Citations

AbstractBACKGROUNDDelirium, a common syndrome with heterogeneous etiologies and clinical presentations, is associated with poor long‐term outcomes. Recording and analyzing all delirium equally could be hindering the field's understanding of pathophysiology and identification of targeted treatments. Current delirium subtyping methods reflect clinically evident features but likely do not account for underlying biology.METHODSThe Delirium Subtyping Initiative (DSI) held three sessions with an international panel of 25 experts.RESULTSMeeting participants suggest further characterization of delirium features to complement the existing Diagnostic and Statistical Manual of Mental Disorders Fifth Edition Text Revision diagnostic criteria. These should span the range of delirium‐spectrum syndromes and be measured consistently across studies. Clinical features should be recorded in conjunction with biospecimen collection, where feasible, in a standardized way, to determine temporal associations of biology coincident with clinical fluctuations.DISCUSSIONThe DSI made recommendations spanning the breadth of delirium research including clinical features, study planning, data collection, and data analysis for characterization of candidate delirium subtypes.Highlights Delirium features must be clearly defined, standardized, and operationalized. Large datasets incorporating both clinical and biomarker variables should be analyzed together. Delirium screening should incorporate communication and reasoning.

AbstractGynecological malignancies are a significant cause of morbidity and mortality across the globe. Due to delayed presentation, gynecological cancer patients are often referred late in the disease's course, resulting in poor outcomes. A considerable number of patients ultimately succumb to chemotherapy‐resistant disease, which reoccurs at advanced stages despite treatment interventions. Although efforts have been devoted to developing therapies that demonstrate reduced resistance to chemotherapy and enhanced toxicity profiles, current clinical outcomes remain unsatisfactory due to treatment resistance and unfavorable off‐target effects. Consequently, innovative biological and nanotherapeutic approaches are imperative to strengthen and optimize the therapeutic arsenal for gynecological cancers. Advancements in nanotechnology‐based therapies for gynecological malignancies offer significant advantages, including reduced toxicity, expanded drug circulation, and optimized therapeutic dosing, ultimately leading to enhanced treatment effectiveness. Recent advances in nucleic acid therapeutics using microRNA, small interfering RNA, and messenger RNA provide novel approaches for cancer therapeutics. Effective single‐agent and combinatorial nucleic acid therapeutics for gynecological malignancies have the potential to transform cancer treatment by giving safer, more tailored approaches than conventional therapies. This review highlights current preclinical studies that effectively exploit these approaches for the treatment of gynecological malignant tumors and malignant ascites.

Introduction: Oral glucose tolerance testing is recommended for all children with CF older than 9 years, yet compliance remains poor across centers. Methods: We performed a small pilot study assessing the glycemic curves and participant satisfaction in seven children and adolescents. Results: We chose a dextrose-based candy (Nerds®) free of any fat, fiber, gelatin, or corn syrup and performed the candy OGTT 1–4 days following the standard oral dextrose solution OGTT. Glucose values at 120 min were similar between the candy and oral dextrose solution (p = 0.8986). Conclusions: Our small pilot suggests that a carefully selected candy alternative may result in similar glycemic OGTT when compared to the standard oral dextrose solution. However, some participants preferred the oral dextrose solution to candy due to having to consume a large volume in a short period of time. This may have significant implications as centers consider candy alternatives to increase OGTT adherence rates.

AbstractObjectiveVisual assessment of magnetic resonance imaging (MRI) from the Human Epilepsy Project 1 (HEP1) found 18% of participants had atrophic brain changes relative to age without known etiology. Here, we identify the underlying factors related to brain volume differences in people with focal epilepsy enrolled in HEP1.MethodsEnrollment data for participants with complete records and brain MRIs were analyzed, including 391 participants aged 12–60 years. HEP1 excluded developmental or cognitive delay with intelligence quotient <70, and participants reported any formal learning disability diagnoses, repeated grades, and remediation. Prediagnostic seizures were quantified by semiology, frequency, and duration. T1‐weighted brain MRIs were analyzed using Sequence Adaptive Multimodal Segmentation (FreeSurfer v7.2), from which a brain tissue volume to intracranial volume ratio was derived and compared to clinically relevant participant characteristics.ResultsBrain tissue volume changes observable on visual analyses were quantified, and a brain tissue volume to intracranial volume ratio was derived to compare with clinically relevant variables. Learning difficulties were associated with decreased brain tissue volume to intracranial volume, with a ratio reduction of .005 for each learning difficulty reported (95% confidence interval [CI] = −.007 to −.002, p = .0003). Each 10‐year increase in age at MRI was associated with a ratio reduction of .006 (95% CI = −.007 to −.005, p < .0001). For male participants, the ratio was .011 less than for female participants (95% CI = −.014 to −.007, p < .0001). There were no effects from seizures, employment, education, seizure semiology, or temporal lobe electroencephalographic abnormalities.SignificanceThis study shows lower brain tissue volume to intracranial volume in people with newly treated focal epilepsy and learning difficulties, suggesting developmental factors are an important marker of brain pathology related to neuroanatomical changes in focal epilepsy. Like the general population, there were also independent associations between brain volume, age, and sex in the study population.

Objective Surgical treatment of velopharyngeal insufficiency (VPI) includes a wide array of procedures. The purpose of this study was to develop a classification for VPI procedures and to describe variations in how they are performed. Design/participants/setting/outcomes: We completed an in-depth review of the literature to develop a preliminary schema that encompassed existing VPI procedures. Forty-one cleft surgeons from twelve hospitals across the USA and Canada reviewed the schema and either confirmed that it encompassed all VPI procedures they performed or requested additions. Two surgeons then observed the conduct of the procedures by surgeons at each hospital. Standardized reports were completed with each visit to further explore the literature, refine the schema, and delineate the common and unique aspects of each surgeon's technique. Results Procedures were divided into three groups: palate-based surgery; pharynx-based surgery; and augmentation. Palate-based operations included straight line mucosal incision with intravelar veloplasty, double-opposing Z-plasty, and palate lengthening with buccal myomucosal flaps. Many surgeons blended maneuvers from these three techniques, so a more descriptive schema was developed classifying the maneuvers employed on the oral mucosa, nasal mucosa, and muscle. Pharynx-based surgery included pharyngeal flap and sphincter pharyngoplasty, with variations in design for each. Augmentation procedures included palate and posterior wall augmentation. Conclusions A comprehensive schema for VPI procedures was developed incorporating intentional adaptations in technique. There was substantial variation amongst surgeons in how each procedure was performed. The schema may enable more specific evaluations of surgical outcomes and exploration of the mechanisms through which these procedures improve speech.

AbstractBackgroundThe HIV Organ Policy Equity (HOPE) act afforded transplantation of organs from donors who have HIV. Herein we compared the long‐term outcomes of recipients with HIV by donor HIV testing status.MethodsUsing the Scientific Registry of Transplant Recipients, we identified all primary adult kidney transplant recipients who were HIV‐positive between 1/1/16‐12/31/21. Recipients were grouped into three cohorts according to the donor HIV status based on antibody (Ab) and nucleic acid testing (NAT): Donor Ab−/NAT− (n = 810), Donor Ab+ /NAT− (n = 98), and Donor Ab+/NAT+ (n = 90). We compared recipient and death‐censored graft survival (DCGS) by donor HIV testing status using Kaplan–Meier curves and Cox proportional hazards regression, censored at 3 years posttransplant. Secondary outcomes were delayed graft function (DGF) and the following 1‐year outcomes: acute rejection, re‐hospitalization, and serum creatinine.ResultsIn Kaplan–Meier analyses, patient survival and DCGS were similar by donor HIV status (log rank p = .667; log rank p = .388). DGF occurred more frequently in donors with HIV Ab−/NAT− testing compared with Ab+/NAT− or Ab+/NAT+ testing (38.0% vs. 28.6% vs. 26.7%, p = .028). Average dialysis time before transplant was twice as long for recipients who received organs from donors with Ab−/NAT− testing (p < .001). Acute rejection, re‐hospitalization and serum creatinine at 12 months did not differ between the groups.ConclusionsPatient and allograft survival for recipients living with HIV remains comparable irrespective of donor HIV testing status. Utilizing kidneys from deceased donors with HIV Ab+/NAT− or Ab+/NAT+ testing shortens dialysis time prior to transplant. image

Fibrolamellar hepatocellular carcinoma (FLC) is a usually lethal primary liver cancer driven by a somatic dysregulation of protein kinase A. We show that the proteome of FLC tumors is distinct from that of adjacent nontransformed tissue. These changes can account for some of the cell biological and pathological alterations in FLC cells, including their drug sensitivity and glycolysis. Hyperammonemic encephalopathy is a recurrent problem in these patients, and established treatments based on the assumption of liver failure are unsuccessful. We show that many of the enzymes that produce ammonia are increased and those that consume ammonia are decreased. We also demonstrate that the metabolites of these enzymes change as expected. Thus, hyperammonemic encephalopathy in FLC may require alternative therapeutics.

Introduction: Shared decision-making (SDM) about anticoagulant treatment in patients with atrial fibrillation (AF) is widely recommended but its effectiveness is unclear. We assessed the extent to which using an SDM tool promotes high-quality SDM. Hypothesis: SDM will improve communication quality, knowledge, and decisional conflict and will translate to improved medication adherence and outcomes. Methods: In this multicentre encounter-randomized trial, we included patients with nonvalvular AF considering starting/reviewing anticoagulation, and their clinicians. We compared usual care with or without ANTICOAGULATION CHOICE, an SDM conversation tool for use during the clinical encounter that presents individualized risk estimates and compares anticoagulation options across patient important issues. Results: We enrolled and video-recorded 922 patient-clinician encounters. So far, our data have shown that participants in both arms reported near-optimal communication quality, knowledge, and decisional conflict (JAMA IM-2020). Patients in intervention-arm estimated their stroke risks more accurately and were more involved in decision-making (JAMA IM-2020), clinicians were more satisfied (JAMA IM-2020), and cost conversation were more common (JAMA NO-2021). Use of the intervention had no effect on treatment decisions, encounter duration (JAMA IM-2020), treatment adherence, clinical outcomes (JAHA-epub) or patient-perceived sense of the care plan (PEC-epub). New analyses have shown that compared to eligible white participants, black participants more frequently did not enrol to the study. Enrolment of Black, indigenous, and people of colour benefited most form including and prioritizing practices most likely to care for them. We found no evidence of contamination (tool use, functional, or learned) between study arms. Conclusions: Use of an SDM tool improved some measures of SDM quality, without affecting treatment decisions and their sensibility, encounter duration, patient adherence, or clinical outcomes. Our results should calibrate expectations as to what could be accomplished by implementing SDM tools about anticoagulation in the care of patients with AF

Background: RCTs studying the effect of sodium-glucose co-transporter 2 inhibitors (SGLT2i) on cardiovascular (CV) risk factors and outcomes have been underpowered to assess patients with overweight or obesity, thus presenting the need for a meta-analysis. Methods: Electronic databases were queried up till February 2022 for RCTs comparing SGLT2i with placebo in patients with overweight (BMI ≥25 kg/m2) or obesity (BMI ≥30 kg/m2) - irrespective of diabetes status - with a follow-up of ≥24 weeks. Meta-analyses were performed using the generic inverse variance technique and a random-effects model. Results are presented as weighted mean differences (WMD) for continuous outcomes, and hazard ratios (HR) for dichotomous outcomes. Outcomes studied were: (i) weight; (ii) systolic BP; (iii) diastolic BP; (iv) heart rate; (v) HDL-C; (vi) LDL-C; (vii) major adverse cardiac events (MACE), i.e., composite of CV death, non-fatal myocardial infarction (MI) and non-fatal stroke; (viii) composite of heart failure hospitalization and CV death (HFH/CV death); (ix) mortality; (x) MI; and (xi) stroke. Results: Seventeen RCTs (47,649 patients) were included. Compared with placebo, SGLT2i significantly reduced weight (WMD: -2.32 kg [-2.77, -1.88]), HbA1c (WMD: -0.79 % [-0.98, - 0.61]) and systolic BP (WMD: -2.15 mm Hg [-3.08, - 1.22]). SGLT2i did not have a significant effect on diastolic BP (WMD: -0.55 mmHg [-1.51, 0.41]), heart rate (WMD: 0.08 bpm. [-0.21, 0.37]), HDL-C (WMD: 1.62 mmol l -1 [-0.21, 3.45]) or LDL-C (WMD: 0.53 mmol l -1 [-0.88, 1.94]). Amongst CV outcomes, SGLT2i reduced the risk of MACE (HR: 0.90 [0.81, 0.99]), HFH/CV death (HR: 0.82 [0.75, 0.90]), and mortality (HR: 0.85 [0.77, 0.94]). No effect was noted on stroke (HR: 0.99 [0.85, 1.26]) or MI (HR: 0.89 [0.77, 1.02]). Conclusions: In patients with overweight or obesity, SGLT2i produce a modest but significant reduction in weight, systolic BP and HbA1c. SGLT2i may also reduce the risk of MACE, HFH/CV death, and mortality.

Introduction: COVID-19 pandemic has had an unprecedented impact worldwide, co-infections with neglected tropical diseases like Malaria can occur and affect the heart. Objective: Describe a unique case of Malaria and SARS CoV2 infection occurring concurrently with cardiac complications. Clinical Case: A 69-year-old male, retired canoeing athlete, with well-controlled arterial hypertension, presented odynophagia, cough, and dyspnea on slight exertion for 2 days. On examination, O2 saturation was 91%, blood pressure 100/60 mmHg, regular heart rate of 110 bpm, positive PCR for SARS-CoV-2, elevated D-Dimer, and chest X-ray with evidence of viral pneumonia. He received supplemental oxygen, steroids, and paracetamol. Two days later, he presented with choluria, afternoon episodes of high fever preceded by chills and myalgia, and a thick blood smear showed Plasmodium falciparum (PF) trophozoites. Antimalarial treatment was started with primaquine 15mg, 20 mg of artemether, and 120 mg of Lumefantrine daily with the disappearance of fever until day 14 of onset of symptoms when he presented with acute heart failure (AHF) with a reduced ejection fraction of 45%. NYHA Class IV, arterial hypotension, sudden onset palpitations, and afternoon febrile episode. The electrocardiogram showed atrial fibrillation (AF) with a rapid irregular ventricular response of 120 bpm; The echocardiogram revealed a 7mm circumferential pericardial effusion, right ventricular dysfunction. Treatment with colchicine, enoxaparin, spironolactone, and bisoprolol was started. A new thick smear demonstrated the persistence of PF. A new antimalarial regimen was restarted, with the disappearance of the fever 48 hours after its onset, with the reversion of AF to sinus rhythm. Discussion: A unique case of concurrent COVID-19 and Malaria, which cause challenges to the heart and lead to cardiovascular complications. Conclusion: An exceptional case is presented, the coexistence of SARS-CoV-2 and PF infection-associated complications of myocarditis, pericarditis, new-onset AF, and AHF. This interaction should not go unnoticed, physicians’ awareness is key, and early diagnosis and treatment can be lifesaving, mitigate and offer the best chance of cure.