Clinical Consequences Research Articles

Pulmonary nodules and the psychological harm they can cause: A scoping review

More than 1.6 million pulmonary nodules are diagnosed in the United States each year. Although the majority of nodules are found to be benign, nodule detection and the process of ruling out malignancy can cause patients psychological harm to varying degrees. The present study undertakes a scoping review of the literature investigating pulmonary nodule-related psychological harm as a primary or secondary outcome. Online databases were systematically searched to identify papers published through June 30, 2023, from which 19 publications were reviewed. We examined prevalence by type, measurement, associated factors, and behavioral or clinical consequences. Of the 19 studies reviewed, 11 studies investigated distress, anxiety (n = 6), and anxiety and depression (n = 4). Prevalence of distress was 24.0 %-56.7 %; anxiety 9.9 %-42.1 %, and 14.6 %-27.0 % for depression. A wide range of demographic and social characteristics and clinical factors were associated with nodule-related psychological harm. Outcomes of nodule-related harms included experiencing conflict when deciding about treatment or surveillance, decreased adherence to surveillance, adoption of more aggressive treatment, and lower health-related quality of life. Our scoping review demonstrates that nodule-related psychological harm is common. Findings provide evidence that nodule-related psychological harm can influence clinical decisions and adherence to treatment recommendations. Future research should focus on discerning between nodule-related distress and anxiety; identifying patients at risk; ascertaining the extent of psychological harm on patient behavior and clinical decisions; and developing interventions to assist patients in managing psychological harm for better health-related quality of life and treatment outcomes.

Holter monitoring in neuromuscular disorders: frequency and importance in clinical management

Abstract Introduction Cardiac involvement is a common manifestation in a variety of neuromuscular disorders (NMD) and initial cardiac manifestations in these patients are often asymptomatic. Hence, regular 24h-Holter monitoring is recommended to identify conduction disturbances and rhythm disturbances. Purpose In this study, we aimed to assess abnormal findings in 24h-Holter monitoring to screen for conduction disturbances and arrhythmias in patients with NMD and evaluate its impact in patients’ treatment. Methods A retrospective single-centre study was conducted including all adult patients with NMD who received a 24h-Holter from January 2013 to September 2023. Results A total of 76 patients with NMD were included, 39 (51.3%) were male, and mean age was 46,3 ± 11,5 years. Most patients were asymptomatic. A total of 220 Holter recording was analysed. An average of 2,9 ± 1,6 Holter recordings per patient was performed. Abnormal Holter results were found in 47 (61,8%) patients, and mainly consisted of conduction disorders such as atrioventricular block in 31 (65,9%) patients. Other abnormalities included atrial fibrillation/flutter in 6 (12,8%) patients, supraventricular tachycardia in 4 (8,5%) patients, and non-sustained ventricular tachycardia in 6 (12,8) patients. Out of the group of the patients with abnormal Holter findings, ten patients had direct clinical treatment consequences, namely implantation of cardiac electronic devices or initiation of anticoagulation therapy. Conclusion In this study, holter findings resulted in relevant clinical treatment consequences in 10 out of 76 patients (13,2%). These results suggest that 24h-Holter monitoring may improve routine cardiac screening in patients with NMD.

Impact and consequences of the error of estimated GFR in patients with heart failure

Heart failure is a highly prevalent disease, which courses with frequent readmissions, mainly by Acute Heart Failure (AHF). Reduced renal function is associated with increased mortality in patients with HF. Therefore, an accurate and precise evaluation of renal function in patients with HF is crucial. The error of estimated GFR (eGFR) is wide and common, showing a ± 30% variability compared to measured GFR (mGFR). However, there is no evidence on the error of formulas in reflecting real renal function and particularly the consequences of this error in patients with AHF. This is a prospective study comparing the impact of mGFR versus eGFR in the onset of cardiovascular (CV) outcomes in patients with AHF. This was tested with cox survival analysis. Measured GFR was determined by the plasma clearance of iohexol-dbs and eGFR by Cockroft-Gould, MDRD, CKD-EPI creatinine, CKD-EPI cystatin-C and CKD-EPI creatinine + cystatin-C equations formulas. Also the agreement between mGFR and eGFR was analyzed. A total of 90 patients were included. Average age was 66 (± 12 years) and 52 (58%) were male. Of them 53 patients (59%) had a cardiovascular event during follow-up, 22 fatal (41%). The agreement between mGFR and eGFR indicated moderate precision and accuracy (concordance correlation coefficient of 0.77; CI = 0.73–0.82). In multiple cox survival analysis, mGFR was significantly associated with cardiovascular events together with NTproBNP, BMI, LVEF and previous coronary artery disease (p = 0.037; HR = 0.98, 95% CI = 0.95–0.99). Estimated GFR by formulas was not significant. In patients with AHF the error of formulas is large, frequent and random, also, mGFR and not eGFR predicted future CV events. The error of eGFR may have clinical consequences in specific subpopulations.

Hemorrhagic encephalopathies and myelopathies in dogs and cats: a focus on classification

The prevalence of hemorrhagic diseases of the central nervous system of dogs and cats is low compared to other diseases such as neoplasia and inflammation. However, the clinical consequences can be devastating. Several etiological and localization-based classification systems have been reported for intracerebral and spinal cord hemorrhage or hematomyelia in humans but similar systems do not exist in veterinary medicine. The authors propose an etiologic classification system for both intraparenchymal hemorrhagic encephalopathy and myelopathy following a review of the literature detailing the presentation, diagnosis, therapy, and prognosis of these diseases. A summary of the investigative and therapeutic approach to these cases is also provided.

The impact of peptide receptor radionucleotide therapy with Lutetium-177 DOTATATE on cardiac metastases in neuroendocrine tumors

Abstract Background Cardiac metastasis from neuroendocrine tumors (NET) is rare and has been thought to potentially result in life threatening sequalae. Peptide receptor radionucleotide therapy (PRRT), such as Lutetium-177 (Lu-177) DOTATATE, has been validated as effective treatment for patients with NET who have progressed on somatostatin analogue (SSA) therapy and more recently suggested for use in SAA-naïve higher risk grade 2 and grade 3 NETs. However, Lu-177 DOTATATE therapy has been found to have potentially serious adverse effects both locally and systemically. Overall, the clinical significance of cardiac metastasis of NET, as well as the safety and efficacy of Lu-177 DOTATATE in this cohort, has not been thoroughly evaluated. Purpose This study assessed the outcomes and clinical consequences of cardiac metastatic involvement in patients with NET. Furthermore, this study investigated the safety of Lu-177 DOTATATE therapy in patients with cardiac metastases from NET. Methods All patients who underwent 68Ga-DOTATATE positron emission tomography for evaluation of NET across three tertiary centers between 2016 and 2022 were retrospectively evaluated. Patients with evidence of cardiac metastasis were further evaluated. Baseline characteristics, treatment modality, and clinical outcomes including mortality, arrhythmia or conduction disease, carcinoid heart disease, and heart failure admissions were recorded. Patients with cardiac metastases were grouped and compared based on therapeutic modality (conservative therapy with surveillance or SSA, Lu-177 DOTATATE therapy, or surgical resection of metastases). Results From 3253 patients with NET, 51 patients were identified to have cardiac metastases (mean age 66.7 ± 12.2 years, 54% male). Three patients underwent surgical resection of cardiac metastases, and in two of whom this was concomitant while undergoing valve surgery for carcinoid heart disease. Patients with cardiac metastasis had significantly higher mortality than patients without cardiac metastasis (HR 2.12, 95%CI 1.00 – 4.52, p = 0.049, Figure 1A). Median follow-up from diagnosis of cardiac metastasis was 3.64 years [IQR 1.59 – 5.64]. There was no significant difference in clinical outcomes between patients that received Lu-177 DOTATATE therapy (n = 27) and conservative therapy (n = 21). Specifically, there was no significant difference in mortality risk at five years post the diagnosis of cardiac metastasis between these groups (p = 0.47, Figure 1B). Conclusion Patients with cardiac metastasis from NETs have worse clinical outcomes than NET patients without cardiac metastatic involvement. Lu-177 DOTATATE therapy appears to be safe in patients with cardiac metastasis from NET.Figure 1AFigure 1B

Renal hyperfiltration as risk factor of major adverse cardiovascular events in patients with acute myocardial infarction

Abstract Objectives While the interaction between heart and kidney potentially contributes the development of renal hyperfiltration (RHF), its clinical consequence of is not clear in patients with acute myocardial infarction (AMI). Methods A total of 9,561 AMI patients with estimated GFR (eGFR) ≥60 mL/min/1.73 m² were enrolled from a large nationwide, multi-center, prospective, observational cohort between November 2011 and December 2015. RHF was defined as eGFR >90th percentile after multiple adjustments. The primary endpoint was a combination of 3-year major adverse cardiovascular events (MACEs) after AMI treatment. Results The cumulative event rate of MACEs was significantly higher in patients with RHF. In multivariable Cox-regression analysis, RHF increased the 1.34-fold risk of MACE (95% confidence interval [CI] 1.12-1.62) compared to those without RHF. Patients with RHF had a significantly higher risk of all-cause mortality (hazard ratio [HR] 1.64; 95% CI 1.25-2.14) and cardiac death (HR 1.78; 95% CI 1.26-2.51). There was a linear correlation between the adjusted risk of MACEs and eGFR, with the risk increasing as eGFR exceeded approximately 100 mL/min/1.73 m². In the 1:1 propensity-score matched population, the cumulative event rate of MACEs, all-cause mortality, and cardiac death were consistently higher in patients with RHF (all p <0.05). Conclusion RHF was significantly associated with an increased risk of MACEs, all-cause mortality, and cardiac death following AMI compared to patients without RHF. Our study offers new insights into the risk stratification of AMI patients presenting with RHF.

Prolonged dual antiplatelet therapy in an extended Phase 3 Cardiac Rehabilitation Program following myocardial infarction

Abstract Background Prolonged dual antiplatelet therapy (P-DAPT) is recommended in selected patients beyond 12 months after myocardial infarction (MI). Several risk scores have been developed to estimate the ischemic and bleeding risk and individualize the decision-making process. Purpose We aim to analyse the factors, including ischemic and bleeding scores, associated with P-DAPT prescription in MI patients submitted to a Cardiac Rehabilitation Program (CRP). Methods Patients with ST-segment elevation MI (STEMI) or occlusion MI (OMI) who were submitted to our CRP underwent Phase 2 CRP and were prospectively included. Patients were followed in an extended Phase 3 CRP, and a follow-up visit was scheduled 12 months after hospital discharge. Baseline and follow-up clinical characteristics and treatment after the 12-months visit were registered, specifically P-DAPT. Ischemic (DAPT score) and bleeding (PRECISE-DAPT and CRUSADE scores) risk scores were retrospectively computed. Predictors of P-DAPT were studied by univariate analysis and multivariable binary logistic regression. The model was tested by area under the curve (AUC) analysis in receiver operating characteristic curves. A p<0.05 was considered statistically significant. Results The cohort comprised 78 patients (mean age 61±11 years, 84.6% male). Anterior and inferior STEMI were the most common presentations (43.6% and 47.4%, respectively). The most prevalent cardiovascular risks factors were hypercholesterolemia (85.9%), hypertension (53.8%), smoking habit (46.2%) and diabetes mellitus (23.1%). P-DAPT was prescribed in 39 (50%) patients beyond 12 months after MI, primarily combining aspirin 100mg o.d. and ticagrelor 60mg b.i.d. (n=33, 84.6%). On multivariate analysis, variables associated with P-DAPT prescription were hypertension (HR 4.92 [1.37-17.68], p=0.02), diabetes mellitus (HR 5.13 [1.09-24.09], p=0.04), multivessel disease (HR 5.54 [1.55-19.79], p=0.008), and stent diameter <3mm (HR 5.46 [1.25-23.78], p=0.02). The predictive power of the model was excellent (AUC 0.88 [0.8-0.96], p<0.001). Ischemic (DAPT score) and bleeding (PRECISE-DAPT and CRUSADE) risk scores were not associated with P-DAPT neither in continuous form nor by using their standard cutoffs (≥2, <25 and >40 points, respectively). Conclusions In a real-life cohort of MI patients undergoing extended Phase 3 Cardiac Rehabilitation, P-DAPT was prescribed in half of the population. Clinical (hypertension and diabetes mellitus) and angiographic (multivessel disease and stent diameter <3mm) variables straightforwardly predict the likelihood of receiving P-DAPT, unlike ischemic and bleeding risk scores. The clinical consequences of this management should be further explored.Prolonged DAPT in Cardiac Rehabilitation

Automatic quantification of pressure waveform damping during cardiac catheterisation using artificial intelligence

Abstract Background Undetected abnormalities in the aortic pressure waveform caused by damping of the signal can lead to complications during coronary angiography. Most commonly caused by over engagement of the catheter into the coronary ostium, the severity of pressure damping can be visually quatified by experience operators: it starts with the loss of the dicrotic notch, progresses to varying degrees of waveform "ventricularisation" and finally reaches a severe form with loss of the typical coronary waveform. The clinical consequences of undetected pressure damping are proportional to its severity, and include underestimation of stenosis severity during physiological assessment, vessel injury and, catastrophically, ventricular fibrillation. An automated approach to quantify pressure damping severity would improve patient safety by eliminating the need for constant operator attention during the procedure. Purpose To develop an index to automatically quantify the degree of pressure waveform damping using artificial intelligence. Methods 761 aortic pressure recordings obtained during pressure wire assessments and ranging from normal to severely damped, were manually processed into 1561 shorter recordings of 6-8 beats each. Recordings were then randomly allocated into separate training and validation datasets in a 70:30 ratio. The training and validation datasets were labelled by two separate groups of experts: 5 labelled the training dataset and 4 labelled the validation dataset. All experts were practicing interventional cardiologists who had undertaken doctoral and post-doctoral research in coronary physiology. 14490 individual expert discriminations were used to train the neural network. A purpose-built platform was used to label pressure waveforms. A neural network was trained using the training dataset. The validation dataset was then assessed by the neural network. The score output was transformed into an index which ranged from 0 (normal waveform) to 1 (severely damped). The correlation between expert consensus and the AI derived index was compared using Spearman’s Rho and numerical agreement assessed with Bland and Altman analysis. Results The AI derived index was able to continuously discriminate progressive degrees of pressure damping and demonstrated excellent correlation with the expert consensus score (Spearman’s rho 0.89) and numerical agreement on Bland and Altman analysis (bias +0.05 and limits of agreement ±0.21). Individual expert’s scores showed a range of agreement with the expert consensus score (Spearman’s rho 0.75-0.94, mean 0.86). The AI index agreed with expert consensus more closely than each expert agreed with each other. Conclusion An AI derived index can provide an automated, real-time and operator-independent quantification of the degree of aortic pressure waveform damping, improving precision of physiological assessment and potentially increasing patient safety during coronary angiography.

Remote monitoring and prioritisation for patients awaiting transcatheter aortic valve implantation safely mitigates longer waiting times

Abstract Background • The UK National Health Service (NHS) faces an unprecedented backlog of over 400,000 patients awaiting critical cardiac procedures, incurring thousands of excess deaths (1). • Longer waiting times to transcatheter aortic valve implantation (TAVI) can increase rates of unplanned hospitalisation and death (2). • Remote patient monitoring (RPM) can improve cardiovascular clinical outcomes (3), but its effectiveness in detecting and managing TAVI waiting list deterioration is untested. Purpose 1. Measure the systemic increase in waiting time to TAVI 2. Determine if RPM and prioritisation: · Is acceptable to patients · Detects clinical deterioration · Mitigates the expected increase in adverse events associated with longer waiting times · Does not unfairly disadvantage patients who are not prioritised Methods • We performed an observational cohort study including all patients awaiting TAVI at one UK regional centre between 24th April and 15th November 2023. • Patients were supported to complete an online or telephone-based weekly symptom questionnaire. • Responses were monitored by non-specialist nurses staffing a 'hub', with rule-based escalation to the TAVI team, who could prioritise treatment (Figure 1). • A historical control cohort who did not receive RPM was identified, as sequential unselected patients on the TAVI waiting list in reverse order, from 24th April 2023 to 1st January 2023. This cohort was propensity score-matched to adjust for age, sex, ethnicity and comorbidities. • Waiting time was defined as the date difference between a patient being placed on the waiting list and TAVI completion. • We defined patient acceptability as >80% engagement with at least one symptom questionnaire. • Sensitivity was calculated as the percentage of escalations to the TAVI Consultant resulting in prioritisation. • Kaplan-Meier survival analysis was performed for the primary endpoint of adverse events, defined as emergency department presentation, unplanned hospitalisation or death. Results • The median waiting time to TAVI increased by one month (104 days versus 75 days, p<0.001). • There was 99% (200/202) engagement with RPM • Despite the increased waiting time, there was no significant difference in rate of adverse events between the propensity score-matched RPM and historical control groups (12.5% versus 13.7%, p=0.86) (Figure 2) • 87% (27/31) of escalations to the TAVI Consultant resulted in treatment prioritisation • There was a non-significant difference in median waiting time between prioritised and non-prioritised patients during the study period, but with no clinical consequence to the delay (97 versus 120 days, p=0.16). Conclusions • An RPM pathway can detect patient deterioration on TAVI waiting lists with high sensitivity • RPM-based prioritisation for patients awaiting TAVI can mitigate the increased risk of adverse events associated with longer waiting times, without unfairly disadvantaging non-prioritised patients.Figure 1.RPM pathwayFigure 2

Pediatric Obstructive Sleep Apnea: Clinical Manifestations and Consequences

Obstructive sleep apnea (OSA) significantly impacts the quality of life in children, affecting their physical and mental health. The pathophysiology involves a complex interaction between anatomical factors (such as enlarged tonsils, adenoids, and structural abnormalities) and obesity, along with neuromuscular compensations. Clinical manifestations include loud snoring, breathing pauses, restless sleep, unusual sleeping positions, and frequent awakenings. OSA can lead to enuresis, growth impairment, poor academic performance, and neurocognitive and behavioral difficulties. Long-term consequences are cardiovascular morbidity, metabolic dysfunction, and neurocognitive impairment. Many studies have explored these associations and the impact of adenotonsillectomy. This review provides an overview of clinical manifestations and consequences of OSA, aiming to enhance diagnosis and treatment strategies for pediatric OSA.

Epstein–Barr virus reactivation in pediatric allogeneic stem cell transplant recipients: an 11-year experience on viral load and B lymphocyte monitoring strategy

BackgroundEpstein–Barr virus (EBV) reactivation represents a frequent condition after allogeneic hematopoietic stem cell transplantation (allo-HCT) and can cause the development of a severe complication: post-transplant lymphoproliferative disease (PTLD). This retrospective study aims at investigating the incidence of EBV reactivations and analyzing the potential impact of recipient/donor-related transplant-related factors in pediatric patients. The secondary objective was to study the consequences of the approach used at our center regarding the initiation of pre-emptive therapy.MethodsThis study used a retrospective evaluation of patients aged ≤25 years who received an allo-HCT at IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Giannina Gaslini, between 2012 and 2022, with follow-up censored in July 2023. Criteria to start rituximab were as follows: a viral load ≥20,000 copies/105 PBMCs or ≥10,000/105 PBMCs associated with a rise in the proportion of CD 20+ lymphocytes.ResultsOverall, 214 allo-HCTs were performed in 189 patients. A total of 127 (59.3%) procedures were complicated by at least one EBV reactivation, but in only one rituximab was administered. All other reactivations were characterized by viremia below reference ranges and no increase in CD20+ lymphocytes, without clinical consequences. Risk factors for EBV reactivation identified were associated with delayed immune reconstitution.ConclusionThese results could suggest the effectiveness of the approach used in providing pre-emptive therapy. The strategy adopted differs from that highlighted by other studies and allowed the reduction of the number of children who received rituximab. It has proven effective considering the low incidence rate of PTLD and reduces the risk of rituximab-related adverse events.

Modulation of Multispecific Transporters by Uncaria tomentosa Extract and Its Major Phytoconstituents

Background/Objectives: One of the major risks associated with the concomitant use of herbal products and therapeutic drugs is herb–drug interactions (HDIs). The most common mechanism leading to HDIs is the inhibition and/or induction of transport proteins and drug-metabolizing enzymes by herbal ingredients, causing changes in the pharmacokinetic disposition of the victim drug. The present study aimed to determine the potential interactions of Uncaria tomentosa (UT) (cat’s claw), a popular herb due to its supposed health benefits. Methods: The effect of UT extract and its major oxindole alkaloids was investigated on multispecific solute carrier (SLC) and ATP-binding cassette (ABC) drug transporters, using SLC transporter-overexpressing cell lines and vesicles prepared from ABC transporter-overexpressing cells. Results: UT extract significantly inhibited all ABC transporters and the majority of the SLC transporters tested. Of the investigated oxindole alkaloids, isopteropodine significantly inhibited OATP, OCT1 and OCT2, OAT3, ENT4, MDR1, and BCRP transporters. OCTs, OCTN1-, ENT1-, and MDR1-mediated substrate accumulation was below 50% in the presence of mitraphylline. Conclusions: Based on the calculated intestinal concentration of UT extract, interactions with intestinal transporters, especially OATP2B1, ENTs, MRP1, MRP2, MDR1, and BCRP could be relevant in vivo. Our data can help to predict the clinical consequences of UT co-administration with drugs, such as increased toxicity or altered efficacy. In conclusion, the use of these in vitro models is applicable for the analysis of transporter-mediated HDIs similar to drug–drug interaction (DDI) prediction.

Clinical relevance of protein-truncating variants of germline DNA repair genes in prostate cancer

BackgroundInterpreting genetic variants remains a challenge in prostate cancer (PCa). Although many annotation tools are available for prioritizing causal variants, the clinical relevance of these variants is rarely studied.MethodsWe collected a cohort study that included 274 PCa patients from June 2017 to December 2020 and sequenced 19 DNA damage repair (DDR) genes in these patients and explored the clinical consequence of these different approaches. We also examined all-cause and PCa-specific survival in DDR gene mutation carriers compared to non-carriers after androgen receptor (AR)-directed therapy.ResultsWe identified 13 variants from 19 DDR genes in a total of 14 (5.1%) patients who had at least one presumed pathogenic mutation using different annotation methods. Four variants were annotated as pathogenic, 11 variants were predicted as protein-truncating variants (PTVs), four variants received proxy-deleterious (Combined Annotation-Dependent Depletion scores of > 30), and only one variant was identified as a pathogenic variant or as having a functional effect by all three methods. PCa patients with PTVs were significantly associated with early onset, high cancer stage, and a worse response to AR-directed treatment. However, patients carrying a proxy-deleterious variant were only associated with a higher T (tumor) stage and N (node) stage than those without such a variant, but not associated with other clinical characteristics. In patients treated with AR-directed therapy, patients with a PTV showed an increased risk of all-cause death (adjusted hazard ratio (aHR) = 3.51, 95% confidence interval (CI): 1.06 ~ 11.56) and PCa-specific death (aHR = 4.49, 95% CI: 1.87 ~ 10.77) compared to non-PTV carriers after adjustment. We were unable to examine gene-specific risks due to the small number of patients.ConclusionsPTVs may assist in guiding treatment and early screening in PCa, while population-specific data for pathogenic variants are still being amassed.

Molecular Biology for Diagnosis of Congenital and Neonatal Infections in the Cerebrospinal Fluid of Newborns from a Brazilian Tertiary Hospital

The risk of infection transmission from mother to fetus depends on the pathogen. TORCH agents cause some neuroinfections, including Toxoplasmosis, rubella, Cytomegalovirus, herpes simplex 1 and 2, and others (Varicella Zoster, Parvovirus B-19, Epstein–Barr virus, and Zika virus). The consequences can be stillbirth, prematurity, uterine growth restriction, and congenital malformations. The detection of DNA/RNA from CSF by molecular methods is a marker of the involvement of congenital infection in the central nervous system. This study aimed to identify the frequency of these pathogens in CSF samples from newborns (1 to 28 days old) at a tertiary hospital, using PCR, and determine the clinical consequences. Methods: This was a prospective descriptive study involving the molecular analysis of 151 CSF samples from neonates, collected for cytological and biochemical diagnosis from 2017 to 2021. After the results and consent from the participants’ caregivers were obtained, the leftover material was sent to the University’s Virology Laboratory and submitted for DNA/RNA extraction and Nested-PCR/RT-PCR. A review of the patients’ medical records and descriptive statistics was performed. This work was approved by the Ethics Committee (CAAE: 86760218.3.0000.5404). Results: A total of 151 CSF samples were obtained, 16 of which were positive (10.6% [95% CI%: 6.18–16.63%]). Two of these were PCR-positive for HSV-1 (1.3%), four for VZV (2.6%), one for CMV (0.67%), two for Toxoplasmosis (1.3%), four for Parvovirus B-19 (2.6%), and four for Zika (2.6%). The proportion of positive PCR results was higher in the group that presented with malformations (25.0% vs. 8.4%, p = 0.040). Conclusions: The pathogens identified by PCR were mostly Zika virus, VZV, and B-19, and these were mainly found in newborns with malformations.

Exogenous Opioids and the Human Endocrine System: An Endocrine Society Scientific Statement.

The use and misuse of opioids are a growing global problem. Although the effects of these drugs on the human endocrine system have been studied for decades, attention on their related clinical consequences, particularly on the hypothalamic-pituitary system and bone health, has intensified over recent years. This Statement appraises research data related to the impact of opioids on the gonadal and adrenal function. Whereas hypogonadism is well recognized as a side effect of opioids, the significance of their inhibitory actions on the hypothalamic-pituitary-adrenal system and the occurrence of clinically relevant adrenal insufficiency is not fully elucidated. The often-inconsistent results of studies investigating how opioids affect the secretion of GH, prolactin, arginine vasopressin, and oxytocin are assessed. The accumulating evidence of opioid actions on bone metabolism and their negative sequelae on bone mineral density and risk of fracture are also reviewed. In each section, available data on diagnostic and management approaches for opioid endocrine sequelae are described. This Statement highlights a plethora of gaps in research associated with the effects and clinical consequences of opioids on the endocrine system. It is anticipated that addressing these gaps will improve the care of people using or misusing opioids worldwide. The Statement is not intended to serve as a guideline or dictate treatment decisions.

Association of initial serum sodium change and clinical outcome in patients with diabetes receiving sodium-glucose cotransporter-2 inhibitor therapy: A multicentre database analysis in Taiwan.

The study aimed to assess the impact of varying degrees of initial serum sodium change among patients with type 2 diabetes (T2D) starting sodium-glucose cotransporter-2 inhibitor (SGLT2i) therapy and their subsequent clinical outcome. We used medical data from a multicentre health care provider in Taiwan and recruited 4400 patients with T2D with baseline normal serum sodium (135-145 mmol/L) and follow-up serum sodium measures available after 3 months of SGLT2i treatment from 1 June 2016 to 31 December 2021. After a median of 2.9 (2.4, 3.4) months of SGLT2i treatment, overall, there was a minimal change in serum sodium levels (from 139.6 ± 2.4 to 139.5 ± 3.7 mmol/L). Most patients (87.8%) maintained normal sodium levels, while 8.6% (n = 378) experienced hyponatraemia (<135 mmol/L) and 3.6% (n = 158) hypernatraemia (>145 mmol/L). Factors independently associated with hyponatraemia included cancer history, chronic lung disease, insulin use, higher glycated haemoglobin, impaired liver function, lower baseline sodium and greater initial decline in kidney function. Conversely, factors linked to hypernatraemia included older age, absence of cancer history, loop diuretic and non-steroidal anti-inflammatory drug use, higher baseline sodium and a lesser initial decline in kidney function. Over a median of 26.0 months of follow-up, hyponatraemia shortly after starting SGLT2i therapy was associated with significantly increased risks of major adverse cardiovascular events [hazard ratio (HR): 2.52; 95% confidence interval (CI): 1.83-3.48], heart failure for hospitalization (HR: 1.66; 95% CI: 1.16-2.37), major adverse renal events (HR: 2.27; 95% CI: 1.73-2.96) and all-cause death (HR: 2.98; 95% CI: 2.17-4.11) after adjusting for clinically relevant factors. Non-linear analysis indicated that a more pronounced initial decline in serum sodium levels correlated steeply with higher risks of these adverse events. While most patients with T2D maintain stable serum sodium homeostasis on SGLT2i therapy, a subset may experience dysnatraemic events with potential worse clinical consequences. Physicians should be vigilant about monitoring sodium levels and considering the associated risks when initiating SGLT2i therapy in patients with risk.

Serial manual bolus irrigation leads to critical intrarenal pressures during flexible ureterorenoscopy - time to abandon this manoeuvre.

To characterise the effect of solitary and serial manual bolus irrigations on intrarenal pressures (IRPs) and observe the clinical consequences. A pressure guidewire was used for IRP measurement during routine flexible ureterorenoscopy for management of renal stone disease, including manual bolus irrigation when required to maintain vision. The fluid bolus was either as a solitary manual bolus or a series of manual boluses in quick succession. The pre-bolus, maximal and difference between IRPs were calculated. A total of 50 procedures in 46 patients were analysed. In all, 68 solitary manual boluses and 38 serial manual boluses were observed to have been undertaken during these procedures. After a solitary manual bolus, the median (standard deviation [SD], range) increase in IRP was 22.4 (34.0, 0.1-160.8) mmHg, and the mean (SD, range) maximum IRP was 46.1 (41.7, 15.8-190.0) mmHg, with elevated IRPs persisting for a median (range) duration of 19 (4-66) s. After serial manual boluses, the median (SD, range) rise in IRP was 58.4 (64.7, 10.2-242.84) mmHg and the mean (SD, range) maximum IRP reached was 100.8 (69.7, 34.3-303.5) mmHg. The elevated IRPs endured for a median (range) of 42 (9-121 s; P < 0.01 in all comparisons), suggesting a much greater elevation of IRP with instances where serial bolus irrigation was undertaken. Manual bolus irrigation, both solitary but particularly serial boluses, produces significant rises in IRP and could logically result in pyelovenous backflow and sepsis. We suggest that this manoeuvre should be avoided to reduce complications during ureterorenoscopy.

Clinical Consequences of Delayed Gastric Emptying With GLP-1 Receptor Agonists and Tirzepatide.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are established therapeutics for type 2 diabetes and obesity. Among other mechanisms, they slow gastric emptying and motility of the small intestine. This helps limiting postprandial glycemic excursions and reducing chylomicron formation and triglyceride absorption. Conversely, motility effects may have detrimental consequences, e.g., retained gastric contents at endoscopy or general anesthesia, potentially complicated by pulmonary aspiration, or bowel obstruction. We searched the PubMed database for studies involving GLP-1RA therapy and adverse gastrointestinal/biliary events. Retained gastric contents at the time of upper gastrointestinal endoscopy are found more frequently with GLP-1 RAs, but rarely are associated with pulmonary aspiration. Well-justified recommendations for the peri-procedural management of GLP-1RAs (e.g., whether to withhold these medications, and for how long) are compromised by limited evidence. Important aspects to be considered are (a) their long half-lives, (b) the capacity of GLP-1 receptor agonism to slow gastric emptying even at physiological GLP-1 concentrations, (c) tachyphylaxis observed with prolonged treatment, and (d) the limited effect on gastric emptying in individuals with slow gastric emptying before initiating treatment. Little information is available on the influence of diabetes mellitus itself (i.e., in the absence of GLP-1 RA treatment) on retained gastric contents and pulmonary aspiration. Prolonged fasting periods regarding solid meal components, point-of-care ultrasound examination for retained gastric content, and the use of prokinetic medications like erythromycin may prove helpful, and are an important area needing further study to increase patient safety for those treated with GLP-1 RAs.

Hemoincompatibility in Hemodialysis-Related Therapies and Their Health Economic Perspectives

Hemobiologic reactions associated with the hemoincompatibility of extracorporeal circuit material are an undesirable and inevitable consequence of all blood-contacting medical devices, typically considered only from a clinical perspective. In hemodialysis (HD), the blood of patients undergoes repetitive (at least thrice weekly for 4 h and lifelong) exposure to different polymeric materials that activate plasmatic pathways and blood cells. There is a general agreement that hemoincompatibility reactions, although unavoidable during extracorporeal therapies, are unphysiological contributors to non-hemodynamic dialysis-induced systemic stress and need to be curtailed. Strategies to lessen the periodic and direct effects of blood interacting with artificial surfaces to stimulate numerous biological pathways have focused mainly on the development of ‘more passive’ materials to decrease intradialytic morbidity. The indirect implications of this phenomenon, such as its impact on the overall delivery of care, have not been considered in detail. In this article, we explore, for the first time, the potential clinical and economic consequences of hemoincompatibility from a value-based healthcare (VBHC) perspective. As the fundamental tenet of VBHC is achieving the best clinical outcomes at the lowest cost, we examine the equation from the individual perspectives of the three key stakeholders of the dialysis care delivery processes: the patient, the provider, and the payer. For the patient, sub-optimal therapy caused by hemoincompatibility results in poor quality of life and various dialysis-associated conditions involving cost-impacting adjustments to lifestyles. For the provider, the decrease in income is attributed to factors such as an increase in workload and use of resources, dissatisfaction of the patient from the services provided, loss of reimbursement and direct revenue, or an increase in doctor–nurse turnover due to the complexity of managing care (nephrology encounters a chronic workforce shortage). The payer and healthcare system incur additional costs, e.g., increased hospitalization rates, including intensive care unit admissions, and increased medications and diagnostics to counteract adverse events and complications. Thus, hemoincompatibility reactions may be relevant from a socioeconomic perspective and may need to be addressed beyond just its clinical relevance to streamline the delivery of HD in terms of payability, future sustainability, and societal repercussions. Strategies to mitigate the economic impact and address the cost-effectiveness of the hemoincompatibility of extracorporeal kidney replacement therapy are proposed to conclude this comprehensive approach.

PET clinical study of novel antipsychotic LB-102 demonstrates unexpectedly prolonged dopamine receptor target engagement.

Regulation of dopamine activity has important clinical consequences, most notably in schizophrenia. LB-102, N-methyl amisulpride, is a novel dopamine D2/3/5-HT7 inhibitor being developed as a treatment for schizophrenia and other psychiatric disorders. The characteristic that is common to all current antipsychotics is their engagement of D2 dopamine receptors. The goal of this study was to measure the dopamine receptor occupancy of orally administered LB-102 at three different doses (50, 75, and 100 mg as single doses and 50 and 100 mg as multiple doses) and at different timepoints in healthy volunteers using positron emission tomography (PET) with 11C raclopride as a radiotracer. Results of this study (NCT04588129) showed that steady-state once daily oral dosing of 50 mg LB-102 afforded striatal dopamine occupancy (RO) in the desired 60-80% range consistently over the course of 24 h. Contrary to the often observed relationship between RO vs plasma concentrations, maximum dopamine RO significantly lagged maximum plasma concentration and showed little variability under steady state conditions. A similar phenomenon has recently been reported with a non-racemic version of amisulpride [1]. LB-102 was generally safe and well-tolerated at all doses. Results of this study were used to inform dosing in a subsequent Phase 2 clinical study in schizophrenia patients.