The proper connection between shelterin components is required for telomeric heterochromatin assembly.

Telomeric regions contain prominent sites of heterochromatin, which is associated with unique histone modification profiles such as the methylation of histone H3 at Lys9 (H3K9me). In fission yeast, the conserved telomeric shelterin complex recruits the histone H3K9 methyltransferase complex CLRC to establish subtelomeric heterochromatin. Although many shelterin mutations affect subtelomeric heterochromatin assembly, the mechanism remains elusive due to the diverse functions of shelterin. Through affinity purification, we found that shelterin directly associates with CLRC through the Ccq1 subunit. Surprisingly, mutations that disrupt interactions between shelterin subunits compromise subtelomeric heterochromatin without affecting CLRC interaction with shelterin component Pot1, located at chromosome ends. We further discovered that telomeric repeats are refractory to heterochromatin spreading and that artificial restoration of shelterin connections or increased heterochromatin spreading rescued heterochromatin defects in these shelterin mutants. Thus, subtelomeric heterochromatin assembly requires both the recruitment of CLRC by shelterin to chromosome ends and the proper connection of shelterin components, which allows CLRC to skip telomeric repeats to internal regions.

Changing resuscitation strategies during a pandemic: lessons from the consecutive surges in New York and global challenges.

PURPOSE OF REVIEW: To provide a framework for resuscitation of COVID-19 critical illness for emergency and intensive care clinicians with the most up to date evidence and recommendations in the care of COVID-19 patients in cardiac arrest or in extremis. RECENT FINDINGS: Performing cardiopulmonary resuscitation (CPR) on COVID-19 patients requires the clinicians to adopt infection mitigation strategies such as full personal protective equipment, mechanical chest compression devices, and restricting the number of people present during the resuscitation. The time of intubation is a subject of ongoing research and clinicians should use their best judgment for each patient. Clinicians should prepare for CPR in prone position. Particular attention should be given to the psychological well-being of the staff. Point of care ultrasound has proved to be an invaluable diagnostic tool in assessing ventricular dysfunction and parenchymal lung disease. Although novel therapies to supplant the function of diseased lungs have shown promise in select patients the evidence is still being collected. The end-of-life discussions have been negatively impacted by prognostic uncertainty as well as barriers to in person meetings with families. SUMMARY: The resuscitation of critically ill COVID-19 patients poses new challenges, but the principles remain largely unchanged.

Chromosome boundary elements and regulation of heterochromatin spreading.

Chromatin is generally classified as euchromatin or heterochromatin, each with distinct histone modifications, compaction levels, and gene expression patterns. Although the proper formation of heterochromatin is essential for maintaining genome integrity and regulating gene expression, heterochromatin can also spread into neighboring regions in a sequence-independent manner, leading to the inactivation of genes. Because the distance of heterochromatin spreading is stochastic, the formation of boundaries, which block the spreading of heterochromatin, is critical for maintaining stable gene expression patterns. Here we review the current understanding of the mechanisms underlying heterochromatin spreading and boundary formation.

Doppler ultrasound peak systolic velocity versus end tidal carbon dioxide during pulse checks in cardiac arrest.

BACKGROUND: An accurate, non-invasive measure of return of spontaneous circulation (ROSC) is needed to improve management of cardiac arrest patients. OBJECTIVES: During a pulse check in Emergency Department (ED) cardiac arrest patients, we compared the correlation between 1) end tidal carbon dioxide (ETCO2) and systolic blood pressure (SBP), and 2) Doppler ultrasound peak systolic velocity (PSV) and SBP. Additionally, we assessed the accuracy of PSV ≥ 20 cm/sec in comparison to previously suggested ETCO2 ≥ 20 or ≥ 25 mmHg thresholds to predict ROSC with SBP ≥ 60 mmHg. METHODS: This was a secondary analysis of a previously published prospective observational study of ED cardiac arrest patients with an advanced airway and femoral arterial line in place. During each pulse check, highest SBP, highest PSV, and ETCO2 at the end of the pulse check were recorded. Spearman correlation coefficients were calculated and compared using a Fisher Z-transformation. Accuracy of previously determined PSV and ETCO2 thresholds for detecting ROSC with SBP ≥ 60 mmHg were compared using McNemar's tests. RESULTS: Based on data from 35 patients with 111 pulse checks, we found a higher correlation between PSV and SBP than ETCO2 and SBP (0.71 vs 0.31; p < 0.001). Diagnostic accuracy of PSV ≥ 20 cm/sec for detecting ROSC with SBP ≥ 60 mmHg was 89% (95% CI: 82%-94%) versus 59% (95% CI: 49%-68%) and 58% (95% CI: 48%-67%) for ETCO2 ≥ 20 and ≥ 25 mmHg, respectively. CONCLUSIONS: During a pulse check, Doppler ultrasound PSV outperformed ETCO2 for correlation with SBP and accuracy in detecting ROSC with SBP ≥ 60 mmHg.

Emergency Medical Services handoff of patients in cardiac arrest in the Emergency Department: A retrospective video review study of duration and details of handoff.

STUDY OBJECTIVES: We aimed to evaluate the duration and frequency of communication between EMS (Emergency Medical Services) and ED (Emergency Department) staff during handoff and the subsequent time to critical cardiac care (rhythm determination, defibrillation) using CA (cardiac arrest) video review. METHODS: A single-center retrospective study of video-recorded adult CAs between August 2020 and December 2022 was performed. Two investigators assessed the communication of 17 data points, time intervals, EMS initiation of handoff, and type of EMS agency. Median times from initiation of handoff to first ED rhythm determination and defibrillation were compared between the groups above versus below the median number of data points communicated. RESULTS: Overall, 95 handoffs were reviewed. The handoff was initiated in a median of 2 seconds (interquartile range (IQR) 0-10) after arrival. EMS initiated handoff in 65 (69.2%) patients. The median number of data points communicated was 9 and median duration was 66 seconds (IQR 50-100). Age, location of arrest, estimated down time, and medications administered were communicated > 80% of the time, initial rhythm 79%, and bystander cardiopulmonary resuscitation and witnessed arrest < 50%. The median times from initiation of handoff to first ED rhythm determination and defibrillation were 188 (IQR 106-256) and 392 (IQR 247-725) seconds, though not statistically different between handoffs with <9 vs. ≥9 data points communicated (p > 0.40). CONCLUSION: There is no standardization for handoff reports from EMS to ED staff for CA patients. Using video review, we demonstrated the variable communication during handoff. Improvements to this process could reduce the time to critical cardiac care interventions.

Femoral artery Doppler ultrasound is more accurate than manual palpation for pulse detection in cardiac arrest.

OBJECTIVES: Our primary objective was to assess the accuracy of Doppler ultrasound versus manual palpation in detecting any pulse with an arterial line waveform in cardiac arrest. Secondarily, we sought to determine whether peak systolic velocity (PSV) on Doppler ultrasound could detect a pulse with a systolic blood pressure (SBP) ≥ 60 mmHg. METHODS: We conducted a prospective, cross-sectional, diagnostic accuracy study on a convenience sample of adult, Emergency Department (ED) cardiac arrest patients. All patients had a femoral arterial line. During a pulse check, manual pulse detection, PSV and Doppler ultrasound clips, and SBP were recorded. A receiver operator characteristic curve analysis was performed to determine the optimal cut-off of PSV associated with a SBP ≥ 60 mmHg. Accuracy of manual palpation and Doppler ultrasound for detection of any pulse and SBP ≥ 60 mmHg were compared with McNemar's test. RESULTS: 54 patients and 213 pulse checks were analysed. Doppler ultrasound demonstrated higher accuracy than manual palpation (95.3% vs. 54.0%; p < 0.001) for detection of any pulse. Correlation between PSV and SBP was strong (Spearman correlation coefficient = 0.89; p < 0.001). The optimal cut-off value of PSV associated with a SBP ≥ 60 mmHg was 20 cm/s (area under the curve = 0.975). To detect SBP ≥ 60 mmHg, accuracy of a PSV ≥ 20 cm/s was higher than manual palpation (91.4% vs. 66.2%; p < 0.001). CONCLUSIONS: Among ED cardiac arrest patients, femoral artery Doppler ultrasound was more accurate than manual palpation for detecting any pulse. When using a PSV ≥ 20 cm/s, Doppler ultrasound was also more accurate for detecting a SBP ≥ 60 mmHg.

Noncoding RNAs and the borders of heterochromatin.

Eukaryotic genomes contain long stretches of repetitive DNA sequences, which are the preferred sites for the assembly of heterochromatin structures. The formation of heterochromatin results in highly condensed chromosomal domains that limit the accessibility of DNA to the transcription and recombination machinery to maintain genome stability. Heterochromatin has the tendency to spread, and the formation of boundaries that block heterochromatin spreading is required to maintain stable gene expression patterns. Recent work has suggested that noncoding RNAs (ncRNAs) are involved in regulating boundary formation in addition to their well-established roles in chromatin regulation. Here, we present a review of our current understanding of the involvement of ncRNA at the boundaries of heterochromatin, highlighting their mechanisms of action in different settings.

The association of circulating angiogenic factors and HbA1c with the risk of preeclampsia in women with preexisting diabetes.

OBJECTIVE: To assess whether glycemic control, soluble fms-like tyrosine kinase 1 (sFlt1) and placental growth factor (PlGF) were associated with the development of preeclampsia (PE) or gestational hypertension (GHTN) in women with preexisting diabetes. METHODS: Maternal circulating angiogenic factors (sFlt1 and PlGF) measured on automated platform were studied at four time points during pregnancy in women with diabetes (N = 159) and reported as multiples of the median (MOM) of sFlt1/PlGF ratio (median, 25th-75th percentile) noted in non-diabetic non-hypertensive control pregnant population (N = 139). Diagnosis of PE or GHTN was determined by review of de-identified clinical data. RESULTS: PE developed in 12% (N = 19) and GHTN developed in 23% (N = 37) of the women with diabetes. Among diabetic women without PE or GHTN, median sFlt1/PlGF levels at 35-40 weeks was threefold higher than in non-diabetic controls [MOM 3.21(1.19-7.24), p = 0.0001]. Diabetic women who subsequently developed PE had even greater alterations in sFlt1/PlGF ratio during the third trimester [MOM for PE at 27-34 weeks 15.18 (2.37-26.86), at 35-40 weeks 8.61(1.20-18.27), p ≤ 0.01 for both windows compared to non-diabetic controls]. Women with diabetes who subsequently developed GHTN also had significant alterations in angiogenic factors during third trimester; however, these findings were less striking. Among women with diabetes, glycosylated hemoglobin (HbA1c) during the first trimester was higher in subjects who subsequently developed PE (7.7 vs 6.7%, p = 0.0001 for diabetic PE vs diabetic non-PE). CONCLUSIONS: Women with diabetes had a markedly altered anti-angiogenic state late in pregnancy that was further exacerbated in subjects who developed PE. Altered angiogenic factors may be one mechanism for the increased risk of PE in this population. Increased HbA1c in the first trimester of pregnancies in women with diabetes was strongly associated with subsequent PE.