%), and total cholesterol (14.1%): all other covariates had <10% missing.17 Propensity scores  were estimated using a multivariable logistic regression model. We included a missing category for covariates with missing data. The area under the receiver operating characteristic curve was 0.74. Each patient was weighted by the inverse probability of receiving the exposure of interest, with the goal of balancing observable characteristics between treatment groups. After IPT weighting, the distribution of propensity scores between the treatment groups overlapped nearly perfectly (We used inverse probability of treatment (IPT) weighting to estimate the marginal treatment effect. We first modeled the probability of receiving the exposure of interest as a function of all measured covariates .erfectly . We calcerfectly . Thus, t20 We therefore displayed cumulative adjusted incidence rates by treatment group treating discharge as a competing event . We nonetheless chose to display cause-specific rather than sub-distribution hazard ratios as our question was etiological in nature.21 These cause-specific hazard ratios were interpreted as the effect of prophylactic anticoagulation on each of the outcomes irrespective of its effect on discharge. Proportional hazards were checked by examining the complementary log-log (or the log of negative log) of estimated survivor functions for exposed and unexposed groups versus the log of survival time. There was no evidence of proportional hazards violations.Covariates were summarized using descriptive statistics, stratified by treatment group. We generated IPT-weighted Kaplan Meier plots. We used Cox regression models with days since hospital admission as the timescale to estimate IPT-weighted hazard ratios (HRs) and 95% confidence intervals (CIs) for the effect of early initiation of prophylactic doses of anticoagulation on 30-day mortality, inpatient mortality, and initiating therapeutic anticoagulation. Both secondary outcomes occur during hospitalization, wherein discharge from hospital was considered a competing event. If patients were censored at discharge, absolute risks derived from Kaplan-Meier analyses would be overestimated.22 To assess for undue effects from outliers with very high or very low estimated propensity of treatment, we capped propensity score distributions at the 1st/99th and again at the 5th/95th percentiles. To account for potentially biased estimation of standard errors or influence from very high or very low weights, we performed sensitivity analyses using combinations of robust standard error estimation23 and stabilized weighting.24 We re-ran the primary analyses extending the exposure ascertainment window from 24 to 48 hours. Given the low frequency of DOAC use in the cohort, we re-ran analyses excluding DOACs from the exposure definition. In post-hoc analyses, we assessed the effect of prophylactic anticoagulation separately by the two most commonly prescribed drugs in the cohort, heparin and enoxaparin. We used Microsoft SQL Server Management Studio v17.4 for data management and SAS version 9.4  and Stata 16 MP for statistical analyses.For each outcome, we used quantitative bias analysis to calculate an e-value, which demonstrates the strength of association between an unmeasured confounder and exposure or outcome, conditional on measured covariates, that would be necessary to fully explain observed effects.This study was approved by the institutional review boards of VA Connecticut Healthcare System and Yale University. It has been granted a waiver of informed consent and is Health Insurance Portability and Accountability Act compliant. This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) and REporting of studies Conducted using Observational Routinely collected health Data for pharmacoepidemiology (RECORD-PE) guidelines .We identified 4,297 patients hospitalized with COVID-19 between March 1 and July 31, 2020 who were included in this analysis .Median age in the cohort was 68 years (interquartile range [IQR] 58–75); most were non-Hispanic Black , non-Hispanic White , or Hispanic . The majority were male , geographically located in the South , and lived in an urban area  . By montIn this cohort, 3,627 (84.4%) patients received prophylactic anticoagulation within the first 24 hours of hospital admission. Among those who received prophylactic anticoagulation, the most common drugs were heparin-based: either subcutaneous heparin  or enoxaparin  that occurred within 30 days of hospital admission, 513 among those who received prophylactic anticoagulation . Most deQuantitative bias analysis demonstrated that an unmeasured confounder would need to be strongly associated with receipt of prophylactic anticoagulation and each outcome to explain the observed associations: e-value lower 95% CI was 1.77 for 30-day mortality, 1.92 for inpatient mortality, and 1.46 for initiating therapeutic anticoagulation . ResultsIn a nationwide cohort of 4,297 patients hospitalized with COVID-19 in the largest integrated healthcare system in the United States, initiation of predominantly heparin-based prophylactic anticoagulation within the first 24 hours of admission was associated with a relative risk reduction of 30-day mortality as high as 34% and an absolute risk reduction of 4.5% in the context of an absolute risk of 18.7% among patients who did not receive prophylactic anticoagulation. These results persisted in sensitivity analyses. We observed similar protective effects for secondary outcomes including inpatient mortality and initiation of therapeutic anticoagulation - a proxy for the development of a thromboembolic event.32 Variations in reported associations likely derive from different exposure definitions of anticoagulation, both form and dose. Additionally, different patient populations , comparator groups, and inclusion/exclusion criteria were used. One of the largest observational studies to date by Nadkarni et al reported that both prophylactic and therapeutic anticoagulation were associated with a reduction in inpatient mortality by up to 55% compared to those not receiving anticoagulation across five New York City hospitals.11 However, the study allowed patients to switch exposure groups during follow-up without comprehensively accounting for time-updated confounding by indication that may have impacted results.Previous studies investigating the role of anticoagulation among patients with COVID-19 have had varied results, but none have reported harm.10 Until clinical trial data are available, our results provide strong evidence for the use of prophylactic anticoagulation as initial therapy for COVID-19 patients upon hospital admission.Our study was designed to emulate a hypothetical clinical trial in which we excluded prevalent users of anticoagulation, balanced covariate distribution at hospital admission  and ascertained exposure within 24 hours of admission. We conducted an intention-to-treat analysis since the data required to account for time-updated exposures and confounders  may not be available within acute hospitalizations. For example, many hospital systems report all diagnoses that occur during a given hospitalization at discharge. Therefore, we could not determine if initiation of prophylactic anticoagulation later in hospitalization confers benefit. There are multiple clinical trials in progress to determine dosing and timing for anticoagulation during the clinical course of COVID-19.34 The etiology of heightened thrombosis remains unclear, although proposed mechanisms have included systemic inflammation, endothelialitis, and activation of the complement system.37 Increases in a variety of inflammatory pathways, including bradykinin, interleukin-6, C-reactive protein, and growth differentiation factor 15, have been described in COVID-19.47 Further, heparin has been shown to block SARS-CoV-2 viral spike protein binding in experimental studies.50 We postulate that the combination of heparin’s known antithrombotic and anti-inflammatory effects,7 in addition to viral infectivity attenuation may, at least in part, explain the observed benefit associated with prophylactic anticoagulation.Thromboembolic events in the context of COVID-19 are strongly associated with mortality.58 We surmised that an intensification of anticoagulation indicated an adverse change in clinical condition. Third, this study was conducted on Veterans currently receiving care in the VA, who are older and have a higher prevalence of chronic health conditions and risk behaviors than the general US population.61 However, prior research has established that after adjusting for age, sex, race/ethnicity, region, and rural/urban residence, all of which were accounted for in this study, there is no difference in total disease burden between Veterans and non-Veterans.61 Our key finding has also been shown in non-Veteran populations;12 thus, effects reported in this study are likely generalizable to the wider US population. Fourth, while individuals in VA care represent a diversity of backgrounds, women represented a small proportion of individuals in the sample.While this study had many strengths, including the availability of detailed, longitudinal, electronic health record data on a nationwide cohort of patients hospitalized with COVID-19, rigorous methodology and findings that were robust to sensitivity analyses, we recognize possible limitations. First, due to the observational nature of the study, a degree of uncertainty persists that can only be addressed through randomized trials. Nonetheless, we took several steps to mitigate potential confounding. We comprehensively accounted for chronic and acute health conditions at hospital admission in addition to other potential COVID-19 treatments to achieve balance of these potential confounders between treatment groups. Further, we showed that our results were robust to unmeasured confounding using quantitative bias analysis, which demonstrated that a confounder would need to be strongly associated with receipt of prophylactic anticoagulation and each of the outcomes considered to explain the observed effects. Second, we did not have available a validated algorithm to identify thromboembolic events as an outcome. However, the use of therapeutic anticoagulation may occur as a result of many reported complications of COVID-19 including venous thromboembolism, arterial thromboembolism, cardiac arrhythmia, and disseminated intravascular coagulation.We studied a nationwide cohort of patients hospitalized with COVID-19 and found that initiation of prophylactic, heparin-based anticoagulation within 24 hours of admission was associated with a lower risk of 30-day mortality, in-hospital mortality, and initiation of therapeutic-dose anticoagulation likely indicative of a thromboembolic event. Our results provide strong real-world evidence to support guidelines recommending the use of prophylactic anticoagulation as initial therapy for COVID-19 patients upon hospital admission.Supplement 1


Irritable bowel syndrome (IBS) is a prevalent gastrointestinal disorder, which impacts the quality of life, work productivity and social activities of patients. Diarrhea-predominant IBS (IBS-D) is one of several subtypes, and accounts for approximately one third of all cases. Currently available treatments are typically unable to alleviate the cardinal symptoms of IBS-D, including abdominal pain and diarrhea, and a clinical unmet need remains for an effective treatment which simultaneously relieves multiple symptoms. Patients may benefit from a multipronged, individualized approach, including dietary modifications, and psychological and pharmacological therapies. The aim of this review is to provide an update on the available and upcoming treatment options for IBS-D in Canada, with reference to the recently updated Canadian IBS consensus guidelines. Initial treatment approaches include lifestyle modifications, dietary modifications, and non-prescription therapies such as peppermint oil. While some medications such as tricyclic antidepressants are also used to treat IBS-D symptoms, eluxadoline and rifaximin are the only two pharmacological therapies approved for the treatment of IBS-D in Canada. Key clinical trial data for the currently available pharmacological options are presented to provide an overview of the efficacy and safety of these agents Irritable bowel syndrome (IBS) is a common disorder, affecting approximately 11% of the global population , or 10 tPatients with IBS report significant impact on their work productivity, time management, and participation in social activities due to their symptoms . One stuThe pathogenesis of IBS is thought to be multifactorial, involving visceral hypersensitivity, abnormal gut motility, and dysregulation of the brain–gut axis, among other factors . Newer pTreatment options are currently limited for patients with IBS-D in Canada, and the heterogeneous nature of this condition presents a challenge in the management of the wide range of observed symptoms; currently available options largely target only one of a wide constellation of symptoms . RecentlThe aim of this review is to describe the available and upcoming treatment options for IBS-D in Canada, particularly in relation to the recently updated Canadian IBS consensus guidelines, with a particular focus on eluxadoline and rifaximin, two recent additions to the IBS-D armamentarium.The management of IBS-D symptoms involves lifestyle and diet modifications, over-the-counter therapies, and prescription medications. There is no standard treatment protocol for IBS-D , and theP = 0.84)  ,23–25.In combination with the low number of participants and heterogeneity in the study design, these factors led to the efficacy of a low-FODMAP diet being designated as having a ‘low quality of evidence’ . In addiIBS-D is associated with a high disease burden and low quality of life, which psychological interventions may help to address . Referran = 69), loperamide was shown to improve stool consistency (by 32%), reduce defecation frequency (by 36%) and reduce the intensity of pain (by 30%) throughout the 5-week study period  is a novel µ- and κ-opioid receptor agonist and δ-opioid receptor antagonist administered orally twice daily at a dose of 100 mg . The CAGRifaximin  is a minimally absorbed broad spectrum antibiotic derived from rifamycin administered orally three times daily at a dose of 550 mg for a total of 14 days ,38. The In a Phase 2 trial (NCT01130272), 807 patients meeting Rome III criteria for IBS-D were randomized to receive either placebo or eluxadoline 5, 25, 100 or 200 mg twice daily for 12 weeks . A signiTwo randomized, double-blind, placebo-controlled Phase 3 trials enrolled 2428 patients with IBS-D who met Rome III criteria  to receive placebo or eluxadoline 75 or 100 mg twice daily . The priA significantly greater proportion of patients receiving either dose of eluxadoline were stool consistency responders at Week 12  40). El. El40). In the two Phase 3 trials, 36.0% reported prior loperamide use  and of tP = 0.002), which was also reflected in the component endpoints  in IBS-D patients who reported inadequate symptom control with prior loperamide . A signindpoints .Eluxadoline was well tolerated in clinical trials. The most common adverse events (AEs) were constipation, abdominal pain and nausea ,40,44 T. In the Eluxadoline has been reported to interact with cyclosporine, strong CYP inhibitors, and drugs that cause constipation ,36. WhilP = 0.02) , 87 patients who met Rome I criteria for IBS were enrolled and randomized to receive rifaximin 400 mg three times daily or placebo for 10 days and were followed for 10 weeks post-treatment . Rifaxim = 0.02) .In two double-blind, placebo-controlled Phase 3 trials , 1260 patients with IBS without constipation were randomly assigned to rifaximin 550 mg or placebo three times daily for 2 weeks, and were followed for 10 subsequent weeks  and B. IIn order to investigate the need for rifaximin re-treatment for long-term response, a randomized, placebo-controlled, 51-week Phase 3 trial (NCT01543178) enrolled patients with IBS without constipation . The proThe AE rates observed during the clinical trials were low overall and were similar between the rifaximin and placebo groups . The mosClostridium difficile was highly susceptible to rifaximin. In addition, rifaximin exposure was not associated with long-term cross resistance to rifampin or tested nonrifamycin antibiotics (Rifaximin is administered orally three times daily at a dose of 550 mg for a total of 14 days, with up to two re-treatments for patients who experience symptom recurrences ,38. In tibiotics .While data indicate that rifaximin is effective in patients with IBS-D and mixed IBS, the mechanism of action for its benefits is largely unknown and warrants further investigation . AlthougIBS is a prevalent gastrointestinal disorder, which significantly impacts patients’ quality of life. Presentation of patients with IBS is common in gastroenterology clinics and practices, and physicians need to be aware that safe and effective treatments exist and can help their patients. The heterogeneous presentation and multifactorial pathogenesis of IBS-D require an individualized approach to the management of IBS-D symptoms. Eluxadoline and rifaximin are two novel treatments for adults with IBS-D that show promising efficacy and safety for this disorder with a high burden of illness. Real-world studies are warranted to provide information on which patients would most benefit from various treatment regimens.