Clinical implications of dextrocardia based on four visceroatrial situs studies.

BACKGROUND: Previous studies on congenital heart diseases (CHD) associated with dextrocardia were based on selective patient databases and did not reflect the full spectrum of dextrocardia in the general population. Additionally, these studies had complex classification and presentation. Nor did these studies elaborate on the distribution of the associated CHD's complexity, the various segmental connections, and associated CHD among the four visceroatrial situs. METHODS: We retrospectively reviewed the medical records of 211 children with primary dextrocardia. We used a segmental approach to diagnose CHD. We then analyzed and compared the distribution of the above-mentioned issues among the four visceroatrial situs. RESULTS: Dextrocardia occurred most commonly with situs inversus (52.6%), followed by situs solitus (28.4%), asplenia (17.1%), and polysplenia (1.9%). Although some patients had a structurally normal heart (22.7%) or they were associated with simple CHD (17.5%), most patients had complex CHD (59.7%) consisting of a single ventricle (34.6%) or conotruncal anomaly (25.1%) (double-outlet right ventricle [7.6%], corrected transposition of the great arteries [6.2%], complete transposition of the great arteries [5.7%], tetralogy of Fallot [4.7%], etc.). Situs inversus or polysplenia had a higher prevalence of a structurally normal heart or associated with simple CHD, two patent atrioventricular (AV) valves connections, and biventricular AV connections. Situs solitus or asplenia had a higher prevalence of associated complex CHD, common AV valve connection, univentricular AV connection, pulmonary outflow tract obstruction, and anomalous pulmonary venous drainage. CONCLUSION: Our study finds that situs inversus is the most common visceroatrial situs in dextrocardia. Although some patients had a structurally normal heart or were associated with simple CHD, most patients have associated complex CHD consisting of a single ventricle or conotruncal anomaly. Dextrocardia is associated with a higher incidence of complex CHD in situs solitus and asplenia groups than in situs inversus and polysplenia groups.

Activation of gp130 signaling in T cells drives TH17-mediated multi-organ autoimmunity.

The IL-6-gp130-STAT3 signaling axis is a major regulator of inflammation. Activating mutations in the gene encoding gp130 and germline gain-of-function mutations in STAT3 (STAT3GOF) are associated with multi-organ autoimmunity, severe morbidity, and adverse prognosis. To dissect crucial cellular subsets and disease biology involved in activated gp130 signaling, the gp130-JAK-STAT3 axis was constitutively activated using a transgene, L-gp130, specifically targeted to T cells. Activating gp130 signaling in T cells in vivo resulted in fatal, early onset, multi-organ autoimmunity in mice that resembled human STAT3GOF disease. Female mice had more rapid disease progression than male mice. On a cellular level, gp130 signaling induced the activation and effector cell differentiation of T cells, promoted the expansion of T helper type 17 (TH17) cells, and impaired the activity of regulatory T cells. Transcriptomic profiling of CD4+ and CD8+ T cells from these mice revealed commonly dysregulated genes and a gene signature that, when applied to human transcriptomic data, improved the segregation of patients with transcriptionally diverse STAT3GOF mutations from healthy controls. The findings demonstrate that increased gp130-STAT3 signaling leads to TH17-driven autoimmunity that phenotypically resembles human STAT3GOF disease.

The efficacy and safety of cupping as complementary and alternative therapy for metabolic syndrome: A systematic review and meta-analysis.

INTRODUCTION: This systematic review and meta-analysis aimed to assess the efficacy and safety of cupping therapy in patients with metabolic syndrome (MetS). METHODS: This systematic review focused on patients with MetS and included randomized controlled trials (RCTs) that compared the effects of cupping therapy with control groups. A total of 12 electronic databases were searched from inception until February 03, 2023. The main outcome after the meta-analysis was waist circumference; the others included anthropometric variables, blood pressure, lipid profile, fasting blood glucose level, and high-sensitivity C-reactive protein level. The incidence of adverse events and the follow-up courses were also evaluated. Risk of bias (ROB) was evaluated using ROB 2.0 from the Cochrane Handbook. RESULTS: This systematic review included five studies involving 489 patients. Some risks of bias were also identified. The meta-analysis revealed a statistically significance in waist circumference (MD = -6.07, 95% CI: -8.44 to -3.71, P < .001, I2 = 61%, τ2 = 3.4), body weight (MD = -2.46, 95% CI: -4.25 to -0.68, P = .007, I2 = 0%, τ2 = 0) and body mass index (MD = -1.26, 95% CI: -2.11 to -0.40, P = .004, I2 = 0%, τ2 = 0) between the cupping therapy and control groups. However, there were no significant results in total fat percentage and blood pressure values. Regarding biochemical markers, cupping significantly lowered the concentration of low-density lipoprotein cholesterol (MD = -3.98, 95% CI: -6.99 to -0.96, P = .010, I2 = 0%, τ2 = 0) but had no significant effect on total cholesterol, triglyceride, high-density lipoprotein cholesterol, fasting blood glucose, and high-sensitivity C-reactive protein. 3 RCTs reported no adverse events. CONCLUSIONS: Despite some ROB and low to substantial heterogeneity of the included studies, cupping therapy can be considered a safe and effective complementary intervention for reducing waist circumference, body weight, body mass index, and low-density lipoprotein cholesterol in patients with MetS. In the future, well-designed, high-quality, rigorous methodology, and long-term RCTs in this population are required to assess the efficacy and safety of cupping therapy.

Universality and scaling in complex networks from periods of Chinese history.

Critical physical systems with large numbers of molecules can show universal and scaling behaviors. It is of interest to know whether human societies with large numbers of people can show the same behaviors. Here, we use network theory to analyze Chinese history in periods 209 BCE-23 CE and 515-618 CE) related to the Western Han-Xin Dynasty and the late Northern Wei-Sui Dynasty, respectively. Two persons are connected when they appear in the same historical event. We find that the historical networks from two periods separated about 500 years have interesting universal and scaling behaviors, and they are small-world networks; their average cluster coefficients as a function of degree are similar to the network of movie stars. In the historical networks, the persons with larger degrees prefer to connect with persons with a small degree; however, in the network of movie stars, the persons with larger degrees prefer to connect with persons with large degrees. We also find an interesting similar mechanism for the decline or collapse of historical Chinese dynasties. The collapses of the Xin dynasty (9-23 CE) and the Sui dynasty (581-618 CE) were initiated from their arrogant attitude toward neighboring states.

Impact of Inspiratory Muscle Training on Weaning Parameters in Prolonged Ventilator-Dependent Patients: A Preliminary Study.

Introduction: Patients require prolonged mechanical ventilation to overcome respiratory failure in the chronic respiratory care ward; however, how to facilitate ventilator weaning using a nurse-led strategy is limited. Objectives: This study aimed to examine the impact of adjusting ventilator trigger sensitivity as inspiratory muscle training on weaning parameters in patients with prolonged ventilator dependence. Methods: Multiple pre-test-post-test with a non-equivalent control group design was conducted at a chronic respiratory care ward in southern Taiwan. A convenience sampling method was used to recruit patients who received prolonged mechanical ventilation for more than 21 days into control (n = 20) and intervention groups (n = 22). Adjustment of ventilator trigger sensitivity started from 10% of the initial maximum inspiratory pressure and increased to 40% after a training period of six weeks. The weaning parameters were collected for pre-test and multiple post-tests, and statistical analysis of treatment effects was performed using the generalized estimating equation. Results: Magnitude of weaning parameters was significantly higher in the intervention group after the six-week training, including maximum inspiratory pressure, rapid shallow breathing index, tidal volume, and ratio of arterial-to-inspired oxygen. Conclusion: Adjustment of ventilator trigger sensitivity as inspiratory muscle training can help prolonged ventilator-dependent patients improve their respiratory muscle strength, breathing patterns, and oxygenation.

Improvement in Violacein Production by Utilizing Formic Acid to Induce Quorum Sensing in Chromobacterium violaceum.

Violacein has attracted increasing attention due to its various biological activities, such as antibacterial, antifungal, antioxidative, and antitumor effects. To improve violacein production, formic acid (FA) was added to a culture medium, which resulted in a 20% increase (1.02 g/L) compared to the no-FA-addition group (0.85 g/L). The use of a stirred-tank bioreactor system also improved violacein production (by 0.56 g/L). A quorum-sensing (QS)-related gene (cviI) was induced by FA treatment, which revealed that the mechanism induced by FA utilized regulation of the cviI gene to induce the vio gene cluster for violacein production. To analyze the antioxidative properties of the violacein produced, 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) and 2,2'-azinobis-(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) scavenging tests were conducted, and results reveal that the values of the 50% inhibitory concentration (IC50) of DPPH and ABTS were 0.286 and 0.182 g/L, respectively. Violacein also showed strong inhibitory activity against Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis). In summary, this study found that the addition of formic acid can promote QS of Chromobacterium violaceum, thereby promoting the synthesis of violacein. Subsequently, the promoting effect was also evaluated in a bioreactor system. These findings will be helpful in establishing an economically beneficial production model for violacein in future work.

Identification of subtypes of anticancer peptides based on sequential features and physicochemical properties.

Anticancer peptides (ACPs) are a kind of bioactive peptides which could be used as a novel type of anticancer drug that has several advantages over chemistry-based drug, including high specificity, strong tumor penetration capacity, and low toxicity to normal cells. As the number of experimentally verified bioactive peptides has increased significantly, various of in silico approaches are imperative for investigating the characteristics of ACPs. However, the lack of methods for investigating the differences in physicochemical properties of ACPs. In this study, we compared the N- and C-terminal amino acid composition for each peptide, there are three major subtypes of ACPs that are defined based on the distribution of positively charged residues. For the first time, we were motivated to develop a two-step machine learning model for identification of the subtypes of ACPs, which classify the input data into the corresponding group before applying the classifier. Further, to improve the predictive power, the hybrid feature sets were considered for prediction. Evaluation by five-fold cross-validation showed that the two-step model trained with sequence-based features and physicochemical properties was most effective in discriminating between ACPs and non-ACPs. The two-step model trained with the hybrid features performed well, with a sensitivity of 86.75%, a specificity of 85.75%, an accuracy of 86.08%, and a Matthews Correlation Coefficient value of 0.703. Furthermore, the model also consistently provides the effective performance in independent testing set, with sensitivity of 77.6%, specificity of 94.74%, accuracy of 88.99% and the MCC value reached 0.75. Finally, the two-step model has been implemented as a web-based tool, namely iDACP, which is now freely available at http://mer.hc.mmh.org.tw/iDACP/ .

Pre-treatment high body mass index is associated with poor survival in Asian premenopausal women with localized breast cancer.

Background: Obesity is associated with poor prognosis in breast cancer patients. This study aimed to evaluate the effect of obesity measured by body mass index (BMI) on survival of Taiwanese breast cancer patients in a single institution. Methods: We observed 5000 patients who were diagnosed with stage I-III breast cancer between 1990 and 2005. Information on BMI at diagnosis, and clinical follow-up for disease recurrence and death, up to 20 years post-diagnosis were available. BMI (in kg/m2) categories included normal weight (BMI<24), overweight (24≤BMI<27), and obesity (BMI≥27), according to recommendations from the Bureau of Health Promotion of Taiwan. The role of BMI and other known prognostic factors for patient survival were evaluated in this patient cohort. Results: Obesity was associated with advanced stage, higher nuclear grade, and higher percentages of estrogen receptor (ER) positive. The median age of patients with a higher BMI was greater than the median age of patients with a lower BMI. Obesity was an independent prognostic factor of overall survival (OS) (P<0.001), but not disease-free survival (DFS) (P=0.067). We subsequently analyzed the impact of age-stratified BMI (age<50 and age≥50 years) to ameliorate the impact of age bias. Following subset analyses, obesity correlated with shorter DFS (P=0.004) and OS (P=0.009) only in women<50 years of age. Multivariate analysis revealed that BMI was an independent prognostic factor for both DFS and OS in this group of patients. Subset analysis revealed that in women <50 years old, the impact of BMI on survival was associated with higher stage, ER negativity. Conclusion: BMI is an independent prognostic factor of OS and DFS in breast cancer patients aged<50 years. Although the cause-effect relationship between obesity and survival is unclear, we recommend that weight control measures in young breast cancer survivors should be considered.

VPS34 K29/K48 branched ubiquitination governed by UBE3C and TRABID regulates autophagy, proteostasis and liver metabolism.

The ubiquitin-proteasome system (UPS) and autophagy are two major quality control processes whose impairment is linked to a wide variety of diseases. The coordination between UPS and autophagy remains incompletely understood. Here, we show that ubiquitin ligase UBE3C and deubiquitinating enzyme TRABID reciprocally regulate K29/K48-branched ubiquitination of VPS34. We find that this ubiquitination enhances the binding of VPS34 to proteasomes for degradation, thereby suppressing autophagosome formation and maturation. Under ER and proteotoxic stresses, UBE3C recruitment to phagophores is compromised with a concomitant increase of its association with proteasomes. This switch attenuates the action of UBE3C on VPS34, thereby elevating autophagy activity to facilitate proteostasis, ER quality control and cell survival. Specifically in the liver, we show that TRABID-mediated VPS34 stabilization is critical for lipid metabolism and is downregulated during the pathogenesis of steatosis. This study identifies a ubiquitination type on VPS34 and elucidates its cellular fate and physiological functions in proteostasis and liver metabolism.

Point-of-Care Ultrasound May Reduce Misdiagnosis of Pediatric Intussusception.

Aim: Intussusception, the most common abdominal emergency in early childhood, is frequently misdiagnosed at initial presentation. The effect of using point-of-care ultrasonography (POCUS) by emergency medicine physicians on pediatric intussusception misdiagnosis rate remains unclear. Here, we summarize outcomes and misdiagnoses before and after training junior and senior physicians on using POCUS for diagnosing intussusception and compared their performance levels. Materials and Methods: This observational cohort analysis included patients with suspected intussusception who visited a pediatric emergency department (ED) between January 2017 and December 2019. All enrolled patients were evaluated by junior (<10-year experience) or senior attending physicians. Misdiagnosis was defined as a finding of negative air reduction or confirmation of diagnosis on ED revisit or admission. The misdiagnosis rates and outcomes before and after POCUS training for intussusception diagnosis were evaluated and performance of the junior and senior physicians was compared. Results: Of the 167 enrolled patients, 130 were confirmed to have intussusception by air reduction. Misdiagnosis rate was significantly lower in the post-training patient group after training than in the pre-training patient group (43.7 vs. 12.7%, P < 0.001). After training, fewer misdiagnoses were made by the junior (59.1 vs. 25.9%, P = 0.003) and senior (31.7 vs. 0%, P < 0.001) physicians. In the post-training patient group, the door-to-reduction time and rate of ultrasonography consultation with an expert also decreased significantly (118.2 ± 124.5 vs. 198 ± 250.2 min, P = 0.006). Abdominal pain (80.9%) was the most common symptom of intussusception, followed by vomiting (58.3%), fever (17.8%), bloody stool (15.4%), and diarrhea (14.2%). Even after training, the presenting symptoms of intussusception often leading junior physicians to misdiagnosis were diarrhea and fever. Conclusions: A brief POCUS training leads to decreased misdiagnosis rates in both the senior and junior physicians. Junior physicians should increase their awareness regarding diarrhea and fever being the presenting symptoms of intussusception, particularly in early childhood. Combining clinical judgment and POCUS results forms the core principle of the evaluation of children with intussusception.

Low acuity paediatric emergency visits under single-payer universal health insurance in Taiwan, 2000-2015: a population-based repeated cross-sectional design.

OBJECTIVES: Emergency services utilisation is a critical policy concern. The paediatric population is the main user of emergency department (ED) services, and the main contributor to low acuity (LA) ED visits. We aimed to describe the trends of ED and LA ED visits under a comprehensive, universal health insurance programme in Taiwan, and to explore factors associating with potentially unnecessary ED utilisation. DESIGN AND SETTING: We used a population-based, repeated cross-sectional design to analyse the full year of 2000, 2005, 2010 and 2015 National Health Insurance claims data individually for individuals aged 18 years and under. PARTICIPANTS: We identified 5 538 197, 4 818 213, 4 401 677 and 3 841 174 children in 2000, 2005, 2010 and 2015, respectively. PRIMARY AND SECONDARY OUTCOME MEASURES: We adopted a diagnosis grouping system and severity classification system to define LA paediatric ED (PED) visits. Generalised estimating equation was applied to identify factors associated with LA PED visits. RESULTS: The annual LA PED visits per 100 paediatric population decreased from 10.32 in 2000 to 9.04 in 2015 (12.40%). Infectious ears, nose and throat, dental and mouth diseases persistently ranked as the top reasons for LA visits (55.31% in 2000 vs 33.94% in 2015). Physical trauma-related LA PED visits increased most rapidly between 2000 and 2015 (0.91-2.56 visits per 100 population). The dose-response patterns were observed between the likelihood of incurring LA PED visit and either child's age (OR 1.06-1.35 as age groups increase, p<0.0001) or family socioeconomic status (OR 1.02-1.21 as family income levels decrease, p<0.05). CONCLUSION: Despite a comprehensive coverage of emergency care and low cost-sharing obligations under a single-payer universal health insurance programme in Taiwan, no significant increase in PED utilisation for LA conditions was observed between 2000 and 2015. Taiwan's experience may serve as an important reference for countries considering healthcare system reforms.

Comprehensive Cohort Analysis of Mutational Spectrum in Early Onset Breast Cancer Patients.

Early onset breast cancer (EOBC), diagnosed at age ~40 or younger, is associated with a poorer prognosis and higher mortality rate compared to breast cancer diagnosed at age 50 or older. EOBC poses a serious threat to public health and requires in-depth investigation. We studied a cohort comprising 90 Taiwanese female patients, aiming to unravel the underlying mechanisms of EOBC etiopathogenesis. Sequence data generated by whole-exome sequencing (WES) and whole-genome sequencing (WGS) from white blood cell (WBC)-tumor pairs were analyzed to identify somatic missense mutations, copy number variations (CNVs) and germline missense mutations. Similar to regular breast cancer, the key somatic mutation-susceptibility genes of EOBC include TP53 (40% prevalence), PIK3CA (37%), GATA3 (17%) and KMT2C (17%), which are frequently reported in breast cancer; however, the structural protein-coding genes MUC17 (19%), FLG (16%) and NEBL (11%) show a significantly higher prevalence in EOBC. Furthermore, the top 2 genes harboring EOBC germline mutations, MUC16 (19%) and KRT18 (19%), encode structural proteins. Compared to conventional breast cancer, an unexpectedly higher number of EOBC susceptibility genes encode structural proteins. We suspect that mutations in structural proteins may increase physical permeability to environmental hormones and carcinogens and cause breast cancer to occur at a young age.

Control of DNA structure and function by phytochemicals/DNA interaction: Resveratrol/piceatannol induces Cu2+-independent, cleavage of supercoiled plasmid DNA.

Topoisomerases are enzymes that catalyze DNA unwinding and scissions to resolve topological entanglements possibly arising during DNA replication/transcription. Chemicals which disrupt or inhibit topoisomerase-mediated DNA unwinding can induce breaks that subsequently lead to programmed cell death. Herein we perform experiments guided by the following considerations. First, topoisomerase 1 initiates DNA cleavage utilizing the hydroxyl group of tyrosine 723 on its catalytic site as a nucleophile to attack the electrophilic phosphate on the DNA sugar-phosphate backbone. Secondly, the grape polyphenol resveratrol displays both topoisomerase inhibitory and Cu2+-dependent DNA-cutting activities, which contribute to its DNA replication/transcription inhibitory/anti-tumorigenic effects. Lastly, resveratrol contains a tyrosine-like phenolic ring; thus, upon binding to DNA whether resveratrol could act as a tyrosine mimetic to unwind and cut DNA via its hydroxyl groups warrants investigation. Polyphenol-DNA interactions (PDIs) were investigated using UV-visible spectral analysis; additionally, PDI mediated DNA changes were further analyzed by agarose gel electrophoresis using 3 supercoiled plasmid DNAs (pBR322, pSJ3, pHOT-1) as substrates. Resveratrol mediates time- and temperature-dependent, Cu2+-independent, non-enzymatic cleavage of supercoiled plasmid DNA into open, circular DNA products. Varying degree of unwinding of supercoiled DNA nucleolytic activity was also observed with other polyphenols including, piceatannol, quercetin, myricetin and EGCG. Interestingly, we found that piceatannol mediated Cu2+-independent DNA-cleavage activity was abolished by EDTA. The PDI-mediated nucleolytic cleavage of supercoiled DNA reported herein shows that polyphenolic phytochemicals display genome-active, nuclear effects by directly targeting the DNA topology which in turn could impact macromolecular processes associated with faithful replication and transmission of genetic information.

Two forms of human DNA polymerase δ: Who does what and why?

DNA polymerase δ (Pol δ) plays a central role in lagging strand DNA synthesis in eukaryotic cells, as well as an important role in DNA repair processes. Human Pol δ4 is a heterotetramer of four subunits, the smallest of which is p12. Pol δ3 is a trimeric form that is generated in vivo by the degradation of the p12 subunit in response to DNA damage, and during entry into S-phase. The biochemical properties of the two forms of Pol δ, as well as the changes in their distribution during the cell cycle, are reviewed from the perspective of understanding their respective cellular functions. Biochemical and cellular studies support a role for Pol δ3 in gap filling during DNA repair, and in Okazaki fragment synthesis during DNA replication. Recent studies of cells in which p12 expression is ablated, and are therefore null for Pol δ4, show that Pol δ4 is not required for cell viability. These cells have a defect in homologous recombination, revealing a specific role for Pol δ4 that cannot be performed by Pol δ3. Pol δ4 activity is required for D-loop displacement synthesis in HR. The reasons why Pol δ4 but not Pol δ3 can perform this function are discussed, as well as the question of whether helicase action is needed for efficient D-loop displacement synthesis. Pol δ4 is largely present in the G1 and G2/M phases of the cell cycle and is low in S phase. This is discussed in relation to the availability of Pol δ4 as an additional layer of regulation for HR activity during cell cycle progression.

Accuracy of cone beam computed tomography in measuring thicknesses of hard-tissue-mimicking material adjacent to different implant thread surfaces.

BACKGROUND/PURPOSE: To evaluate the measurement accuracy of hard-tissue thicknesses adjacent to dental implants with different thread designs on images obtained from cone beam computed tomography (CBCT) using an in vitro model. MATERIALS AND METHODS: On 4 × 13-mm implant, the neck of the implant was designed with micro-threads, and the apical part was covered by macro-threads; these implants were placed in a vinyl polysiloxane block that mimicked hard-tissue. Models were prepared with various thicknesses of 2.0, 1.0, 0.5 and 0.3 mm adjacent to the dental implant. Each model was scanned using CBCT, and the thickness of the cortical bone from the outer surface of the micro-threads and macro-threads were recorded. Ground sections were prepared, and the thickness was measured with electronic calipers as the gold standard (GS) measurement. RESULTS: CBCT measurements of the micro-thread surface were consistently underestimated compared to the GS measurement when the thickness of the hard-tissue-mimicking material was ≤1.0 mm. In comparison, CBCT measurements of the macro-thread surface closely approximated the standard measurement, except when the thickness of the hard-tissue-mimicking material was 0.3 mm. The mean percentage errors from the standard measurement for the 2.0-, 1.0-, 0.5-, and 0.3-mm thickness groups were 4.8%, 16.4%, 37.8%, and 92.6%, respectively, for the micro-thread group, and were 0.6%, 2.9%, 9.5%, and 40.8%, respectively, for the macro-thread group. CONCLUSION: Within the limitations of this study, we conclude that CBCT may not produce sufficient resolution for thin sections of hard tissue-mimicking materials adjacent to micro-thread surfaces.

Clinical Survey and Predictors of Outcomes of Pediatric Out-of-Hospital Cardiac Arrest Admitted to the Emergency Department.

Pediatric out-of-hospital cardiac arrest (OHCA) is a rare event with severe sequelae. Although the survival to hospital-discharge (STHD) rate has improved from 2-6% to 17.6-40.2%, only 1-4% of OHCA survivors have a good neurological outcome. This study investigated the characteristics of case management before and after admittance to the emergency department (ED) associated with outcomes of pediatric OHCA in an ED. This was a retrospective study of data collected from our ED resuscitation room logbooks dating from 2005 to 2016. All records of children under 18 years old with OHCA were reviewed. Outcomes of interest included sustained return of spontaneous circulation (SROSC), STHD, and neurological outcomes. From the 12-year study period, 152 patients were included. Pediatric OHCA commonly affects males (55.3%, n = 84) and infants younger than 1 year of age (47.4%, n = 72) at home (76.3%, n = 116). Most triggers of pediatric OHCA were respiratory in nature (53.2%, n = 81). Sudden infant death syndrome (SIDS) (29.6%, n = 45), unknown medical causes (25%, n = 38), and trauma (10.5%, n = 16) were the main causes of pediatric OHCA. Sixty-two initial cardiac rhythms at the scene were obtained, most of which were asystole and pulseless electrical activity (PEA) (93.5%, n/all: 58/62). Upon ED arrival, cardiopulmonary resuscitation (CPR) was continued for 32.66 ± 20.71 min in the ED and 34.9% (n = 53) gained SROSC. Among them, 13.8% (n = 21) achieved STHD and 4.6% (n = 7) had a favorable neurological outcome. In multivariate analyses, fewer ED epinephrine doses (p < 0.05), witness of OHCA (p = 0.001), and shorter ED CPR duration (p = 0.007) were factors that increased the rate of SROSC at the ED. A longer emergency medical service (EMS) scene interval (p = 0.047) and shorter ED CPR interval (p = 0.047) improved STHD.

Analysis of clinical parameters and echocardiography as predictors of fatal pediatric myocarditis.

Pediatric myocarditis symptoms can be mild or as extreme as sudden cardiac arrest. Early identification of the severity of illness and timely provision of critical care is helpful; however, the risk factors associated with mortality remain unclear and controversial. We undertook a retrospective review of the medical records of pediatric patients with myocarditis in a tertiary care referral hospital for over 12 years to identify the predictive factors of mortality. Demographics, presentation, laboratory test results, echocardiography findings, and treatment outcomes were obtained. Regression analyses revealed the clinical parameters for predicting mortality. During the 12-year period, 94 patients with myocarditis were included. Of these, 16 (17%) patients died, with 12 succumbing in the first 72 hours after admission. Fatal cases more commonly presented with arrhythmia, hypotension, acidosis, gastrointestinal symptoms, decreased left ventricular ejection fraction, and elevated isoenzyme of creatine kinase and troponin I levels than nonfatal cases. In multivariate analysis, troponin I > 45 ng/mL and left ventricular ejection fraction < 42% were significantly associated with mortality. Pediatric myocarditis had a high mortality rate, much of which was concentrated in the first 72 hours after hospitalization. Children with very high troponin levels or reduced ejection fraction in the first 24 hours were at higher risk of mortality, and targeting these individuals for more intensive therapies may be warranted.

Loss of the p12 subunit of DNA polymerase delta leads to a defect in HR and sensitization to PARP inhibitors.

Human DNA polymerase δ is normally present in unstressed, non-dividing cells as a heterotetramer (Pol δ4). Its smallest subunit, p12, is transiently degraded in response to UV damage, as well as during the entry into S-phase, resulting in the conversion of Pol δ4 to a trimer (Pol δ3). In order to further understand the specific cellular roles of these two forms of Pol δ, the gene (POLD4) encoding p12 was disrupted by CRISPR/Cas9 to produce p12 knockout (p12KO) cells. Thus, Pol δ4 is absent in p12KO cells, leaving Pol δ3 as the sole source of Pol δ activity. GFP reporter assays revealed that the p12KO cells exhibited a defect in homologous recombination (HR) repair, indicating that Pol δ4, but not Pol δ3, is required for HR. Expression of Flag-tagged p12 in p12KO cells to restore Pol δ4 alleviated the HR defect. These results establish a specific requirement for Pol δ4 in HR repair. This leads to the prediction that p12KO cells should be more sensitive to chemotherapeutic agents, and should exhibit synthetic lethal killing by PARP inhibitors. These predictions were confirmed by clonogenic cell survival assays of p12KO cells treated with cisplatin and mitomycin C, and with the PARP inhibitors Olaparib, Talazoparib, Rucaparib, and Niraparib. The sensitivity to PARP inhibitors in H1299-p12KO cells was alleviated by expression of Flag-p12. These findings have clinical significance, as the expression levels of p12 could be a predictive biomarker of tumor response to PARP inhibitors. In addition, small cell lung cancers (SCLC) are known to exhibit a defect in p12 expression. Analysis of several SCLC cell lines showed that they exhibit hypersensitivity to PARP inhibitors, providing evidence that loss of p12 expression could represent a novel molecular basis for HR deficiency.