Two-component symmetrical diarylation of ynamides.

The present study describes a method for the dicarbofunctionalization of ynamide via a palladium-catalyzed two-component diarylation with aryl boronic acids. The reaction involves a consecutive transmetalation of the aryl boronic acids with a Pd(II)-complex making the transformation stereoselective. Importantly, the reaction proceeds under mild conditions and tolerates a broad range of functional groups. Control experiments validate the role of the oxidant (useful for catalyst regeneration) in the reaction mechanism.

Confirmation of Cause of Death Via Comprehensive Autopsy and Whole Exome Molecular Sequencing in People With Epilepsy and Sudden Unexpected Death.

Background Sudden cardiac arrest is the leading mode of death in the United States. Epilepsy affects 1% of Americans; yet epidemiological data show a prevalence of 4% in cases of sudden cardiac arrest. Sudden unexpected death in epilepsy (SUDEP) may share features with sudden cardiac arrest. The objective of this study was to report autopsy and genomic findings in a large cohort of SUDEP cases. Methods and Results Mayo Clinic Sudden Death Registry containing cases (ages 0-90 years) of sudden unexpected and unexplained deaths 1960 to present was queried. Exome sequencing performed on decedent cases. From 13 687 cases of sudden death, 656 (4.8%) had a history of seizures, including 368 confirmed by electroencephalography, 96 classified as SUDEP, 58 as non-SUDEP, and 214 as unknown (insufficient records). Mean age of death in SUDEP was 37 (±19.7) years; 56 (58.3%) were male; 65% of deaths occurred at night; 54% were found in bed; and 80.6% were prone. Autopsies were obtained in 83 cases; bystander coronary artery disease was frequently reported as cause of death; nonspecific fibrosis was seen in 32.6% of cases, in structurally normal hearts. There were 4 cases of Dravet syndrome with pathogenic variants in SCN1A gene. Using whole exome sequencing in 11 cases, 18 ultrarare nonsynonymous variants were identified in 6 cases including CACNB2, RYR2, CLNB, CACNA1H, and CLCN2. Conclusions This study examined one of the largest single-center US series of SUDEP cases. Several cases were reclassified as SUDEP, 15% had an ECG when alive, and 11 (11.4%) had blood for whole exome sequencing analysis. The most frequent antemortem genetic finding was pathogenic variants in SCN1A; postmortem whole exome sequencing identified 18 ultrarare variants.

The Role of Palliative Care in Withdrawal of Venoarterial Extracorporeal Membrane Oxygenation for Cardiogenic Shock.

CONTEXT: As the use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) increases, decisions regarding withdrawal from VA-ECMO increase. OBJECTIVES: To evaluate the clinical characteristics of patients withdrawn from VA-ECMO and the role of palliative care consultation in the decision. METHODS: We retrospectively reviewed adult patients with cardiogenic shock requiring VA-ECMO at our institution, who were withdrawn from VA-ECMO between January 1, 2014 and May 31, 2019. The relationship between clinical characteristics and palliative care visits was assessed, and documented reasons for withdrawal were identified. RESULTS: Of 460 patients who received VA-ECMO, 91 deceased patients (19.8%) were included. Forty-two patients (44.8%) had a palliative care consultation. The median duration on VA-ECMO was 4.0 days (interquartile range 8.8), and it was significantly longer for patients with palliative care consultation than those without (8.8 days vs. 2.0 days, P < 0.001). Among those with palliative care consultation, those with early consultation (within three days) had significantly shorter duration of VA-ECMO compared with those with late consultation (7.6 days vs. 13.5 days, t = 2.022, P = 0.008). Twenty-two (24.2%) had evidence of brain injury, which was significantly associated with patient age, number of comorbidities, duration of VA-ECMO, number of life-sustaining therapies, and number of palliative care visits (Wilks lambda 0.8925, DF 5,121, P = 0.016). Presence of brain injury was associated with fewer palliative care visits (t = 2.82, P = 0.006). CONCLUSION: Shorter duration of VA-ECMO support and presence of brain injury were associated with fewer palliative care visits. Decisions around withdrawal of VA-ECMO support might be less complicated when patient's medical conditions deteriorate quickly or when neurological prognosis seems poor.

A community-based study of demographics, medical and psychiatric conditions, and gender dysphoria/incongruence treatment in transgender/gender diverse individuals.

BACKGROUND: Current understanding about health care in the gender diverse population is limited by the lack of community-based, longitudinal data, especially in the USA. We sought to characterize a community-based cohort of transgender individuals including demographics, gender identities, social characteristics, psychiatric and medical conditions, and medical therapy for gender dysphoria/incongruence. PATIENTS AND METHODS: We performed a retrospective chart review of gender diverse residents of Olmsted County, Minnesota, who sought gender-specific healthcare from January 1, 1974, through December 31, 2015, using an infrastructure that links medical records of Olmsted County residents from multiple institutions. RESULTS: The number of patients seeking gender-specific healthcare increased from 1 to 2 per 5-year interval during the 1970s-1990s to 41 from 2011 to 2015 (n = 82). Forty-nine (59.8%) were assigned male sex at birth (AMAB), 31 (37.8%) were assigned female (AFAB), and 2 (2.4%) were intersex. Gender identities evolved over time in 16.3% and 16.1% of patients AMAB and AFAB, respectively, and at most recent follow-up, 8.2% and 12.9% of patients AMAB and AFAB, respectively, were non-binary. Depression affected 78%, followed by anxiety (62.2%), personality disorder (22%), and post-traumatic stress disorder (14.6%). 58.5% experienced suicidal ideation, 22% attempted suicide, and 36.6% were victims of abuse. The most prevalent medical conditions and cardiovascular (CV) risk factors included obesity (42.7%), tobacco use (40.2%), fracture [34.1% (86.2% traumatic)], hypertension (25.6%), hyperlipidemia (25.6%), and hypertriglyceridemia (15.9%). 67.3% of patients AMAB used feminizing and 48.4% of patients AFAB used masculinizing hormone therapy. When compared to US CDC National Health Statistics, there was a significantly greater prevalence of depression and anxiety but no difference in the prevalence of obesity, hypertension, hypercholesterolemia, type 2 diabetes, or stroke. CONCLUSION: Transgender and gender diverse individuals represent a population who express various gender identities and are seeking gender-specific healthcare at increasing rates. Psychiatric illness is highly prevalent compared to the US population but there is no difference in the prevalence of CV risk factors including obesity, type 2 diabetes, hypertension, and dyslipidemia.

TDP-43 and Alzheimer's Disease Pathologic Subtype in Non-Amnestic Alzheimer's Disease Dementia.

BACKGROUND: TDP-43 has been shown to be strongly associated with memory loss, smaller hippocampal volumes, and faster rates of hippocampal atrophy in Alzheimer's disease (AD) patients with an amnestic presentation. Whether TDP-43 has any clinical or anatomical associations in AD patients with non-amnestic phenotype is unknown. OBJECTIVE: To determine whether TDP-43 plays a significant role in the clinic-anatomic features of non-amnestic AD. METHODS: All cases with pathologically confirmed intermediate-high probability AD from 1996-2012 were identified and retrospectively sub-classified into amnestic versus non-amnestic dementia at the time of presentation. Neurofibrillary tangle counts were performed in those with a non-amnestic presentation using thioflavin-S microscopy in the hippocampus and three neocortical regions, and all cases were subtyped into hippocampal-sparing, limbic-predominant, and typical AD pathology. TDP-43 immunoreactivity was used to assess for the presence of TDP-43. Statistical analyses helped determine whether pathologic subtype or TDP-43 was more strongly associated with clinico-imaging features. RESULTS: Out of 172 pathologically confirmed AD cases, 36 (19%) were classified as non-amnestic. Twenty-five of these 36 (69%) had typical pathology, 0 limbic-predominant pathology, and 11 (31%) hippocampal-sparing pathology. Eleven (44%) of the 25 cases with typical pathology were TDP-43+. Of the 11 cases with hippocampal-sparing pathology, 4 (36%) were TDP-43+. There were no differences in demographic, clinical, or neuroimaging features in those with TDP-43 versus those without except for older age at onset (p = 0.02) and age at death (p = 0.02) in those with TDP-43. AD pathological subtype accounted for slightly more of the variances in the neocortex than TDP-43. CONCLUSION: In non-amnestic AD, we find little evidence that clinical or anatomical features of the disease are related to TDP-43.

A Neuropsychiatric Analysis of the Cotard Delusion.

Cotard's syndrome, a condition in which the patient denies his or her own existence or the existence of body parts, is a rare illness that has been reported in association with several neuropsychiatric diagnoses. The majority of published literature on the topic is in the form of case reports, many of which are several years old. The authors evaluated associated diagnoses, neuroimaging, and treatments recorded in patients diagnosed with Cotard's syndrome at their institution. A search of the Mayo Clinic database for patients with mention of signs and symptoms associated with Cotard's in their records between 1996 and 2016 was conducted. The electronic medical records of the identified patients were then reviewed for evidence of a true diagnosis of Cotard's. Clinical and neuroimaging data were also recorded for these patients. The search identified 18 patients, 14 of whom had Cotard delusions. Two of the 14 were excluded due to them being under age 18. The resulting 12 patients had a median age of 52 years (range: 30-85 years). On neuroimaging, four patients exhibited frontal lobe changes, four demonstrated generalized volume loss, and five had ischemic changes; seven patients demonstrated right-sided or bilateral hemisphere lesions. Treatments included ECT, pharmacotherapy, behavioral therapy, psychotherapy, rehydration, and removal of offending drugs. To conclude, Cotard delusions occur in the context of a relatively wide spectrum of neurological, psychiatric, and medical disorders and present with various neural changes. Nondominant hemisphere lesions may play a role in the pathophysiology. A number of effective treatments are available.