Programmatic approach to patients with advanced ischemic cardiomyopathy: Integrating microaxial support into strategies for the modern era.

Patients with advanced ischemic cardiomyopathy manifesting as left ventricular dysfunction exist along a spectrum of severity and risk, and thus decision-making surrounding optimal management is challenging. Treatment pathways can include medical therapy as well as revascularization through percutaneous coronary intervention or coronary artery bypass grafting. Additionally, temporary and durable mechanical circulatory support, as well as heart transplantation, may be optimal for select patients. Given this spectrum of risk and the complexity of treatment pathways, patients may not receive appropriate therapy given their perceived risk, which can lead to sub-satisfactory outcomes. In this review, we discuss the identification of high-risk ischemic cardiomyopathy patients, along with our programmatic approach to patient evaluation and perioperative optimization. We also discuss our strategies for therapeutic decision-making designed to optimize both short- and long-term patient outcomes.

Clinical performance, safety, and patient-reported outcomes of an active osseointegrated bone-conduction hearing implant system at 24-month follow-up.

PURPOSE: To investigate 2-year post-operative hearing performance, safety, and patient-reported outcomes of hearing-impaired adults treated with the Osia® 2 System, an active osseointegrated bone-conduction hearing implant that uses piezoelectric technology. METHODS: A prospective, multicenter, open-label, single-arm, within-subject clinical study conducted at three tertiary referral clinical centers located in Melbourne, Sydney and Hong Kong. Twenty adult recipients of the Osia 2 System were enrolled and followed up between 12 and 24 months post-implantation: 17 with mixed or conductive hearing loss and 3 with single-sided sensorineural deafness. Safety data, audiological thresholds, speech recognition thresholds in noise, and patient-reported outcomes were collected and evaluated. In addition, pre-and 6-month post-implantation data were collected retrospectively for this recipient cohort enrolled into the earlier study (ClinicalTrials.gov NCT04041700). RESULTS: Between 6- and 24-month follow-up, there was no statistically significant change in free-field hearing thresholds or speech reception thresholds in noise (p = > 0.05), indicating that aided improvements were maintained up to 24 months of follow-up. Furthermore, improvements in health-related quality of life and daily hearing ability, as well as clinical and subjective measures of hearing benefit remained stable over the 24-month period. No serious adverse events were reported during extended follow-up. CONCLUSIONS: These study results provide further evidence to support the longer term clinical safety, hearing performance, and patient-related benefits of the Osia 2 System in patients with either a conductive hearing loss, mixed hearing loss, or single-sided sensorineural deafness. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04754477. First posted: February 15, 2021.

Extended DNA-binding interfaces beyond the canonical SAP domain contribute to the function of replication stress regulator SDE2 at DNA replication forks.

Elevated DNA replication stress causes instability of the DNA replication fork and increased DNA mutations, which underlies tumorigenesis. The DNA replication stress regulator silencing-defective 2 (SDE2) is known to bind to TIMELESS (TIM), a protein of the fork protection complex, and enhances its stability, thereby supporting replisome activity at DNA replication forks. However, the DNA-binding activity of SDE2 is not well defined. Here, we structurally and functionally characterize a new conserved DNA-binding motif related to the SAP (SAF-A/B, Acinus, PIAS) domain in human SDE2 and establish its preference for ssDNA. Our NMR solution structure of the SDE2SAP domain reveals a helix-extended loop-helix core with the helices aligned parallel to each other, consistent with known canonical SAP folds. Notably, we have shown that the DNA interaction of this SAP domain extends beyond the core SAP domain and is augmented by two lysine residues in the C-terminal tail, which is uniquely positioned adjacent to the SAP motif and conserved in the pre-mRNA splicing factor SF3A3. Furthermore, we found that mutation in the SAP domain and extended C terminus not only disrupts ssDNA binding but also impairs TIM localization at replication forks, thus inhibiting efficient fork progression. Taken together, our results establish SDE2SAP as an essential element for SDE2 to exert its role in preserving replication fork integrity via fork protection complex regulation and highlight the structural diversity of the DNA-protein interactions achieved by a specialized DNA-binding motif.

Combined Liver Transplant and Cardiac Surgery: Long-Term Outcomes and Predictors of Success.

OBJECTIVE: We aim to report our institutional outcomes of single-staged combined liver transplantation (LT) and cardiac surgery (CS). SUMMARY BACKGROUND DATA: Concurrent LT and CS is a potential treatment for combined cardiac dysfunction and end-stage liver disease, yet only 54 cases have been previously reported in the literature. Thus, the outcomes of this approach are relatively unknown, and this approach has been previously regarded as extremely risky. METHODS: Thirty-one patients at our institution underwent combined cardiac surgery and liver transplant. Patients with at least one-year follow-up were included. The Leave-One-Out Cross-Validation (LOOCV) machine-learning approach was used to generate a model for mortality. RESULTS: Median follow-up was 8.2 years (IQR 4.6-13.6 y). One- and five-year survival was 74.2% (N=23) and 55% (N=17), respectively. Negative predictive factors of survival included recipient age>60 years (P=0.036), NASH-cirrhosis (P=0.031), Coronary Artery Bypass-Graft (CABG)-based CS (P=0.046) and pre-operative renal dysfunction (P=0.024). The final model demonstrated that renal dysfunction had a relative weighted impact of 3.2 versus CABG (1.7), age ≥60y (1.7) or NASH (1.3). Elevated LT+CS risk score was associated with an increased five-year mortality after surgery (AUC=0.731, P=<0.001). Conversely, the widely accepted STS-PROM calculator was unable to successfully stratify patients according to 1- (P>0.99) or 5-year (P=0.695) survival rates. CONCLUSIONS: This is the largest series describing combined LT+CS, with joint surgical management appearing feasible in highly selected patients. CABG and pre-operative renal dysfunction are important negative predictors of mortality. The four-variable LT+CS score may help predict patients at high risk for post-operative mortality.

Coronary artery bypass grafting in left ventricular dysfunction: when and how.

PURPOSE OF REVIEW: The surgical management of patients undergoing coronary artery bypass grafting (CABG) with low ejection fraction presents unique challenges that require meticulous attention to details and good surgical technique and judgement. This review details the latest evidence and best practices in the care of such patients. RECENT FINDINGS: CABG in patients with low ejection fraction carries a significant risk of perioperative mortality and morbidity related to the development of postcardiotomy shock. Preoperative optimization with pharmacological or mechanical support is required, especially in patients with cardiogenic shock. Rapid and complete revascularization is what CABG surgeons aim to achieve. Multiple arterial revascularization should be reserved to selected patients. Off-pump CABG, on-pump breathing heart CABG, and new cardioplegic solutions remain of uncertain benefit compared with traditional CABG. SUMMARY: Tremendous advancements in CABG allowed surgeons to offer revascularization to patients with severe left ventricular dysfunction and multivessel disease with acceptable risk. Despite that, there is a lack of comprehensive and robust studies particularly on long-term outcomes. Individualized patient assessment and a heart team approach should be used to determine the optimal surgical strategy for each patient.

Cadaver Study on Transoral Thyroid Chondrolaryngoplasty and Transoral Sistrunk Operation, Possibility from Transoral Thyroidectomy.

OBJECTIVE: Transoral approaches in surgery are gaining global popularity. Transoral endoscopic and robotic thyroidectomies are well established due to the benefit of being truly scarless. Thyroid chondrolaryngoplasty reduces protrusion of the thyroid notch in transgender patients. The Sistrunk operation involves removal of the thyroglossal cyst and the central portion of the hyoid bone. In this cadaveric study, we developed a transoral thyroidectomy approach and assessed the feasibility of applying this technique to thyroid chondrolaryngoplasty and Sistrunk operation with the proper usage of a special endoscopic burr. METHODS: We performed surgery using the transoral vestibular approach with 13 fresh-frozen human cadavers. Unlike transoral thyroid surgery, which requires high-resolution detailed anatomical view, this technique uses a 5-mm 30-degree endoscope with a 5-mm central port. A smaller central port can reduce the risk of mental nerve paresthesia. A special endoscopic burr for functional endoscopic sinus surgery is used to thin the thyroid notch cartilage and cut the central portion of the hyoid bone. RESULTS: We successfully performed transoral thyroid chondrolaryngoplasty and transoral Sistrunk operation in 13 cadavers. CONCLUSION: Transoral chondrolaryngoplasty and transoral Sistrunk operation are feasible for transgender or thyroglossal cyst patients. It offers the additional benefit of being a scarless surgery and could play a promising role in minimally invasive thyroid surgeries. Proper use of an endoscopic drilling burr to thin thyroid notch cartilage and cutting the central portion of the hyoid bone can make transoral thyroid chondrolaryngoplasty and transoral Sistrunk operation safe and feasible .

Protection of the marginal mandibular branches of the facial nerves by different surgical procedures in comprehensive cervical lymphadenectomy for locally advanced oral and oropharyngeal cancer: a multicenter experience.

OBJECTIVE: According to the different characteristics of patients and cervical lymph node metastasis of oral and oropharyngeal cancer, the marginal mandibular branches of facial nerves were treated by different surgical procedures, and the safety and protective effects of different surgical procedures were investigated. METHODS: One hundred ninety-seven patients with oral and oropharyngeal cancer satisfying the inclusion criteria were selected. According to the different characteristics of patients and cervical metastatic lymph nodes, three different surgical procedures were used to treat the marginal mandibular branches of the facial nerve: finding and exposing the marginal mandibular branches of the facial nerves at the mandibular angles of the platysma flaps, finding and exposing the marginal mandibular branches of facial nerves at the intersections of the distal ends of facial arteries and veins with the mandible, and not exposing the marginal mandibular branches of the facial nerves. The anatomical position, injury, and complications of the marginal mandibular branches of the facial nerves were observed. RESULTS: The marginal mandibular branches of the facial nerves were found and exposed at the mandibular angles of the platysma flaps in 102 patients; the marginal mandibular branches of facial nerves were found and exposed at the intersections of the distal ends of the facial arteries and veins with the mandibles in 64 patients; the marginal mandibular branches of facial nerves were not exposed in 31 patients; among them, four patients had permanent injury of the marginal mandibular branches of the facial nerves, and temporary injury occurred in seven patients. There were statistically significant differences in the protection of the mandibular marginal branch of the facial nerve among the three different surgical methods (P = 0.0184). The best protective effect was to find and expose the mandibular marginal branch of the facial nerve at the mandibular angle of the platysma muscle flap, and the injury rate was only 2.94%. CONCLUSION: The three different surgical procedures were all safe and effective in treating the marginal mandibular branches of the facial nerves, the best protective effect was to find and expose the mandibular marginal branch of the facial nerve at the mandibular angle of the platysma muscle flap.

Surgical Approaches for Pericardial Diseases: What Is New?

PURPOSE OF REVIEW: The purpose of this review is to discuss the evolving techniques and approaches for pericardiectomy, with a focus on the use of cardiopulmonary bypass (CPB) and the extent of radical pericardial resection. The review aims to highlight the benefits and considerations associated with these modifications in radical pericardiectomy. RECENT FINDINGS: Recent studies have demonstrated that the use of CPB during pericardiectomy does not increase procedural risk or negatively impact survival. In fact, it has been shown to contribute to a more radical resection and improve postoperative outcomes, which is associated with less recurrence and better survival. The review emphasizes the importance of radical pericardiectomy and the use of CPB in achieving successful outcomes. Radical resection of the pericardium, facilitated by CPB, helps minimize the risk of recurrent constrictions and the need for reinterventions. The findings highlight the correlation between postoperative outcomes and survival, further supporting the use of CPB.

Endoscopic and observational findings of swallowing of traditional and molded puree in healthy individuals.

Puree is commonly prescribed for patients with mastication and bolus formation difficulties, but its appearance might negatively impact appetite and intake. Molded puree is marketed to be an alternative to traditional puree, but the process of molding puree could alter the properties of the food significantly and lead to different swallowing physiology as compared to puree. The current study investigated the differences between traditional and molded puree in terms of swallowing physiology and perception in healthy individuals. Thirty two participants were included. Two outcomes were used to quantify the oral preparatory and oral phase. Fibreoptic endoscopic evaluation of swallowing was used to assess the pharyngeal phase as it could retain the purees in their original form. Six outcomes were collected. Perceptual rating of the purees were provided by participants in six domains. Molded puree required significantly more masticatory cycles (p < 0.001) and longer time for ingestion (p < 0.001). Molded puree had longer swallow reaction time (p = 0.001) and more inferior site of swallow initiation (p = 0.007) compared with traditional puree. Participants' satisfaction with the appearance, texture and overall of molded puree was significantly greater. Molded puree was perceived to be more difficult to chew and swallow. This study established that the two types of puree were different in various aspects. The study also provided important clinical implications regarding the use of molded puree as a form of texture modified diet (TMD) in patients with dysphagia. The results could serve as the foundation of larger cohort studies on the effect of various TMDs on patients with dysphagia.

Feasibility and self-perceived effectiveness of an online training program on dysphagia in residential aged care homes in mainland China.

BACKGROUND: With a rapidly aging population in mainland China, dysphagia has become one of the common geriatric disorders which creates a huge demand on speech and language therapists (SLTs). The major challenge is the shortage of SLTs in China. In addition, frontline practitioners in mainland China may not be well equipped with the knowledge and practical skills in dysphagia management due to lack of systematic training and the work nature. AIMS: This study evaluates the self-perceived effectiveness and feasibility of an online training program that aims to enhance the self-assessed knowledge and skills of SLTs providing dysphagia care in residential aged care homes. METHODS AND PROCEDURES: Sixteen SLTs working in a residential aged care homes in mainland China attended a three-hour pilot online training program which consists of didactic lecture and practical skills activity components. A total of 10 participants completed an online questionnaire one month after the training to evaluate the feasibility and effectiveness of this online training program. OUTCOMES AND RESULTS: The preliminary results demonstrated participants' self-perception of high training effectiveness in theoretical knowledge and practical skills. A majority of the participants perceived that the training enhanced their theoretical knowledge and all of them perceived that they acquired practical skills. All respondents were satisfied with the online training approach. They also highlighted the advantage and challenges of the online training approach. CONCLUSIONS AND IMPLICATIONS: Online training is an effective and feasible approach for theoretical knowledge and practical skills transfer in SLT training and could ultimately benefit the delivery of services for individuals with dysphagia in mainland China. WHAT THIS PAPER ADDS: What is already known on the subject Previous studies have shown that online training approach is as effective as face-to-face training in increasing professional knowledge. Online training programs may be more cost efficient and time efficient when compared with face-to-face training. What this study adds The present study provided preliminary evidence to support the feasibility and effectiveness of using online training on dysphagia for speech and language therapists working in residential aged care homes in mainland China. What are the clinical implications of this work? From the participants' perception, online training approach is effective and feasible in delivering theoretical knowledge and practical skills. It may be a better training approach for mainland China considering the lack of expertise and accessibility to training.

Speech Telepractice and Treatment Intensity in a Cantonese-Speaking Case with 22q11.2 Deletion Syndrome Following Late Diagnosis and Management of Velopharyngeal Dysfunction.

This case report explores clinical treatment efficacy in a Cantonese-speaking child with 22q11.2 Deletion Syndrome where diagnosis and management of velopharyngeal dysfunction can be considered late. All treatment sessions were undertaken via telepractice during the peak of the COVID-19 pandemic in Hong Kong. A hybrid of specialized cleft palate speech treatment techniques and traditional treatment approaches in Speech Sound Disorders were utilized. Treatment intensity components including dose, dose form, session duration, and total intervention duration were documented.

Applying computer-based language test to young children.

INTRODUCTION: This study aims at exploring the feasibility of applying a computer-based language test to young children aged 2-4 years. METHODS: Thirty-two Cantonese-speaking children, aged 2-4 years, were recruited from local kindergartens. All participants underwent assessment using both the computer-based and paper-pencil versions of the Macau Cantonese Language Screening Scale for Preschool Children, following a crossover study design. A short break of 15-30 minutes was provided between the two assessments. The data were analysed at three levels: the overall test, subcategory, and individual item levels. At the overall test and subcategory levels, data were analysed using the paired samples t-test and ICC. At the item level, the percentage of agreement and Cohen's kappa value were selected to assess the agreement of the two test formats. RESULTS: Excellent agreement was found for the overall test level, and good agreement was observed for four of the five subcategories. At the individual item level, 28 of the 35 items showed more than 80% agreement, and 16 items showed substantial to almost perfect agreement. CONCLUSION: These results suggest that the two test formats give similar total scores and subcategory scores for children aged 2-4. For children older than 2 years, 6 months, the agreement for matching items is as high as 83.68% (1318/1575). The computer-based test is thus highly recommended for this group of children. For children younger than 2 years, 6 months, a modified computer-based test is suggested to accommodate their needs.

Lexical tone perception and production in Cantonese-speaking children with childhood apraxia of speech: a pilot study.

Childhood apraxia of speech (CAS) is a paediatric motor speech disorder. We investigated the lexical tone perception and production abilities of children with CAS and the relationships between the two. Three children with CAS, aged between 3;7 and 5;8, were given the Cantonese Tone Identification Test (CANTIT) and the Hong Kong Cantonese Articulation Test (HKCAT) for assessment of tone perception and production, respectively. Accuracy and error patterns were investigated based on their performance on the two tests. Correlation analysis was performed on children's perception and production scores. Two children scored at the lowest rank on the CANTIT, while one child obtained a Z score of 0. All children scored three standard deviations below the mean on the HKCAT. No statistical differences were found among the six tones with respect to perception accuracy, H(5) = 3.731, p = 0.589. Error analysis showed that children with CAS demonstrated more confusion on perceiving tones compared with TD peers. There were no main effects for task (F(1,2) = 0.040, p = 0.859) or tone (F(5,10 = 0.997, p = 0.467); nor were there task or tone interaction effects on perception versus production accuracy (F(5,10) = 1.772, p = 0.206). Tone perception and production accuracy were not significantly correlated (r2 = 0.181, p = 0.078). Tone perception deficits were evident in two out of three children with CAS, while all children had lexical tone production difficulties. In this small sample, tone production was more universally affected than tone perception.

The emerging role of transcription factor FOXP3 in thyroid cancer.

Transcription factor FOXP3 is a crucial regulator in the development and function of regulatory T cells (Treg) that are essential for immunological tolerance and homeostasis. Numerous studies have indicated the correlation of tumor infiltrating FOXP3+ Treg upregulation with poor prognostic parameters in thyroid cancer, including lymph node metastases, extrathyroidal extension, and multifocality. Most immune-checkpoint molecules are expressed in Treg. The blockage of such signals with checkpoint inhibitors has been approved for several solid tumors, but not yet for thyroid cancer. Thyroid abnormalities may be induced by checkpoint inhibitors. For example, hypothyroidism, thyrotoxicosis, painless thyroiditis, or even thyroid storm are more frequently associated with anti-PD-1 antibodies (pembrolizumab and nivolumab). Therefore, Targeting FOXP3+ Treg may have impacts on checkpoint molecules and the growth of thyroid cancer. Several factors may impact the role and stability of FOXP3, such as alternative RNA splicing, mutations, and post-translational modification. In addition, the role of FOXP3+ Treg in the tumor microenvironment is also affected by the complex regulatory network formed by FOXP3 and its transcriptional partners. Here we discussed how the expression and function of FOXP3 were regulated and how FOXP3 interacted with its targets in Treg, aiming to help the development of FOXP3 as a potential therapeutic target for thyroid cancer.

Understanding current and projected emergency department presentations and associated healthcare costs in a changing thermal climate in Adelaide, South Australia.

BACKGROUND: Exposure to extreme temperatures is associated with increased emergency department (ED) presentations. The resulting burden on health service costs and the potential impact of climate change is largely unknown. This study examines the temperature-EDs/cost relationships in Adelaide, South Australia and how this may be impacted by increasing temperatures. METHODS: A time series analysis using a distributed lag nonlinear model was used to explore the exposure-response relationships. The net-attributable, cold-attributable and heat-attributable ED presentations for temperature-related diseases and costs were calculated for the baseline (2014-2017) and future periods (2034-2037 and 2054-2057) under three climate representative concentration pathways (RCPs). RESULTS: The baseline heat-attributable ED presentations were estimated to be 3600 (95% empirical CI (eCI) 700 to 6500) with associated cost of $A4.7 million (95% eCI 1.8 to 7.5). Heat-attributable ED presentations and costs were projected to increase during 2030s and 2050s with no change in the cold-attributable burden. Under RCP8.5 and population growth, the increase in heat-attributable burden would be 1.9% (95% eCI 0.8% to 3.0%) for ED presentations and 2.5% (95% eCI 1.3% to 3.7%) for ED costs during 2030s. Under the same conditions, the heat effect is expected to increase by 3.7% (95% eCI 1.7% to 5.6%) for ED presentations and 5.0% (95% eCI 2.6% to 7.1%) for ED costs during 2050s. CONCLUSIONS: Projected climate change is likely to increase heat-attributable emergency presentations and the associated costs in Adelaide. Planning health service resources to meet these changes will be necessary as part of broader risk mitigation strategies and public health adaptation actions.

Incidence, Outcomes, and Risk Factors for Preincision Cardiac Arrest in Cardiac Surgery Patients.

BACKGROUND: We examined the incidence, postoperative outcomes, and patient-related factors associated with preincision cardiac arrest in patients undergoing cardiac surgery. METHODS: We retrospectively examined adult patients undergoing elective or urgent cardiac surgery at the Cleveland Clinic between 2008 and 2019. The incidence of preincision cardiac arrest, defined as arrest between induction of general anesthesia and surgical incision, was reported. In a secondary analysis, we assessed the association between preincision cardiac arrest and major postoperative outcomes. In a tertiary analysis, we used adjusted linear regression models to explore the association between preincision cardiac arrest and prespecified patient risk factors, including severe left main coronary artery stenosis, left ventricular ejection fraction, moderate/severe right ventricular dysfunction, low-flow low-gradient aortic stenosis, and moderate/severe pulmonary hypertension. RESULTS: Preincision cardiac arrests occurred in 75 of 41,238 (incidence of 0.18%; 95% CI, 0.17-0.26) patients who had elective or urgent cardiac surgery. Successful cardiopulmonary resuscitation with return of spontaneous circulation or bridge to cardiopulmonary bypass occurred in 74 of 75 (98.6%) patients. Patients who experienced preincision cardiac arrest had significantly higher in-hospital mortality than those who did not (11% vs 2%; odds ratio [OR] (95% CI), 4.14 (1.94-8.84); P < .001). They were also more likely to suffer postoperative respiratory failure (46% vs 13%; OR [95% CI], 3.94 [2.40-6.47]; P < .001), requirement for renal replacement therapy (11% vs 2%; OR [95% CI], 3.90 [1.82-8.35]; P < .001), neurologic deficit (7% vs 2%; OR [95% CI], 2.49 (1.00-6.21); P = .05), and longer median hospital stay (15 vs 8 days; hazard ratio (HR) [95% CI], 0.68 [0.55-0.85]; P < .001). Reduced left ventricular ejection fraction (per 5% decrease) (OR [95% CI], 1.13 [1.03-1.22]; P = .006) and moderate/severe pulmonary hypertension (OR [95% CI], 3.40 [1.95-5.90]; P < .001) were identified as independent risk factors for cardiac arrest. CONCLUSIONS: Cardiac arrest after anesthetic induction is rare in cardiac surgical patients in our investigation. Though most patients are rescued, morbidity and mortality remain higher. Reduced left ventricular ejection fraction and moderate/severe pulmonary hypertension are associated with greater risk for preincision cardiac arrest.

Prolyl isomerization of FAAP20 catalyzed by PIN1 regulates the Fanconi anemia pathway.

The Fanconi Anemia (FA) pathway is a multi-step DNA repair process at stalled replication forks in response to DNA interstrand cross-links (ICLs). Pathological mutation of key FA genes leads to the inherited disorder FA, characterized by progressive bone marrow failure and cancer predisposition. The study of FA is of great importance not only to children suffering from FA but also as a model to study cancer pathogenesis in light of genome instability among the general population. FANCD2 monoubiquitination by the FA core complex is an essential gateway that connects upstream DNA damage signaling to enzymatic steps of repair. FAAP20 is a key component of the FA core complex, and regulated proteolysis of FAAP20 mediated by the ubiquitin E3 ligase SCFFBW7 is critical for maintaining the integrity of the FA complex and FA pathway signaling. However, upstream regulatory mechanisms that govern this signaling remain unclear. Here, we show that PIN1, a phosphorylation-specific prolyl isomerase, regulates the integrity of the FA core complex, thus FA pathway activation. We demonstrate that PIN1 catalyzes cis-trans isomerization of the FAAP20 pSer48-Pro49 motif and promotes FAAP20 stability. Mechanistically, PIN1-induced conformational change of FAAP20 enhances its interaction with the PP2A phosphatase to counteract SCFFBW7-dependent proteolytic signaling at the phosphorylated degron motif. Accordingly, PIN1 deficiency impairs FANCD2 activation and the DNA ICL repair process. Together, our study establishes PIN1-dependent prolyl isomerization as a new regulator of the FA pathway and genomic integrity.

Implications of Causes of Intracranial Hemorrhage During Left Ventricular Assist Device Support.

BACKGROUND: Intracranial hemorrhage (ICH) is a frequent complication in patients with an implanted left ventricular assist device (LVAD) for advanced heart failure. Bloodstream infection is known to be associated with ICH in patients with LVAD, but its effects on ICH-associated mortality are unknown. We compared characteristics and mortality of infection-associated, traumatic, and spontaneous hemorrhages. METHODS: Patients in an LVAD registry at a tertiary care center were reviewed for this cohort study. ICH included intraparenchymal hemorrhage, subarachnoid hemorrhage, and subdural hemorrhage. Hemorrhages were categorized into infectious, traumatic, and spontaneous by the presence or absence of concurrent device-associated infection or antecedent trauma. RESULTS: Of 683 patients with an LVAD, 73 experienced ICH (10.7%). Intraparenchymal hemorrhage was the most prevalent (72%), followed by subarachnoid hemorrhage (27%) and subdural hemorrhage (23%), with multiple concurrent hemorrhage subtypes in 16 patients (22%). Median time from implantation to ICH was shorter in spontaneous ICH than in infection-associated ICH (100 days vs. 252 days, p = 0.048). The prevalence of the different subtypes of ICH were similar between spontaneous and infection-associated ICH, and no differences were seen in mortality between the different causes of ICH. CONCLUSIONS: Although spontaneous ICH occurred earlier after LVAD implantation than infection-associated ICH, no difference in mortality was seen between the different causes of ICH.

Incremental Value of Global Longitudinal Strain to Michigan Risk Score and Pulmonary Artery Pulsatility Index in Predicting Right Ventricular Failure Following Left Ventricular Assist Devices.

BACKGROUND: The incremental utility of right ventricular (RV) strain on predicting right ventricular failure (RVF) following left ventricular assist device (LVAD) implantation, beyond clinical and haemodynamic indices, is not clear. METHODS: Two hundred and forty-six (246) patients undergoing LVAD implantation, who had transthoracic echocardiograms pre and post LVAD, pulmonary artery pulsatility index (PAPI) measurements and Michigan risk score, were included. We analysed RV global longitudinal strain (GLS) using speckle tracking echocardiography. RVF following LVAD implantation was defined as the need for medical support for >14 days, or unplanned RV assist device insertion after LVAD implantation. RESULTS: Mean preoperative RV-GLS was -7.8±2.8%. Among all, 27% developed postoperative RVF. A classification and regression tree analysis identified preoperative Michigan risk score, PAPI and RV-GLS as important parameters in predicting postoperative RVF. Eighty per cent (80%) of patients with PAPI <2.1 developed postoperative RVF, while only 4% of patients with PAPI >6.8 developed RVF. For patients with a PAPI of 2.1-3.2, having baseline Michigan risk score >2 points conferred an 81% probability of subsequent RVF. For patients with a PAPI of 3.3-6.8, having baseline RV-GLS of -4.9% or better conferred an 86% probability of no subsequent RVF. The sensitivity and specificity of this algorithm for predicting postoperative RVF were 67% and 93%, respectively, with an area under the curve of 0.87. CONCLUSION: RV-GLS has an incremental role in predicting the development of RVF post-LVAD implantation, even after controlling for clinical and haemodynamic parameters.

The Impact of Maxillary Osteotomy on Fricatives in Cleft Lip and Palate: A Perceptual Speech and Acoustic Study.

INTRODUCTION: Abnormal facial growth is a recognized outcome in cleft lip and palate (CLP), resulting in a concave profile and a class III occlusal status. Maxillary osteotomy (MO) is undertaken to correct this facial deformity, and the surgery can impact speech articulation, although the evidence remains limited and ill-defined for the CLP population. AIMS: The aim of the study was to investigate the impact of MO on the production of the fricatives /f/ and /s/, using perceptual and acoustic analyses, and to explore the nature of speech changes. METHODS: Twenty participants with CLP were seen 0-3 months pre-operatively (T1) and 3 months (T2) and 12 months (T3) after MO. A normal group (N = 20) was similarly recruited. Perceptual speech data was collected according to a validated framework and ratings made on audio and audio-video recordings (VIDRat). Spectral moments were centre of gravity (CG), standard deviation (SD), skewness (SK) and kurtosis (KU). Reliability studies were carried out for all speech analyses. RESULTS: For the CLP group, VIDRat identified dentalization/interdentalization as the main type of pre-operative error for /s/ with a statistically significant improvement over time, χ2(2) = 6.889, p = 0.032. Effect sizes were medium between T1 and T3 (d = 0.631) and small between T2 and T3 (d = 0.194). For the acoustic data, effect sizes were similarly medium between T1 and T2 (e.g., SK, /f/ d = 0.579, /s/ d = 0.642) and small between T1 and T3 across all acoustic parameters. Independent t tests showed mainly statistically significant differences between both groups at all time points with large effect sizes (e.g., T2 CG, t = -4.571, p < 0.001, d =1.581), indicating that /s/ was not normalized post-operatively. For /f/, differences tended to be at T1 with large effect sizes (e.g., CG, t = -2.307, p = 0.028, d = 0.797), reflecting normalization. CONCLUSIONS AND IMPLICATIONS: This is the first speech acoustic study on /f/ for individuals with CLP undergoing MO. The surgery has a positive impact on /f/ and /s/, which appear to stabilize 3 months post-operatively. Speech changes are an automatic and a direct consequence of the physical changes brought about by MO, effecting articulatory re-organization. The results of the study have direct clinical implications for the clinical care pathway for patients with CLP undergoing MO.