Efficacy of antipsychotics in delusional infestation.

BACKGROUND: Data remain scarce for the first-line antipsychotic choice in treating delusional infestation (DI). OBJECTIVES: We evaluated the treatment responses associated with different antipsychotics in DI patients. METHODS: We undertook a multicentre, retrospective observational study using anonymised electronic patient records from two hospitals in the United Kingdom from 1 January 2011 to 1 January 2023. Eligible participants were adults (≥18 years) diagnosed with DI treated with an antipsychotic, and had both an assigned baseline and follow-up Clinical Global Impression Scale (CGI-S) score. The CGI-S is a validated psychiatric research tool. Participants were excluded if they had known limited or non-adherence to an antipsychotic, or if no CGI-S scores were present at follow-up. First clinic visits before the initiation of an antipsychotic were assigned as the baseline CGI-S score. The last available CGI-S score before the patient either changed antipsychotic or left the clinic for any reason was used to assign follow-up CGI-S scores. The primary outcome was the response to each individual antipsychotic treatment, measured by the difference in the baseline and last available follow-up CGI-S scores. Differences in CGI-S changes between antipsychotic episodes were tested by analysis of variance (ANOVA). RESULTS: In total, 414 patient records were analysed, and data were extracted. The mean age was 61.8 years (SD 14.1). One hundred seventy (41%) of 414 patients were men and 244 (59%) were women. In total, 156 (38%) of 414 patients were eligible, yielding a total of 315 antipsychotic prescribing episodes. The ANOVA, ranking in order of treatment response, showed that the highest mean score (expressing highest treatment response) was observed in amisulpride (31 [67%] of 46) and risperidone (95 [57%] of 167), followed by some distance by quetiapine (9 [36%] of 25), aripiprazole (13 [28%] of 46) and olanzapine (7 [25%] of 28). CONCLUSIONS: Amisulpride and risperidone were associated with a higher treatment response than quetiapine, aripiprazole and olanzapine. Amisulpride and risperidone should therefore be considered the first-line treatment options in DI patients.

Defining the Sarcomeric Proteoform Landscape in Ischemic Cardiomyopathy by Top-Down Proteomics.

Ischemic cardiomyopathy (ICM) is a prominent form of heart failure, but the molecular mechanisms underlying ICM remain relatively understudied due to marked phenotypic heterogeneity. Alterations in post-translational modifications (PTMs) and isoform switches in sarcomeric proteins play important roles in cardiac pathophysiology. Thus, it is essential to define sarcomeric proteoform landscape to better understand ICM. Herein, we have implemented a top-down liquid chromatography (LC)-mass spectrometry (MS)-based proteomics method for the identification and quantification of sarcomeric proteoforms in the myocardia of donors without heart diseases (n = 16) compared to end-stage ICM patients (n = 16). Importantly, quantification of post-translational modifications (PTMs) and expression reveal significant changes in various sarcomeric proteins extracted from ICM tissues. Changes include altered phosphorylation and expression of cardiac troponin I (cTnI) and enigma homologue 2 (ENH2) as well as an increase in muscle LIM protein (MLP) and calsarcin-1 (Cal-1) phosphorylation in ICM hearts. Our results imply that the contractile apparatus of the sarcomere is severely dysregulated during ICM. Thus, this is the first study to uncover significant molecular changes to multiple sarcomeric proteins in the LV myocardia of the end-stage ICM patients using liquid chromatography-mass spectrometry (LC-MS)-based top-down proteomics. Raw data are available via the PRIDE repository with identifier PXD038066.

Author Correction: Nanopore native RNA sequencing of a human poly(A) transcriptome.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Nanopore native RNA sequencing of a human poly(A) transcriptome.

High-throughput complementary DNA sequencing technologies have advanced our understanding of transcriptome complexity and regulation. However, these methods lose information contained in biological RNA because the copied reads are often short and modifications are not retained. We address these limitations using a native poly(A) RNA sequencing strategy developed by Oxford Nanopore Technologies. Our study generated 9.9 million aligned sequence reads for the human cell line GM12878, using thirty MinION flow cells at six institutions. These native RNA reads had a median length of 771 bases, and a maximum aligned length of over 21,000 bases. Mitochondrial poly(A) reads provided an internal measure of read-length quality. We combined these long nanopore reads with higher accuracy short-reads and annotated GM12878 promoter regions to identify 33,984 plausible RNA isoforms. We describe strategies for assessing 3' poly(A) tail length, base modifications and transcript haplotypes.

The role of surgery for secondary mitral regurgitation and heart failure in the era of transcatheter mitral valve therapies.

The approach to the management of mitral valve (MV) disease and heart failure (HF) has dramatically changed over the last decades. It is well recognized that severe mitral regurgitation secondary to ischemic or non-ischemic cardiomyopathy is associated with an excess risk of mortality. Understanding the impact of the surgical treatment modality on mortality outcomes has been difficult due to the broad spectrum of secondary mitral regurgitation (SMR) phenotypes and lack of randomized surgical clinical trials. Over the last 30 years, surgeons have failed to provide compelling evidence to convince the medical community of the need to treat SMR in patients with severe HF. Therefore, the surgical treatment of SMR has never gained uniform acceptance as a significant option among patients suffering from SMR. Recent evidence from randomized trials in a non-surgical eligible patients treated with transcatheter therapies, has provided a new perspective on SMR treatment. Recently published European and American guidelines confirm the key role of percutaneous treatment of SMR and in parallel, these guidelines reinforce the role of mitral valve surgery in patients who require surgical revascularization. Complex mitral valve repair combining subvalvular apparatus repair along with annuloplasty seems to be a promising approach in selected patients in selected centers. Meanwhile, mitral valve replacement has become the preferred surgical strategy in most patients with advanced heart failure and severe LV remodeling or high risk of recurrent mitral regurgitation. In this comprehensive review, we aimed to discuss the role of mitral surgery for SMR in patients with heart failure in the contemporary era and to provide a practical approach for its surgical management.

Determining optimal donor heart ischemic times in adult cardiac transplantation.

OBJECTIVES: Unsupervised statistical determination of optimal allograft ischemic time (IT) on heart transplant outcomes among ABO donor heart types. METHODS: We identified 36,145 heart transplants (2000-2018) from the United Network for Organ Sharing database. Continuous and categorical variables were analyzed with parametric and nonparametric testing. Determination of IT cutoffs for survival analysis was performed using Contal and O'Quigley univariable method and Vito Muggeo multivariable segmented modeling. RESULTS: Univariable and multivariable IT threshold determination revealed a cutoff at about 3 h. The hourly increase in survival risk with ≥3 h IT is asymmetrically experienced at the early 90 days (hazard ratio [HR] = 1.29, p < .001) and up to 1-year time point (HR = 1.16, p < .001). Beyond 1 year the risk of prolonged IT is less impactful (HR = 1.04, p = .022). Longer IT was associated with more postoperative complications such as stroke (2.7% vs. 2.3, p = .042), dialysis (11.6% vs. 9.1%, p < .001) and death from primary graft dysfunction (1.8% vs. 1.2%, p < .001). O blood type donor hearts with IT ≥ 3 h has significantly increased hourly mortality risk at 90 days (HR = 1.27, p < .001), 90 days to 1 year (HR = 1.22, p < .001) and >1 year (HR = 1.05, p = .041). For non-O blood types with ≥3 h IT hourly mortality risk was increased at 90 days (HR = 1.33, p < .001), but not at 90 days to 1 year (HR = 1.09, p = .146) nor ≥1 year (HR = 1.08, p = .237). CONCLUSIONS: The donor heart IT threshold for survival determined from unbiased statistical modeling occurs at 3 h. With longer preservation times, transplantation with O donor hearts was associated with worse survival.

Untargeted metabolomics identifies succinate as a biomarker and therapeutic target in aortic aneurysm and dissection.

AIMS: Aortic aneurysm and dissection (AAD) are high-risk cardiovascular diseases with no effective cure. Macrophages play an important role in the development of AAD. As succinate triggers inflammatory changes in macrophages, we investigated the significance of succinate in the pathogenesis of AAD and its clinical relevance. METHODS AND RESULTS: We used untargeted metabolomics and mass spectrometry to determine plasma succinate concentrations in 40 and 1665 individuals of the discovery and validation cohorts, respectively. Three different murine AAD models were used to determine the role of succinate in AAD development. We further examined the role of oxoglutarate dehydrogenase (OGDH) and its transcription factor cyclic adenosine monophosphate-responsive element-binding protein 1 (CREB) in the context of macrophage-mediated inflammation and established p38αMKOApoe-/- mice. Succinate was the most upregulated metabolite in the discovery cohort; this was confirmed in the validation cohort. Plasma succinate concentrations were higher in patients with AAD compared with those in healthy controls, patients with acute myocardial infarction (AMI), and patients with pulmonary embolism (PE). Moreover, succinate administration aggravated angiotensin II-induced AAD and vascular inflammation in mice. In contrast, knockdown of OGDH reduced the expression of inflammatory factors in macrophages. The conditional deletion of p38α decreased CREB phosphorylation, OGDH expression, and succinate concentrations. Conditional deletion of p38α in macrophages reduced angiotensin II-induced AAD. CONCLUSION: Plasma succinate concentrations allow to distinguish patients with AAD from both healthy controls and patients with AMI or PE. Succinate concentrations are regulated by the p38α-CREB-OGDH axis in macrophages.

Fate of preoperative moderate mitral regurgitation following left ventricular assist device implantation.

OBJECTIVE: We examined for improvements in preoperative moderate mitral regurgitation following continuous-flow left ventricular assist device (cfLVAD) implantation. METHODS: From 2006 to 2020, 190 patients with moderate MR underwent cfVLAD implant without concomitant mitral valve (MV) surgery. Cardiac dimensions and contractility, as well as valve function, were assessed with an echocardiogram (echo) pre-cfLVAD, and at approximately 1 month post-cfLVAD. Outcomes were determined by retrospective chart review. RESULTS: Median echo follow-up was 0.94 (0.53, 1.38) months. Residual significant moderate or greater MR was present in 30/190 (15.8%) on follow-up. Patients with significant residual MR had larger preoperative left ventricular internal diameters in diastole (74.4 ± 8.7 vs. 71.1.0 ± 9.1 mm, p = .034). Significant residual MR was associated with higher preoperative mean pulmonary artery pressures (OR = 1.055, p = .035) and pulmonary capillary wedge pressures (OR = 1.060, p = .034). Significant residual MR on echo was not associated with any survival difference (p = .325). The 1, 5, and 10 year survival were 89.9%, 55.2%, and 34.2%, respectively. CONCLUSIONS: For patients with moderate MR undergoing LVAD implantation, the likelihood of significant residual MR is low and mitral intervention in this population is not recommended. However, select patients with larger preoperative left heart dimensions and pulmonary vascular pressures may be at risk for persistent residual MR.

Risk factors for heart transplant survival with greater than 5 h of donor heart ischemic time.

OBJECTIVE: Implantation of donor hearts with prolonged ischemic times is associated with worse survival. We sought to identify risk factors that modulate the effects of prolonged preservation. METHODS: Retrospective review of the United Network for Organ Sharing database (2000-2018) to identify transplants with >5 (n = 1526) or ≤5 h (n = 35,733) of donor heart preservation. In transplanted hearts preserved for >5 h, Cox-proportional hazards identify modifiers for survival. RESULTS: Compared to ≤5 h, transplanted patients with >5 h of preservation spent less time in status 1B (76 ± 160 vs. 85 ± 173 days, p = .027), more commonly had ischemic cardiomyopathy (42.3% vs. 38.3%, p = .002), and less commonly received a blood type O heart (45.4% vs. 50.8%, p < .001). Longer heart preservation time was associated with a higher incidence of postoperative stroke (4.5% vs. 2.5%, p < .001), and dialysis (16.4% vs. 10.6%, p < .001). Prolonged preservation was associated with a greater likelihood of death from primary graft dysfunction (2.8% vs. 1.5%, p < .001) but there was no difference in death from acute (2.0% vs. 1.7%, p = .402) or chronic rejection (2.0% vs. 1.9%, p = .618). In transplanted patients with >5 h of heart preservation, multivariable analysis identified greater mortality with ischemic cardiomyopathy etiology (hazard ratio [HR] = 1.36, p < 0.01), pre-transplant dialysis (HR = 1.84, p < .01), pre-transplant extracorporeal membrane oxygenation (ECMO, HR = 2.36, p = .09), and O blood type donor hearts (HR = 1.35, p < .01). CONCLUSION: Preservation time >5 h is associated with worse survival. This mortality risk is further amplified by preoperative dialysis and ECMO, ischemic cardiomyopathy etiology, and use of O blood type donor hearts.

STratification risk analysis in OPerative management (STOP score) for drug-induced endocarditis.

BACKGROUND: The opioid epidemic has seen a drastic increase in the incidence of drug-associated infective endocarditis (IE). No clinical tool exists to predict operative morbidity and mortality in patients undergoing surgery. METHODS: A multi-institutional database was reviewed between 2011 and 2018. Multivariate logistic regression was fitted in an automated stepwise fashion. The STratification risk analysis in OPerative management of drug-associated IE (STOP) score was constructed. Morbidity was defined as reintubation, prolonged ventilation, pneumonia, renal failure, dialysis, stroke, reoperation for bleeding, and a permanent pacemaker. Cross-validation provided an unbiased estimate of out-of-sample performance. RESULTS: A total of 1181 patients underwent surgery for drug-associated IE (median age, 39; interquartile range [IQR], 30-54, 386 women [32.7%], 341 reoperations for prosthetic valve endocarditis [28.9%], 316 patients with multivalve disease [26.8%]). Operative morbidity and mortality were 41.1% and 5.9%, respectively. Predictors of morbidity were dialysis (95% confidence interval [CI], 1.16-2.82), emergent intervention (1.83-4.73), multivalve procedure (1.01-1.98), causative organisms other than Streptococcus (1.09-2.02), and type of valve procedure performed [aortic valve procedure (1.07-2.15), mitral valve replacement (1.03-2.05), tricuspid valve replacement (1.21-2.60)]. Predictors of mortality were dialysis (1.29-5.74), active endocarditis (1.32-83), lung disease (1.25-5.43), emergent intervention (1.69-6.60), prosthetic valve endocarditis (1.24-3.69), aortic valve procedure (1.49-5.92) and multivalve disease (1.00-2.95). Variables maximizing explanatory power were translated into a scoring system. Each point increased odds of morbidity and mortality by 22.0% and 22.4% with an accuracy of 94.0% and 94.1%, respectively. CONCLUSION: Drug-related IE is associated with significant morbidity and mortality. An easily-applied risk stratification score may aid in clinical decision-making.

Endothelin signaling activates Mef2c expression in the neural crest through a MEF2C-dependent positive-feedback transcriptional pathway.

Endothelin signaling is essential for neural crest development, and dysregulated Endothelin signaling is associated with several neural crest-related disorders, including Waardenburg and other syndromes. However, despite the crucial roles of this pathway in neural crest development and disease, the transcriptional effectors directly activated by Endothelin signaling during neural crest development remain incompletely elucidated. Here, we establish that the MADS box transcription factor MEF2C is an immediate downstream transcriptional target and effector of Endothelin signaling in the neural crest. We show that Endothelin signaling activates Mef2c expression in the neural crest through a conserved enhancer in the Mef2c locus and that CRISPR-mediated deletion of this Mef2c neural crest enhancer from the mouse genome abolishes Endothelin induction of Mef2c expression. Moreover, we demonstrate that Endothelin signaling activates neural crest expression of Mef2c by de-repressing MEF2C activity through a Calmodulin-CamKII-histone deacetylase signaling cascade. Thus, these findings identify a MEF2C-dependent, positive-feedback mechanism for Endothelin induction and establish MEF2C as an immediate transcriptional effector and target of Endothelin signaling in the neural crest.

Natural history of the proximal aorta in patients with descending thoracic aortic disease.

OBJECTIVE: This study investigated the growth and behavior of the ascending aorta in patients with descending thoracic aortic disease. METHODS: We examined 200 patients with descending thoracic aortic disease including acute type B dissection (n = 95), chronic type B dissection (n = 38), intramural hematoma (n = 23), and thoracoabdominal aortic aneurysms (n = 44). Images from computed tomography and magnetic resonance imaging were evaluated after three-dimensional reconstruction to examine the growth rate in those with >1 year of imaging follow-up (n = 108). Survival data were derived from all 200 patients in this study. RESULTS: Average proximal aortic dimensions at the index image were relatively small, measuring 3.65 ± 0.51 cm in the root, 3.67 ± 0.48 cm in the ascending aorta, and 3.50 ± 0.44 cm in the proximal arch. Average growth rate was low for the aortic root, ascending aorta, and proximal arch at 0.36 ± 0.64 mm/y, 0.26 ± 0.44 mm/y, and 0.25 ± 0.44 mm/y, respectively. There was no difference in baseline proximal aortic dimensions and growth rate between the four subgroups. An index aortic diameter ≥4.1 cm grew faster than those <4.1 cm at the ascending aorta (P = .028) and proximal arch (P = .019). There was no difference in aortic growth rates at the aortic root (P = .887). After the index scan, five patients underwent six ascending aortic replacement procedures, leading to a 3% ascending aortic intervention rate. Overall median life expectancy was 86.15 years. CONCLUSIONS: Native ascending aortic growth in patients with descending thoracic aortic disease is slow. We suggest regular follow-up for index ascending aorta ≥4.1 cm because of its larger initial size and more rapid growth.

DLX4 is associated with orofacial clefting and abnormal jaw development.

Cleft lip and/or palate (CL/P) are common structural birth defects in humans. We used exome sequencing to study a patient with bilateral CL/P and identified a single nucleotide deletion in the patient and her similarly affected son­c.546_546delG, predicting p.Gln183Argfs*57 in the Distal-less 4 (DLX4) gene. The sequence variant was absent from databases, predicted to be deleterious and was verified by Sanger sequencing. In mammals, there are three Dlx homeobox clusters with closely located gene pairs (Dlx1/Dlx2, Dlx3/Dlx4, Dlx5/Dlx6). In situ hybridization showed that Dlx4 was expressed in the mesenchyme of the murine palatal shelves at E12.5, prior to palate closure. Wild-type human DLX4, but not mutant DLX4_c.546delG, could activate two murine Dlx conserved regulatory elements, implying that the mutation caused haploinsufficiency. We showed that reduced DLX4 expression after short interfering RNA treatment in a human cell line resulted in significant up-regulation of DLX3, DLX5 and DLX6, with reduced expression of DLX2 and significant up-regulation of BMP4, although the increased BMP4 expression was demonstrated only in HeLa cells. We used antisense morpholino oligonucleotides to target the orthologous Danio rerio gene, dlx4b, and found reduced cranial size and abnormal cartilaginous elements. We sequenced DLX4 in 155 patients with non-syndromic CL/P and CP, but observed no sequence variants. From the published literature, Dlx1/Dlx2 double homozygous null mice and Dlx5 homozygous null mice both have clefts of the secondary palate. This first finding of a DLX4 mutation in a family with CL/P establishes DLX4 as a potential cause of human clefts.

Acute retrograde type A aortic dissection: morphologic analysis and clinical implications.

BACKGROUND: This study compares the morphology and outcomes of acute retrograde type A dissections (RTADs) with acute antegrade type A dissections (ATADs), and acute type B dissections. MATERIALS AND METHODS: From 2000 to 2016, there were 12 acute RTADs, 96 ATADs, and 92 type B dissections with available imaging. Dissections were characterized using computerized tomography angiography images. We examined clinical features, tear characteristics, and various morphologic measurements. RESULTS: Compared with acute type B dissections, RTAD primary tears were more common in the distal arch (75% versus 43%, P = 0.04), and the false-to-true lumen contrast intensity ratio at the mid-descending thoracic aorta was lower (0.46 versus 0.71, P = 0.020). RTAD had less false lumen decompression because there were fewer aortic branch vessels distal to the subclavian that were perfused through the false lumen (0.40 versus 2.19, P < 0.001). Compared with ATAD, RTAD had less root involvement where root true-to-total lumen area ratio was higher (0.88 versus 0.76, P = 0.081). Furthermore, RTAD had a lower false-to-true lumen contrast intensity ratio at the root (0.25 versus 0.57, P < 0.05), ascending aorta (0.25 versus 0.72, P < 0.001), and proximal arch (0.39 versus 0.67, P < 0.05). RTAD were more likely to undergo aortic valve resuspension (100% versus 74%, P = 0.044). CONCLUSIONS: RTAD tends to occur when primary tears occur in close proximity to the aortic arch and when false lumen decompression through the distal aortic branches are less effective. Compared with ATAD, RTAD has less root involvement, and successful aortic valve resuspension is more likely.

Genetic analysis of consanguineous families presenting with congenital ocular defects.

Anophthalmia and microphthalmia (A/M) are a group of rare developmental disorders that affect the size of the ocular globe. A/M may present as the sole clinical feature, but are also frequently found in a variety of syndromes. A/M is genetically heterogeneous and can be caused by chromosomal aberrations, copy number variations and single gene mutations. To date, A/M has been caused by mutations in at least 20 genes that show different modes of inheritance. In this study, we enrolled eight consanguineous families with A/M, including seven from Pakistan and one from India. Sanger and exome sequencing of DNA samples from these families identified three novel mutations including two mutations in the Aldehyde Dehydrogenase 1 Family Member A3 (ALDH1A3) gene, [c.1310_1311delAT; p.(Tyr437Trpfs*44) and c.964G > A; p.(Val322Met)] and a single missense mutation in Forkhead Box E3 (FOXE3) gene, [c.289A > G p.(Ile97Val)]. Additionally two previously reported mutations were identified in FOXE3 and in Visual System Homeobox 2 (VSX2). This is the first comprehensive study on families with A/M from the Indian subcontinent which provides further evidence for the involvement of known genes with novel and recurrent mutations.

Association of Single Nucleotide Polymorphisms with Atrial Fibrillation and the Outcome after Catheter Ablation.

BACKGROUND: The association of gene variants with atrial fibrillation (AF) type and the recurrence of AF after catheter ablation in Taiwan is still unclear. In this study, we aimed to investigate the relationships between gene variants, AF type, and the recurrence of AF. METHODS: In our investigation, we examined 383 consecutive patients with AF (61.9 ± 14.0 years; 63% men); of these 383 patients, 189 underwent catheter ablation for drug-refractory AF. Thereafter, the single nucleotide polymorphisms rs2200733, and rs7193343 were genotyped using real-time polymerase chain reaction. RESULTS: The rs7193343 variant was independently associated with non-paroxysmal AF (non-PAF). In the PAF group, the rs7193343 variant was independently associated with AF recurrence after catheter ablation. However, the rs2200733 variant was not associated with AF recurrence in this group. The combination of the rs7193343 and rs2200733 risk alleles was associated with a better predictive power in the PAF patients. In contrast, in the non-PAF group, the SNPs were not associated with recurrence. The rs7193343 and rs2200733 variants were not associated with different atrial voltage and activation times. CONCLUSIONS: The rs7193343 variants were associated with AF recurrence after catheter ablation in PAF patients but not in non-PAF patients. The rs7193343 CC variant was independently associated with non-PAF.

Focal facial dermal dysplasia, type IV, is caused by mutations in CYP26C1.

Focal facial dermal dysplasia (FFDD) Type IV is a rare syndrome characterized by facial lesions resembling aplasia cutis in a preauricular distribution along the line of fusion of the maxillary and mandibular prominences. To identify the causative gene(s), exome sequencing was performed in a family with two affected siblings. Assuming autosomal recessive inheritance, two novel sequence variants were identified in both siblings in CYP26C1-a duplication of seven base pairs, which was maternally inherited, c.844_851dupCCATGCA, predicting p.Glu284fsX128 and a missense mutation, c.1433G>A, predicting p.Arg478His, that was paternally inherited. The duplication predicted a frameshift mutation that led to a premature stop codon and premature chain termination, whereas the missense mutation was not functional based on its in vitro expression in mammalian cells. The FFDD skin lesions arise along the sites of fusion of the maxillary and mandibular prominences early in facial development, and Cyp26c1 was expressed exactly along the fusion line for these facial prominences in the first branchial arch in mice. Sequencing of four additional, unrelated Type IV FFDD patients and eight Type II or III TWIST2-negative FFDD patients revealed that three of the Type IV patients were homozygous for the duplication, whereas none of the Type II or III patients had CYP26C1 mutations. The seven base pairs duplication was present in 0.3% of healthy controls and 0.3% of patients with other birth defects. These findings suggest that the phenotypic manifestations of FFDD Type IV can be non-penetrant or underascertained. Thus, FFDD Type IV results from the loss of function mutations in CYP26C1.

Mechanosensory and command contributions to the Drosophila grooming sequence.

Flies groom in response to competing mechanosensory cues in an anterior-to-posterior order using specific legs. From behavior screens, we identified a pair of cholinergic command-like neurons, Mago-no-Te (MGT), whose optogenetic activation elicits thoracic grooming by the back legs. Thoracic grooming is typically composed of body sweeps and leg rubs in alternation, but clonal analysis coupled with amputation experiments revealed that MGT activation only commands the body sweeps: initiation of leg rubbing requires contact between the leg and thorax. With new electron microscopy (EM) connectome data for the ventral nerve cord (VNC), we uncovered a circuit-based explanation for why stimulation of posterior thoracic mechanosensory bristles initiates cleaning by the back legs. Our previous work showed that flies weigh mechanosensory inputs across the body to select which part to groom, but we did not know why the thorax was always cleaned last. Here, the connectome for the VNC enabled us to identify a pair of GABAergic inhibitory neurons, UMGT1, that receives diverse sensory inputs and synapses onto both MGT and components of its downstream circuits. Optogenetic activation of UMGT1 suppresses thoracic cleaning, representing a mechanism by which mechanosensory stimuli on other body parts could take precedence in the grooming hierarchy. We also anatomically mapped the pre-motor circuit downstream of MGT, including inhibitory feedback connections that may enable rhythmicity and coordination of limb movement during thoracic grooming. The combination of behavioral screens and connectome analysis allowed us to identify a neural circuit connecting sensory-to-motor neurons that contributes to thoracic grooming.

Primary graft dysfunction in heart transplantation: the challenge to survival.

Primary graft dysfunction (PGD) is a life-threatening clinical condition with a high mortality rate, presenting as left, right, or biventricular dysfunction within the initial 24 h following heart transplantation, in the absence of a discernible secondary cause. Given its intricate nature, definitive definition and diagnosis of PGD continues to pose a challenge. The pathophysiology of PGD encompasses numerous underlying mechanisms, some of which remain to be elucidated, including factors like myocardial damage, the release of proinflammatory mediators, and the occurrence of ischemia-reperfusion injury. The dynamic characteristics of both donors and recipients, coupled with the inclination towards marginal lists containing more risk factors, together contribute to the increased incidence of PGD. The augmentation of therapeutic strategies involving mechanical circulatory support accelerates myocardial recovery, thereby significantly contributing to survival. Nonetheless, a universally accepted treatment algorithm for the swift management of this clinical condition, which necessitates immediate intervention upon diagnosis, remains absent. This paper aims to review the existing literature and shed light on how diagnosis, pathophysiology, risk factors, treatment, and perioperative management affect the outcome of PGD.