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Viruses Nov 2023The aim of this study was to investigate the reinfection rates and characteristics of SARS-CoV-2 in individuals with SARS-CoV-2 RNA present in their clinical specimens...
The aim of this study was to investigate the reinfection rates and characteristics of SARS-CoV-2 in individuals with SARS-CoV-2 RNA present in their clinical specimens for COVID-19. Our data from the COVID-19 Laboratory of Istanbul University were analyzed for 27,240 cases between 27 March 2020 to 8 February 2022. Demographic characteristics, vaccination statuses, comorbidities, and laboratory findings were evaluated in cases with suspected reinfection, as determined by the presence of SARS-CoV-2 RNA at a rate of 0.3% in clinical specimens. When comparing laboratory values, leukocyte counts were lower in the second and third infections compared with the first infection ( = 0.035), and neutrophil counts were lower in the second infection ( = 0.009). Symptoms varied, with coughing being common in the first infection and malaise being common in subsequent infections. These results suggest that it is important to continue to monitor reinfection rates and develop strategies to prevent reinfection. Our results also suggest that clinicians should be aware of the possibility of reinfection and monitor patients for recurrent symptoms.
Topics: Humans; SARS-CoV-2; RNA, Viral; Reinfection; COVID-19; Cough
PubMed: 38005899
DOI: 10.3390/v15112222 -
Nature Communications Feb 2024Obesity, a global health challenge, is a major risk factor for multiple life-threatening diseases, including diabetes, fatty liver, and cancer. There is an ongoing need...
Obesity, a global health challenge, is a major risk factor for multiple life-threatening diseases, including diabetes, fatty liver, and cancer. There is an ongoing need to identify safe and tolerable therapeutics for obesity management. Herein, we show that treatment with artesunate, an artemisinin derivative approved by the FDA for the treatment of severe malaria, effectively reduces body weight and improves metabolic profiles in preclinical models of obesity, including male mice with overnutrition-induced obesity and male cynomolgus macaques with spontaneous obesity, without inducing nausea and malaise. Artesunate promotes weight loss and reduces food intake in obese mice and cynomolgus macaques by increasing circulating levels of Growth Differentiation Factor 15 (GDF15), an appetite-regulating hormone with a brainstem-restricted receptor, the GDNF family receptor α-like (GFRAL). Mechanistically, artesunate induces the expression of GDF15 in multiple organs, especially the liver, in mice through a C/EBP homologous protein (CHOP)-directed integrated stress response. Inhibition of GDF15/GFRAL signalling by genetic ablation of GFRAL or tissue-specific knockdown of GDF15 abrogates the anti-obesity effect of artesunate in mice with diet-induced obesity, suggesting that artesunate controls bodyweight and appetite in a GDF15/GFRAL signalling-dependent manner. These data highlight the therapeutic benefits of artesunate in the treatment of obesity and related comorbidities.
Topics: Mice; Male; Animals; Artesunate; Growth Differentiation Factor 15; Obesity; Primates; Macaca
PubMed: 38310105
DOI: 10.1038/s41467-024-45452-3 -
Journal of Clinical Medicine Jan 2024Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease characterized by profound fatigue, post-exertional malaise (PEM), and neurocognitive...
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease characterized by profound fatigue, post-exertional malaise (PEM), and neurocognitive dysfunction. Immune dysregulation and gastrointestinal symptoms are commonly observed in ME/CFS patients. Despite affecting approximately 0.89% of the general population, the underlying pathophysiological mechanisms remain poorly understood. This study aimed to elucidate the relationship between immunological characteristics and intestinal barrier function in ME/CFS patients. ME/CFS patients were stratified into two groups based on their immune competence. After documentation of detailed medical records, serum and plasma samples were collected for the assessment of inflammatory immune mediators and biomarkers for intestinal barrier integrity by ELISA. We found reduced complement protein C4a levels in immunodeficient ME/CFS patients suggesting a subgroup-specific innate immune dysregulation. ME/CFS patients without immunodeficiencies exhibit a mucosal barrier leakage, as indicated by elevated levels of Lipopolysaccharide-binding protein (LBP). Stratifying ME/CFS patients based on immune competence enabled the distinction of two subgroups with different pathophysiological patterns. The study highlights the importance of emphasizing precise patient stratification in ME/CFS, particularly in the context of defining suitable treatment strategies. Given the substantial health and socioeconomic burden associated with ME/CFS, urgent attention and research efforts are needed to define causative treatment approaches.
PubMed: 38202282
DOI: 10.3390/jcm13010275 -
Blood Advances Apr 2024The US Food and Drug Administration (FDA)'s authorization of etranacogene dezaparvovec (Hemgenix) is a significant milestone, constituting not only the first FDA... (Review)
Review
The US Food and Drug Administration (FDA)'s authorization of etranacogene dezaparvovec (Hemgenix) is a significant milestone, constituting not only the first FDA approval of a gene therapy for hemophilia but also the first approval of a liver-targeted adeno-associated virus vector gene therapy. This review summarizes the nonclinical studies and clinical development that supported regulatory clearance. Similar to other gene therapies for single gene disorders, both the short-term safety and the phenotypic improvement were unequivocal, justifying the modest-sized safety and efficacy database, which included 57 participants across the phase 2b (3 participants) and phase 3 (54 participants) studies. The most common adverse reactions included liver enzyme elevation, headache, flu-like symptoms, infusion-related reactions, creatine kinase elevation, malaise, and fatigue; these were mostly transient. One participant had hepatocellular carcinoma on a study-mandated liver ultrasound conducted 1 year after vector infusion; molecular analysis of the resected tumor showed no evidence of vector-related insertional mutagenesis as the etiology. A remarkable 96% of participants in the phase 3 trial were able to stop factor IX (FIX) prophylaxis, with the study demonstrating noninferiority to FIX prophylaxis in terms of the primary end point, annualized bleeding rate. Key secondary end points such as the annualized infusion rate, which declined by 97%, and the plasma FIX activity level at 18 months after infusion, with least squares mean increase of 34.3 percentage points compared with baseline, were both clinically and statistically significant. The FDA's landmark approval of Hemgenix as a pioneering treatment for hemophilia stands on the shoulders of >20 years of gene therapy clinical research and heralds a promising future for genomic medicines.
Topics: United States; Humans; Hemophilia B; Hemophilia A; Factor IX; Databases, Factual; Fatigue
PubMed: 38592711
DOI: 10.1182/bloodadvances.2023010511 -
Cancer Chemotherapy and Pharmacology Aug 2023Aberrant alterations of ERBB receptor tyrosine kinases lead to tumorigenesis. Single agent therapy targeting EGFR or HER2 has shown clinical successes, but drug...
A phase I trial of the pan-ERBB inhibitor neratinib combined with the MEK inhibitor trametinib in patients with advanced cancer with EGFR mutation/amplification, HER2 mutation/amplification, HER3/4 mutation or KRAS mutation.
PURPOSE
Aberrant alterations of ERBB receptor tyrosine kinases lead to tumorigenesis. Single agent therapy targeting EGFR or HER2 has shown clinical successes, but drug resistance often develops due to aberrant or compensatory mechanisms. Herein, we sought to determine the feasibility and safety of neratinib and trametinib in patients with EGFR mutation/amplification, HER2 mutation/amplification, HER3/4 mutation and KRAS mutation.
METHODS
Patients with actionable somatic mutations or amplifications in ERBB genes or actionable KRAS mutations were enrolled to receive neratinib and trametinib in this phase I dose escalation trial. The primary endpoint was determination of the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Secondary endpoints included pharmacokinetic analysis and preliminary anti-tumor efficacy.
RESULTS
Twenty patients were enrolled with a median age of 50.5 years and a median of 3 lines of prior therapy. Grade 3 treatment-related toxicities included: diarrhea (25%), vomiting (10%), nausea (5%), fatigue (5%) and malaise (5%). The MTD was dose level (DL) minus 1 (neratinib 160 mg daily with trametinib 1 mg, 5 days on and 2 days off) given 2 DLTs of grade 3 diarrhea in DL1 (neratinib 160 mg daily with trametinib 1 mg daily). The treatment-related toxicities of DL1 included: diarrhea (100%), nausea (55.6%) and rash (55.6%). Pharmacokinetic data showed trametinib clearance was significantly reduced leading to high drug exposures of trametinib. Two patients achieved stable disease (SD) ≥ 4 months.
CONCLUSION
Neratinib and trametinib combination was toxic and had limited clinical efficacy. This may be due to suboptimal drug dosing given drug-drug interactions.
TRIAL REGISTRATION ID
NCT03065387.
Topics: Humans; Middle Aged; Proto-Oncogene Proteins p21(ras); Antineoplastic Combined Chemotherapy Protocols; Neoplasms; Protein Kinase Inhibitors; Genes, erbB; Mutation; ErbB Receptors; Nausea; Diarrhea; Mitogen-Activated Protein Kinase Kinases; Receptor, ErbB-2
PubMed: 37314501
DOI: 10.1007/s00280-023-04545-4 -
JMIR Dermatology Sep 2023Psychogenic purpura is an idiopathic psychodermatologic condition of recurrent, painful purpura precipitated by psychological stress, predominantly affecting young... (Review)
Review
BACKGROUND
Psychogenic purpura is an idiopathic psychodermatologic condition of recurrent, painful purpura precipitated by psychological stress, predominantly affecting young females. Little consensus exists on the diagnostic guidelines for this rare condition, often resulting in costly, unnecessary, and stressful investigations as well as prolonged hospital admissions.
OBJECTIVE
With this first up-to-date systematic review of 134 cases of psychogenic purpura in over a decade, we aim to thoroughly investigate the diagnostic strategy and treatment regimens used in the last decade. With a sooner diagnosis, patient stress and nosocomial ecchymoses can be minimized, and treatment can be expedited.
METHODS
We conducted a literature review of 4 databases (PubMed, Ovid Embase, Ovid MEDLINE, and Web of Science) on October 5, 2022 that yielded 46 full-text articles, which were reviewed and extracted by 2 independent reviewers.
RESULTS
We analyzed a total of 134 cases, consisting largely of females (125/134, 93.3%) with purpura on the upper (103/134, 76.9%) or lower limbs (112/134, 83.6%). Apart from a paresthesia prodrome, patients commonly experienced headaches, malaise, and arthralgia or myalgia. Approximately 70% (95/134) of patients reported a physiological or psychological stressor or psychiatric diagnosis before the development of the purpura. Laboratory testing almost always revealed unremarkable results. The intradermal washed autoerythrocyte sensitization test was positive in 98% (42/43) of cases. Histopathology biopsy findings commonly revealed dermal erythrodiapedesis or hemorrhage (n=34) and perivascular inflammatory infiltrates (n=17). Approximately 42% (56/134) of patients received a novel psychiatric diagnosis, with depression being the most common (40/72, 56%). In both patients with and those without a novel psychiatric diagnosis, observation, counseling, treatment with antidepressants (ie, selective serotonin reuptake inhibitors), and psychotherapy (ie, cognitive behavioral therapy) prevailed in the resolution of the purpura.
CONCLUSIONS
Due to the unclear etiology and infrequent presentation of this condition, it remains a diagnosis of exclusion based on clinical suspicion evaluating the presence of stressors or psychiatric comorbidities and exclusion of systemic conditions. Clinical confirmation can be sought through a positive autoerythrocyte sedimentation test, characteristic histopathology findings, and remission of purpura after psychiatric treatment.
PubMed: 37703091
DOI: 10.2196/48153 -
Pathology, Research and Practice Aug 2023This paper aims to present a detailed overview of fibrolamellar carcinoma (FLC), a variant of hepatocellular carcinoma (HCC) that accounts for approximately 1-9% of all... (Review)
Review
This paper aims to present a detailed overview of fibrolamellar carcinoma (FLC), a variant of hepatocellular carcinoma (HCC) that accounts for approximately 1-9% of all cases a. according to the SEER database. Despite ongoing research, the aetiology of FLC tumours remains unclear. Nevertheless, FLC is believed to have a better overall prognosis than other primary liver tumours, such as hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma. This study aims to present a comprehensive overview of fibrolamellar carcinoma (FLC), with a focus on its epidemiology, pathogenesis, diagnosis, treatment, and prognosis. FLC frequently incorporate features of stomach pain, weight loss, and malaise in their clinical signs and symptoms, which are generally nonspecific Ultimately, the most common physical finding is an abdominal mass or hepatomegaly. With this said, several unusual presentations have been documented such as Budd Chiari syndrome, severe anaemia, non-bacterial thrombotic endocarditis and many more. In regards to this tumour's genetic analysis, it is characterised by a 400 kb deletion on chromosome 19 leading to a functional DNAJB1-PRKACA chimeric transcript in addition to tetraploidy in 50% of cases. FLC is chromosomally stable as compared to typical HCC. mTOR pathway activation has also been found to play a critical role in 47% of these tumours and EFGR over-expression is also evident. Fibrolamellar carcinomas (FLCs) exhibit a distinctive gross appearance, characterized by a yellow to pale tan colour, with a consistency that can vary from soft to firm and hard. In addition, a central scar is observed in 60-70% of FLC cases. The central scar is typically white or grey in colour and has a fibrous appearance, which is often surrounded by nodular, tumour-like tissue. Its histologic appearance is characterized by large polygonal cells with abundant eosinophilic cytoplasm, large vesiculated nuclei, large nucleoli, and arranged in lamellar bands of collagen fibres. Lamellar bands of fibrosis, consisting of collagen type I, III and IV, have also been identified as a distinctive histologic feature that is observed under low power magnification. Ultrasound, CT and MRI along with image guided biopsy are the primary modalities in diagnosis. Current management options include systemic therapy which has thus far been unremarkable with platinum-based therapies as well combination therapy with interferon alpha-2b being the most successful options. Surgical resection remains the primary treatment modality and there have been no advances in targeted therapies. Although the prognosis for FLC is favourable as compared to other hepatic cancer subtypes such as intrahepatic cholangiocarcinoma, there is a high rate of recurrence ranging from 33% to 100% with a median recurrence-free survival of 20-48 months. As a result of this there is a low overall cure rate associated with this tumour type and much more research is required to gain an in-depth understanding of the molecular mechanisms occurring in order to provide more adequate treatment to patients who suffer from this condition.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Cicatrix; Cholangiocarcinoma; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; HSP40 Heat-Shock Proteins
PubMed: 37429175
DOI: 10.1016/j.prp.2023.154655 -
BioRxiv : the Preprint Server For... Dec 2023The melanocortin-3 receptor (MC3R) acts presynaptically to regulate GABA release from agouti-related protein (AgRP) nerve terminals and thus may be a negative regulator...
The melanocortin-3 receptor (MC3R) acts presynaptically to regulate GABA release from agouti-related protein (AgRP) nerve terminals and thus may be a negative regulator of multiple circuits involved in feeding behavior and energy homeostasis. Here, we examined the role of MC3R in regulating the response to various anorexigenic agents. Our findings reveal that genetic deletion or pharmacological inhibition of MC3R improves the dose responsiveness to Glucagon-like peptide 1 (GLP1) agonists, as assayed by inhibition of food intake and weight loss. An enhanced anorectic response to other agents, including the acute satiety factors peptide YY (PYY) and cholecystokinin (CCK) and the long-term adipostatic factor, leptin, demonstrated that increased sensitivity to anorectic agents is a generalized result of MC3R antagonism. Enhanced neuronal activation in multiple nuclei, including ARH, VMH, and DMH, was observed using Fos immunohistochemistry following low-dose liraglutide in MC3R knockout mice (), supporting the hypothesis that the MC3R is a negative regulator of circuits regulating multiple aspects of feeding behavior. The enhanced anorectic response in mice after administration of GLP1 analogs was also independent of the incretin effects and malaise induced by GLP1R analogs, suggesting that MC3R antagonists may have value in enhancing the dose-response range of obesity therapeutics.
PubMed: 38106197
DOI: 10.1101/2023.12.05.570114 -
Cureus Sep 2023A lung abscess is characterized as a clinical ailment arising from the localized suppurative necrosis of lung parenchyma. This condition primarily results from the...
A lung abscess is characterized as a clinical ailment arising from the localized suppurative necrosis of lung parenchyma. This condition primarily results from the complications of aspiration pneumonia due to anaerobic microorganisms originating from the oral cavity. Clinically, patients typically manifest symptoms such as fever, malaise, and a productive cough persisting over several weeks. The majority of lung abscess cases acquired within the community stem from anaerobic bacterial infections, often exhibiting a polymicrobial nature. We present a 51-year-old female with intrapulmonary abscess and empyema, with isolation of species. She has a 25-pack-year smoking history. Two weeks prior to arrival at our facility, she experienced intermittent shortness of breath, fever, and subjective fever. Her primary care physician ordered an outpatient computed tomography (CT) which showed evidence of a large right-sided fluid collection. Initial chest X-ray at our facility revealed extensive opacification of the middle and right lower hemithorax, believed to be a large-sized pleural effusion with adjacent pneumonia or atelectasis. She was given a working diagnosis of right-sided empyema. Cardiothoracic surgery was consulted and video-assisted thoracoscopic surgery (VATS) was performed. A very large collection of grossly purulent material was evacuated and revealed a large intrapulmonary abscess. Over 400 cc of frank pus was collected and sent for microbiological analysis. Anaerobic culture demonstrated 3+ species and 3+ species. The genus consists of a small, strictly anaerobic, gram-negative cocci that lacks flagella, spores, and capsules. This genus obtains energy from the utilization of short-chain organic acids that are present in the oral cavity and intestinal tract. Oral is strongly associated with biofilms, causing human oral infectious diseases such as periodontitis and dental caries. Literature states that this organism has been isolated in a limited number of chronic pneumonitis cases. To date, the most common organism isolated from lung abscesses is in adult patients and in pediatric patients. We strive to elucidate the distinctive clinical presentation evident in this case, alongside a comprehensive understanding of the unusual pathogens identified in the disease's pathogenesis.
PubMed: 37842426
DOI: 10.7759/cureus.45210 -
Journal of Internal Medicine Nov 2023The long-term effects of COVID-19 on cognitive function have become an area of increasing concern. This paper provides an overview of characteristics, risk factors,... (Review)
Review
The long-term effects of COVID-19 on cognitive function have become an area of increasing concern. This paper provides an overview of characteristics, risk factors, possible mechanisms, and management strategies for cognitive dysfunction in post-COVID-19 condition (PCC). Prolonged cognitive dysfunction is one of the most common impairments in PCC, affecting between 17% and 28% of the individuals more than 12 weeks after the infection and persisting in some cases for several years. Cognitive dysfunctions can be manifested as a wide range of symptoms including memory impairment, attention deficit, executive dysfunction, and reduced processing speed. Risk factors for developing PCC, with or without cognitive impairments, include advanced age, preexisting medical conditions, and the severity of acute illness. The underlying mechanisms remain unclear, but proposed contributors include neuroinflammation, hypoxia, vascular damage, and latent virus reactivation not excluding the possibility of direct viral invasion of the central nervous system, illustrating complex viral pathology. As the individual variation of the cognitive impairments is large, a neuropsychological examination and a person-centered multidimensional approach are required. According to the World Health Organization, limited evidence on COVID-19-related cognitive impairments necessitates implementing rehabilitation interventions from established practices of similar conditions. Psychoeducation and compensatory skills training are recommended. Assistive products and environmental modifications adapted to individual needs might be helpful. In specific attention- and working memory dysfunctions, cognitive training-carefully monitored for intensity-might be effective for people who do not suffer from post-exertional malaise. Further research is crucial for evidence-based interventions specific to COVID-19-related cognitive impairments.
PubMed: 37766515
DOI: 10.1111/joim.13720