While pre-existing cardiovascular disease (CVD) appears to be associated with poor outcomes in patients with Coronavirus Disease 2019 (COVID-19), data on patients with CVD and concomitant cancer is limited. The purpose of this study is to evaluate the effect of underlying CVD and CVD risk factors with cancer history on in-hospital mortality in those with COVID-19.Data from symptomatic adults hospitalized with COVID-19 at 86 hospitals in the US enrolled in the American Heart Association’s COVID-19 CVD Registry was analyzed. The primary exposure was cancer history. The primary outcome was in-hospital death. Multivariable logistic regression models were adjusted for demographics, CVD risk factors, and CVD. Interaction between history of cancer with concomitant CVD and CVD risk factors were tested.p < 0.0001 in those with a smoking history and aOR = 1.33, 95%CI: 1.01—1.76; p = 0.04 in non-smokers). Among the cancer subgroup, prior use of chemotherapy within 2 weeks of admission was associated with in-hospital death . Underlying CVD demonstrated a numerical but statistically nonsignificant trend toward increased mortality .Among 8222 patients, 892 (10.8%) had a history of cancer and 1501 (18.3%) died. Cancer history had significant interaction with CVD risk factors of age, body mass index (BMI), and smoking history, but not underlying CVD itself. History of cancer was significantly associated with increased in-hospital death (among average age and BMI patients, adjusted odds ratio [aOR] = 3.60, 95% confidence interval [CI]: 2.07–6.24; Among hospitalized COVID-19 patients, cancer history was a predictor of in-hospital mortality. Notably, among cancer patients, recent use of chemotherapy, but not underlying CVD itself, was associated with worse survival. These findings have important implications in cancer therapy considerations and vaccine distribution in cancer patients with and without underlying CVD and CVD risk factors. The novel coronavirus Severe Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to the ongoing and relentless global Coronavirus Disease 2019 (COVID-19) pandemic, and was the leading cause of death in the United States in 2020 (US) . PatientGet With The Guidelines (GWTG).To address this evidence gap, we evaluated the association of history of CVD, history of cancer, and recent cancer-related therapy with in-hospital death, as well as other adverse cardiovascular, pulmonary, and venous thromboembolic outcomes among adult patients hospitalized with COVID-19 in the multicenter American Heart Association’s (AHA) COVID-19 Cardiovascular disease (CVD) Registry powered by We obtained patient-level data from 86 US hospitals in the GWTG® COVID-19 CVD registry . The GWTG® programs are provided by the AHA. The registry is a voluntary effort, and enrollment is available to all health systems in the US treating adult patients with active COVID-19. Participating hospitals are instructed to abstract detailed demographic and clinical data from the medical record of consecutive patients for the duration of the hospital stay. Data are entered into an electronic interactive case record form, which has error checks embedded within the software platform to ensure data quality and prevent erroneous data entry by trained clinical personnel. As the registry is designed as a quality improvement tool, with no intervention or participant contact, informed consent was not obtained and institutional review board exemption was obtained. Detailed methods of the registry have been previously described .The study cohort for the present analyses included all hospitalized adults (≥ 18 years old) with at least one documented admission symptom (Table) associated with confirmed active COVID-19. An active infection was described as having a postivie RT-PCR test either prior to or during hospitalization, a positive IgM antibody test, or a clinical diagnosis using hospital specific criteria. The primary exposure of interest was history of cancer. Patients were determined to have a history of cancer if they had active or prior solid or hematological cancer regardless of active therapy. Key variables of interest included patient’s having a history of CVD or recent chemotherapy or biologic therapy . CVD was defined as a composite of history of cerebrovascular accident (CVA), history of heart failure (HF), prior myocardial infarction (MI), prior coronary artery bypass graft (CABG), or prior percutaneous coronary intervention (PCI). Other covariates included CVD risk factors , pulmonary disease , and chronic kidney disease .The primary outcome was in-hospital death. Four secondary outcomes were evaluated. Secondary outcomes included major adverse cardiovascular events , severe disease complications , or thromboembolic disease (a composite of deep vein thrombosis (DVT) or pulmonary embolism [PE]).p-value < 0.05 was considered statistically significant. All analyses were performed with SAS version 9.4  using a deidentified data collected and coordinated via IQVIA  and housed on the American Heart Association Precision Medicine Platform (precision.heart.org)  with 95% confidence intervals (CI). In addition to the main effect term of history of cancer, interaction terms for history of cancer with CVD and CVD risk factors were tested for the primary outcome of in-hospital mortality. Interaction terms that were significant for in-hospital mortality were retained and presented in the final multivariable model. Similar, separate, modeling was done for each of the secondary outcomes. For the primary outcome of in-hospital mortality, a sensitivity analysis was conducted by limiting the cohort to only those with a history of cancer and generating an adjusted model with remaining covariates. All models were adjusted for body mass index (BMI), sex, race, diabetes, dyslipidemia, hypertension, chronic kidney disease, smoking history, and history of pulmonary disease. Generalized estimating equation method was used to estimate the parameters for the multivariable logistic regression models and to account for the correlated structure of the data due to clustering within hospitals. All statistical tests were two-sided, and a art.org) .Among 86 US hospitals, 8,222 patients through August 20, 2020 were included in the analysis. Among these patients, 892 10.8%) patients had a history of cancer, 1,805 (22.0%) had a history of CVD, and 261 (3.2%) had both a history of cancer and CVD. Among cancer patients, 124 (14.0%) had recent use of chemotherapy . Patients with COVID-19 and a history of cancer were older and had a higher prevalence of CKD, pulmonary disease, and CVD (Table 0.8% patip < 0.0001). Although no significant interaction between a history of cancer and a history of CVD was found, there were significant interactions between history of cancer with the CVD risk factors of age, BMI and history of smoking for in-hospital mortality. In multivariable analysis, history of cancer was a significant predictor of in-hospital mortality . The largest effect of cancer history on in-hospital mortality was observed in those patients with a history of smoking who were younger and had lower BMIs , it did not reach statistical significance for in-hospital mortality in multivariable analysis . Additional significant predictors of in-hospital mortality included age, male gender, BMI among those without a history of cancer, hypertension, diabetes, chronic kidney disease, pulmonary disease, and smoking among those with a history of cancer.In the entire cohort of adult patients hospitalized with symptomatic COVID-19, 1501 (18.3%) died during their hospitalization [median occurrence on hospital day 7 (interquartile range [IQR] 3–13 days)], 25.4% those with cancer and 17.3% of those without cancer. In univariate analysis, history of cancer was a significant predictor of in-hospital mortality  (Table p = 0.03) , but not males (Table MACE occurred in 76 (8.6%) patients with and 397 (5.5%) without a history of cancer with a median occurrence on day 1 of hospitalization (IQR 0–5 days). Although no significant interaction between history of cancer and history of CVD was found, there were significant interactions between history of cancer and gender. In multivariable analysis, history of cancer was a significant predictor of MACE among females  (Table Severe disease complications occurred in 1587 (21.8%) patients with and 214 (24.2%) without a history of cancer with a median occurrence on day 1 of hospitalization IQR 0–3 days). Although no significant interaction between history of cancer and history of CVD was found for severe disease complications, there were significant interactions between history of cancer with the CVD risk factors of age and smoking history. In multivariable analysis, a history of cancer was a significant predictor of severe disease among smokers  patients with and 198 (2.7%) without a history of cancer with a median occurrence on day 6 of hospitalization . History of cancer was not associated with thromboembolic disease in univariable or multivariable analysis  and cancer (N = 195) had a higher short-term mortality as compared to either cancer or CVD alone [In 2020, COVID-19, heart disease, and malignant neoplasms have been the leading causes of death in the US , 11. WitVD alone . In addiIn the present study, history of cancer was a robust predictor of in-hospital mortality among hospitalized symptomatic adult COVID-19 patients. Given older age and obesity have previously been shown to be associated with mortality in the setting of COVID-19, it is not surprising that the most predominant effect of history of cancer on mortality we observed was in younger patients with lower BMIs. The increased mortality appears to be driven by increased severe disease complications in patients with history of cancer, particularly in those with a history of smoking, independent of prior pulmonary disease. Additionally, while male gender was unsurprisingly associated with higher MACE in those without cancer history, females with a history of cancer exhibited higher rates of MACE. However, interpretation is limited for MACE given the overall low event rate. Other factors that may also explain the increased mortality rate observed in cancer patients compared with non-cancer patients include: 1) residual confounding due to unaccounted for differences between cancer and non-cancer patients, such as use of vasoactive medications and code status; and 2) inadequate power to detect a difference in venous thromboembolism (VTE) given low event rates.Venous thromboembolism (VTE) has been of particular interest in COVID-19 patients with underlying cancer given the perceived elevated risk of VTE from both the hypercoagulable/inflammatory milieu of COVID-19 and cancer itself. Data has shown that elevated D-dimers levels are independently associated with thrombotic events, and subsequently those with thrombotic events have higher all-cause mortality . HoweverTo the best of our knowledge, this AHA COVID-19 registry-based study is the largest multicenter prospective analysis to date to evaluate the effect of recent use of cancer-related therapy in hospitalized symptomatic COVID-19 patients. In contrast to prior studies, among cancer patients, we observed a strong independent association of cancer-specific therapy with in-hospital mortality. Importantly, cancer patients with underlying CVD did not have higher in-hospital mortality rates compared with those without CVD. Taken together, these findings suggest that oncologists and cardio-oncologists alike should discuss with their patients the optimal timing for and possible delay of cancer-related therapy in areas where COVID-19 viral transmission is high and hospital resources are limited, but that the presence of CVD should not be a major determinant of therapy in the cardio-oncology population. However, this be balanced with the need of urgent therapy based on cancer type and cancer status. Multiple societal documents have similarly discussed the need to potentially curtailing the frequency of cardiotoxicity surveillance for selected patients .This study has important limitations. First, the AHA CVD COVID-19 registry does not provide granular data regarding the type of cancer, status of cancer , or cancer-specific therapies that patients are receiving to allow for stratification of cancer severity. Second, the initial registry data did not include information regarding code status and advanced directives, which may be disproportionately high in those with cancer and thus possibly impact in-hospital outcomes. Third, these data only pertain to in-hospital outcomes and thus post-discharge outcomes are not known. Lastly, the voluntary hospital participation in the registry is weighted toward urban academically affiliated institutions, and so the results may not be generalizable; however, we adjusted for site-specific clustering of outcomes to address this issue.In summary, in the large national AHA COVID-19 CVD registry, history of cancer is a significant predictor of in-hospital mortality. Notably, among cancer patients, those with underlying CVD had similar outcomes to those without CVD, while recent use of cancer-related therapy was significantly associated with in hospital mortality. Further studies focusing on malignancy type and specific treatments, and their interactions with concomitant CVD and CVD risk factors, are warranted to identify vulnerable subgroups of the cancer population that may benefit from aggressive interventions during the COVID-19 pandemic including earlier prioritization for vaccine initiation.


There is solid evidence that olfactory dysfunction (OD) can present in COVID-19 patients. Anosmia can be the only presentation or can be accompanied by other symptoms of COVID-19. Multiple cross-sectional studies have demonstrated that the incidence rate of olfactory dysfunction is high in COVID-19 patients with good prognosis. The aim of our study is to investigate the presence of OD with the radiologic and laboratory findings among COVID-19 positive patients.P value 0.000) denoting that anosmia sign mostly occur in mild COVID. Also, there was significance in D dimer between two groups  denoting that D dimer could be a sign of clinical severity and it is usually not elevated in anosmia. All anosmia group had normal CT chest denoting that it is a mild form of COVID-19.There was statistical significance in clinical severity between anosmia and non-anosmia group (Olfactory dysfunction (OD) is an imminent sign of COVID-19 patient, which can be presented as a sole symptom or with other symptoms. As anosmia could be the sole clinical presentation of COVID-19 patients without any other significant signs and so otolaryngologists should be aware of this presentation in COVID-19 diagnosis. Coronavirus disease 2019 (COVID-19) is on-going pandemic started in Wuhan, China, in December 2019. It is caused by novel enveloped single-stranded ribonucleic acid (RNA) beta-coronavirus, which is known as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [To date, over 108.2 million COVID-19 cases and 2.3 million deaths have been reported to WHO till February 2021 [COVID symptoms range from mild symptoms to severe illness. Symptoms may appear 2-14 days after exposure to the virus. Typical symptoms include fever, cough, and shortness of breath .A team at King’s College, London, added loss of sense of smell to the COVID-19 symptom tracker. And it is a stronger predictor of coronavirus infection than fever .In 17th April 2020, Center of Disease Control (CDC) set isolated anosmia as COVID-19 symptom followed by WHO in May 2020 .In COVID-19 positive patients, 59% reported losing their sense of smell or taste, compared with only 18% testing negative. So, anosmia is an early warning sign of infection, and patients should be self-isolated to reduce the spread of the disease .Olfactory dysfunction often accompanied by dysgeusia in COVID-19 patients, suggesting a probable association between the two .A lot of studies correlate anosmia with the severity of COVID-19 illness. Mayo clinic systematic review suggested that OD may be associated with a milder course of COVID-19 infection .Novelty of our study is to investigate the presence of OD with the radiologic and laboratory findings among COVID-19 positive patients.Our study included total of 146 patients that were admitted to our institute. All patients were either mild or moderate COVID-19 that were admitted in inpatient wards.Approval of the local ethical committee of the hospital was obtained to conduct the current study. Besides that, written informed consents were obtained from all participants clarifying the purpose of the study conforming Helsinki Declarations (1964).In the absence of full objective smell assessment and nasopharyngoscope (contraindicated in the current situation), it is acceptable to depend on subjective self-assessment of olfactory dysfunction .All included patients have been subjected to full medical history taking and were proven to be COVID-19 positive by PCR . Prior to admission, all patients performed computed tomography (CT) of the chest and laboratory investigations in the form of CBC with differential count, ALT, AST, ferritin, CRP, D dimer, urea, and creatinine and detection of oxygen saturation by pulse oximetry. According to this initial assessment, severity of the condition could be determined.Severity was classified into mild, moderate, or severe.Mild type means mild symptoms in the absence of any radiological abnormalities in CT chest, moderate type includes fever and respiratory tract symptoms, and pneumonia is observed on imaging while severe type include any of the following criteria are met: respiratory distress as evidenced by respiratory rate ≥ 30 breaths/min, oxygen saturation ≤ 93% at rest, and arterial blood oxygen partial pressure/oxygen concentration ≤ 300 mmHg with the lesions significantly progressing > 50% within 24–48 h on pulmonary imaging [To be enrolled in the study, patients had to meet the following inclusion criteria: adults over 18 years of age, nasopharyngeal swab positive for COVID patients and acceptance for participation in the study.On the other hand, the study exclusion criteria were uncooperative patients, patients on ventilators, psychiatric or neurological disorders, previous surgery, and radiation or trauma in nasal cavity.A rapid office-based screening of smell disorder can be done, using a subjective olfaction score. The patient is asked to estimate his sense of smell on a 10-point scale bar with 0: anosmia, 10: normal smell and scores from 1 to 9 mean progressive increase in the degree of smell toward normal. As olfactory affection is a pertinent feature of COVID-19, ENT surgeons should pay attention to this particular disorder during patients’ examination. The use of subjective olfaction score for rapid screening of patients may be beneficial to early diagnose the disease and prevent its spread .We investigated the presence of OD with the radiologic and laboratory findings among COVID-19 positive patients.Data was entered and statistically analyzed on the Statistical Package of Social Science Software program, version 25 . Data was presented using range, mean, standard deviation, median and interquartile range for quantitative variables, and frequency and percentage for qualitative ones. Comparison between groups for qualitative variables was performed using Chi square or Fisher’s exact tests while for quantitative variables the comparison was conducted using Mann-Whitney test. P values less than or equal to 0.05 were considered statistically significant.The current study included a total of 146 COVID-19 positive patients who were laboratory confirmed by RT-PCR , and were admitted to the hospital. All participants were Egyptians with mean age 38.34 ± 11.72 including 100 males (68.5%) and 46 females (31.5%) denoting male gender susceptibility to COVID-19  denoting that anosmia sign mostly occur in mild COVID  receptor .ACE2 is a functional receptor for SARS-CoV-2, and its expression and distribution in the nervous system suggest that SARSCoV-2 can cause neurological manifestations through direct or indirect pathways .There is strong evidence that the nasal cavity is a crucial area susceptible to SARS-CoV-2 infection .Viral loads in the patient’s nasal cavity were higher than that present in the pharynx, both symptomatic individuals and asymptomatic ones, hinting the nasal cavity as nasal mucosa may be the initial site of SARS-CoV-2 infection, in which the mode of transmission of SARS-CoV-2 is through infectious droplets .However, COVID-19 case series reports showed a high rate of recovery of olfaction within 1-2 weeks after the onset of the dysfunction .For these reasons, it is reasonable to put a hypothesis that the olfactory disorders (OD) are not related to, directly or indirectly, definitive viral damage to the neuronal cells. Conversely, the virus target may not be the neurons but other non-neuronal cells that express ACE2 receptors such as the olfactory epithelium sustentacular cells, microvillus cells, Bowman’s gland cells, horizontal basal cells, and olfactory bulb pericytes .Brann et al. supposed that the anosmia reported by COVID-19 patients is due to the infection of the supporting cells and vascular pericytes of the olfactory epithelium and bulb which, consequently, alters the function of the olfactory neurons .Several cross-sectional studies about the prevalence rate of OD in COVID-19 patients have been released in many countries through non-contact methods such as online questionnaires and telephone interviews –15.This study is novel as it correlates anosmia to radio-laboratory findings in COVID-19 patients.Along with our study, incidence of OD in COVID-19 patients was around 25% in these studies –16.The studies also showed that individuals with smell disorders tend to have a taste disorder, suggesting a probable association between the two symptoms , 12–16.Contrary to our results, most studies have found that the incidence of smell disorders in COVID-19 patients is higher in females than males , 11, 14.In Hornuss D et al., mean age of anosmic patients was 56 years, total leukocytic count was 6.3, lymphocyte was 0.8, CRP was 60 (mg/L), and shortness of breath was in 65% of our patients study.Our study mean age was 36 years; total leukocytic count was 6.6 while lymphocytic count was 0.2. Moderate severity was found in 13% of patients.Along with Mayo clinic systematic review , most ofMajority of cases were of normal D dimer, leukocytic count, and lymphocytic count with no available studies to compare with.The subjective olfaction score is not a meticulous scoring. Psychophysical tests for evaluation of smell such as the Sniffing’ Sticks test  and the University of Pennsylvania Smell Identification test  are more reliable in the evaluation of olfaction, but they are not usually available during general health examination, besides being time consuming and costly.The lack of consistent follow-up of our patients limits us from calculating the recovery time olfactory and gustatory functions, and, therefore, the percentage of permanent anosmia or ageusia.OD is a prominent finding in COVID-19 patient, which can occur independently or with other symptoms, but its pathogenesis is not well understood. Otolaryngologists should be aware of anosmia as a presentation of COVID-19 infection to avoid delaying the diagnosis of COVID-19. As anosmia could be the sole clinical presentation of COVID-19 patients without any other significant signs, it pushes otolaryngologists not to delay COVID-19 diagnosis. To avoid cross-infection, the otolaryngologist may consider a remote olfactory evaluation for COVID-19 patient with OD.


COVID-19, caused by the SARS-CoV-2 virus, is a severe inflammatory condition. Patients with pre-existing conditions including diabetes, hypertension, and cardiovascular disease are at particularly high risk of complications. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare and debilitating genetic disorder that is characterized by a pro-inflammatory state, which leads to progressive heterotopic ossification and complications after trauma, including intramuscular vaccinations. To better understand the impact of COVID-19 on patients with FOP, we first examined the social impact of the pandemic using data from the FOP Registry managed by the International FOP Association. We also identified patients with FOP who were exposed to or contracted the SARS-CoV-2 virus, or who received a COVID-19 vaccine, to investigate if patients with FOP were at increased risks of complications from SARS-CoV2 exposure.Data from 326 individuals in 69 countries were examined in the International FOP Association FOP Connection Registry using patient-reported outcomes measurement information system (PROMIS) global health scale scores. Twenty-six (28.9%) participants aged ≥ 15 years old rated their satisfaction with their social activities and relationships as poor in 2020, which was an increase from 18 (18.9%) in 2019, prior to the SARS-CoV-2 outbreak. Similar trends were noted for physical and mental health in the pediatric population. Frequency of physician visits was not changed, but a larger portion of patients reported missing dental visits in 2020 compared with 2019 (31.5% vs. 41.7%). A second cohort with 32 subjects was tracked after SARS-CoV-2 exposure or vaccination. Ten subjects were positively diagnosed with COVID-19, 15 received a COVID-19 vaccine, and seven had high-risk SARS-CoV-2 exposure but either did not have a confirmed clinical diagnosis or tested negative. Subjects who tested positive for the virus showed no major complications or increased FOP disease activity, though our sample size is very limited. Among the 15 subjects who received a COVID-19 vaccine, using the International Clinical Council on FOP guidelines for prophylaxis with ibuprofen or acetaminophen, only one person experienced flare activity at the injection site.Patients with FOP showed a significant decrease in social activities that was reflective of the isolation and mobility changes in this debilitated population. In our limited cohort, the majority of the patients with FOP who tested positive for COVID-19 showed no major complications. Also, although limited in sample size, the majority of patients who received a COVID-19 vaccination and followed guidelines from the FOP International Clinical Council tolerated vaccination well. Only one person experiencing flare activity following their injection. Thus, the risks and benefits of COVID-19 vaccination needs to be discussed carefully so as to support informed decisions. Coronaviruses (CoVs) are a class of enveloped, single-stranded RNA viruses found globally in humans . While cFibrodysplasia ossificans progressiva (FOP) is a rare genetic condition characterized by progressive heterotopic ossification (HO) of tendons, ligaments, and other soft tissues within the body . This ecACVR1 gene, which encodes ACVR1 , a bone morphogenic protein (BMP) type 1 receptor [ACVR1 R206H mutation in causing this heightened immune response [FOP is caused by heterozygous activating mutations to the receptor . The mosreceptor , which creceptor . Barruetreceptor . Specifiresponse . In FOP response , and depresponse . Furtherresponse , and is response .Clinically, FOP progression appears to be promoted by viral-like illnesses. A prior study assessed if FOP patients who had symptoms of influenza during the 2000–2001 influenza season experienced an increase in the incidence of HO-related flare-ups . The FOPThe severe respiratory compromise from thoracic insufficiency induced by HO formation in the chest wall, as well as the high risk of complications from intubation, put patients with FOP at particularly high risk of adverse outcomes in the event of severe COVID-19 complications . The thoA study looking at serum samples of patients with severe, active COVID-19 infections found that Activin A, Activin B, and follistatin were all upregulated during the time when COVID-19 patients tended to deteriorate . In a COSurprisingly, a small number of patients with severe COVID-19 appear at higher risk for developing HO , suggestA recent case report implicated the COVID-19 vaccine as a potential trigger for myositis ossificans-related intramuscular nodule formation and internal calcifications in a 51-year-old male patient . Three mIn this study, we set out to answer three main questions. First, how has the COVID-19 pandemic impacted the care and mental health of patients with FOP? Second, do patients with FOP who were exposed to SARS-CoV-2 have increased FOP disease activity? And third, does vaccination against SARS-CoV-2 impact FOP flare activity?The social impact of the COVID-19 pandemic on patients with FOP was examined using the FOP Patient Registry sponsored by the International FOP Association (IFOPA). The FOP Registry was launched by the IFOPA in 2015 with a vision to develop one unified global registry that assembles the most comprehensive data on patients with FOP. The FOP Registry is an ongoing international, voluntary, observational resource that captures demographic and disease data directly from individuals with FOP approximately every six months via a patient portal, and clinical data from treating FOP physicians on an annual basis via a secure web-based medical portal. The design of the FOP registry is described separately . All parTo participate in the FOP Registry, patients were required to confirm their FOP diagnosis and provide informed consent via an electronic acceptance. As of March 24, 2021, 326 individuals from 69 countries were enrolled and active, representing ~ 36% of the known global FOP populations based on IFOPA estimates. Thus, this cohort is representative of the global FOP community.Domain scores of the PROMIS Global Health Scale  were calPatients with FOP who had either a known high risk exposure to the SARS-CoV-2 virus , tested positive for COVID-19, or received a COVID-19 vaccine, were recruited and enrolled into the study between July 14th, 2020 and August 23rd, 2021. The study was approved by the UCSF Institutional Review Board . After obtaining written consent, subjects with known exposure to the virus were given questionnaires covering symptoms experienced and their duration, test results, hospitalizations, complications, and any flare activity around the time of contracting the virus. Symptoms in the questionnaire included fever, chills or shakes, cough, sore throat, difficulty breathing, weakness or fatigue, unexplained muscle aches, loss of taste or smell, runny or congested nose, diarrhea, and eye redness. Subjects were followed at 2 weeks and 4 weeks to assess for any progression or changes in health status. For patients who reported their exposure retroactively, data was collected but follow-up in the aforementioned manner was forgone. Exposed subjects were considered positive if they developed COVID-19 symptoms within 2 weeks of exposure, or if they tested positive.Subjects who received a COVID-19 vaccine were given questionnaires to collect information about the vaccine manufacturer , injection route  and location, side effects, any hospitalizations or complications, and any flare activity. All subjects were asked to follow the FOP International Clinical Council (ICC) guidelines for vaccination  of the cohort . One-hunOverall, 26 (28.9%) participants aged ≥ 15 years rated their satisfaction with their social activities and relationships as poor in 2020, which was an increase from 18 (18.9%) in 2019 . Adult rThe number of times participants had at least one visit with a physician related to their physical health changed only slightly during the COVID-19 pandemic. In 2019, 146 (85.4%) participants reported seeing a physician one or more times, compared with 134 (84.2%) in 2020. The number of participants reporting zero visits to a physician related to their physical health remained unchanged, with 25 (14.6%) reporting no visits in 2019 and 25 (15.7%) in 2020 . SimilarPatients with FOP have an increased risk of HO formation after trauma, intramuscular vaccinations, and viral infections. Although the COVID-19 pandemic had a significant social impact on patients with FOP, we also wanted to understand how patients with FOP fared after SARS-CoV-2 virus infection or COVID-19 vaccination. We identified 25 patients with FOP who either had a confirmed COVID-19 diagnosis by positive testing, or received a vaccine .Of these 25 subjects, 10 were confirmed to have contracted the virus. The mean age for the COVID-19 (+) group was 31.2 years with an even gender split . InfecteACVR1 R206H mutation and clinical signs of FOP. She reported a new flare in her left hip without any suspected trauma. 2–3 days later, she developed diarrhea, anosmia, and ageusia. Over the following 12 days, she reported a cough, sore throat, weakness/fatigue, runny/congested nose, and eye redness. Two weeks after reporting the flare, she tested positive for SARS-CoV-2. She experienced swelling and restricted mobility in the affected area of her hip. She was prescribed prednisone at a reduced dose of 50 mg/day for 4 days  followeWe recruited 15 patients with FOP who received a COVID-19 vaccine: 10 received the Pfizer-BioNTech vaccine, two received the Johnson & Johnson vaccine, two received the Moderna vaccine, and one received the CoronaVac vaccine. The mean age for the vaccination group was 31.2 years with females comprising 53.3% of the subjects . Twelve Subject Y is a 47-year-old male with FOP who received both doses of the Pfizer-BioNTech vaccine intramuscularly in the left arm. He reported some pain at the injection site. Subject Z is a 51-year-old male with FOP who received the first dose of the Pfizer-BioNTech vaccine subcutaneously, against recommendations. This patient did not develop detectable anti-SARS-CoV-2 IgG antibodies in his blood after this first injection. The second injection was given in accordance with the vaccination schedule, via an intramuscular route. Subsequent testing was positive for anti-SARS-CoV-2 IgG antibodies. The patient had mild arm pain but no flare or HO formation.Subject W is a 29-year-old female with FOP who received the first dose of the Pfizer-BioNTech vaccine intramuscularly in her right deltoid. She experienced swelling, redness, and warmth at the injection site for five days. Subject W also experienced increased tension when extending her right arm and she was concerned about potential bone growth. Her antibody titer after this first injection was positive. Subject W chose not to receive the second dose of the Pfizer-BioNTech vaccine due to concern over additional side effects.The COVID-19 pandemic has disproportionately affected individuals with disabilities . While tUsing the IFOPA Patient Connection Registry, we identified that adult and pediatric patients with FOP had decreased participation in social activities between 2019 and 2020. In addition to mandated lockdowns, quarantining, and social distancing, early prediction of the adverse effects that COVID-19 infection may have on patients with FOP may have contributed to this decrease by favoring a more cautious approach to social interactions. However, the data also suggested that patients with FOP still went to see their physicians at least once during the pandemic, suggesting a strong connection to their health providers. A limitation of this study is that we do not know if these visits were telemedicine or in-person. Notably, there was a large decrease in the number of visits to a dentist. Since dental health is a major concern in FOP, encouraging patients with FOP to resume adequate care for their mental, physical, and dental health will be critical over the next several years.Although FOP is a genetic disease characterized by progressive and severe HO and an overactive immune system, we found that most patients in our cohort with FOP and COVID-19 did not report major complications, hospitalizations, or an increase in FOP disease activity as a result of contracting COVID-19. This contrasts with recent case reports, including a 45-year-old female patient with known FOP who reported disease progression potentially linked to viral illness . A monthhttp://www.iccfop.org) and are summarized in Although intramuscular immunizations are largely avoided in patients with FOP due to the risks of complications , 18, we There are several limitations to this study. Since the reported cohort of patients with FOP who received a COVID-19 vaccine is very small, the absence of a pattern of complications or HO formation at the injection site is reassuring, but patients should be reminded that COVID-19 and any intramuscular injection still has risks in patients with FOP. Patients with FOP should still consult with their physicians before deciding to get the vaccine as there may be other factors that should be considered. Notably, Subject Z did not show IgG antibody production after receiving the first injection of the Pfizer-BioNTech vaccine subcutaneously, but did after the second dose that was given intramuscularly. While this is not proof that subcutaneous injections are ineffective, we support the ICC guidelines, which recommend that the COVID-19 vaccine be administered via the route recommended by the manufacturer, including intramuscularly, with anti-inflammatory medications given post-innoculation.Our results show that patients with FOP are at risk of decreased physical, mental, and dental health as a result of the COVID-19 pandemic. Among our limited cohort of patients with FOP, no one reported life-threatening complications with SARS-CoV-2 viral infection, although patients with FOP remain at high risk of complications from any respiratory illness because of cardiopulmonary involvement of FOP. Only one patient with FOP reported increased FOP disease activity in response to a COVID-19 vaccine; however, case reports in the literature and our own case studies suggest that patients with FOP remain at significant risk for complications such as flares and heterotopic ossification. Thus, the risks and benefits of COVID-19 vaccination needs to be discussed carefully so as to support informed decisions. Finally, our results provide a clinical foundation for future studies to understand the specific triggers of FOP-related immune responses.


Since the outbreak of the novel coronavirus disease (COVID-19), the therapeutic and management options to reduce the burden of the COVID-19 disease are under investigation. IVIG therapy is used as an effective treatment for immunodeficient patients and patients with inflammatory or autoimmune conditions. The therapeutic effect of IVIG in COVID-19 patients has been investigated. But, the results are controversial and some studies reported no benefit of IVIG therapy. More clinical trials on the effect of IVIG therapy in COVID-19 patients should be performed to establish a certain conclusion about IVIG effectiveness. In late 2019, a new type of Coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was introduced and soon gave rise to a world-level pandemic . This leA major pathophysiological finding in relatively more severe COVID-19 patients has been hyper inflammation, which will be targeted in this study. Elevated levels of interleukin (IL)-2, IL-6, IL-7, interferon-gamma (IFN-γ) inducible protein 10 (IP-10), and tumor necrosis factor-alpha (TNF-α) indicates a cytokine cascade and a cytokine release syndrome as an underlying immunopathology , 6. Furt.In the 1960s, a new method of treatment for inflammation-related diseases was introduced.  ImmunoglIVIG is routinely used as an effective treatment for primary immunodeficiency, immune thrombocytopenic purpura, Kawasaki disease, dermatomyositis, and Guillain-Barré syndrome primarily as an antibody moderator . IVIG isMoreover, IVIG therapy has multi-level effects on the immune system in the second type (high-dose IVIG). It has been shown that the positive effects of the IVIG therapy remain far beyond the IgG half-life, which extends IVIG function from a simple injection of antibodies to a more stable and effective method of treatment . FurtherIt was found that continuous injection of IVIG influences the process of lymphocyte differentiation and maturation, which finally leads to the normal immune response of white blood cells and prevents the production of inflammatory factors. Therefore, it decreases the injury caused by inflammation –21.Several studies have reported the results of IVIG therapy in different respiratory syndromes, including severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), acute respiratory distress syndrome (ARDS), influenza pandemics, and seasonal influenza , 23. TheMycoplasma pneumoniae pneumonia [M. pneumoniae pneumonia. Moreover, the advantage of IVIG therapy in the early phase of the disease in patients unresponsive to corticosteroid and initial antibiotic therapy has been reported [As an adjunct treatment in severe influenza, IVIG is an efficacious treatment for the pulmonary lesions in influenza pneumonia and neumonia –30. Prevreported .Studies highlight the advantage of systemic immune modulators like IVIG and corticosteroids in the acute phase of the ARDS. Reduced morbidity, inhibition of disease progression, and preventing permanent systemic organ injury are identified as outcomes of these treatments under sufficient dose and early administration . On the . as well as the reported case of COVID-19 with mucous membrane pemphigoid (MMP) by Daneshpazhooh et al., administration of IVIG improved the condition rapidly and showed its effect primarily by reducing patients’ fever. All the cases above were discharged in less than a week with considerable improvements [In the three cases reported by Cao et alovements , 36. Furovements .In line with these findings, Mohtadi et al. reported 5 cases of COVID-19, in whom administering hydroxychloroquine and antibacterial agents failed to improve the condition. Patients received IVIG at the dose of 0.3–0.5 g/kg for five days, in a way that no one received less than 25 g of IVIG. The clinical condition ameliorated markedly so that the patients were discharged from the hospital after that .Another study reported a reduction in 28-day-mortality rates, the length of hospital stay, and the need for mechanical ventilation by IVIG treatment within 48 h after admission. However, IVIG administration in 24 h did not show this result. This highlights the relation between the time of IVIG administration and the mitigation of the mortality rate .Furthermore, a multicenter retrospective cohort study by Shao et al. included 325 patients, from which 174 cases received IVIG. Consequently, only patients with severe COVID-19 from the IVIG group had better 28-day mortality rates. No effects were apparent on the total duration of the disease or the length of hospital stay . A recenThe studies mentioned above have limitations that make it difficult to persuade the use of IVIG. Two of the main confounding factors are the small sample size and the simultaneous administration of other therapy methods (such as glucocorticoids and plasma exchange). To achieve a more accurate result, Gharebaghi et al. have recently performed a randomized placebo-controlled double-blind clinical trial with a total of 59 patients. They found out that administering 20 g/day of IVIG for three days reduces mortality, despite increasing hospital stay duration. Patients in the IVIG group survived and stayed longer in the hospital until full recovery, while patients in the control group died earlier. They suggested IVIG treatment in patients who were not improved with the antiviral and chloroquine-class drugs, whose oxygen saturation is persistently under 90%, patients with more than 30% of lung involvement in CT scan, and patients whose lungs are progressively being involved in serial CT scans .There are also a few studies highlighting the effect of IVIG on neurologic complications associated with COVID-19. A case report by El-Zein et al. described a 40-year-old man with SARS-CoV-2-associated meningitis/encephalitis infection whose condition markedly improved with administration of IVIG for five days . MucciolPatients commonly go through three clinical stages of the COVID-19: the acute or pneumonia stage, the viremia stage, and the recovery stage. The possible pathogenesis of COVID-19 is that lymphocyte count in the early phase of the disease (1–14 days) is normal or slightly low . HoweverIVIG treatment inhibits inflammatory mechanisms, including reduced production of IL-6 , 35, TNFAs mentioned earlier, several studies have shown the beneficial effects of using IVIG therapy against COVID-19 , 48–50. Liu et al. found no notable impact on the patients with ARDS . FurtherIn addition to the controversies in using the IVIG, some other challenges need to be discussed. First of all, the life of many immunodeficient patients depends on the IVIG lots . The COVSecond, adverse effects of IVIG do not arise very often but happen in 10% of patients. In rare cases, thromboembolism happened to the patients upon receiving IVIG. Since COVID-19 itself is a hypercoagulable state , it is rThird, using intravenous immunoglobulins can suppress the normal antibody response in the patients, leading to ineffective immunization against COVID-19. As a result, even if the patient recovers from the COVID-19, he/she may still be vulnerable and must be vaccinated as soon as possible .Fourth, If the sera collected from the general population lacks the anti-SARS-CoV-2 antibodies, its use provides no benefit . Sera deSome other risks should be considered too. Transferring of pathogens, serum sickness, transfusion-related acute lung injury (TRALI) , 68, andIn conclusion, it is still difficult to determine whether or not IVIG should be included in the treatment strategy of COVID-19 patients. More randomized clinical trials with large sample sizes are required to decide the amount of IVIG efficacy.This study does not recommend IVIG therapy as a definitive cure for the acute phase of COVID-19 but instead summarizes the evidence and gives clues for upcoming trials. Several studies reported the advantage of IVIG therapy for COVID-19 patients. However, these studies are primarily case reports with small sample sizes and uncontrolled confounding factors. These uncertainties and the shortage of IVIG supply and its high cost suggest that its use must be supported with strong evidence. Therefore, more clinical trials on the effect of IVIG therapy in COVID-19 patients should be performed to establish a certain conclusion about IVIG effectiveness.


Background: Left vocal cord paralysis (LVCP) is a known complication of patent ductus arteriosus (PDA) surgery in extremely preterm (EP) born neonates; however, consequences of LVCP beyond the first year of life are insufficiently described. Both voice problems and breathing difficulties during physical activity could be expected with an impaired laryngeal inlet. More knowledge may improve the follow-up of EP-born subjects who underwent PDA surgery and prevent confusion between LVCP and other diagnoses.Objectives: Examine the prevalence of LVCP in a nationwide cohort of adults born EP with a history of PDA surgery, and compare symptoms, lung function, and exercise capacity between groups with and without LVCP, and vs. controls born EP and at term.Methods: Adults born EP  in Norway during 1999–2000 who underwent neonatal PDA surgery and controls born EP and at term were invited to complete questionnaires mapping voice-and respiratory symptoms, and to perform spirometry and maximal treadmill exercise testing. In the PDA-surgery group, exercise tests were performed with a laryngoscope positioned to evaluate laryngeal function.Results: Thirty out of 48 (63%) eligible PDA-surgery subjects were examined at mean (standard deviation) age 19.4 (0.8) years, sixteen (53%) had LVCP. LVCP was associated with self-reported voice symptoms and laryngeal obstruction during exercise, not with lung function or peak oxygen consumption (VO2peak). In the PDA-surgery group, forced expiratory volume in 1 second z-score (z-FEV1) was reduced compared to EP-born controls (n = 30) and term-born controls (n = 36); mean  z-FEV1 was −1.8 , −0.7  and −0.3 , respectively. For VO2peak, corresponding figures were 37.5 , 38.1 , and 43.6  ml/kg/min, respectively.Conclusions: LVCP was common in EP-born young adults who had undergone neonatal PDA surgery. Within the PDA-surgery group, LVCP was associated with self-reported voice symptoms and laryngeal obstruction during exercise, however we did not find an association with lung function or exercise capacity. Overall, the PDA-surgery group had reduced lung function compared to EP-born and term-born controls, whereas exercise capacity was similarly reduced for both the PDA-surgery and EP-born control groups when compared to term-born controls. Extreme preterm (EP) birth is associated with a number of perinatal complications causing short- and long-term morbidity , 2. A paThe left recurrent laryngeal nerve loops around the aorta in close proximity to the ductus arteriosus and left-sided vocal cord paralysis (LVCP) caused by iatrogenic nerve injury is a recognized complication of PDA surgery . AffecteLong-term consequences of LVCP in EP-born subjects beyond the first year of life are insufficiently described. A previous small study on EP-born adults who underwent neonatal PDA surgery discussed the possibility that LVCP occurring in the neonatal period may contribute to the long-term development of airway obstruction in this population , howeverAs a group, premature infants who undergo PDA surgery may be particularly vulnerable to long-term health problems. PDA surgery has been associated with both bronchopulmonary dysplasia (BPD) and poor neurological outcomes , 8. FurtWe aimed to investigate the prevalence of LVCP in young adults born EP who underwent open PDA surgery in Norway during 1999–2000. Secondly, we aimed to compare self-reported voice and breathing symptoms, lung function, exercise capacity, and laryngeal obstruction during exercise between subjects with and without LVCP. Finally, we aimed to compare the lung function and exercise capacity in those who underwent PDA surgery with those of comparable EP-born controls and term-born controls.This was a nationwide observational follow-up study of all individuals born in Norway at gestational age (GA) <28 weeks or birth weight (BW) <1,000 gram during 1999–2000 . The incThe present study was conducted during 2018–2020, enrolling three groups :(1) PDA-surgery: All individuals who had undergone neonatal PDA surgery and were enrolled in the nationwide cohort described above. This PDA-surgery group has two subgroups: those with and those without LVCP.(2) EP-born controls: A regional sub-sample (Western Norway) of the same nationwide cohort from which the PDA-surgery group was recruited; however, with no history of neonatal PDA surgery.(3) Term-born controls: At 11 years of age, term born children were recruited as controls for the regional subsample of the EP-born children. The term born children were identified from birth protocols at the maternity ward and were invited as the next-born child of the same gender as the EP born child, with GA >37 weeks and BW >3,000 grams, corresponding to the Norwegian 10th-centile for BW.® PNEUMO spirometer  was used to perform spirometry according to guidelines (1) and FEV1/FVC were recorded. Raw data were transformed to z-scores using the reference equations of the Global Lung Function Initiative  exercise test according to a modified Bruce protocol  using a 2peak). VO2peak was reported as ml/kg/min and as the percentage of predicted using reference equations from a large sample of Norwegian subjects of relevant age (i/Ttot%) was used to describe the breathing pattern. Breathing reserve was the difference between maximal voluntary ventilation (FEV1 x 35) and peak minute ventilation reported as the percentage of maximal voluntary ventilation.Variables of gas exchange and airflow were measured breath by breath and averaged over 10 s. The highest values for oxygen uptake determined during the last 60 s were recorded as peak values  as described previously . LVCP waDo you have breathing problems beyond normal during physical exertion?” Do you make scraping sounds or other abnormal sounds from the throat during physical exertion? Is your voice hoarser than in others of the same age? and “Does your voice affect participation in singing?” were custom-made for the project.All participants were asked to complete an online questionnaire mapping several health issues. The PDA-surgery group filled in an additional paper-based questionnaire adapted from the Voice Handicap Index with questions regarding voice symptoms . The quet-tests  with 95% confidence intervals (95% CI), Mann-Whitney U-tests, or Fisher's exact tests, as appropriate. Analysis of covariance was used when the outcome for completed distance and VO2peak was adjusted for gender and self-reported physical activity (hours of exercise per week) and to adjust for bronchopulmonary dysplasia (BPD) when comparing lung function variables between the PDA-surgery group and the EP-born control group. To examine whether the difference in VO2peak between all EP-born and term-born controls differed by gender, an interaction term for gender and group affiliation was included. Linear regression with the modified CLE-score and gender as predictors was used to investigate whether VO2peak was associated with the CLE-score after adjusting for gender. P-values ≤ 0.05 was characterized as statistically significant.Data were analyzed using the statistical software SPSS version 26  and MedCalc version 19.5.3 . Group comparisons were performed using the independent samples The Regional Committee for Medical and Health Research Ethics in Western Norway approved the study. Informed written consents were obtained from all participants, or their parents if subjects were not competent to give consent.Thirty of 48 (63%) eligible subjects in the nationwide PDA-surgery cohort consented to participate . One parother pathology and they were excluded from further analysis). Thirteen subjects (43%) had a normal laryngeal exam (no LVCP or major anatomic pathology). One subject with LVCP and all three subjects with other pathology were aware of their laryngeal pathology before entering this study, the remaining 12 were not. Within the PDA-surgery group, those with LVCP had more often received postnatal steroids compared to those with a normal larynx, whereas other neonatal characteristics were similar  subjects were diagnosed with LVCP. Two subjects (7%) had laryngeal stenosis in addition to LVCP, and one subject (3%) presented right-sided arytenoid prolapse with overlying left-sided arytenoid fold making vocal cord assessment during phonation difficult, and LVCP could therefore not be determined (these three subjects are referred to as  similar .p = 0.006)  . Around other pathology were excluded from the analyses of lung function and exercise capacity. Within the PDA-surgery group, we did not find statistically significant differences in spirometry values between subjects with or without LVCP. However, clinically relevant differences could not be excluded given the wide the confidence intervals  difference of 0.89 , p = 0.02.The PDA surgery group had reduced z-FVC, z-FEVcontrols . Neonata2peak (ml/kg/min as well as the percentage of predicted), or self-reported physical activity for subjects with and without LVCP  difference between those with LVCP vs. all the other groups combined was 2.8%  p < 0.001.All participants ran to perceived maximal exhaustion and all achieved RER above 1.05 or heart rate above 95% predicted. Within the PDA-surgery group, we did not find statistically significant differences in completed distance, VOout LVCP . However2peak (ml/kg/min), and reported less physical activity compared to term-born controls  meters, p < 0.001, and 4.9  ml/kg/min, p = 0.002, respectively. There was no significant interaction effect between gender and group affiliation  on VO2peak (p = 0.16). After additional controlling for physical activity, the completed distance on the treadmill was still shorter for EP-born participants compared to the term-born control group . Moreover, VO2peak difference was slightly reduced [3.2  ml/kg/min] and no longer statistically significant (p = 0.07).The PDA-surgery group had similar exercise capacity and self-reported physical activity as the EP-born control group. All EP-born participants combined (PDA-surgery and EP-born controls), ran a shorter distance, had lower VOcontrols . AdjusteIn the PDA-surgery group, 27/30 participants performed a CLE test. Among these, the modified CLE-score at moderate and maximal effort could not be determined in three subjects, and the total score was derived from the sub-scores at rest and maximal effort, or at rest and moderate effort.In the group with LVCP, all but one had a modified CLE-score >4, indicating laryngeal obstruction during exercise. In those with no LVCP, only three subjects had a modified CLE-score >4 , which s2peak after adjusting for gender (p = 0.40).The group of subjects reporting breathing difficulties during exercise and those reporting abnormal sounds from the throat during exercise did not have a higher modified CLE-score than those without these symptoms . FurtherThis is the first study to report the prevalence of LVCP in a national cohort of young adults with a history of EP birth and surgical closure of PDA during their neonatal period. Within the PDA-surgery group, more than half of the participating subjects were diagnosed with LVCP, which was associated with characteristic voice symptoms, prolonged inspiratory to total respiratory time, and laryngeal obstruction during exercise. We did not find an association between LVCP and lung function or exercise capacity, however, the power to detect such associations was low due to the limited sample size. Overall, the PDA-surgery group had impaired lung function compared to EP-born as well as term-born controls, whereas exercise capacity was similarly reduced for both PDA-surgery and EP-born controls compared to term-born controls.Studies examining LVCP after PDA surgery in EP-born neonates have mainly been performed in the immediate postoperative period or during infancy . Our groDysphonia is a known long-term complication of preterm birth and is associated with extreme prematurity, emergency intubations, and multiple intubations, as well as PDA surgery , 30, 31.Local traumas related to intubation and prolonged time on invasive mechanical ventilation are known risk factors for laryngeal injury . We founIn the PDA-surgery group in this present study, more had BPD and the lung function was poorer in adulthood, compared to the EP-born control group. There is convincing evidence that preterm-born survivors with or without BPD have an increased risk for poor adult lung function . The ass2peak. This finding is in line with our previous study, where no association between VO2peak and LVCP was found in EP-born adults  than term-born, in line with the ~11% (-4.9 ml/kg/min) lower VO2peak observed for all our EP-born participants combined (2peak (A number of long-term sequelae of EP birth may affect subsequent exercise capacity, such as cardiopulmonary and neuromuscular impairment, reduced skeletal muscle mass, and behavioral issues such as less participation in physical activity . A reviecombined . Similard (2peak . It is sd (2peak . We enco2peak and physical activity.The strengths of this study were a population-based design with several centers responsible for the PDA surgery, and a high rate of participation. It was a limitation that only the PDA-surgery group was examined with laryngoscopy. Undiscovered LVCP or other laryngeal pathology might have been present in the EP-born control group, due to e.g., pressure from a large PDA or a large pulmonary trunk . FurtherThe number of eligible subjects was determined by the number of EP-born infants who underwent PDA surgery in Norway during 1999–2000. The sample size was relatively small with large variation within the groups, resulting in a reduced power to detect differences in the subgroup analyses. About one-third of the eligible EP-born adults who had undergone PDA surgery were lost to follow-up . RecruitManagement of PDA in EP-born individuals is still under debate . ReportsIn this nationwide study, LVCP was present in 53% of EP-born young adults who had undergone neonatal PDA surgery. Within the PDA-surgery group, LVCP was associated with self-reported voice symptoms and laryngeal obstruction during exercise. We did not find an association between LVCP and lung function and exercise capacity, however; the power to detect such associations was low. Overall, the PDA-surgery group had impaired lung function compared to EP-born and term-born controls, whereas exercise capacity was similarly reduced for both PDA-surgery and EP-born controls compared to term-born controls.Clinicians caring for EP-born children and adults should be aware of possible laryngeal sequelae after PDA surgery. Furthermore, EP-born subjects with a history of PDA surgery represent a population that needs follow-up to monitor lung function. Despite a high-risk start to life, EP-born individuals who underwent PDA surgery seem to achieve an exercise capacity only modestly decreased compared to term born individuals.maria.vollseter@helse-bergen.no.The datasets presented in this article are not readily available because in accordance with the approvals granted for this study by the Regional Committee on Medical Research Ethics and the Norwegian Data Inspectorate, the data files are stored securely and in accordance with the Norwegian Law of Privacy Protection. The data file cannot be made publicly available as this might compromise the respondents' privacy. Some of the participating centers are small and the number of extremely preterm births is limited with a risk of identifying anonymous participants. A subset of the data file with anonymized data can be made available to interested researchers upon reasonable request, providing Norwegian privacy legislation and GDPR are respected, and that permission is granted from The Norwegian Data Inspectorate and the data protection officer at Haukeland University Hospital. Requests to access the datasets should be directed to Maria Vollsæter, The studies involving human participants were reviewed and approved by the Regional Committees for Medical and Health Research Ethics West, The University of Bergen, 5021 Bergen, Norway. Informed written consents were obtained from all participants, or their parents if subjects were not competent to give consent.ME and MSE have coordinated and collected data, organized data, carried out the analyses, drafted the initial manuscript, and revised the manuscript. MV has designed the data collection instruments, collected and organized data, and has reviewed and revised the manuscript. LS, OG, and IE have collected and organized data and critically reviewed the manuscript for important intellectual content. KH has given advice on the analysis of data, participated in the interpretation of the data, and critically reviewed the manuscript for important intellectual content. KØ, OR, and TH have provided funding, designed the data collection instruments, coordinated and supervised data collection, and have critically reviewed the manuscript for important intellectual content. HC has conceptualized and designed the study, designed the data collection instruments, drafted the initial manuscript, and has critically reviewed the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.This study was financially supported by the Western Norway Regional Health Authority grant number F-11526.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Diabetes mellitus affects almost 10% of U.S. adults, leading to human and financial burden. Underserved populations experience a higher risk of diabetes and related complications resulting from a combination of limited disposable income, inadequate diet, and lack of insurance coverage. Without the requisite resources, underserved populations lack the ability to access healthcare and afford prescription drugs to manage their condition. The aim of this systematic review is to synthesize the findings from cost-effectiveness studies of diabetes management in underserved populations.Original, English, peer-reviewed cost-effectiveness studies of diabetes management in U.S. underserved populations were obtained from 8 databases, and PRISMA 2009 reporting guidelines were followed. Evidence was categorized as strong or weak based on a combination of GRADE and American Diabetes Association guidelines. Internal validity was assessed by the Cochrane methodology. Studies were classified by incremental cost-effectiveness ratio as very cost-effective , cost-effective , marginally cost-effective  or cost-ineffective . Reporting and quality of economic evaluations was assessed using the CHEERS guidelines and Recommendations of Second Panel for Cost-Effectiveness in Health and Medicine, respectively.Fourteen studies were included. All interventions were found to be cost-effective or very cost-effective. None of the studies reported all 24 points of the CHEERS guidelines. Given the considered cost categories vary significantly between studies, assessing cost-effectiveness across studies has many limitations. Program costs were consistently analyzed, and a third of the included studies (n = 5) only examined these costs, without considering other costs of diabetes care.Cost-effectiveness studies are not based on a standardized methodology and present incomplete or limited analyses. More accurate assessment of all direct and indirect costs could widen the gap between intervention and usual care. This demonstrates the urgent need for a more standardized and comprehensive cost-effectiveness framework for future studies. Diabetes mellitus (DM) affected 30.3 million U.S. adults in 2015, and an estimated 1.5 million new cases of DM annually makes diabetes the most common chronic disease in the U.S. , 5. T2DMSupport given to diabetes patients is a first step in the public health approach to successfully managing the disease and preventing complications. Many initiatives are considering improved care for underserved populations, although the real cost of such interventions has not been assessed. By underserved populations, we refer to populations that face barriers and challenges in accessing and using resources due to residence in impoverished urban sectors, poverty or low socio-economic status, the uninsured, persons from disadvantaged backgrounds, or individuals with low income . The useWe followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines , and a sTwo independent reviewers screened titles and abstracts, followed by retrieval and screening of full texts. Eligibility was based on the following criteria: original cost-effectiveness studies focusing on DM that include 1) lack of disposable income, insurance status or socio-economic status and a measure of cost assessment; 2) all adult type 2 diabetes management interventions–both interventions for diabetes prevention and diabetes care; 3) any publication date–from inception to the search date of December 21, 2020; 4) published literature concerning the U.S. only; and 5) any type of model used–meaning all cost-effectiveness studies meeting the inclusion criteria are included, regardless of the model to predict costs and effectiveness of the interventions based on the best available evidence. Short-term and long-term studies and studies from the payer or societal perspective were included. Finally, analyses with and without control groups are taken into account. Conference abstracts were excluded for providing insufficient detail. Studies published in languages other than English, reviews and unpublished studies (grey literature) were excluded. Therefore, additional web-based platforms–such as google searches for grey literature and the World Health Organization Global Health Library–were not searched. Care could be delivered by any provider type and could be individual- or group-based. Studies could be of any duration and intensity. Disagreements were resolved by consensus.Data extraction was based on the Cochrane Consumers and Communication Review Group’s data extraction template: (1) publication year; (2) journal; (3) population; (4) sample size; (5) intervention; (6) study design; (7) clinical and economic outcomes. Full text review of relevant articles and reference crawling was carried out. Missing information was sought from the authors. Data extraction was unblinded since blinding does not decrease bias in systematic reviews , 18. A sData were charted as follows: 1) results for each study were summarized, both key features and compliance with the Recommendations of the Second Panel on Cost-Effectiveness in Health and Medicine , and 2) The studies’ results were synthesized as follows: 1) for multiple-study interventions, the median ICER was reported; and 2) for studies reporting short- and long-term results, only long-term results were reported, since outcomes are mostly long-term in nature. To make outcomes across studies comparable, costs are expressed as 2019 dollars, using the Consumer Price Index [Interventions are classified based on cost-effectiveness result . An inteTwo independent reviewers appraised the reporting and quality of the economic component of the studies using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS)  checklisInternal validity was checked using the Cochrane methodology  Table 2Table 2. Finally, we assessed the studies’ external validity, considered adequate if the study population represented the target population. Another requirement was random subject selection or referral-based selection without significant differences between groups at baseline.The search resulted in 10,879 screened titles. After exclusion of non-relevant titles  and duplicates , 389 potentially relevant articles were independently reviewed. Among these, 351 studies were discarded since they did not meet the inclusion criteria. One-hundred nine studies examined cost-effectiveness in non-U.S. settings, 218 studies focused on non-underserved populations, and 24 studies analyzed claims. Forty-six additional studies were identified for full text review by hand-searching references. After full text review, an additional 70 studies were non-eligible because they analyzed only claims (14 studies) or the intervention was not compared to usual care (56 studies). Thirteen discrete studies, published in 14 articles, met the inclusion criteria. The evaluated interventions are to prevent T2DM in high-risk populations (2 studies) , 38, andSeven of 14 studies evaluated the cost-effectiveness of diabetes interventions from a long-term analytical time horizon –36, withClassification of the interventions based on the quality of their evidence and adherence to CHEERS reporting guidelines is presented in Five interventions are based on strong evidence  34, 35,–42. Six Furthermore, five interventions are classified as very cost-effective, based on weak evidence: 1) monthly CHW visits in poor or medically indigent populations ; 2) diabNone of the 14 analyses reported all 24 points of the CHEERS guidelines, though most studies reported relatively well . Six stuTwelve papers excluded patients with T1DM or gestational diabetes, one intervention (2 studies) included both type 1 and 2 subjects , 30. ThiTwo studies assessed the cost-effectiveness of T2DM prevention. Analyses demonstrate improvement with diabetes education/management , 38. RobFour studies examined the economic impact of CHW interventions, compared to diabetes management without a CHW , 35, 41.Three studies investigated the cost-effectiveness of telephonic T2DM interventions , 40, 42,Two studies assessed the cost-effectiveness of diabetes self-management training , 37, givThe cost-effectiveness of a nurse case and peer education T2DM intervention was examined by two Project Dulce studies , 30. In One study focused on the cost-effectiveness of a Quality Improvement Collaborative on glycemic control . The proThis review suggests T2DM interventions are associated with improved health outcomes for underserved populations, with favorable cost-effectiveness. Almost all interventions were cost-effective or very cost-effective ; none of the studies were cost-saving. The evidence on which cost-effectiveness analyses were based varied. Nine out of 14 studies were based on strong evidence. Although the search covers a long period, from inception to December 21, 2020, the 14 studies that are included in the review are all relatively recent. The oldest paper has been published in 2004, while most included cost-effectiveness studies have been performed the last 10 years. This indicates the cost-effectiveness of diabetes management for underserved populations in the United States is a relatively new research area.The World Health Organization endorses the use of cost-effectiveness analyses in advising policy-recommendations, and interventions with an ICER ≤ US$50,000/QALY are usually recommended . Cost-efOur systematic analysis has some limitations. First, we used the same threshold for all studies, regardless of whether ICERs were expressed as dollars per QALY or another outcome measure (such as dollars per percentage point decrease in HbA1C). QALYs consider patients’ quality of life, while other outcomes measures do not. The intervention’s impact on patients’ quality of life is hard to assess when studies do not express results as dollars per QALY, making it difficult to compare studies with different ICERs. Second, we excluded unpublished research, which may bias (publication bias) the results. Third, the review includes only a small number of studies. The two biggest drivers of limited research in this area is the urgent need for more resources to conduct cost-effectiveness studies as part of RCTs  as well The strengths of this review include presenting a PRISMA reporting guideline-compliant review to guide current research in T2DM in underserved populations–clearly identifying limitations in current cost-effectiveness studies. Consequently, this review also serves as an important “policy agenda” to open the dialogue in economic research, to find the best way to improve future cost-effectiveness studies.Further economic evaluations of T2DM interventions for vulnerable populations should consider the following. First, much greater emphasis needs to be placed on the scientific evidence for both the effectiveness and the cost-effectiveness of healthcare interventions to ensure patients receive the best possible care. The decision to use a particular intervention can be facilitated by identifying its cost-effectiveness in addition to its health benefits. Second, in cases where randomization is too difficult or impossible, a quasi-experimental non-randomized design is recommended . FinallyThe findings reported in this review are particularly timely given the high incidence of diabetes as well as the large and growing diabetes inequities in the United States. Prevalence of diabetes is particularly high among underserved individuals.This review has shown the vast heterogeneity of cost calculation, and the urgent need for standardization. At present, there is no global consensus about the cost calculation in cost-effectiveness analyses. Therefore, studies use different techniques to account for the costs of the intervention. Cost calculation is currently non-standardized and causes difficulties when cross-comparing cost-effectiveness analyses. Future studies should make the necessary efforts to calculate costs from a societal perspective, independent from who bears the costs. This will provide robust and comprehensive cost-effectiveness analyses.S1 Checklist(DOC)Click here for additional data file.S1 File(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.


A randomized, placebo-controlled clinical trial (FDREST) of a novel formulation of caraway oil and L-menthol (COLM-SST) demonstrated symptom relief in patients with functional dyspepsia (FD). Two follow-up studies were conducted to evaluate patient satisfaction, self-regulated dosing, and long-term safety data: FDACT, Functional Dyspepsia Adherence and Compliance Trial, and FDSU36, Functional Dyspepsia Safety Update at 36 months.A patient reported outcomes (PRO) questionnaire was designed and distributed online to assess real-world satisfaction and dosing frequency of open-label COLM-SST in patients with FD. A separate study analyzing voluntary safety surveillance data evaluated the frequency and severity of reported adverse events (AEs).A total of 600 FD patients were enrolled in the PRO study. Ninety five percent of respondents reported a major or moderate improvement in their FD symptoms and 91.7% indicated a major or moderate improvement in quality of life (QOL) using COLM-SST. Between 1 and 4 capsules were consumed daily by 91.2% of respondents, with 56.2% taking them before meals. Symptom relief was rapid, with 86.4% of respondents indicating relief within 2 h of taking COLM-SST. Few adverse events (AEs) were reported (0.0187%) by patients using COLM-SST. No serious AEs were identified.COLM-SST is safe, well tolerated, and provides rapid relief of FD symptoms. These findings, demonstrated in the FDREST trial, were further supported by a large prospective PRO study evaluating self-regulated dosing frequency, symptom improvement, and QOL. COLM-SST was well-tolerated based on review of AE data at 36 months. Functional dyspepsia (FD) is a disorder of gut-brain interaction (DGBI) that affects the upper portion of the gastrointestinal tract. The disorder is more frequently diagnosed in women than men . While t4 receptor agonist, was removed from the market due to safety concerns related to QT prolongation. [While no medication is approved for the treatment of FD, physicians prescribe a variety of treatments in off-label fashion to patients with FD to improve their symptoms. This approach has met with varying degrees of success. Commonly used classes of medications for FD include, but are not limited to, histamine type 2 receptor antagonists (H2RAs), proton pump inhibitors (PPIs), prokinetic agents, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and selective serotonin and norepinephrine reuptake inhibitors (SNRIs) . While sngation. . Metoclongation. . Taking ngation. . Proton ngation. . Patientngation. .As an alternative to using off-label prescription drugs, non-prescription therapies, including herbal-based treatments, have been used by patients and health care providers to address the multiple symptoms of FD. The combination of peppermint oil and caraway oil has been studied in a number of clinical trials and has consistently been shown to be effective at treating FD symptoms –24. One To better understand the efficacy and safety profile of COLM-SST, real-world evidence was gathered from two separate populations. One was a post-marketing evaluation of open label COLM-SST: The Functional Dyspepsia Adherence and Compliance Trial (FDACT), and the other was an adverse event reporting analysis: The Functional Dyspepsia Safety Update at 36 months (FDSU36). FDACT was conducted to determine real-world daily COLM-SST capsule usage frequency and patient satisfaction in a general population of patients with FD. FDSU36 relied on data gathered from adverse event reports originating from patients using COLM-SST over a 3-year period. In the current analysis, we report the overall satisfaction with symptom relief and usage patterns of COLM-SST users as well as the 36-month safety event profile.FDACT included patients with FD symptoms from the general population who were using open label COLM-SST . FDACT participants either received a sample of COLM-SST from their healthcare provider, after evaluation of their symptoms, or purchased COLM-SST in the pharmacy. Those who selected COLM-SST at the pharmacy were not confirmed to have a FD diagnosis prior to participation. Although COLM-SST was available to HCPs and in pharmacies nationwide, geographical distribution of participants was not assessed. An invitation to access the FDACT web-based survey questionnaire was included in COLM-SST packages. The non-validated 10-question survey  was provided on all boxes containing COLM-SST. The call center was staffed with pharmacovigilance-trained health care personnel, in accordance with the FDA and global regulatory guidelines on properly reporting AEs, to receive and record customer AEs. The internationally harmonized Medical Dictionary for Regulatory Activities (MedDRA) was used for coding AEs. Version 19 was used for the period between 2016 and 2017. Version 20 was used for the period between 2017 and 2018. Version 21 was used for the period between 2018 and 2019.Six hundred patients with FD who either purchased a box of COLM-SST or received a sample of COLM-SST from their health care provider completed the FDACT survey. Demographic information  was not collected. Most patients in FDACT reported suffering from FD symptoms daily (75.5%) or twice a week or more (16.7%). Additional survey questions focused on frequency of COLM-SST dosage, symptom relief, and patient satisfaction.Most respondents (93.8%) in the survey reported that they took COLM-SST on a daily basis. Generally, patients took 1 to 2 capsules per day (47.5%) or 3 to 4 capsules per day (43.7%). Most respondents took COLM-SST in association with consumption of food. More than half (56.2%) indicated that they took the capsules before a meal, while 27.5% indicated that they took it after a meal. Sixteen percent of respondents reported using COLM-SST for on-demand symptom relief.Most patients indicated that relief of FD symptoms came within 2 h of taking COLM-SST. Achievement of relief within 1 h was reported by 39.2% of respondents, and 47.2% achieved relief between 1 and 2 h. Almost all respondents experienced improvement in FD symptoms while taking COLM-SST, with 35.3% experiencing a major improvement, and 59.7% experiencing a moderate improvement. To further explore symptom relief, patients were asked about the improvement in their upper abdominal pain and epigastric fullness. Ninety-two percent of patients indicated a major or moderate improvement in their upper abdominal pain, while 86.5% indicated a major or moderate improvement in their symptom of epigastric fullness attributable to COLM-SST. Figure When asked to rate their improvement in QOL while on COLM-SST, 91.7% of respondents indicated a major or moderate improvement with COLM-SST and 97.7% indicated that they would be either likely or very likely to continue taking COLM-SST for their FD symptoms. Furthermore, 95.3% indicated that they would be either likely or very likely to recommend COLM-SST to family or friends.The total number of people who were considered to have been unique users of COLM-SST was calculated based on adding the number of sample boxes distributed by physicians and the number of boxes sold through retail distribution. Both numbers were adjusted to reflect an estimate for the samples that became active purchasers and repeat buyers of COLM-SST. Using this framework, it was estimated that over 1 million unique patients tried COLM-SST over the 3-year period of monitoring, thus establishing a denominator estimate for rate calculations.Over the 3-year monitoring period, a total of 205 adverse events were reported to the pharmacovigilance team from 171 Individual Case Safety Reports (ICSRs). No serious adverse events were reported. Of the 205 AEs, 74 were considered unrelated to COLM-SST and 131 were conservatively considered related to COLM-SST due to the temporal relationship of the AE and the consumption of the product and where no meaningful assessment of causality could be established with little to no additional relevant medical history, comorbid condition or concomitant information provided. The 3 most common AEs reported were dyspepsia , diarrhea , and nausea . Table Functional dyspepsia is a highly prevalent and chronic disorder that causes significant patient distress, negatively affects quality of life, and incurs significant costs to the health care system. At present, no medication is approved by the FDA for the treatment of FD. This means that FD patients use lifestyle modifications and/or off-label products (either prescription or over the counter) to manage their FD symptoms, with varying degrees of success , 29. ManThe results from the PRO study FDACT indicate a high level of user satisfaction with COLM-SST as a treatment for the symptoms of FD. We believe that there are multiple possible explanations for this finding. COLM-SST appears to be effective at mitigating or even preventing FD symptoms, with the vast majority of respondents indicating major or moderate FD symptom improvement while taking this therapy. Patient responses indicate that COLM-SST was also effective at relieving both subgroups of FD symptoms according to the Rome IV criteria, those with abdominal pain and/or burning (EPS) and those with fullness or early satiation (PDS). The observations from FDACT support previous clinical trial data from the FDREST study on COLM-SST . AnotherImportantly, no serious AEs have been reported in association with COLM-SST since its launch in 2016. Of the 205 AE reports (out of an estimated 1 million unique users), 74 were subsequently considered to be unrelated to COLM-SST. The remaining 131 AE could not be conclusively linked directly to COLM-SST use but were conservatively included due to the inability to conclusively identify any other cause. Nonetheless, using this most conservative estimate of AE, the COLM-SST rate drops to 0.0119%. This value equates to a number needed to harm of 8,403. Moreover, most AEs reported were associated with symptoms that are either closely related to the condition for which COLM-SST was being taken, or the condition itself. Most reported AEs were considered gastrointestinal in nature; dyspepsia, diarrhea, nausea, and various types of abdominal pain/discomfort. Considering that the population of patients who would use COLM-SST are likely to be suffering from one or more of these symptoms, it is likely that a number of these reports may have been confounded by the underlying condition itself. For example, it is well known that patients with FD frequently have co-existing IBS symptoms , and thust Century Cures Act, there has been an increasingly strident call to include real-world evidence in the evaluation of potential therapies for medical disorders. One of the objectives of this act was to measure and evaluate patient experience information to facilitate more rapid drug and device approval [With the US Congress’ approval in 2016 of the 21approval , 38. Thiapproval , such asThe studies reported here are subject to several limitations. Although the data set for the FDSU36 was quite large, the PRO sample size from the FDACT study was small by comparison. Demographic data with a breakdown of age, gender, and race as well as concomitant medication history was not available for either of the FDACT datasets, preventing further analysis of patient characteristics to identify who would most benefit from COLM-SST. Therefore, gathering and analyzing additional data surrounding the real-world experience with COLM-SST is important to better understand who might benefit most from the therapy, and even more importantly, whether it is safe.Patient generalizability is another potential limitation of these studies. The population of participants for the FDACT study was gathered from individuals who obtained COLM-SST samples from their health care provider or purchased COLM-SST from the pharmacy and then went online to fill out a survey. The survey did not specifically differentiate first time users from repeated users or whether the COLM-SST was obtained from the HCP or pharmacy, therefore contributing to possible bias of subject selection method. Those individuals who might have been regular frequent users may have already had a previous positive experience with COLM-SST and this inherently could bias the results. In addition, the small incentive offered towards future purchase of COLM-SST could be construed as a tacit indicator of patient satisfaction. Future studies are being considered to gather additional PRO data including number of days with symptoms, number of days using COLM-SST, dosing patterns and symptom relief in relation to meals, as well as validated numerical scales to measure quality of life changes before and after using COLM-SST.In summary, the data reported here, combined with the previous RCT conducted on COLM-SST  provide