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JAMA Psychiatry ; 80(3): 211-219, 2023 03 01.
Article in English | MEDLINE | ID: covidwho-2208847


Importance: Concerns have been raised that the use of antipsychotic medication for people living with dementia might have increased during the COVID-19 pandemic. Objective: To examine multinational trends in antipsychotic drug prescribing for people living with dementia before and during the COVID-19 pandemic. Design, Setting, and Participants: This multinational network cohort study used electronic health records and claims data from 8 databases in 6 countries (France, Germany, Italy, South Korea, the UK, and the US) for individuals aged 65 years or older between January 1, 2016, and November 30, 2021. Two databases each were included for South Korea and the US. Exposures: The introduction of population-wide COVID-19 restrictions from April 2020 to the latest available date of each database. Main Outcomes and Measures: The main outcomes were yearly and monthly incidence of dementia diagnosis and prevalence of people living with dementia who were prescribed antipsychotic drugs in each database. Interrupted time series analyses were used to quantify changes in prescribing rates before and after the introduction of population-wide COVID-19 restrictions. Results: A total of 857 238 people with dementia aged 65 years or older (58.0% female) were identified in 2016. Reductions in the incidence of dementia were observed in 7 databases in the early phase of the pandemic (April, May, and June 2020), with the most pronounced reduction observed in 1 of the 2 US databases (rate ratio [RR], 0.30; 95% CI, 0.27-0.32); reductions were also observed in the total number of people with dementia prescribed antipsychotic drugs in France, Italy, South Korea, the UK, and the US. Rates of antipsychotic drug prescribing for people with dementia increased in 6 databases representing all countries. Compared with the corresponding month in 2019, the most pronounced increase in 2020 was observed in May in South Korea (Kangwon National University database) (RR, 2.11; 95% CI, 1.47-3.02) and June in the UK (RR, 1.96; 95% CI, 1.24-3.09). The rates of antipsychotic drug prescribing in these 6 databases remained high in 2021. Interrupted time series analyses revealed immediate increases in the prescribing rate in Italy (RR, 1.31; 95% CI, 1.08-1.58) and in the US Medicare database (RR, 1.43; 95% CI, 1.20-1.71) after the introduction of COVID-19 restrictions. Conclusions and Relevance: This cohort study found converging evidence that the rate of antipsychotic drug prescribing to people with dementia increased in the initial months of the COVID-19 pandemic in the 6 countries studied and did not decrease to prepandemic levels after the acute phase of the pandemic had ended. These findings suggest that the pandemic disrupted the care of people living with dementia and that the development of intervention strategies is needed to ensure the quality of care.

Antipsychotic Agents , COVID-19 , Dementia , Aged , Humans , Female , United States , Male , Antipsychotic Agents/therapeutic use , Pandemics , Cohort Studies , Medicare , Reflex
Clin Chem ; 68(7): 953-962, 2022 07 03.
Article in English | MEDLINE | ID: covidwho-2188630


BACKGROUND: Epstein-Barr virus (EBV) DNA detection in the nasopharynx is considered a biomarker for nasopharyngeal carcinoma (NPC). We evaluated its performance as a reflex test to triage EBV seropositives within an NPC screening program in China. METHODS: The study population was embedded within an ongoing NPC screening trial and included 1111 participants who screened positive for anti-EBV VCA (antibodies against EBV capsid antigens)/EBNA1 (EBV nuclear antigen1)-IgA antibodies (of 18 237 screened). Nasopharynx swabs were collected/tested for EBNA1 gene EBV DNA load. We evaluated performance of EBV DNA in the nasopharynx swab as a reflex test to triage EBV serological high-risk (those referred to endoscopy/MRI) and medium-risk (those referred to accelerated screening) individuals. RESULTS: By the end of 2019, we detected 20 NPC cases from 317 serological high-risk individuals and 4 NPC cases from 794 medium-risk individuals. When used to triage serological high-risk individuals, nasopharynx swab EBV DNA was detected in 19/20 cases (positivity rate among cases: 95.0%; 95% CI, 75.1%-99.9%), with a referral rate of 63.4% (201/317, 95% CI, 57.8%-68.7%) and NPC detection rate among positives of 9.5% (19/201, 95% CI, 5.8%-14.4%). The performance of an algorithm that combined serology with triage of serology high-risk individuals using EBV DNA testing yielded a sensitivity of 72.4% (95% CI, 3.0%-81.4%) and specificity of 97.6% (95% CI, 97.2%-97.9%). When used to triage EBV serological medium-risk individuals, the positivity rate among cases was 75.0% (95% CI, 19.4%-99.4%), with a referral rate of 61.8% (95% CI, 58.4%-65.2%) and NPC detection rate among positives of 0.6% (95% CI, 0.1%-1.8%). CONCLUSIONS: Nasopharynx swab EBV DNA showed promise as a reflex test to triage serology high-risk individuals, reducing referral by ca. 40% with little reduction in sensitivity compared to a serology-only screening program.

Epstein-Barr Virus Infections , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms , Antibodies, Viral , DNA , DNA, Viral , Epstein-Barr Virus Infections/diagnosis , Herpesvirus 4, Human/genetics , Humans , Immunoglobulin A , Nasopharyngeal Carcinoma/diagnosis , Nasopharyngeal Neoplasms/diagnosis , Nasopharynx , Reflex , Triage
J Physiol ; 600(20): 4383-4384, 2022 10.
Article in English | MEDLINE | ID: covidwho-2103171

Inflammation , Reflex , Humans
Mol Med ; 28(1): 57, 2022 05 16.
Article in English | MEDLINE | ID: covidwho-1846786


BACKGROUND: Severe COVID-19 is characterized by pro-inflammatory cytokine release syndrome (cytokine storm) which causes high morbidity and mortality. Recent observational and clinical studies suggest famotidine, a histamine 2 receptor (H2R) antagonist widely used to treat gastroesophageal reflux disease, attenuates the clinical course of COVID-19. Because evidence is lacking for a direct antiviral activity of famotidine, a proposed mechanism of action is blocking the effects of histamine released by mast cells. Here we hypothesized that famotidine activates the inflammatory reflex, a brain-integrated vagus nerve mechanism which inhibits inflammation via alpha 7 nicotinic acetylcholine receptor (α7nAChR) signal transduction, to prevent cytokine storm. METHODS: The potential anti-inflammatory effects of famotidine and other H2R antagonists were assessed in mice exposed to lipopolysaccharide (LPS)-induced cytokine storm. As the inflammatory reflex is integrated and can be stimulated in the brain, and H2R antagonists penetrate the blood brain barrier poorly, famotidine was administered by intracerebroventricular (ICV) or intraperitoneal (IP) routes. RESULTS: Famotidine administered IP significantly reduced serum and splenic LPS-stimulated tumor necrosis factor (TNF) and IL-6 concentrations, significantly improving survival. The effects of ICV famotidine were significantly more potent as compared to the peripheral route. Mice lacking mast cells by genetic deletion also responded to famotidine, indicating the anti-inflammatory effects are not mast cell-dependent. Either bilateral sub-diaphragmatic vagotomy or genetic knock-out of α7nAChR abolished the anti-inflammatory effects of famotidine, indicating the inflammatory reflex as famotidine's mechanism of action. While the structurally similar H2R antagonist tiotidine displayed equivalent anti-inflammatory activity, the H2R antagonists cimetidine or ranitidine were ineffective even at very high dosages. CONCLUSIONS: These observations reveal a previously unidentified vagus nerve-dependent anti-inflammatory effect of famotidine in the setting of cytokine storm which is not replicated by high dosages of other H2R antagonists in clinical use. Because famotidine is more potent when administered intrathecally, these findings are also consistent with a primarily central nervous system mechanism of action.

COVID-19 , Famotidine , Animals , Anti-Inflammatory Agents , Cytokine Release Syndrome , Famotidine/pharmacology , Histamine , Histamine H2 Antagonists , Lipopolysaccharides , Mice , Reflex , Vagus Nerve , alpha7 Nicotinic Acetylcholine Receptor
Nat Rev Immunol ; 20(8): 462-463, 2020 08.
Article in English | MEDLINE | ID: covidwho-1550302
Skin Res Technol ; 28(1): 54-57, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1455654


BACKGROUND: A histamine skin prick test (SPT) generally evokes a wheal and a flare. The present study was initiated by an observation that histamine did not evoke a flare around a wheal in the skin of an 86-year-old man. Could that be of relevance to the findings that old men are prone to a more severe COVD-19 infection with a higher mortality than young ones? MATERIALS AND METHODS: Histamine SPT was performed on the forearm of six old men, all above the age of 80. The skin reactions were photographed from above and from the side. The photographs taken from above were treated in a computer with LYYN, a program that increases color differences. With the help of ImageJ (NIH), the size relation between flare and wheal was calculated. On the photographs, taken as side views, areas, heights, and diameters of wheals were measured. Controls consisted of three groups of younger people. RESULTS: Among the old men, no or only a small flare was seen. All the controls had prominent flares. Histamine SPT evoked small wheals in the group of old men as compared to young men. CONCLUSION: Reduced neurogenic inflammation evoked by histamine from mast cells in blood and tissue may reduce the defense against COVID-19 infection.

COVID-19 , Neurogenic Inflammation , Aged, 80 and over , Histamine , Humans , Male , Reflex , SARS-CoV-2 , Skin , Skin Tests
Cardiovasc Res ; 117(4): 1015-1032, 2021 03 21.
Article in English | MEDLINE | ID: covidwho-1369073


The motivation for this review comes from the emerging complexity of the autonomic innervation of the carotid body (CB) and its putative role in regulating chemoreceptor sensitivity. With the carotid bodies as a potential therapeutic target for numerous cardiorespiratory and metabolic diseases, an understanding of the neural control of its circulation is most relevant. Since nerve fibres track blood vessels and receive autonomic innervation, we initiate our review by describing the origins of arterial feed to the CB and its unique vascular architecture and blood flow. Arterial feed(s) vary amongst species and, unequivocally, the arterial blood supply is relatively high to this organ. The vasculature appears to form separate circuits inside the CB with one having arterial venous anastomoses. Both sympathetic and parasympathetic nerves are present with postganglionic neurons located within the CB or close to it in the form of paraganglia. Their role in arterial vascular resistance control is described as is how CB blood flow relates to carotid sinus afferent activity. We discuss non-vascular targets of autonomic nerves, their possible role in controlling glomus cell activity, and how certain transmitters may relate to function. We propose that the autonomic nerves sub-serving the CB provide a rapid mechanism to tune the gain of peripheral chemoreflex sensitivity based on alterations in blood flow and oxygen delivery, and might provide future therapeutic targets. However, there remain a number of unknowns regarding these mechanisms that require further research that is discussed.

Arteries/innervation , Autonomic Nervous System/physiopathology , Cardiovascular Diseases/physiopathology , Carotid Body/blood supply , Hemodynamics , Oxygen/blood , Reflex , Animals , Autonomic Nervous System/metabolism , Cardiovascular Diseases/blood , Humans , Regional Blood Flow , Species Specificity
J Pediatr Rehabil Med ; 14(1): 1-3, 2021.
Article in English | MEDLINE | ID: covidwho-1314543

Reflex , Equipment Design , Humans
Ther Umsch ; 78(4): 181-186, 2021.
Article in German | MEDLINE | ID: covidwho-1201274


Cough from a cardiologic perspective Abstract. A cough is at the efferent end of a complex reflex arc and, due to its well-known mechanical respiratory cleaning function, usually the first symptom prompting a pneumological clarification. However, the chemical and mechanical afferent neuronal parts of the reflex, the cough receptors, are distributed over a variety of organ systems, some of which directly and indirectly affect the heart. Cardiology therefore plays a central role in the clarification of coughs. In cardiology, a cough is most frequently caused by acute and chronic heart failure resulting from different types of cardiomyopathies. It can, however, be caused by other pathologies as well. The connection between cough and cardiac arrhythmia is interesting, although cough can be cause, consequence and therapy. Last but not least, almost all drugs frequently prescribed in cardiology can cause cough in one way or another. In addition, a cough is the current number 1 warning sign when it comes to COVID-19 infection. On the one hand, it must be differentiated from cardiac-induced coughs, but on the other hand it can also be closely related to them.

COVID-19 , Cardiology , Cough/etiology , Humans , Reflex , SARS-CoV-2