Synthetic Cannabinoids: A Pharmacological and Toxicological Overview.

Synthetic cannabinoids (SCs) are a chemically diverse group of new psychoactive substances (NPSs) that target the endocannabinoid system, triggering a plethora of actions (e.g., elevated mood sensation, relaxation, appetite stimulation) that resemble, but are more intense than, those induced by cannabis. Although some of these effects have been explored for therapeutic applications, anticipated stronger psychoactive effects than cannabis and reduced risk perception have increased the recreational use of SCs, which have dominated the NPS market in the United States and Europe over the past decade. However, rising SC-related intoxications and deaths represent a major public health concern and embody a major challenge for policy makers. Here, we review the pharmacology and toxicology of SCs. A thorough characterization of SCs' pharmacodynamics and toxicodynamics is important to better understand the main mechanisms underlying acute and chronic effects of SCs, interpret the clinical/pathological findings related to SC use, and improve SC risk awareness.

Cannabinoid-mediated targeting of mitochondria on the modulation of mitochondrial function and dynamics.

Mitochondria play a critical role in the regulation of several biological processes (e.g., programmed cell death, inflammation, neurotransmission, cell differentiation). In recent years, accumulating findings have evidenced that cannabinoids, a group of endogenous and exogenous (synthetic and plant-derived) psychoactive compounds that bind to cannabinoid receptors, may modulate mitochondrial function and dynamics. As such, mitochondria have gained increasing interest as central mediators in cannabinoids' pharmacological and toxicological signatures. Here, we review the mechanisms underlying the cannabinoids' modulation of mitochondrial activity and dynamics, as well as the potential implications of such mitochondrial processes' disruption on cell homeostasis and disease. Interestingly, cannabinoids may target different mitochondrial processes (e.g., regulation of intracellular calcium levels, bioenergetic metabolism, apoptosis, and mitochondrial dynamics, including mitochondrial fission and fusion, transport, mitophagy, and biogenesis), by modulating multiple and complex signaling pathways. Of note, the outcome may depend on the experimental models used, as well as the chemical structure, concentration, and exposure settings to the cannabinoid, originating equivocal data. Notably, this interaction seems to represent not only an important feature of cannabinoids' toxicological signatures, with potential implications for the onset of distinct pathological conditions (e.g., cancer, neurodegenerative diseases, metabolic syndromes), but also an opportunity to develop novel therapeutic strategies for such pathologies, which is also discussed in this review.

The Synthetic Cannabinoids THJ-2201 and 5F-PB22 Enhance In Vitro CB1 Receptor-Mediated Neuronal Differentiation at Biologically Relevant Concentrations.

Recreational use of synthetic cannabinoids (SCs) before and during pregnancy poses a major public health risk, due to the potential onset of neurodevelopmental disorders in the offspring. Herein, we report the assessment of the neurotoxic potential of two commonly abused SCs, THJ-2201 and 5F-PB22, particularly focusing on how they affect neuronal differentiation in vitro. Differentiation ratios, total neurite length, and neuronal marker expression were assessed in NG108-15 neuroblastoma x glioma cells exposed to the SCs at non-toxic, biologically relevant concentrations (≤1 µM), either in acute or repeated exposure settings. Both SCs enhanced differentiation ratios and total neurite length of NG108-15 cells near two-fold compared to vehicle-treated cells, in a CB1R activation-dependent way, as the CB1R blockade with a specific antagonist (SR141718) abrogated SC-induced effects. Interestingly, repeated 5F-PB22 exposure was required to reach effects similar to a single THJ-2201 dose. Cell viability and proliferation, mitochondrial membrane potential, and intracellular ATP levels were also determined. The tested SCs increased mitochondrial tetramethyl rhodamine ethyl ester (TMRE) accumulation after 24 h at biologically relevant concentrations but did not affect any of the other toxicological parameters. Overall, we report firsthand the CB1R-mediated enhancement of neurodifferentiation by 5F-PB22 and THJ-2201 at biologically relevant concentrations.

Methodological quality of guidelines in gastroenterology.

BACKGROUND AND STUDY AIMS: Clinical guidelines are a common feature in modern endoscopy practice and they are being produced faster than ever. However, their methodological quality is rarely assessed. This study evaluated the methodological quality of current clinical guidelines in the field of gastroenterology, with an emphasis on endoscopy. MATERIALS AND METHODS: Practice guidelines published by the American College of Gastroenterology (ACG), American Gastroenterological Association (AGA), American Society for Gastrointestinal Endoscopy (ASGE), European Society of Gastrointestinal Endoscopy (ESGE), British Society of Gastroenterology (BSG), National Institute for Health and Care Excellence (NICE), and the Scottish Intercollegiate Guidelines Network (SIGN) were searched between September and October 2012 and evaluated using the AGREE II (Appraisal of Guidelines for Research and Evaluation) instrument (23 items, scores 1 - 7 for each item; higher scores mean better quality). RESULTS: A total of 100 guidelines were assessed. The mean number of items scoring 6 or 7 per guideline was 9.2 (out of 23 items). Overall, 99 % of guidelines failed to include the target population in the development process, and 96 % did not report facilitators and barriers to guideline application. In addition, 86 % did not include advice or tools, and 94 % did not present monitoring or auditing criteria. CONCLUSION: The global methodological quality of clinical guidelines in the field of gastroenterology is poor, particularly regarding involvement of the target population in the development of guidelines and in the provision of clear suggestions to practitioners.

Löfgren Syndrome: A Mosaic of Sarcoidosis Phenotypes.

Sarcoidosis is an autoimmune multisystemic granulomatous disease with an unknown etiology. Löfgren syndrome (LS), an infrequent initial presentation of acute sarcoidosis, is characterized by the classic triad of acute arthritis, erythema nodosum (EN), and bilateral hilar lymphadenopathy (BHL). The presence of this triad offers high diagnostic specificity for sarcoidosis, eliminating the need for a confirmatory biopsy. Typically, LS follows a predictable, self-limiting clinical course. However, atypical presentations require early suspicion and closer monitoring. This case report highlights an unusual clinical manifestation of LS, marked by an incomplete presentation with acute panniculitis and joint lesions in the absence of EN. Acute sarcoidosis should be considered among the differential diagnoses when these clinical manifestations are present, and chest radiography should be performed to rule out BHL. In atypical cases, the disease course becomes less predictable, as exemplified in our case, where recurrence of the disease may occur, necessitating consistent monitoring.

Cerebral Tuberculosis After Therapy With Adalimumab for Hidradenitis Suppurativa: A Rare Case.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with limited therapeutic options. Adalimumab, an anti-tumor necrosis factor-alpha (TNF-α) monoclonal antibody, was the first biological agent approved for the treatment of moderate to severe HS. Tuberculosis (TB) is a highly prevalent global public health problem, affecting individuals worldwide. Continuous immunosuppression from TNF-α treatment increases the risk of TB development. Isolated neurotuberculosis, in the absence of other symptoms, emerges as a rarely observed infection pattern in such patients. We present a case of a 23-year-old woman with severe HS undergoing treatment with adalimumab. After two years, she developed a pronounced occipital tension headache, constant nausea, and persistent fever. The patient's latent TB status was unknown without annual screening. Subsequent magnetic resonance imaging revealed a lesion in the cerebellar vermis. Immunosuppressive therapy was suspended and an etiological study was conducted; the only positive result was the interferon-gamma release assay. Empirically, antituberculosis treatment and prednisolone were initiated, leading to clinical and neurological improvement. After one year of treatment, symptoms resolved without neurological sequelae. This case highlights the importance of vigilant monitoring before, during, and after immunosuppressive treatment. Early recognition, discontinuation of anti-tumor necrosis factor medications, and appropriate management of TB are crucial to prevent complications.

Seroprevalence of antibodies against SARS-CoV-2 among health care workers in a Portuguese hospital.

Background: Health care workers (HCW) are presumably exposed to a higher risk of infection by SARS-CoV-2 and could possibly represent a source of transmission to susceptible patients. Thus, characterization of SARS-CoV-2 infection among HCW is necessary to better understand the determinants of viral transmission and properly implement strategies to prevent dissemination and protect HCW and vulnerable patients. The aim of this study was to estimate the seroprevalence of antibodies against SARS-CoV-2 in a Portuguese tertiary hospital, in the period of July 2020 to March 2021, before the generalized use of the SARS-CoV-2 vaccine, characterize its evolution over time, and identify risk factors associated with seroconversion. Methods: HCW were approached to collect serum samples for qualitative SARS-CoV-2 antibody testing and completion of an online survey capturing demographics, previous symptoms, and details of health care and community exposure. Odds ratio with bivariable and multivariable logistic regression was used to assess characteristics associated with seroprevalence. Results: One thousand HCW were included for analysis. Two hundred nineteen HCW (22%) were seropositive for immunoglobulin G against SARS-CoV-2, and 166 (17%) were seropositive for immunoglobulin M, most of whom reported a previous diagnosis of SARS-CoV-2 infection. The risk factors associated with seroconversion included a previous COVID-19 diagnosis, contact with patients, occupational contact with colleagues, and outside contact. However, in a multivariate logistic regression analysis, only a previous diagnosis and outside contact were associated with seroconversion. Seropositivity decreased over time, especially 28 weeks after infection. Conclusion: HCWs have a high seroprevalence for SARS-CoV-2 infection, probably due to a combination of health care and community exposure. Seropositivity decreases over time, but further studies are needed to better understand our adaptive immune response.

Surveillance of surgical site infection after colorectal surgery: comprehensiveness and impact of risk factors.

OBJECTIVE: The incidence of surgical site infection (SSI) is highest after colorectal surgery. We assessed the impact of risk factors for SSI using the population attributable fraction (PAF). DESIGN: Retrospective cohort study. SETTING: Portuguese hospitals performing regular surveillance. PATIENTS: We identified patients who underwent colorectal procedures in hospitals that reported colorectal surgeries every year between 2015 and 2019. Among 42 reporting hospitals, 18 hospitals were included. METHODS: Risk-factor incidence was estimated using the National Epidemiological Surveillance platform from 2015 to 2019. This platform follows the methodology recommended by the European Centre for Disease Prevention and Control. American Society of Anaesthesiologists (ASA) physical classification, wound classification, open surgery, urgent operation, antibiotic prophylaxis, operation time, and male sex were included as risk factors. Measures of association were retrieved from published meta-analyses. PAFs were calculated using the Levin formula. To account for interaction between risk factors, communality of risk factors was used in a weighted-sum approach, providing a combined value that serves as a measure of the comprehensiveness of surveillance. RESULTS: Among 11,219 reported procedures, the cumulative SSI incidence was 16.8%. The proportion of SSI attributed to all risk factors was 61%. Modifiable variables accounted for 31% of procedures; the highest was laparotomy (16.8%), and urgent operations (2.7%) had the lowest value. Nonmodifiable factors accounted for 28.7%; the highest was wound classification (14.3%). CONCLUSIONS: A relevant proportion (39%) of SSI remains unaccounted for by current surveillance. Almost one-third of SSI cases have potentially modifiable factors. Interventions focusing on shorter, less invasive procedures may be optimally effective in reducing the SSI incidence.

Antidotal effect of cyclosporine A against α-amanitin toxicity in CD-1 mice, at clinical relevant doses.

Amanita phalloides is one of the most toxic mushrooms worldwide, being responsible for the majority of human fatal cases of mushroom intoxications. α-Amanitin, the most deleterious toxin of A. phalloides, inhibits RNA polymerase II (RNAP II), causing hepatic and renal failure. Herein, we used cyclosporine A after it showed potential to displace RNAP II α-amanitin in silico. That potential was not confirmed either by the incorporation of ethynyl-UTP or by the monitoring of fluorescent RNAP II levels. Nevertheless, concomitant incubation of cyclosporine A with α-amanitin, for a short period, provided significant protection against its toxicity in differentiated HepaRG cells. In mice, the concomitant administration of α-amanitin [0.45 mg/kg intraperitoneal (i.p.)] with cyclosporine A (10 mg/kg i.p. plus 2 × 10 mg/kg cyclosporine A i.p. at 8 and 12 h post α-amanitin) resulted in the full survival of α-amanitin-intoxicated mice, up to 30 days after the toxin's administration. Since α-amanitin is a substrate of the organic-anion-transporting polypeptide 1B3 and cyclosporine A inhibits this transporter and is a potent anti-inflammatory agent, we hypothesize that these mechanisms are responsible for the protection observed. These results indicate a potential antidotal effect of cyclosporine A, and its safety profile advocates for its use at an early stage of α-amanitin intoxications.

Beyond the operating room: do hospital characteristics have an impact on surgical site infections after colorectal surgery? A systematic review.

BACKGROUND: Hospital characteristics have been recognized as potential risk factors for surgical site infection for over 20 years. However, most research has focused on patient and procedural risk factors. Understanding how structural and process variables influence infection is vital to identify targets for effective interventions and to optimize healthcare services. The aim of this study was to systematically review the association between hospital characteristics and surgical site infection in colorectal surgery. MAIN BODY: A systematic literature search was conducted using PubMed, Scopus and Web of Science databases until the 31st of May, 2021. The search strategy followed the Participants, Exposure/Intervention, Comparison, Outcomes and Study design. The primary outcome of interest was surgical site infection rate after colorectal surgery. Studies were grouped into nine risk factor typologies: hospital size, ownership affiliation, being an oncological hospital, safety-net burden, hospital volume, surgeon caseload, discharge destination and time since implementation of surveillance. The STROBE statement was used for evaluating the methodological quality. A total of 4703 records were identified, of which 172 were reviewed and 16 were included. Studies were published between 2008 and 2021, and referred to data collected between 1996 and 2016. Surgical site infection incidence ranged from 3.2 to 27.6%. Two out of five studies evaluating hospital size adjusted the analysis to patient and procedure-related risk factors, and showed that larger hospitals were either positively associated or had no association with SSI. Public hospitals did not present significantly different infection rates than private or non-profit ones. Medical school affiliation and higher safety-net burden were associated with higher surgical site infection (crude estimates), while oncological hospitals were associated with higher incidence independently of other variables. Hospital caseload showed mixed results, while surgeon caseload and surveillance time since implementation appear to be associated with fewer infections. CONCLUSIONS: Although there are few studies addressing hospital-level factors on surgical site infection, surgeon experience and the implementation of a surveillance system appear to be associated with better outcomes. For hospitals and services to be efficiently optimized, more studies addressing these variables are needed that take into account the confounding effect of patient case mix.

Validation of a semi-automated surveillance system for surgical site infections: Improving exhaustiveness, representativeness, and efficiency.

OBJECTIVES: To assess whether electronic records data could improve the efficiency, exhaustiveness, and representativeness of SSI surveillance by selecting a group of high-risk patients for manual review. METHODS: Colorectal surgeries (2016-2018) and cholecystectomies (2017-2018) were selected. Post-surgical antibiotic use, positive culture, C-reactive protein (CRP) values, body temperature, leukocyte count, surgical re-intervention, admission to the emergency room, and hospital readmission were retrieved. For representativeness, procedures registered in HAI-Net were compared with non-included procedures, and the validity of each variable (or combination) was tested considering the presence of SSI as the gold standard. The proportion of procedures flagged for manual review by each criterion was estimated. RESULTS: Little more than 50% of procedures were included in HAI-Net (SSI risk: 10.6% for colorectal and 2.9% for cholecystectomies). Non-included procedures showed higher proportions of infection markers. Antibiotic use and CRP >100 mg/dl presented the highest sensitivity for both surgical groups, while antibiotic use achieved the highest positive predictive value in both groups (22% and 21%, respectively) and flagged fewer colorectal procedures (47.7%). CONCLUSIONS: Current SSI surveillance has major limitations. Thus, the reported incidence seems unreliable and underestimated. Antibiotic use appears to be the best criterion to select a sub-sample of procedures for manual review, improving the exhaustiveness and efficiency of the system.

Ultrasound detects subclinical joint inflammation in the hands and wrists of patients with systemic lupus erythematosus without musculoskeletal symptoms.

OBJECTIVES: To assess the prevalence and severity of ultrasonographic abnormalities of the hand and wrist of asymptomatic patients with systemic lupus erythematosus (SLE) and compare these findings with those from patients with SLE with musculoskeletal signs or symptoms and healthy controls. METHODS: We conducted a prospective cross-sectional study that evaluated bilaterally, with grey-scale and power Doppler (PD) ultrasound (US), the dorsal hand (2nd to 5th metacarpophalangeal and 2nd to 5th proximal interphalangeal joints) and wrist (radiocarpal, ulnocarpal and intercarpal joints) of 30 asymptomatic patients with SLE, 6 symptomatic patients with SLE and 10 controls. Synovial hypertrophy (SH) and intra-articular PD signal were scored using semiquantitative grading scales (0-3). Individual scores were graded as normal (SH≤1 and PD=0) or abnormal (SH≥2 or PD≥1). Global indexes for SH and PD were also calculated. US findings were correlated with clinical and laboratory data and disease activity indexes. RESULTS: US detected SH (score ≥1) in 77% asymptomatic patients with SLE, mostly graded as minimal (score 1: 63%). 23% of the asymptomatic patients with SLE showed abnormal US PD findings (SH≥2 or PD≥1). SH was present in all symptomatic patients with SLE, mostly graded as moderate (grade 2: 67%), and with associated PD signal (83%). SH (score 1) was identified in 50% of controls, however, none presented abnormal US PD findings. SH index in the asymptomatic SLE group was higher than in the control group (2.0 (0-5) vs 0.5 (0-2), median (range), p=0.01) and lower than in the symptomatic SLE group (7.0 (4-23), median (range), p<0.001). No significant correlation was demonstrated between US PD findings and clinical or laboratory variables and disease activity indexes. CONCLUSION: A small subgroup of asymptomatic patients with SLE may present subclinical joint inflammation. Global US scores and PD signal may be important in disease evaluation and therapeutic monitoring.

A chest wall pulsating mass.

A 34-year-old HIV-positive man with intravenous drug addiction presented with a 2-week history of fever and a pulsatile presternal mass; 2 weeks prior he had suffered a traumatic sternal fracture. The CT scan showed a bulky abscess with presternal and retrosternal extension that contacted the heart (which explained its pulsatile effect) and pulmonary necrotising lesions. Drainage of the thoracic wall abscess was performed, and antibiotics (flucloxacillin plus gentamicin) were started on the presumption of staphylococcal bacteraemia given the patient's intravenous drug habit. Blood cultures and culture of the aspirated pus confirmed growth of methicillin-sensitive Staphylococcus aureus; transoesophageal echocardiography showed endocarditis of the tricuspid valve. We therefore assumed pulmonary septic embolisation from right-sided endocarditis and acute sternal osteomyelitis, and the patient was treated for 6 weeks with clinical resolution.

[Cerebral creatine deficiency syndromes]. / Síndromes de deficiência cerebral de creatina.

INTRODUCTION: Creatine deficiency syndromes are a recently described group of diseases characterized by inborn errors of creatine metabolism. Clinical features include a spectrum of neurodevelopment disorders of diverse severity. They are characterized by low levels of cerebral creatine caused by different pathogenic mutations concerning the genes coding for creatine synthesis enzymes [arginine: glicyne amidinotransferase (AGAT, EC 2.1.4.1) and guanidinoacetate methyltansferase (GAMT, EC 2.1.1.2)], AGAT and GAMT, respectively, or its transporter (CT1 deficiency), SLC6A8. Enzymatic deficiencies are transmitted as autosomal recessive traits, whereas the transporter deficit is X-linked. OBJECTIVES: To characterize the clinical and laboratorial presentation, diagnosis and treatment of cerebral creatine deficiency patients, followed in Hospital Pediátrico Carmona da Mota. The awareness of these inborn errors of metabolism as neurological disorders, namely of neurodevelopment, among the medical community is a secondary aim of the present work. METHODS AND MATERIAL: Retrospective analysis of the clinical files of patients followed in our Hospital and diagnosed with cerebral creatine deficiency syndrome. RESULTS: Twelve patients belonging to seven different families were diagnosed with creatine deficiency syndromes. Five presented GAMT deficiency and seven CT1 deficiency. Present ages are 2 to 38 years old. The most common clinical presentations were: global development delay in seven patients (two with epilepsy), and speech delay in two patients. Only one patient had communication and social interaction dysfunction. In all, global development delay in the range of intellectual delay was identified. The pathognomonic pattern of cerebral creatine deficiency in the brain image was demonstrated in eight patients. Pathogenic mutations in GAMT or SLC6A8 genes were identified in all cases. CONCLUSIONS: The suspicion of cerebral creatine depletion must be considered in all children presenting unexplained global psychomotor development delay. Pre-symptomatic therapy has shown promising results, especially in GAMT deficiency patients. The high rate of asymptomatic carriers of GAMT mutations in our population makes this disorder eligible to neonatal screening in Portugal.