The hustle and bustle of the planet Earth have come to a halt thanks to the novel coronavirus. The virus has affected approximately 219 million people globally; taken the lives of 4.55 million patients as of September 2021; and created an ambiance of fear, social distancing, and economic instability. The purpose of this review article is to trace the historical origin and evolution of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). The virus is highly contagious with a unique feature of rapid mutations—the scientific research is paving the way for discoveries regarding novel coronavirus disease (COVID-19) diagnosis, features, prevention, and vaccination. The connections between the coronavirus pandemic and dental practices are essential because COVID-19 is transmitted by aerosols, fomites, and respiratory droplets, which are also produced during dental procedures, putting both the patient and the dentist at risk. The main emphasis of this paper is to highlight the psychological, economic, and social impact of this pandemic on dental practices throughout the world and under what circumstances and guidelines can dental health care be provided. In the current situation of the pandemic, an appropriate screening tool must be established either by using rapid molecular testing or saliva point-of-care technology, which will be effective in identifying as well as isolating the potential contacts and carriers in hopes to contain and mitigate infection. The blessing in disguise is that this virus has united the leaders, scientists, health care providers, and people of all professions from all around the world to fight against a common enemy. Coronaviruses are a group of viruses causing common cold and flu-like symptoms, infecting both humans and animals . Novel cEpidemiological and genetic studies show that SARS-CoV-2 is zoonotic in origin . The firCoronaviridae family possess a single-stranded RNA with the genomic length ranging from 26 to 32 kilobases  and can The SARS-CoV-2 life cycle , once enThe virus can infect individuals from all ages irrespective of any gender predilection; however, individuals who are above 60 years of age or those possessing co-morbidities like diabetes, asthma, obesity, ischemic heart disease, cancer, or patients who have undergone organ transplant comprise the high-risk group with almost a 12 times greater chance of fatality with SARS-CoV-2 infection than individuals falling in low risk category . AccordiThe most common mode of human–human transmission occurs via droplets  or blood with smaller droplets traveling a longer distance and larger droplets limited to nearby objects . The effFurthermore, the studies of conjunctival samples from suspected as well as confirmed 2019-nCoV cases advocates that exposure of eyes may be an efficient way for the virus entrance ,33; therNasopharyngeal swab.Oropharyngeal swab.Blood sampling for antibody detection (immunization).Expectorated sputum in severe respiratory disease .The CDC, China, reported the viral genome sequence in the international database banks GenBank and Global Initiative on Sharing All Influenza Data ,34. It hIn terms of sensitivity and specificity of diagnostic methods, sensitivity is the test’s capacity to identify all infected individuals. In contrast, specificity is the test’s ability to detect a particular pathogen . SensitiLower and upper respiratory tract → exchange of liquid droplets between the oral cavity and respiratory tract → virus in saliva ,36Blood → virus via gingival crevicular fluid (GCF) enters oral cavity→ saliva SARS-CoV-2 → infection of salivary glands (rhesus macaques) → saliva COVID-19 has also been detected in the saliva of infected patients . There aSaliva is a cheap, accessible, and non-invasive diagnostic method with minimal risk of transmission and is currently serving as a biomarker for diagnosing and screening different diseases ,42, inclThe GCF is an inflammatory exudate or serum transudate of the pathological or healthy periodontal tissues . It is uThe mean incubation period after being infected is 5.1 days. During this period, the patient remains asymptomatic. Three weeks is the crucial period for COVID-19 because patients either died after 15 to 22 days or were discharged between 18 to 25 days from the onset of symptoms  28]..28].At present, there are no approved and specific therapies for 2019-nCoV. Many immunotherapies and antiviral drugs are under investigation for COVID-19  53]..53].(1)Healthcare professionals and inhabitants of long-term care facilities.(2)Essential workers  and individuals aged 75 years or older.(3)Individuals aged 65 to 74 years; individuals aged 16 to 64 years with systemic conditions.Vaccination is considered the most effective defence against infectious diseases. The same is true for COVID-19; therefore, over 214 candidate vaccines from different pharmaceutical companies are being developed. The vaccines are broadly classified as: vaccines based on full-length S-protein, protein (RBD-based or S2 based subunit vaccines), inactivated vaccines, live attenuated vaccine, nucleic acid (DNA/mRNA) based vaccines, replicating and non-replicating viral vectors vaccine, and viral-like particle vaccine . COVID-1Once the people with priority have been successfully vaccinated, only then the general public will get the opportunity of getting vaccinated .hAd5 T-cell (Immunity Bio and NantKwest) .Intranasal COVID-19 vaccine (Ad COVID) .ChAdOx1 nCov-19 inhaled (University of Oxford) .Vaccinations other than parenteral routes are also under development. Following are the examples of some of the vaccines which are under development and do not employ the parenteral route:Similarly, already available vaccines like BCG and MMR are being repurposed for developing immunity against COVID-19 as the literature has suggested that it may offer partial immunity against COVID-19 infection .Evaluation of 666 patients at a temporary field hospital in Spain showed that 45% had mucocutaneous symptoms and more than 25% had oral symptoms as follows : The relPrevotella intermedia. Two cases with Kawasaki disease and Melkerson–Rosenthal syndrome have also been reported . In. In95]. The infection control during dental healthcare amid the COVID-19 pandemic is demonstrated in A study conducted by Ahmadi et al. in Iran concluded that around 10% of the dentists and their staff members had COVID-19 related symptoms. They have also reported that 63% of the dentists had faced financial problems due to COVID-19 pandemic and 43% reported anxiety and depression with almost 50% of these required consultation with a psychiatrist . Kamran Disinfectants containing 1000 mg/Chlorine for the walls, floors, and dental operatory disinfection. Alcohol-based sanitizer (75% to 80%) is beneficial against SARS-CoV-2. The suggested disinfectant for SARS-CoV-2 for waste disinfection before disposal is sodium hypochlorite . PovidonVarious dental procedures are categorized as emergencies and non-emergencies according to COVID-19 guidelines. Their details are presented in Wash hands with alcohol-based soap solution for 20 s.Wear masks when outside.Avoid touching face.Stay 6 feet apart from each other.Cover your face while coughing or sneezing.Disinfect the surfaces used repeatedly .Avoid crowded areas.Isolate yourself if sick or at greater risk.The transmission can be manageable, i.e., decrease the viral transmission (via close contact or droplets), using the point-of-care technology . SeveralThe CDC says that aerosol generating procedures  are the Risks associated with different modes of transmission .The sources, nature, kinetics, and the quantity of microbial load in such aerosols.The efficacy of current and emerging practices in mitigating aerosol-generated microbial load.Aerosol-generating procedures are hazardous because they release micro-droplets into the air through spray generating equipment . Severe The coolant used with rotary handpieces and powered scalers has a flow rate of 10 to 40 mL per minute  which isCataloguing of suspicious or high-risk patients  .Repetition of triage .Preoperative testing after 48 h, i.e., two RT-PCR tests 24 h apart with a sensitivity of at least 71%  :Scalpel use over monopolar cautery for skin/mucosal incision.Avoid intra-oral incision, repeated suctioning, and irrigation.Elective surgery must be delayed for non-critical cancer patients unless it does not affect the prognosis.Substitution of power saw by a low-speed drill or osteotome.Application of a low power bipolar cautery for haemostasis.The therapeutic and surgical procedure for facial fractures as suggested by AO CMF are as follows ,147,151:The following aspergillus flavus, candida albicans, and candida glabrata. The overall incidence of invasive fungal infections along with COVID-19 co-infection was around 5% [Recent literature is showing an association of black fungus  of the lungs and maxillary sinuses with COVID-19 patients. Song et al. have reported an association of COVID-19 with round 5% . Rabaglaround 5% . Waizal-round 5% . Mucormyround 5% . Managemround 5% .Despite scientific advancements, we are still unable to contain the spread of COVID-19, and scientists have yet to develop a definitive treatment for this disease. Currently, there is no evidence that dental healthcare professionals are at a higher risk of airborne viral disease transmission than the general population. Epidemiologic evidence of the prevalence of infections in dental healthcare providers and a comparison to populations as a whole may shine a light on highly protective infection control practices that can be implemented to keep practitioners and patients as safe as possible. Dental professionals should educate patients about the significance of good oral hygiene. Poor oral hygiene is associated with increased plaque deposits and bacterial load, which may lead to bacterial superinfection and risk of complications in COVID-19 patients. Our only preventative measure right now is vaccination and maintenance of cross-infection protocols which can be achieved through proper education of health care workers, patients, and the general public. The COVID-19 pandemic has given us an important message that even the superpowers can collapse and that the most intelligent nations can be startled. Mere weapons cannot defend us and the number of produced medicines cannot suffice our needs. Under the disguise of scientific revolution and industrialization, we have disrupted nature’s equilibrium. A critical question arises: will we realize the importance of our green planet in the post-COVID world?


Background: multisystem inflammatory syndrome in children (MIS-C) is a new disease associated with a recent infection with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Affected children can present predominantly with abdominal symptoms, fever and high inflammatory parameters that might lead to a consult by the pediatric surgeon and an indication for surgery. Methods: clinical data of three patients with MIS-C that underwent surgery were collected. Histopathological analysis of the appendix was performed. Results: we present the clinical course of three children with fever, abdominal pain and vomiting for several days. Clinical examination and highly elevated inflammation markers led to indication for laparoscopy; appendectomy was performed in two patients. Because of intraoperative findings or due to lack of postoperative improvement, all patients were reevaluated and tested positive for MIS-C associated laboratory parameters and were subsequently treated with corticosteroids, intravenous immunoglobulins, acetyl salicylic acid and/or light molecular weight heparin. Conclusions: we discuss the implications of MIS-C as a new differential diagnosis and stress the importance of assessing the previous medical history, identifying patterns of symptoms and critically surveilling the clinical course. We implemented an algorithm for pediatric surgeons to consider MIS-C as a differential diagnosis for acute abdomen that can be integrated into the surgical workflow. Multisystem inflammatory syndrome in children (MIS-C) is a new disease associated with a recent and sometimes even inapparent infection with SARS-CoV-2 (severe acute respiratory syndrome coronavirus type 2) and has first been described in May 2020 ,2,3. ChiPreliminary disease definitions have been published in May 2020 by the World Health Organization (WHO), the Centers for Disease Control and Prevention (CDC) and the Royal College of Pediatrics and Child Health ,20,21. AIn the pediatric emergency room, children with severe abdominal symptoms represent a challenge for both the pediatrician and the pediatric surgeon. In children presenting with an acute abdomen a laparoscopy might be necessary to exclude surgical causes such as perforated appendicitis. Imaging in children with abdominal symptoms and MIS-C by both sonography and CT (computed tomography) scan cannot always clearly differentiate between MIS-C and appendicitis, since appendiceal thickening and ascites have been found in several patients . Due to Although abdominal ultrasound is routinely performed in most centers for suspected appendicitis, ultimate decision-making about laparoscopy still is clinical. Pediatric surgeons should therefore carefully consider MIS-C as a new differential diagnosis in children with acute abdomens.We present a case series of MIS-C in children that initially presented with abdominal symptoms and were treated surgically, but subsequently developed additional organ involvement typical of MIS-C. In order to intergrade this novel differential diagnosis into pediatric surgical evaluation of patients presenting with abdominal symptoms, we propose an algorithm to support surgical workflow.®6800) and serological testing by electrochemiluminescence immunoassay (ECLIA) with normal ranges according to the manufacturer.Case series of 3 pediatric patients admitted at the University Children’s Hospital Basel between November 2020 and February 2021. All patients underwent surgery due to suspected appendicitis and were eventually diagnosed with MIS-C. SARS-CoV-2 detection was performed according to our hospital’s guidelines with RT-PCR .We report the history of three school aged children with MIS-C. All initially presented with abdominal symptoms and underwent exploratory laparoscopy. The clinical characteristics of the described patients are summarized in A 9-year-old boy was admitted with a 5-day history of fever, vomiting, constipation and abdominal pain. Contact and travel history did not include any relevant features. On initial examination, he had stable vital signs, was afebrile, but in a reduced general state with a distended abdomen and severe abdominal tenderness. Chapped lips without conjunctivitis and a maculopapular exanthema were described by the parents.Laboratory work-up showed high inflammatory markers with CRP > 200 mg/L (<10 mg/L) and ESR 68/h (<10 mm/h), low white blood cell count of 5 G/L (4.5–13.5 G/L) with lymphopenia of 0.51 (1.5–6.8), low platelets of 96 G/L (150–450 G/L) and abnormal coagulation parameters with INR 1.3 (0.9–1.1) and fibrinogen of 8 g/L (1.7–4.1 g/L). He showed a hyponatremia of 130 mmol/L (132–145 mmol/L), low chloride ) and phosphate levels ), hypoalbuminemia ), and elevated LDH ), creatinine ) and urea ). Blood cultures were obtained but remained without bacterial growth. A negative PCR for SARS-CoV-2 from nasopharyngeal swab was obtained upon admission. Sonography showed free fluid and increased enlarged lymph nodes in the right lower quadrant with a thickened wall of the cecum and ascending colon. The appendix could not be visualized.Upon pediatric surgical evaluation there was the strong clinical suspicion of a perforated appendicitis with incipient sepsis. Consequently, a diagnostic laparoscopy was performed. Intraoperatively, the patient’s abdominal organs presented with diffuse hyperemia of the entire bowel with free fluid as well as a hyperemic inflamed appendix which was removed. Microbial swabs of the intraabdominal fluid were obtained, and empirical intravenous antibiotic treatment was started. Cultures from the abdominal fluid did not show bacterial growth. The appendix was subjected to histopathological examination, which identified mild signs of acute appendicitis with serositis .The early post-operative course was atypical of uncomplicated appendicitis, with persisting abdominal pain, inappetence and weakness, low urinary output and high levels of procalcitonin ), ferritin ), NT-proBNP ), D-dimers ) and troponin ) with normal creatine kinase on extended laboratory work-up. Given increasing suspicion of MIS-C, a SARS-CoV-2 serological evaluation on the 1st postoperative day detected IgM- and IgG-antibodies. In retrospect, the parents reported that the patient had been suffering from afebrile cough and rhinitis without loss of smell or taste 4 weeks previously but was not tested for SARS-CoV-2 at that time.At the point of diagnosis, the patient was transferred to intensive care due to hypotension and tachycardia. Antibiotic therapy was stopped. Echocardiography on admission to intensive care showed normal cardiac function and no other abnormalities. Steroid therapy with intravenous dexamethasone and thrombosis prophylaxis with low molecular weight heparin was started. The patients’ vital signs normalized within the subsequent 24 h without the need for catecholamines and he improved clinically. After stabilization, the patient was transferred to the pediatric unit. Dexamethasone therapy was stopped after 10 days. Thrombosis prophylaxis was suspended as soon as the patient was sufficiently mobilized. He was discharged in good condition after a hospital stay of 20 days.A 7-year-old boy who presented to a secondary care hospital initially was transferred to our hospital with a febrile syndrome that included a differential diagnosis of appendicitis and MIS-C. He presented with fever for 3 days as well as vomiting, inappetence and abdominal pain. One month before, he had been diagnosed with a SARS-CoV-2 infection. On clinical examination he was in good general condition, febrile, with stable vital signs, but with diffuse abdominal tenderness.Bacteroides vulgatus. Histopathology showed a chronic inflammation with focal lesions of acute inflammation. On the first postoperative day, the patient developed a new maculopapular rash in the right gluteal region, bilateral conjunctivitis and chapped lips.Abdominal sonography showed enlarged lymph nodes in the lower right quadrant, but the appendix could not be identified. The patient was monitored, with new ascites detected on ultrasound the following day, as well as persistent abdominal pain. Again, the patient underwent exploratory laparoscopy with an intraoperative finding of an inflamed appendix and subsequent appendectomy. Microbiological cultures of the abdominal fluid grew On account of the unusual pre- and post-operative presentation, an extended laboratory workup was performed despite the intraoperative finding of appendicitis. This confirmed elevated CRP ), ferritin ), D-dimers ), NT-proBNP ), initially normal troponin levels, hypoalbuminemia ) and positive IgG-antibodies for SARS-CoV-2. Echocardiography and sonography did not show any dilated cardiac or abdominal arteries but bilateral basal pleural effusions. Treatment with intravenous immunoglobulins (IVIG), corticosteroids and aspirin were started. Due to increasing levels of NT-proBNP ) and newly rising troponin ), the patient was transferred to our hospital’s intensive care unit. Here, thrombosis prophylaxis was changed from aspirin to low molecular weight heparin, empirical intravenous antibiotic cover was escalated to cover a possible intraabdominal infection, steroid therapy was continued and IVIG was stopped.After 3 days on the intensive care unit, the patient was sufficiently stabilized and could be transferred to the regular ward. Steroid therapy could be stopped 6 days after first administration and thrombosis prophylaxis after 8 days. He was discharged in good condition 12 days after being first admitted.An 8-year-old girl presented to the emergency room with abdominal pain for one week, fever for two days as well as diarrhea and vomiting. Her parents had been tested positive for SARS-CoV-2 six weeks prior, but she had not been symptomatic then. She was tachycardic but normotensive and afebrile. Laboratory evaluation showed elevated inflammatory markers with CRP 240 mg/L (<10 mg/L) and leukocytosis of 14 G/L (4.5–13.5 G/L). On clinical examination there was diffuse abdominal tenderness, worst in the right lower quadrant, and discrete guarding. There were no apparent skin or mucosal changes. Sonography showed inflammation of the terminal ileum, free abdominal fluid, lymphadenopathy and fatty tissue imbibition. An appendicitis could not be excluded, and free abdominal fluid suggested possible perforation, so the patient underwent exploratory laparoscopy.Intraoperatively, the appendix did not show signs of inflammation, the small intestine was mildly dilated and filled with fluid, and small amounts of free turbid fluid were found in the Douglas’ space. No appendectomy was performed. Analysis of the free fluid and of the blood cultures did not show microbial growth. Based on intraoperatively excluded appendicitis and the known SARS-CoV-2 infection of the patient’s parents, laboratory workup was extended and showed normal cardiac parameters, elevated D-dimers ), fibrinogen ), INR ), low prothrombin time ), high ferritin ) and hypoalbuminemia ). Serologies for SARS-CoV-2 were positive as was PCR with a low viral load. Clinically, the patient always presented with stable vital signs but with ongoing abdominal pain. She was transferred to the pediatric ward and treated with IVIG and corticosteroids. Due to rising NT-proBNP ) with normal troponin levels, an echocardiography was performed which was normal. A prophylaxis with low-dose aspirin was initiated. The patient was discharged 5 days after admission in a good state of health with oral corticosteroids for another week and oral aspirin prescribed for 6 weeks.With regard to the increasing prevalence of children with a history of SARS-CoV-2-infection, MIS-C as a differential diagnosis is of increasing importance for the pediatric surgeon. The three cases clearly demonstrate that MIS-C can present in slightly different variations of the same surgical problem—suspected appendicitis. Patient one suffered from an inflammation of large parts of the intestine, including the appendix. The second patient presented with an isolated appendicitis simultaneously occurring with MIS-C. Additionally, the third patient only suffered from an acute abdomen due to MIS-C without signs of appendicitis. In patient 1, histopathology showed signs of mild appendicitis. Whether a mild appendicitis triggers MIS-C or whether the hyperinflammatory state of children with MIS-C results in infiltration of inflammatory cells in the terminal ileum is not yet understood ,25.Next to surgical causes such as acute or even perforated appendicitis, non-surgical problems such as gastroenteritis, yersiniosis with lymphadenitis mesenterialis or inflammatory bowel disease, and less common causes such as Kawasaki disease should be taken into consideration in the differential diagnosis of abdominal pain with inflammatory signs. In our patients, there was no histological proof of Yersinia enterocolitica, as usually performed. Due to the findings confirming the differential diagnosis of MIS-C, as well as quick response to adequate treatment, no further search for other causes was carried out.Appendicitis has been described as the presenting manifestation of Kawasaki disease (KD) ,27. DigeMIS-C was first described in May 2020 and typically presents as a hyperinflammatory state with fever, abdominal pain, mucocutaneous lesions, cardiac dysfunction, hypotension and activated clotting system that occur four to six weeks after primary COVID-19 infection . HoweverOnly a few cases of children diagnosed with MIS-C that underwent surgery due to suspected and perforated appendicitis have been reported ,29. The As the pandemic proceeds, the share of children with a history of COVID-19 is growing. These may be children who were exposed and not tested, but increasingly also children with a known positive PCR. Our case presentations clearly demonstrate the need for surgeons to consider MIS-C as a differential diagnosis, even when surgery is indicated and indeed when appendicitis is identified on laparoscopy. We therefore suggest an algorithm for the pediatric surgeon to consider MIS-C in the surgical workflow preoperatively, intraoperatively and postoperatively .Preoperatively, MIS-C should be considered as a differential diagnosis if the child with abdominal pain does not seem to match the typical clinical phenotype of acute or perforated appendicitis; if clinical examination reveals mucocutaneous lesions; if the family reports persistent fever and if a SARS-CoV-2 infection within the last four to six weeks can be confirmed or is strongly suspected. In these children, we suggest performance of additional laboratory tests other than inflammatory parameters, namely coagulation laboratory  as well as liver enzymes, ferritin, creatinine and cardiac parameters .Intraoperatively, MIS-C should be considered as a differential diagnosis if the findings do not match the macroscopic appearance of an acute or perforated appendicitis, if a generalized gastrointestinal inflammation is seen, or if after careful exploration no reason for the abdominal pain can be found. Postoperatively, MIS-C should be considered as a differential diagnosis if the child does not recover within a reasonable timeframe after surgery or presents with new clinical signs described in the case definitions, such as skin or mucosal abnormalities ,20,21. T


Patients with autoimmune arthritis (AA) are at increased risk for impaired cardiac function and heart failure. This may be partly due to the effect of inflammation in heart function. The impact of antirheumatic drugs on cardiac dysfunction in AA remains controversial. Therefore, we aimed to examine effects of antirheumatic treatment on serum N-terminal pro-brain natriuretic peptide (NT-proBNP) in AA patients and its relationship to inflammatory markers.We examined 115 patients with AA (64 rheumatoid arthritis (RA), 31 psoriatic arthritis and 20 ankylosis spondylitis) starting with methotrexate (MTX) monotherapy or tumor necrosis factor inhibitors (TNFi) with or without MTX co-medication. NT-proBNP (measured in serum by ECLIA from Roche Diagnostics), and other clinical and laboratory parameters were evaluated at baseline, after 6 weeks and 6 months of treatment.baseline-6weeks = 0.939; pbaseline-6months = 0.485), although there was a modest improvement from 6 weeks to 6 months in the MTX only treatment group . There was no difference in the effects of MTX monotherapy and TNFi regimen on NT-proBNP levels. The changes in NT-proBNP after antirheumatic treatment positively correlated with changes in C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Baseline NT-proBNP levels were related to baseline CRP and ESR levels, and some other established markers of disease activities in crude analyses.NT-proBNP levels did not change significantly after 6 weeks and 6 months of antirheumatic therapy (pCirculating levels of NT-proBNP were related to established inflammatory markers at baseline, and the changes in NT-proBNP after antirheumatic treatment were positively related to these markers. Nevertheless, antirheumatic therapy did not seem to affect NT-proBNP levels compared to baseline, even though inflammatory markers significantly improved. Autoimmune arthritis (AA) such as rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are characterised by excess mortality and morbidity from cardiovascular (CV) events, but this association is not fully explained by traditional risk factors ,2. PatieBrain natriuretic peptide (BNP) is produced by cardiomyocytes mainly in response to their stretch due to volume or pressure overload. On secretion, it splits into biologically active BNP and the remaining N-terminal proBNP (NT-proBNP), which is biologically inactive and more stable than BNP . NT-proBThe impact of biologics and other disease-modifying anti-rheumatic drugs (DMARDs) on CV risks has been investigated in the literature, more extensively in RA as compared to other inflammatory arthritis. Several studies have addressed that tumor necrosis factor inhibitors (TNFi) therapy might improve the cardiac function by lowering the overall inflammatory state, thus slowing down the process of coronary atherosclerosis and subsequently decreasing the risk of developing HF in AA –23. HoweTherefore, the main aim of this study was to examine if antirheumatic treatment in form of Methotrexate (MTX) and TNFi with or without MTX co-medication (TNFi±MTX) affects NT-proBNP levels in AA, and if NT-proBNP levels were related to inflammatory markers.A total of 140 patients with active AA were enrolled in the PSARA (Psoriatic arthritis (n = 40), Ankylosing spondylitis (n = 26), Rheumatoid Arthritis (n = 74)) study at Lillehammer Hospital for Rheumatic Diseases between October 2008 and March 2012.The inclusion criteria for AA group were: age 18–80 years; fulfilling diagnostic criteria for AS by the modified New York diagnostic criteria , ModifiePatients were examined at baseline and after 6 weeks and 6 months of treatment. Of all included patients (n = 140), 115 completed the 6 months follow-up. Reasons for dropout were side-effects (n = 12), insufficient treatment response (n = 11), hepatitis C (n = 1) and loss to follow-up (n = 1).All patients had active disease, and there was indication for starting treatment, either with MTX and/or TNFi-treatment . Medicines were administrated in common recommended doses according to clinical judgment performed by a rheumatologist not involved in this study, in accordance with the Norwegian guidelines that adhere to the main international recommendations –33.Based on the guidelines, all patients starting with TNFi regimen had been previously unsuccessfully treated with MTX. Most of these patients continued to use MTX during TNFi treatment due to the standard protocols, in particular to reduce potential immunological side-effects of TNFi . TNFi waAll patients underwent physical examination by a rheumatologist and completed self-reported questionnaires for evaluation of their disease activity and severity adequate for their condition such as Disease Activity Score for 28 joints (DAS28), Medical health Assessment Questionnaire (MHAQ), Physicians’ Global Assessment Score of disease activity (PGA), Patients’ Global Assessment Score of disease activity (PtGA), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing Spondylitis Metrology Index (BASMI).Demographic data, medical history, life-style parameters and medication were recorded.Endothelial function was assessed by the Reactive Hyperaemia Index (RHI) , measureVenous blood samples were drawn after fasting for eight hours. Routine hematologic and biochemical tests including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), white blood cells (WBC), anti-citrullinated protein antibody (ACPA) and Rheumatoid Factor IgM (RF-IgM) were performed at the local hospital laboratory on the day of collection at all visits. ACPA and RF-IgM were determined by enzyme-linked immunosorbent assays (ELISA), .Additional blood samples for later analyses  were immediately prepared, divided into small aliquots, and stored at −80°C until analyzed. Before analysis of NT-proBNP used in the current study (in April 2020), samples were deep-frozen for median time of 10.4 years , minimal and maximal time of 8.2 and 11.7 years, respectively.Serum concentrations of NT-proBNP were determined by electrochemiluminescence on a Roche cobas e 411, using the Elecsys proBNP II assay (Roche Diagnostics), which uses two monoclonal antibodies, and recognizes epitopes located in the N-terminal part (1–76) of proBNP (1–108). This assay provides valid measurement of NT-proBNP in a range of 5–35000 ng/L. The interassay variability ranges from 1.8%–4.2% and the intraassay variability ranges from 1.2%–4.6%. The NT-proBNP analysis was performed at Vestre Viken Hospital Trust, Drammen, Norway, in a standardized manner, in random order, by assessors blinded for the clinical data.The cut-off value for identification and exclusion of chronic HF in adults is 125 ng/L for the used test kit, as determined by the manufacturer, and in accordance to the recommendations from The European Society of Cardiology Guidelines . At thisThresholds for high NT-proBNP concentrations  according to age and sex are described in Continuous data were expressed as median (interquartile range [IQR]) and categorical data by number (percentage) as appropriate. As most continuous variables were not normally distributed, and particularly because the NT-proBNP measurements contained several extreme values, median regression was applied for comparisons between and within groups. Median regression is analogous to linear regression but provides inference about medians instead of means. The median regression models used the Hall-Sheather bandwidth method as the nonparametric density estimator under the assumption that the residuals are independent and identically distributed. Spearman’s rank-order coefficients, with 95% confidence intervals based on the Fisher Z transformation, were calculated to evaluate correlations between NT-proBNP, AA- and CV related variables at baseline, after 6 weeks and 6 months of antirheumatic treatment. The multiple regression models were adjusted for age and gender (as age and gender are known to influence NT-proBNP levels) and for the baseline characteristics that were statistically significantly related to NT-proBNP in simple regression analysis.A two-tailed probability value of p < 0.05 was considered statistically significant. For statistical calculations we used Stata/SE 16 .The study was registered in “Clinical Trials” (NCT00902005), and the Norwegian Biobank register (2054). The study protocol was approved by The Norwegian Regional Committee for Medical Research Ethics (S-07377b), and all the research participants gave written informed consent.Baseline clinical and cardiovascular characteristics of patients are shown in Tables 2, median cholesterol was 5.2 mmol/L, 14.8% had hyperlipidemia, one third of all the patients (32.2%) smoked, 3.5% had diabetes mellitus, none of the patients had known/symptomatic HF and 13.3% reported previous CV diseases (CVD)  (Median BMI was about 26 kg/mdisease) . The PsAdisease) .Associations between NT-proBNP and selected clinical and laboratory variables at baseline are shown in Median baseline NT-proBNP was 49.6 ng/L [IQR 83.8]. Total, 21 (18.1%) patients presented an NT-proBNP > 125 ng/L which is the cut-off generally set for chronic HF, but only 7 (6.1%) patients had a value above the cut-off value for chronic HF estimated from the distribution of NT-proBNP at the reference laboratory according to age and gender .In crude analyses, NT-proBNP levels positively correlated with ESR and MHAQ in the total patient cohort, and with CRP and DAS28 in patients treated with MTX monotherapy. However, only association with CRP remained significant after adjustment for age and gender .There was no significant difference in NT-proBNP levels between female and male patients, or between patients treated with MTX monotherapy and those treated with TNFi±MTX. No difference in circulating levels of NT-proBNP was observed between ACPA-positive and ACPA-negative patients (data not shown). PsA patients had statistically significantly lower baseline NT-proBNP compared to RA patient  . When acThere was no statistically significant difference in the effect of MTX monotherapy and TNFi±MTX treatment on NT-proBNP levels in RA and PsA patients .Changes in NT-proBNP and some selected markers of diseases activity are shown in Associations of changes in NT-proBNP with changes in selected clinical and laboratory variables after 6 weeks and 6 months of antirheumatic treatment are shown in Tables There was observed a weak association between changes in NT-proBNP and changes in CRP levels after 6 weeks of antirheumatic treatment . ChangesOur data showed a statistically significant association between baseline NT-proBNP and systemic inflammatory markers like CRP and ESR, and the changes in NT-proBNP after antirheumatic treatment positively correlated with changes in these markers, which is in accordance with findings of other studies –17,35. THowever, in contrast to inflammatory and clinical parameters, initiation of MTX or MTX combined with an TNFi in RA and PsA patients and TNFi monotherapy in AS patients, was not related to reduction in circulating levels of NT-proBNP during our 6-month follow-up study. One may expect that reduction of inflammation in AA patients would lower circulating NT-proBNP levels, but a direct effect of antirheumatic therapy on NT-proBNP could not be ruled out in the present study. There are few explanations for this instance.First, this could have been due to the low prevalence of cardiac dysfunction in term of NT-proBNP , and the median values for serum NT-proBNP at baseline is low, indicating a normal cardiac wall tension. Therefore, improvement of NT-proBNP may have been underpowered.Second, as the development of HF is a progressive, chronic process before symptom onset, it is also possible that the duration of follow-up of 6 months was too short a time period to uncover impactful changes on levels of NT-proBNP. Moreover, we cannot rule out that NT-proBNP changes would become manifest if antirheumatic therapy occurred at later pre-symptomatic stages of left ventricular dysfunction at a time when NT-proBNP levels are known to be higher. The impact of therapy in patients with the highest quartile of NT-proBNP levels compared to the lowest would be of future interest to explore in larger studies.Third, although the main regulatory mechanism for synthesis and secretion of BNP is distension of ventricular cardiomyocytes, several mechanisms, such as neuroendocrine activation and systemic inflammation, may ultimately contribute to upregulation of BNP in myocardium ,36. FishThus, in contrast to some previous studies which showed the cardioprotective effect of anti-inflammatory treatment –23, our Furthermore, in this study we found that circulating levels of NT-proBNP were significantly lower in patients with PsA compared to RA patients. There is ample evidence that RA and PsA exhibit independent risks of HF. Recently, Ahlers et al. revealed that patients with RA were at 21% greater risk of HF independent of traditional CV risk factors, compared to non-RA controls . In anotHowever, it is still unknown whether the increased HF risk is similar between RA and PsA. Further studies are warranted to investigate if RA patients really have higher NT-proBNP levels and consequently increased occurrence of subclinical HF than patients with PsA.Several limitations need to be acknowledged. First, our study has limitations mainly related to the observational design of the study. Weaknesses include lack of a healthy control group. The choice of therapy was made by the rheumatologists and patients, which could result in selection bias or confounding by indication. In our study, patients starting TNFi had significant longer disease duration and had failed synthetical DMARDs before switching. However, withholding treatment with proven efficacy from clinically eligible patients or giving medication with considerable side effects (such as MTX and TNFi) to healthy controls poses ethical problems. Second, the relatively small sample sizes increase the risk of Type-II errors, and might lead to underestimation of real differences and associations. Third, although NT-proBNP is a well-established predictor of future CV risk in general populations with and without CVD, with high sensitivity and specificity and strong positive predictive values ,14,44, nOn the other hand, the strength in the study is a well-characterized study population and design which made it feasible to compare the effect of the two antirheumatic treatment regimens on circulating levels of NT-proBNP in AA.In conclusion, our data demonstrated an association between inflammation and cardiac function in terms of NT-proBNP. Nevertheless, the results did not show improvement in NT-proBNP levels in response to antirheumatic therapy over 6 months, although there was a small improvement from 6 weeks to 6 months. Importantly, there was no worsening of this surrogate measure of HF, even though inflammatory markers significantly improved. As patients with AA may be at risk for cardiac dysfunction and future CV events, further research is needed to define if NT-proBNP might be a good biomarker for predicting HF in AA patients.S1 Table(DOCX)Click here for additional data file.S1 FileStata file containing all data underlying the findings described in this study.(DTA)Click here for additional data file.


What is the association between the Hospital-Acquired Conditions Present on Admission program by the Centers for Medicare & Medicaid Services pay-for-performance program and surgical care quality and costs?In this cross-sectional study, the Hospital-Acquired Conditions Present on Admission program was associated with a decreased incidence of surgical site infection (0.3 percentage points) in the targeted procedures and a reduction in length of stay (0.5 days) and hospital costs (8.1%). Deep vein thrombosis and in-hospital mortality did not improve.The findings of this study suggest that the pay-for-performance program was associated with improvement on several dimensions of surgical care, including small reductions in surgical site infection and length of stay, and moderate reductions in hospital costs. Surgical complications increase hospital costs by approximately $20 000 per admission and extend hospital stays by 9.7 days. Improving surgical care quality and reducing costs is needed for patients undergoing surgery, health care professionals, hospitals, and payers.To evaluate the association of the Hospital-Acquired Conditions Present on Admission (HAC-POA) program, a mandated national pay-for-performance program by the Centers for Medicare & Medicaid Services, with surgical care quality and costs.A cross-sectional study of Medicare inpatient surgical care stays from October 2004 through September 2017 in the US was conducted. The National Inpatient Sample and a propensity score–weighted difference-in-differences analysis of hospital stays with associated primary surgical procedures was used to compare changes in outcomes for the intervention and control procedures before and after HAC-POA program implementation. The sample consisted of 1 317 262 inpatient surgical episodes representing 1 198 665 stays for targeted procedures and 118 597 stays for nontargeted procedures. Analyses were performed between November 1, 2020, and May 7, 2021.Implementation of the HAC-POA program for the intervention procedures included in this study .Incidence of surgical site infections and deep vein thrombosis, length of stay, in-hospital mortality, and hospital costs. Analyses were adjusted for patient and hospital characteristics and indicators for procedure type, hospital, and year.P = .02) compared with nontargeted procedures. The program was associated with a reduction in length of stay by 0.5 days  and hospital costs by 8.1% . No significant changes in deep vein thrombosis incidence and mortality were noted.In our propensity score–weighted sample, the intervention procedures group comprised 1 047 351 (88.5%) individuals who were White and 742 734 (60.6%) women; mean (SD) age was 75 (6.9) years. The control procedures group included 94 715 (88.0%) individuals who were White, and 65 436 (60.6%) women; mean (SD) age was 75 (7.1) years. After HAC-POA implementation, the incidence of surgical site infections in targeted procedures decreased by 0.3 percentage points (95% CI, −0.5 to −0.1 percentage points; The findings of this study suggest that the HAC-POA program is associated with small decreases in surgical site infection and length of stay and moderate decreases in hospital costs for patients enrolled in Medicare. Policy makers may consider these findings when evaluating the continuation and expansion of this program for other surgical procedures, and payers may want to consider adopting a similar policy. This cross-sectional study examines the outcomes of Medicare patients who underwent surgery before and after implementation of the Hospital-Acquired Conditions Present on Admission program. This mandatory pay-for-performance (P4P) policy penalizes hospitals by no longer paying for the treatment of preventable complications developed during a patient’s hospitalization. The HAC-POA program targets 14 selected conditions; those directly related to surgery include foreign objects retained after surgery, surgical site infection (SSI) following coronary artery bypass graft, cardiac implantable electronic device, bariatric surgery, certain orthopedic procedures, and deep vein thrombosis (DVT) or pulmonary embolism following certain orthopedic procedures.6 a control group subject to spillover effects,7 and a short study period,8 have limited the evaluation of the HAC-POA program.Although it has been more than 10 years since the HAC-POA program was implemented, little is known about whether the program is associated with improved surgical care outcomes. Three studies have examined surgical outcomes associated with the HAC-POA program, but issues with study design, such as the absence of a comparison with the prepolicy period,The aim of this cross-sectional study was to evaluate the association between the HAC-POA program and surgical care quality and costs using a difference-in-differences method. Specifically, we examined surgical complications , length of stay (LOS), in-hospital mortality, and hospital costs among Medicare patients who underwent the HAC-POA–targeted surgical procedures compared with nontargeted procedures.International Classification of Diseases, Ninth Revision (ICD-9) and International Statistical Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) codes (eTable 1 in the STROBE) reporting guideline for cross-sectional studies.We used the National Inpatient Sample of the Healthcare Cost and Utilization Project (HCUP) from October 2004 through September 2017 to examine the association between the HAC-POA program and the incidence of SSI and DVT, LOS, in-hospital mortality, and hospital costs. The unit of analysis was an episode of inpatient surgical care, defined as the hospital stay with its accompanying events associated with the primary surgical procedure. We identified the primary surgical procedure using 12 (2) transfers from other facilities,13 (3) observations with surgical complications as the first diagnosis ,14 (4) hospitals with fewer than 30 observations for each procedure to avoid unstable estimates due to small sample size,15 (5) hospital stays not paid by Medicare and not subject to the HAC-POA program ,16 and (6) observations with missing information on key study variables. Our sample consisted of Medicare-covered inpatient surgical care, representing 1 198 665 hospital stays for targeted procedures and 118 597 stays for nontargeted procedures. We applied several exclusion criteria: (1) maternal or neonatal inpatient services because the risk of complications and treatment management differs in these populations due to pregnancy-related physiologic changes,17 By comparing outcomes between the intervention and control procedures, the influence of potential confounders, such as using electronic health records to enhance the care process and other efforts to improve quality, is removed, as long as the association with targeted and nontargeted procedures is stable over time. The control group was selected from procedures not affected by the CMS policy. We selected laparoscopic cholecystectomy and laparoscopic appendectomy procedures as control groups because these procedures have similar average outcome levels , total knee arthroplasty, and total hip arthroplasty. We excluded coronary artery bypass graft from the targeted procedures because coronary artery bypass graft was targeted by other P4P programs , making it difficult to isolate the association with HAC-POA. We selected surgical procedures not targeted by the HAC-POA program (henceforth control procedures) from hospitals that performed both targeted and nontargeted procedures. Outcomes in these procedures indicate what would have happened to the targeted procedures (henceforth intervention procedures) without the policy.ICD-9 and ICD-10-CM codes , measured dichotomously for each episode using 26 Although the HAC-POA launched in the fourth quarter of 2007 , the payment implication of the HAC-POA program for the intervention procedures included in this study began in the fourth quarter of 2008 .To measure the association between the HAC-POA program and surgical patients’ outcomes, we used a propensity score–weighted difference-in-differences analysis, a statistical technique that compares changes in an outcome for intervention and control procedures before and after the policy implementation . To estimate hospital costs, linear regression with a log-transformed cost outcome was used, as used in other studies.32 Length of stay was analyzed using negative binomial regression to allow for overdispersion. All models controlled for patient and hospital characteristics and indicators for procedure type, year, and hosptial. Patient characteristics included race/ethnicity , sex, age, median household income for patient’s zip code by quartile, and 29 indicators from the modified Elixhauser comorbidity index. Race/ethnicity was categorized into 5 groups: White, Black, Hispanic, Asian/Pacific Islander, and other. The Asian and Pacific Islander populations were aggregated into a single category as collected by the HCUP. The individual categorized as Native American, multiracial individual, and other were combined into a single category (“other”) because of the small sample size. Hospital characteristics included bed size , ownership (public or private), location and teaching status , log-transformed surgical volume for each hospital, and type of admission (elective and nonelective).We began by estimating propensity score weights for 4 groups To determine whether hospitals may have shifted charges to patients without complications to compensate for potential charge penalties in the surgical complication group, we also estimated costs in linear probability models for stays with and without complications using a 3-way interaction (policy indicator × postpolicy indicator × complication indicator) between the difference-in-differences estimator and the indicator for patients with and without complications  in the noncomplication group. Additional details on these analyses are provided in eMethods in the We conducted a series of sensitivity analyses to assess the robustness of results. These analyses included alternative regression specifications, such as using logistic regression to model surgical complications and mortality and a 1-part generalized linear model with γ distribution and log link to model hospital costs.P < .05. Analyses were performed between November 1, 2020, and May 7, 2021 using Stata MP, version 15.1 (StataCorp).All analyses were estimated with robust SEs clustered by hospital to account for patients in the same hospital. We applied survey weights to obtain nationally representative estimates and account for HCUP’s complex survey designs. Statistical significance was assessed with a 2-sided significance level of Our sample included 1 317 262 inpatient surgical episodes representing 1 198 665 stays for intervention procedures and 118 597 stays for control procedures. In our propensity score–weighted sample, the intervention group included 1 047 351 (88.5%) individuals who were White and 742 734 (60.6%) women; the mean (SD) age was 75 (6.9) years. The control group included 94 715 (88.0%) individuals who were White and 65 436 (60.6%) women; the mean (SD) age was 75 (7.1) years. P = .02). The HAC-POA program was also associated with a significant reduction in LOS of 0.5 days  and hospital costs . The HAC-POA program was, however, not associated with a reduction in DVT incidence  and mortality .To better understand the outcomes of the policy and validate methodologic assumptions, we graphed outcomes over time . CovariaSensitivity analysis showed consistent results across study outcomes, indicating benefits in association with the policy. First, we estimated the likelihood of surgical complications and mortality with average marginal effects using logistic regression and hospital costs with a generalized linear model. The results were nearly identical to those from the linear probability models . To address this issue, we used propensity score weighting to remove substantial differences in the composition of each group. We also performed a series of sensitivity analyses, including difference-in-differences analysis with group-specific time trends49 and analyses using synthetic control methods36 to address selection bias across time and across group and confirmed the robustness of our main results. But there remains a potential for confounding from unmeasured time-variant changes. Third, the difference-in-differences model is susceptible to unobserved time-varying confounding, and we cannot rule out confounding from contemporaneous policies implemented during this study period  and affected the surgical procedures and outcome measures under study. Fourth, hospital costs related to the implementation of the P4P intervention, such as hiring and training staff to oversee program implementation, could not be assessed in these data. Hospital payments are also specific to the service and payer; thus, hospital-specific cost-to-charge ratios may not fully capture the true costs of specific services. Fifth, although the HCUP, a large-scale data set, has been widely used in health care research, it is reported to have a moderate amount of missing data, especially patient race and ethnicity variables, that may bias the estimates.50 To address the concerns about missingness, we used a conditional multiple imputation by chained equation50 and found consistent results. Sixth, this study was based on administrative data, which rely on self-reported complications, and thus inherits limitations in coding practice changes. To minimize this limitation, we adjusted for time effects in our modeling, but the potential for confounding from coding practice change remains and the observed association might be overestimated.This study has several limitations. First, the observed associations with the implementation of the HAC-POA program may be overestimated owing to undetected or underreported surgical complications. The HCUP data only capture SSIs and DVTs detected during hospitalization and not those occurring after discharge.51 likely because health care professionals and hospitals are more responsive to losses than gains.52 Although the incidence of surgical complications is low, the costs of complications are high, and our findings suggest that not paying for hospital-acquired infections might successfully encourage hospitals and health care professionals to improve care for surgical patients. Policy makers can use these findings when evaluating the continuation and expansion of this P4P program for the CMS. Other payers also may want to consider implementing similar policies.Our study found evidence suggesting improved surgical care related to the implementation of CMS’s national P4P program using a penalty design. Penalties have recently become popular in P4P programs,


In March 2020, residents of the Bronx, New York experienced one of the first significant community COVID-19 outbreaks in the United States. Focusing on intensive longitudinal data from 78 Bronx-based older adults, we used a multi-method approach to (1) examine 2019 to early pandemic (February-June 2020) changes in momentary psychological well-being of Einstein Aging Study (EAS) participants and (2) to contextualize these changes with community distress scores collected from public Twitter posts posted in Bronx County. We found increases in mean loneliness from 2019 to 2020; and participants that were higher in neuroticism had greater increases in thought unpleasantness and feeling depressed. Twitter-based Bronx community scores of anxiety, depressivity, and negatively-valenced affect showed elevated levels in 2020 weeks relative to 2019. Integration of EAS participant data and community data showed week-to-week fluctuations across 2019 and 2020. Results highlight how community-level data can characterize a rapidly changing environment to supplement individual-level data at no additional burden to individual participants. Since the onset of the COVID-19 pandemic, individuals and communities have had to adapt to the evolving public health threat. Existing literature has observed increased psychological distress, anxiety, and negative affect among individuals across the pandemic period overall . HoweverWe investigated these changes in psychological well-being from two perspectives: within-person change from a 2019 pre-pandemic baseline to 2020 during the early spike in cases in the New York City area, as well as community-level change over this period in the same area. For this study, the community was defined as a geographic community, specifically Bronx County. To examine within-person change, we used data from the Einstein Aging Study (EAS), an ongoing longitudinal measurement burst study . The EASAlthough some studies have observed a general decline in psychological well-being over the pandemic period, recent research suggests that older adults may be somewhat protected against pandemic-related distress ,11, a fiTo capture this possible heterogeneity in older adults’ psychological well-being during the early pandemic, personality traits and mild cognitive impairment (MCI) measured prior to the pandemic were examined as potential moderators. Extraversion and neuroticism were selected because of their relevance to psychological well-being and aging ,17. MCI Because the pandemic is an unfolding event with varying community public health restrictions, positivity rates, mortality rates, and individuals’ understanding of risk, making conclusions from longitudinal data can be complicated. Real-time alignment with community context is needed to understand such a dynamic event, but few data lend themselves to quantitative study at a large scale. Identifying the “start” of an unfolding event in a community can be difficult, and in the absence of an external gauge, any pre-pandemic to during-pandemic change detected could be due to numerous sources . Thus, to “triangulate”  the likeTo construct well-being scores representing the surrounding Bronx community in which EAS participants resided, we extracted features from public Twitter posts made by Bronx County users during the time periods when EAS participants completed their measurement bursts. The Twitter posts that were assessed were not composed by EAS participants, but rather Twitter users in Bronx County during the time of EAS data collection. Past work has shown that Twitter users can be reliable “canaries in the coal mine” for community well-being ,21. For Lastly, we compared the individual and community. This novel approach of contextualizing individual-level EMA reports with Twitter community markers is uniquely suited to address questions about psychological well-being during a rapidly evolving community-level event. During the early months of 2020, COVID-19 information and risks were rapidly changing, but the way that these larger community changes impacted individuals is unknown. Given the many ways individuals interact with their communities, for psychological and other health researchers understanding the participants’ community environment may provide available, no-burden, and invaluable, but overlooked data on the impact of a shared threat.EAS participants were recruited through systematic random sampling from Medicare and New York City Registered Voter Lists for Bronx County . CollectEAS follows more than 300 participants with follow-up scheduled across the calendar year. To provide the clearest examination of possible initial pandemic effects, this analysis focused on 78 EAS participants who completed a 14-day EMA burst prior to and during the initial COVID-19 outbreak . Language based assessments were conducted on publicly available Twitter posts from the 2019 and 2020 weeks that overlapped with EAS data collection. These posts were created by users whose IDs were mapped to Bronx County following a previously validated approach . This stRetweets and messages containing URLs were excluded because these contain non-original content. The relative frequencies of words and phrases were then extracted and input to artificial intelligence-based models of constructs detailed below. This approach used validated algorithms which extract features  from the language patterns, and then find reliable associations between combinations of features and established self-report scales, such as personality measures of the construct –30.Although EAS participants were not necessarily Twitter users, the posts provide information on the conversations occurring within the Bronx community in which the EAS participants resided, during the same periods when participants were completing their EMA bursts. Twitter was selected as the social media platform for three reasons. First, past work has identified COVID-19 related topics among Tweets . Second,Individual difference measures. Individual difference measures used in this analysis were assessed in 2019. Personality. Participants completed the Big Five Inventory , p = .006) significantly increased from 2019 to 2020. Trait neuroticism moderated within-person changes in thought unpleasantness and depressive feelings. Specifically, those higher in neuroticism increased more in thought unpleasantness  and feeling depressed  from 2019 to 2020 relative to those lower in trait neuroticism  was significant in 87.2% of the 1,000 simulated datasets with a sample size of 10 participants. This suggests a relatively robust effect observed in the full dataset for within-person change in loneliness. This process was repeated for the models that showed significant COVID onset X neuroticism effects. For the thought unpleasantness outcome, the COVID onset X neuroticism effect was significant in 66.4% of the 1,000 simulated datasets with a sample size of 10 participants. For the feeling depressed outcome, the COVID onset X neuroticism effect was significant in 66.5% of the 1,000 simulated datasets with a sample size of 10 participants.Figs r = -.19, p = .31 in 2019 and r = .09, p = .70 in 2020. The correlation between weekly scores of depressivity was r = -.24, p = .19 in 2019 and r = .39, p = .10 in 2020. The correlation between weekly scores of affect and mood valences was r = .21, p = .25 in 2019 and r = -.16, p = .52 in 2020.Individual-level EMA data were aggregated for each week in 2019 and 2020 for which data were available and aligned with community-level data. The correlation between the individual-level data on three outcomes  and the corresponding community-level data on each of these outcomes  were calculated for 2019 and 2020. Figs vs. lower) in neuroticism showed more within-person increases from 2019 to 2020 in momentary thought unpleasantness and feeling depressed. At the community-level, language analysis of Tweets from Bronx County where EAS participants resided showed declines in well-being. Specifically, higher anxiety and depressivity and more negatively valenced affect were observed in community Tweets in the majority of 2020 weeks relative to the same 2019 weeks. Finally, the topics revealed in word clouds derived from Twitter were also used to elucidate the week-to-week fluctuations observed in both the individual-level and the surrounding community across 2019 and 2020. These topics both support the interpretation of pandemic-related threats to well-being at both individual and community levels, as well as other major disruptions that occurred during 2020.This study presents a novel approach of contextualizing longitudinal changes in psychological well-being during the early COVID-19 pandemic by integrating individual-level EMA data with community-level indicators. At the individual-level, we found within-person increases in loneliness from 2019 to 2020 among EAS older adult participants. We also found that participants higher . Two participants’ data are not depicted in this graph because one participant completed their pre-COVID EMA burst in December 2018, another in October 2019. These participants’ observations, however, were included in the analyses of individual-level data. In the EMA portion of the results for this manuscript, we limited our 2020 time window to data completed during the week of June 13, 2020. Thus, the orange bars in panel B do not continue past the week of June 13. The x-axis extends beyond the 2020 data used in our analyses to show the EMA 2019 data collection, as well as to mirror the x-axis in the Twitter data.(TIF)Click here for additional data file.S1 TableResults of separate parallel two-level multilevel models are shown. A total of 7,329 observations from 78 participants were collected in 2019 and a total of 7,204 observations from 78 participants were collected in 2020. One participant did not complete the personality measures and thus these 197 observations were excluded from these models. The number of observations used in each model differs because each outcome was assessed at different frequencies. Thought unpleasantness and stress were assessed 6 times per day and thought control, worry, tense/anxious, lonely, depressed, and frustrated were assessed 5 times per day.(DOCX)Click here for additional data file.


Covid-19 infection may be associated with a higher incidence developing cardiovascular complications, however, the underlying mechanisms contributing to cardiovascular complications are largely unknown, while endothelial cell damage may be present. We want to report a 24-year-old woman with Covid-19 infection who had undergone measurements of vascular reactivity and arterial stiffness, including flow-mediated dilation (FMD), nitroglycerin-mediated dilation (NMD), aortic pulse wave velocity (PWV), augmentation index and carotid intima-media-thickness (cIMT) at the time when Covid-19 was diagnosed. Reduced FMD of 0.0% and NMD of 15.5% were observed, while PWV (5.9 m/s), Aix (27%) and cIMT with 0.4 mm of both common carotid arteries were unremarkable. Repeated measurements of FMD, NMD, PWV, Aix, and cIMT 6 weeks after Covid-19 infection revealed persistently reduced FMD (0.0%), while NMD (17.24%), PWV (5.6 m/s) and augmentation index (13%) ameliorated. This case suggests potential impact of Covid-19 infection on endothelial function, also in young Covid-19 patients without any co-morbidity. Patients with cardiovascular comorbidities have an increased risk of in-hospital death and Covid-19 infection may lead to a higher risk of cardiovascular complications like heart failure, venous thromboembolism or stroke . Althougal cells , 6. Furtal cells –9. We re2 without any known atherosclerotic risk factor and worked as a secretary for a medical office in a hospital. Additionally, she was a non-smoker without a family history of cardiovascular disease and did not take any medications. Due to governmental initiated shutdown in Austria from November 3rd, 2020 to December 23rd, 2020, the patient refrained from sports activities during that shutdown, but she was active with regular sport activity of 30 min three times a week prior to that shutdown.A 24-year-old woman underwent measurements of flow-mediated dilation (FMD), nitroglycerin-mediated dilation (NMD), pulse wave velocity (PWV), and carotid intima-media-thickness (cIMT) due to a preventive medical check-up at the beginning of December 2020. She was otherwise healthy, had a body-mass-index of 23.8 kg/mvia the oscillometric device Mobil-O-Graph®  by an automated analysis. A size-adjusted cuff was placed on the patient's left upper arm about 2-4 centimeters above the antecubital fossa in supine position and subsequent pulse-wave analysis was performed, while the patient did not to speak or move over the whole pulse-wave analysis. Also, during the same rest of 15 min, the patient underwent measurement of the cIMT of both common carotid artery in supine position using a high-resolution linear array probe with 8–13 MHz . The thickness of the intimal and medial layers of the common carotid wall was measured on frozen longitudinal images in at least one-centimeter-long segment of the artery. After that rest of 15 min, the diameter of the right brachial artery was recorded similar to the technique described for FMD before and 5 min after sublingual administration of 0.4 mg glyceryl trinitrate spray. FMD and NMD measurements were performed with an 8–13 MHz linear array transducer using a conventional ultrasound scanner . Most recommendations for the measurement of FMD and NMD were fulfilled according to recent guidelines  and quiet room by one trained technician. At the beginning of the FMD measurement, a blood pressure cuff was placed on the right forearm below the antecubital fossa and the baseline diameter of the right brachial artery was examined in a longitudinal plane between 2 and 7 centimeters proximal to the antecubital fossa in the patient. Three end-diastolic diameters between two intimal layers were measured ECG-gated during image acquisition in a one-centimeter-long segment of the brachial artery. Subsequently, the cuff was inflated >50 mmHg above the resting systolic pressure for 5 min, then deflated and 60 s after cuff release, the post-ischemic diameter of the brachial artery was measured. During a rest of 15 min, pulse-wave analysis including measurement of the aortic PWV and augmentation index was performed on the left arm and calculated idelines . The meaidelines . Pulse-wThe patient was asymptomatic at the time of the respective measurements without potential symptoms of Covid-19 infection or any other infection. One hour after the respective measurements, testing for Covid-19 by polymerase chain reaction (PCR) was performed in that patient due to a routine testing for hospital staff which confirmed an acute Covid-19 infection with a cycle threshold of 22. The initial physical examination including auscultation was unremarkable with a body temperature of 36.6°C and a blood pressure of 127/88 mmHg. Measurement of oxygen level and chest x-ray were not performed as the patient was asymptomatic without respiratory symptoms. There was only a slightly elevated C-reactive protein  without lymphopenia and lipid parameters were also normal. The patient was subsequently home-isolated and was advised to monitor her health. During home-quarantine, the patient developed headache and myalgia within the first 3 days, which were treated by acetaminophen on demand and resolved afterwards, followed by loss of taste and smell as well as by mild dyspnea on exertion after the fifth and seventh day of home quarantine, respectively. On the tenth day of quarantine, Covid-19 PCR was performed again with a cycle threshold of 26. The patient was asymptomatic after 20 days of initial Covid-19 PCR and repeated PCR testing for Covid-19 was negative on the 21st day after initial Covid-19 PCR. A timeline of patient's Covid-19 infection with symptoms and performance of Covid-19 PCR and clinical measurements are shown in Six weeks after initial Covid-19 testing, measurements for FMD, NMD, cIMT, and pulse-wave analysis were repeated by the same measurement methods as describes above evaluating changes of the respective parameters. FMD remained unchanged with 0.0% while NMD ameliorated to 17.24%. Furthermore, also PWV with 5.6% and augmentation index with 13% decreased while cIMT was unchanged.We demonstrated with our case a potential impact of Covid-19 infection on endothelial dysfunction. Prior investigations of endothelial changes in Covid-19 infection have demonstrated direct viral infection of endothelial cells and endothelial inflammation with microthrombi and microangiopathy , 12. As Underlying pathways by which SARS-CoV-2 may contribute to endothelial dysfunction are yet unknown. Our case and previous data suggest that both, direct cytotoxicity and indirect endothelial injury promote to endothelial dysfunction. Besides a potential but unlikely pathway of SARS-CoV-2 with ACE2 receptors, other pathways promoted by inflammatory mediators including interleukin-6 and prothrombotic mediators, like von Willebrand factor and neutrophil extracellular traps, may result in widespread inflammation and also in endothelial dysfunction , 17, 18.One limitation of our measurements was that we did not fulfill all recent recommendations for the assessment of FMD and NMD according to recent guidelines . RecommeOur case demonstrated that endothelial dysfunction may be present at a very early stage of Covid-19 infection and seems to be partly persistent even if SARS-CoV-2 is not detectable anymore. Our patient was asymptomatic at the time of verified Covid-19 infection when measurements of vascular reactivity and arterial stiffness were performed and symptoms occurred a few days later. It needs to be elucidated if parameters differ between asymptomatic and symptomatic patients as well as between patients with a different severity of symptoms. Furthermore, it needs to be elucidated if parameters of vascular reactivity and arterial stiffness remain altered as a long-term consequence of Covid-19 or if these changes may be present only in the acute phase of this infection. Moreover, studies evaluating parameters of vascular reactivity and arterial stiffness as potential predictors for cardiovascular events and mortality need to be performed.In conclusion, we could demonstrate that infection by SARS-CoV-2 may alter different parameters of vascular reactivity and arterial stiffness probably by causing direct and indirectly endothelial dysfunction, which may promote to cardiovascular complications in patients with Covid-19 infection. Further studies evaluating parameters of endothelial dysfunction are urgently needed.philipp.jud@medunigraz.at.The datasets presented in this article are not readily available because all data are listed within the article. Requests to access the datasets should be directed to Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.PJ and MB contributed to conception and design of the study. HK contributed to data analysis. PJ wrote the first draft of the manuscript. All authors contributed to manuscript revision.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.


IntroductionOvarian cancer is the fifth-leading cause of cancer-related mortality in US women. There are survival disparities between non-Hispanic black (NHB) and non-Hispanic white (NHW) women. We assessed if insurance status or extent of disease modified the effect of race/ethnicity on survival for ovarian cancer.MethodsA historical cohort was assembled using the 2007-2015 National Cancer Institute’s Surveillance, Epidemiology, and End Result (SEER) dataset. Adult NHB and NHW (>18 years) diagnosed with regional and distant ovarian cancer were included. The outcome was five-year cause-specific mortality. Multivariable Cox regression models were fitted, including race by the extent of disease and race by insurance status interaction terms.ResultsFor each significant interaction, separate Cox models were fitted. In total 8,043 women were included. The insurance status/race interaction was not statistically significant, but the extent of disease modified the effect of race on survival. NHB survival was lower in regional disease (adjusted hazard ratio (HR) =1.6; 95% confidence interval (CI) 1.1-2.4), while there was no difference in survival between women with distant disease .ConclusionsOvarian cancer mortality is similar between NHB and NHW women with the distant disease but higher in NHB women with regional disease. Further research should clarify whether this difference is due to access to quality cancer treatment or other factors affecting treatment response. In 2018 ovarian cancer accounted for 1.3% of all new cancer cases in the United States (US) with epithelial subtype representing 90% of all ovarian cancers [Despite marked improvements in ovarian cancer treatment, there continues to be a survival difference between non-Hispanic black (NHB) and non-Hispanic white (NHW) women. From 2000 to 2018, the 5-year relative survival in NHB women (22%) was lower than that of NHW women (29%) , 4. PropStudies consistently report lower survival among NHB women compared with NHW women -13 and sThe present study was designed to investigate whether the association between race/ethnicity with survival in NHB and NHW women with regional and distant epithelial ovarian cancer is modified by insurance status, and/or by extent of disease at diagnosis. We hypothesized that the direction and magnitude of the association between race and survival in women with epithelial ovarian cancer differs among subgroups defined by insurance status and/or extent of disease.Study designIn this secondary data analysis, we assembled a historical cohort using data from the 2007- 2015 Surveillance, Epidemiology, and End Results (SEER) database. Briefly, SEER is a surveillance system of the National Cancer Institute (NCI) that routinely collects information and publishes cancer incidence and survival data from population-based cancer registries, covering approximately 28% of the population in the United States. For ovarian cancer, the database defines regional disease as a disease confined to the pelvis, including the regional lymph nodes, and distant disease as spread from the primary tumor to distant organs, tissues, and/or non-regional lymph nodes. Localized disease cases, defined as confined to the ovary, were excluded due to the marked difference in survival and perhaps biology [ParticipantsThe study investigated US NHW and NHB women aged 18 and over with a single primary diagnosis and classified as regional or distant epithelial ovarian cancer initially diagnosed from 2007 to 2015. Other races and ethnicities were excluded to specifically analyze disparities between NHW and NHB women. Younger women (less than age 65 years) were categorized by age groups of 18-50 and 51-64 to delineate pre- and post-menopausal women, as 51 years is the average age of menopause in the United States . The SEEThe extent of disease was defined as regional or distant according to the SEER historic staging system rather than American Joint Committee on Cancer (AJCC) staging system, which was only available after 2010. Race/ethnicity groups other than NHW and NHB women were excluded from this study due to the low representative sample within the SEER database. The study also excluded participants who did not have information on race, staging, insurance status, survival, cases with the unknown or missing cause of death, cases with no information on survival time, and those cases in which the diagnosis of ovarian cancer was established after death (death certificate or autopsy), and therefore, had no survival time after diagnosis.VariablesThe exposure of interest in this study was race/ethnicity: non-Hispanic White (NHW) and non-Hispanic Black (NHB). The outcome was a 5-year cause-specific survival time, computed as the time from diagnosis to cause-specific death or to censoring . The potential effect modifiers included insurance status (uninsured/Medicaid or insured/nonspecific insured) and extent of disease. Potential confounders that were tested and eventually controlled for included age at diagnosis, histologic type, grade, marital status, and surgery.Grading was defined as low grade (grade 1 or 2), high grade (grade 3 or 4), or unknown grade (no information available). Marital status was defined as partnered if married or unmarried/domestic partner, and unpartnered if single, separated, divorced, or widowed. Surgery was defined as any kind of cancer-directed surgery. No specific information on the type of cancer surgery was available in the dataset. We did not adjust for hospital characteristics or volume or chemotherapy as they were not included in SEER.Statistical methodsWe profiled the distributions of the variables of interest and described the characteristics of the study population. Bivariate analysis was used to describe the distribution of variables according to exposure. Discrete control variables were compared using the Chi-square test. Patient 5-year cause-specific survival (CSS) was calculated using the Kaplan-Meier method. SEER defines cause-specific survival as a net survival measure representing the survival of a specified cause of death in the absence of other causes of death. It accounts for causes of death in conjunction with tumor sequence, site of the original cancer diagnosis, and comorbidities. Differences between survival times across groups were tested for statistical significance using the log-rank test. A two-sided p-value < 0.05 was considered statistically significant. Confounders were defined as factors that were found to be unevenly distributed between exposure groups and statistically associated with survival.A multivariable Cox regression model was fitted to compute and compare adjusted estimations of 5-year cause-specific mortality rates between NHB and NHW, adjusting for potential confounders. Potential first-order interaction terms (race-by-insurance status and race-by-extent of disease) were included and tested for significance. If significant interactions were found, only stratified models were presented. All statistical analyses were performed using Stata® 15.0 (StataCorp). EthicsThe study was considered non-human subjects research and therefore exempt from Institutional Review Board (IRB) review (IRB-20-0080).The 2007 to 2015 SEER dataset included 10,122 women over the age of 18 years diagnosed with regional or distant primary epithelial ovarian cancer. Of the 10,122 women with regional or distant epithelial ovarian cancer, 8043 met our inclusion criteria  were significantly different between NHB and NHW women. The NHB group had a greater proportion of women age 18-50 and 51-64 years, a larger proportion of unpartnered women, and a greater proportion of uninsured/Medicaid individuals , a difference that was also evident when comparing unadjusted survival functions by means of Kaplan-Meier curves Figure . A multiFor women with regional disease, NHB race was associated with a 90% increased death hazard (HR 1.9 95%CI 1.3-2.8), which decreased slightly but remained significant after adjustment (HR 1.6 95% CI 1.1-2.4). In contrast, for women with distant disease, and after adjusting for confounders there was no significant difference in the hazard rates  staging. This may make clinical application and comparison to other work challenging. Nevertheless, the local-regional-distant (LRD) staging system used by SEER is an internationally accepted standard for summarizing, reporting, and comparing cancer vital statistics . Lastly,In our study after adjustment, we found that NHB women had worse survival than NHW women with regional disease, but survival appeared to be similar between the two groups with distant disease. The disparity in survival between NHB and NHW women with regional ovarian cancer warrants further investigation. Detailed information regarding surgical and chemotherapy treatments should be collected. There should be further exploration of other effect modifiers of the association between race and survival in ovarian cancer, as they are not reported frequently in the literature. Other factors measuring access to care should be included to assess the effects of treatments based on the stage of the disease. The goal is to identify modifiable variables associated with the disparity in survival from ovarian cancer and intervene at a public health and policy level.There is a survival disparity between non-Hispanic black and non-Hispanic white women with advanced ovarian cancer. Insurance status was not a significant effect modifier of the association between race/ethnicity and survival. The extent of the disease, however, did significantly modify the association. Non-Hispanic black women have worse survival than non-Hispanic white women for regional disease; however, the survival appears to be similar between the two groups for distant disease. Access to quality cancer care and other factors may play a role in these findings.


NGs are essential to eliminate pathogens and promote the wound healing process. For this purpose, there is a need to release various pro- and anti-inflammatory mediators, some of which could ameliorate or enhance pain. However, the contribution of NGs to different pain entities is contradictory for reflex-based tests, and completely unknown in the context of non-evoked pain (NEP) and movement-evoked pain (MEP). First, we combined withdrawal reflex-based assays with novel video-based assessments for NEP- and MEP-related behavior in two mouse pain models. The pain models utilized in this study were incision (INC) and pathogen/adjuvant-induced inflammation (CFA), translating well to postsurgical and inflammatory pain entities. Second, we depleted NGs and applied a set of behavioral assessments to investigate the role of NG migration in different pain modalities. Our comprehensive behavioral approach identified pain-related behaviors in mice that resemble (NEP) or differentiate (MEP) behavioral trajectories in comparison to mechanical and heat hypersensitivity, thereby indicating modality-dependent mechanisms. Further, we show that injury-induced accumulation of NGs minimally affects pain-related behaviors in both pain models. In conclusion, we report a novel assessment to detect NEP in mice after unilateral injuries using a more unbiased approach. Additionally, we are capable of detecting an antalgic gait for both pain entities with unique trajectories. The different trajectories between MEP and other pain modalities suggest that the underlying mechanisms differ. We further conclude that NGs play a subordinate role in pain-related behaviors in incisional and inflammatory pain.In recent years, preclinical pain research has failed to develop genuinely new analgesics for clinical use. This fact is reflected by a high number of patients, limited drug efficacy accompanied by side effects, and a long-term opioid intake. Two main aspects have been addressed, which hinder translation: the use of non-relevant pain models and a mismatch between pain-related outcomes in preclinical and clinical studies. Conversely, disease-specific pain models that mirror more closely the clinical situation and multidimensional behavioral outcome measures that objectively and reproducibly assess relevant pain-related symptoms in a preclinical setting could improve translation. Mechanistically, a matter of debate is the role of Ly6G Although preclinical pain research has increased our understanding of pathophysiological mechanisms related to pain, there is still no major forthcoming initiative in developing effective and safe analgesics. As a result, many patients suffer from acute and chronic pain as current analgesics have limited efficacy and side effects. One reason that hampers the development of new treatment options is a translational gap from basic science to the clinical situation , 2. For In the field of multidimensional pain-related behavioral testing, there have been developments in the past two decades, which, on the one hand, addresses functional components, such as pain-related gait changes, and on the other hand, non-evoked pain- (NEP-) related behavior assessments , 8, 10. Here, we integrated canonical withdrawal reflex-based behavioral assays with novel video-based voluntary assessments of NEP-  and move+ neutrophil granulocytes (NGs) in both pain entities and modalities using a comprehensive multidimensional test battery. NGs represent a significant immune cell population rapidly recruited after injury or during inflammation (neutropenia)  . In addiropenia) . Thereforopenia) –17, and The experiments in this study were reviewed and approved by the Animal Ethics Committee of the State Agency for Nature, Environment, and Consumer Protection North Rhine-Westphalia , with the recommendations of the ARRIVE guidelines 2.0  and weren = 152 mice, 10–12 weeks, weight 26 ± (SD) 2.2 g] were kept in a 12/12 h day/night cycle with ad libitum access to food and water under standardized specific-pathogen-free (SPF) conditions . Additionally, the muscle was elevated and short-term retracted with forceps (Dumount #5)  . A mattrAs shown in previous studies, a CFA reaction was initiated by injecting 20 μl complete Freund's adjuvant  subcutaneously (s.c.) into the plantar aspect of the right hindpaw with a 27-gauge Hamilton microsyringe   injection of a purified anti-mouse Ly6G/GR-1 antibody . Starting 2 days before the induction of pain models, the Ly6G/GR-1 or IgG2b (as vehicle control) antibodies were applied every other day throughout the entire experimental period  was determined by the “percent response” method with a 60% withdrawal response , 23. CalThe paw withdrawal latency (PWL) to heat was explored using a Hargreaves box  . Here, mNon-evoked pain was determined by comparing the weight-bearing (print area) of the affected  with the non-affected paw  at rest  13). Ty. Ty13). Noldus Information Technology, Wageningen, Netherlands)  . Only paerlands) , 26:Print area: area of the whole pawStand duration: duration of ground contact for a single paw.Swing speed: rate at which a paw is not in contact with the glass plate.Stride length: length of one step.Inflammation is characterized by five cardinal signs: calor, tumor, rubor, dolor, and function laesa.Irbis Plus , leading to an average skin temperature of the ipsilateral hindpaw for each time point.A thermal imaging camera  visualized the skin temperature of the ipsilateral hindpaw at each time point. Under short-term isoflurane anesthesia, animals were positioned with free access to the right hindpaw. Out of one image, the temperature of three different locations on the plantar aspect was measured using Following the determination of the hindpaw temperature, the dorsoventral thickness of the ipsilateral hindpaw was examined using a sliding caliper still under short isoflurane anesthesia. Three measurements were taken to estimate the dorsal-ventral paw thickness in millimeters at each time point.n = 104), the expression of myeloperoxidase (MPO), an NG-specific enzyme, was determined by Western blotting to assess NG accumulation in the skin (epidermis and dermis) and muscle biopsies sampled from the plantar aspect of mice ipsilateral to the incision/CFA injection on six different time points after model induction (In cohort 1 (n = 48), mice injected with Ly6G/GR-1 antibody (n = 16) or IgG2b (n = 16) were assessed for behavioral phenotypes and macroscopic parameters in both pain models (n = 16), no antibody was treated. Pain-related behaviors and macroscopic parameters were assessed before (pre) and on different time points  after incision and CFA injection (In cohort 2 (njection . All behpost-hoc tests (a two-tailed Dunnett's test). After the Friedman and Kruskal–Wallis test, multiple comparisons were performed by a Dunnett's test (to the sham group) for non-parametric raw data. Spearman coefficients (two-tailed) were used to determine relationships between the multiple parameters. Correlation analyses were performed after first computing the mean of side-by-side replicates and then analyzing those means. The value of p < 0.05 was accepted as significant. All results are expressed as mean ± SEM.The results of the macroscopic parameters and MPO expression were analyzed by Kruskal–Wallis and Dunnett's multiple comparison tests. To achieve a better comparability of the individual behavioral data across the different pain modalities for this longitudinal study, mean changes in percent were calculated for NEP, PWT, and PWL . In the IgG2b-treated (vehicle) group, MPO peaked significantly at 6 h and 1 day in CFA but only 1 day post-INC the skin  . In IgG2†††p < 0.001), whereas PWT was unchanged in comparison to those injected with IgG2b. After CFA injection, the PWT in NG-depleted mice was only significantly decreased until day 2 in comparison to sham-treated mice and was significantly ameliorated at day 6 in comparison to IgG2b-control treatment. Heat hypersensitivity was ameliorated from day 3 after CFA injection compared to IgG2b-treated mice.Classical reflex-based withdrawal assays were used to determine the thresholds to mechanical stimuli (PWT) and the withdrawal latencies to heat stimuli (PWL) at the hind paw. In IgG2b-treated mice (vehicle group), PWT and PWL were significantly reduced by days 2 and 3 in INC animals, respectively . PWT and+ neutrophil depletion did not modulate NEP in both pain models. Sham-treated mice showed no changes in NEP  at rest. In this assay, NEP is represented by a decrease in the print area at rest of the ipsilateral paw. NEP was significantly reduced in both pain models starting in the acute phase (4–6 h) and remained significant until day 6 in the IgG2b-control mice group . Ly6G+ ns in NEP .+ neutrophil depletion did not significantly affect MEP in both pain models  also represents a relevant symptom in different pain diseases. With the CatWalk XT system, static and dynamic parameters of voluntary ambulatory gait are evaluated under standardized conditions to assess MEP. Two static (print area and stand duration) and two dynamic (swing speed and stride length) gait parameters known to be altered in unilateral pain models were selected to assess MEP . Both stn models .+ neutrophil depletion only showed marginal effects on pain-related behaviors in both pain models, we limited our analysis to mice receiving IgG2b. First, we performed a correlation analysis between macroscopic parameters and reflex-based withdrawal assessments to investigate a link between them (p = 0.07) for a negative correlation with PWT (p = 0.06) between PWT and paw edema in CFA-treated mice  and heat (PWL) hypersensitivity correlate with NEP or differ from MEP, suggesting overlapping and distinct underlying mechanisms, respectively. Further, we show that the depletion of Ly6GThe assessment of “pain” in rodents is a multidimensional approach and presently a matter of ongoing debate. Despite significant preclinical pain research efforts, a translational gap exists between pain-related outcomes in rodents and humans . This leIn line with previous findings in rats after plantar incision  and CFA-A correlation analysis of pain modalities may inform about the entity- and modality-specific mechanisms. We show here a significant correlation between mechanical and heat hypersensitivity in both pain entities. According to previous studies, it is clear that mechanical and heat hypersensitivity underlie different pathophysiological mechanisms , these p+ neutrophils in C57BL/6 mice. While Carreira et al. demonstrated a reduction of mechanical hypersensitivity after Ly6G+ neutrophil depletion post-incision  was used in this study. However, this antibody may deplete, albeit marginally . Based on these data, peripheral Ly6G+ neutrophils in the skin and muscle tissue are not a promising cellular target for developing novel analgetic options in these two pain entities. In the future, a multidimensional behavioral approach lays the foundation for examining new and revisiting known mechanisms for their translational potential to gain novel perspectives, providing potential valuable information for translation to the clinic.Here, we show that Ly6GThe original contributions presented in the study are included in the article/The animal study was reviewed and approved by Animal Ethics Committee of the State Agency for Nature, Environment and Consumer Protection North Rhine-Westphalia .DS contributed to the study design, developed and performed behavioral experiments, determined macroscopic parameters, analyzed behavioral data, and created illustrations. BP contributed to the analysis of behavioral data and the preparation of illustrations. SR contributed to the study design and performed behavioral experiments. LCS determined macroscopic parameters and performed behavioral experiments. EP-Z initiated and designed the study and supervised the experiments and the data analysis. DS, BP, and EP-Z wrote the manuscript. All other authors reviewed the manuscript.This study was supported (in part) by the Interdisciplinary Center for Clinical Research (IZKF) Münster, Grant Pog2/027/20 to EP-Z.In the last 5 years, EP-Z received financial support from Mundipharma GmbH and Grunenthal for research activities and from Grünenthal, MSD Sharp and DOHME GmbH, Mundipharma GmbH, Mundipharma International, Janssen-Cilag GmbH, Novartis AG, Fresenius Kabi, and AcelRx for advisory board activities and/or lecture fees. The remaining 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.