Temperature Control in the Era of Personalized Medicine: Knowledge Gaps, Research Priorities, and Future Directions.

Hypoxic-ischemic brain injury (HIBI) is the leading cause of death and disability after cardiac arrest. To date, temperature control is the only intervention shown to improve neurologic outcomes in patients with HIBI. Despite robust preclinical evidence supporting hypothermia as neuroprotective therapy after cardiac arrest, there remains clinical equipoise regarding optimal core temperature, therapeutic window, and duration of therapy. Current guidelines recommend continuous temperature monitoring and active fever prevention for at least 72 h and additionally note insufficient evidence regarding temperature control targeting 32 °C-36 °C. However, population-based thresholds may be inadequate to support the metabolic demands of ischemic, reperfused, and dysregulated tissue. Promoting a more personalized approach with individualized targets has the potential to further improve outcomes. This review will analyze current knowledge and evidence, address research priorities, explore the components of high-quality temperature control, and define critical future steps that are needed to advance patient-centered care for cardiac arrest survivors.

A Graduate Medical Orientation Intervention Focused on Local Health Inequities.

Background: Residents must understand the social drivers of health in the communities they serve to deliver quality care. While resident orientation provides an opportunity to introduce residents to social and structural drivers of health, inequity, and care delivery relevant to the patient population in their new communities, many graduate medical education orientation curricula do not include this content. Objective: To report the development and implementation of a novel, patient-centered health equity orientation curriculum, including initial feasibility and acceptability data as well as preliminary self-reported outcomes. Methods: The curriculum was developed by academic faculty in collaboration with institutional and local health equity champions. Content centered on the history of inequities and racism within the local communities and included didactic presentations, asynchronous video, and virtual site visits to community resource groups. The curriculum was administered to all 2021 incoming Vanderbilt University Medical Center medical and surgical residents (N=270) over 2 half-days, both in-person and via Zoom. Data were collected anonymously via pre- and post-surveys. Results: A total of 216 residents (80% response rate) provided pre-survey response data, but only 138 residents (51.1%) provided post-survey data, including self-reported demographics (eg, underrepresented in medicine status) and level of agreement with 10 competency-based statements coded as pertaining to knowledge, skills, behaviors, or attitudes (KSBAs). Primary outcomes included improvement in residents' KSBAs from pre- to post-survey. The greatest increases in percentages occurred with content that was specific to local history and population. Conclusions: In a class of incoming residents, this study demonstrated feasibility, acceptability, and pre-post curriculum improvement in self-reported KSBAs when addressing health equity issues.

Escherichia coli DNA repair helicase Lhr is also a uracil-DNA glycosylase.

DNA glycosylases protect genetic fidelity during DNA replication by removing potentially mutagenic chemically damaged DNA bases. Bacterial Lhr proteins are well-characterized DNA repair helicases that are fused to additional 600-700 amino acids of unknown function, but with structural homology to SecB chaperones and AlkZ DNA glycosylases. Here, we identify that Escherichia coli Lhr is a uracil-DNA glycosylase (UDG) that depends on an active site aspartic acid residue. We show that the Lhr DNA helicase activity is functionally independent of the UDG activity, but that the helicase domains are required for fully active UDG activity. Consistent with UDG activity, deletion of lhr from the E. coli chromosome sensitized cells to oxidative stress that triggers cytosine deamination to uracil. The ability of Lhr to translocate single-stranded DNA and remove uracil bases suggests a surveillance role to seek and remove potentially mutagenic base changes during replication stress.

Archaeal Hel308 suppresses recombination through a catalytic switch that controls DNA annealing.

Hel308 helicases promote genome stability in archaea and are conserved in metazoans, where they are known as HELQ. Their helicase mechanism is well characterised, but it is unclear how they specifically contribute to genome stability in archaea. We show here that a highly conserved motif of Hel308/HELQ helicases (motif IVa, F/YHHAGL) modulates both DNA unwinding and a newly identified strand annealing function of archaeal Hel308. A single amino acid substitution in motif IVa results in hyper-active DNA helicase and annealase activities of purified Hel308 in vitro. All-atom molecular dynamics simulations using Hel308 crystal structures provided a molecular basis for these differences between mutant and wild type Hel308. In archaeal cells, the same mutation results in 160000-fold increased recombination, exclusively as gene conversion (non-crossover) events. However, crossover recombination is unaffected by the motif IVa mutation, as is cell viability or DNA damage sensitivity. By contrast, cells lacking Hel308 show impaired growth, increased sensitivity to DNA cross-linking agents, and only moderately increased recombination. Our data reveal that archaeal Hel308 suppresses recombination and promotes DNA repair, and that motif IVa in the RecA2 domain acts as a catalytic switch to modulate the separable recombination and repair activities of Hel308.

Emergency department initiated resuscitative endovascular balloon occlusion of the aorta (REBOA) for out-of-hospital cardiac arrest is feasible and associated with improvements in end-tidal carbon dioxide.

Objectives: Out-of-hospital cardiac arrest (OHCA) claims the lives of approximately 350,000 people in the United States each year. Resuscitative endovascular balloon occlusion of the aorta (REBOA) when used as an adjunct to advanced cardiac life support may improve cardio-cerebral perfusion. Our primary research objective was to determine the feasibility of emergency department (ED)-initiated REBOA for OHCA patients in an academic urban ED. Methods: This was a single-center, single-arm, early feasibility trial that used REBOA as an adjunct to advanced cardiac life support (ACLS) in OHCA. Subjects under 80 years with witnessed OHCA and who received cardiopulmonary rescuitation (CPR) within 6 minutes were eligible. Results: Five patients were enrolled between February 2020 and April 2021. The procedure was successful in all patients and 4 of 5 (80%) patients had transient return of spontaneous circulation (ROSC) after aortic occlusion. Unfortunately, all patients re-arrested soon after intra-aortic balloon deflation and none survived to hospital admission. At 30 seconds post-aortic occlusion, investigators noted a statistically significant increase in end tidal carbon dioxide of 26% (95% confidence interval, 10%, 44%). Conclusion: Initiating REBOA for OHCA patients in an academic urban ED setting is feasible. Aortic occlusion during chest compressions is temporally associated with improvements in end tidal carbon dioxide 30 seconds after aortic occlusion. Four of 5 patients achieved ROSC after aortic occlusion; however, deflation of the intra-aortic balloon quickly led to re-arrest and death in all patients. Future research should focus on the utilization of partial-REBOA to prevent re-arrest after ROSC, as well as the optimal way to incorporate this technique with other endovascular reperfusion strategies.

Comparing the Effects of Design Thinking and A3 Problem-Solving on Resident Attitudes Toward Systems Change.

BACKGROUND: Quality improvement (QI) is a required component of graduate medical education. Many medical educators struggle to foster an improvement mindset within residents. OBJECTIVE: We conducted a mixed-methods study to compare a Design Thinking (DT) approach to QI education with a Lean, A3 problem-solving approach. We hypothesized that a DT approach would better promote a mentality of continuous improvement, measured by residents' resistance to change. METHODS: Thirty-eight postgraduate year 2 internal medicine residents were divided into 4 cohorts during the 2017-2018 academic year. One cohort participated in an experimental QI curriculum utilizing DT while 3 control cohorts participated in the existing curriculum based on Lean principles. Participants voluntarily completed a quantitative Resistance to Change (RTC) scale pre- and post-curriculum. To inform our understanding of these results, we also conducted semistructured interviews for qualitative thematic analysis. RESULTS: The effect size on the overall RTC score (response rate 92%) was trivial in both groups. Three major themes emerged from the qualitative data: factors influencing the QI learning experience, factors influencing creativity, and general attitudes toward QI. Each contained several subthemes with minimal qualitative differences between groups. CONCLUSIONS: This study found similar results in terms of their effect on attitudes toward systems change, ability to promote creative change agency, and educational experience. Despite positive educational experiences, many residents still did not view systems-based problem-solving as part of their professional identity.

Mechanistic insights into Lhr helicase function in DNA repair.

The DNA helicase Large helicase-related (Lhr) is present throughout archaea, including in the Asgard and Nanoarchaea, and has homologues in bacteria and eukaryotes. It is thought to function in DNA repair but in a context that is not known. Our data show that archaeal Lhr preferentially targets DNA replication fork structures. In a genetic assay, expression of archaeal Lhr gave a phenotype identical to the replication-coupled DNA repair enzymes Hel308 and RecQ. Purified archaeal Lhr preferentially unwound model forked DNA substrates compared with DNA duplexes, flaps and Holliday junctions, and unwound them with directionality. Single-molecule FRET measurements showed that binding of Lhr to a DNA fork causes ATP-independent distortion and base-pair melting at, or close to, the fork branchpoint. ATP-dependent directional translocation of Lhr resulted in fork DNA unwinding through the 'parental' DNA strands. Interaction of Lhr with replication forks in vivo and in vitro suggests that it contributes to DNA repair at stalled or broken DNA replication.

Video screen viewing and first intubation attempt success with standard geometry video laryngoscope use.

STUDY OBJECTIVES: Direct laryngoscopy (DL) is the traditional approach for emergency intubation but video laryngoscopy (VL) is gaining popularity. Some studies have demonstrated higher first-attempt success with VL, particularly in difficult airways. In real-world settings, physicians choose whether or not to view the video screen when utilizing VL devices for tracheal intubation. Therefore, we sought to determine whether screen viewing is associated with higher intubation first-attempt success in clinical practice. METHODS: In this retrospective, observational investigation, we studied consecutive adult emergency department intubations at an urban, academic medical center during the calendar year 2013. Cases were identified from the electronic medical record and analyzed using standard video review methodology. We compared first-attempt success rates when standard geometry Macintosh VL was used, stratified by whether the screen was viewed or not. RESULTS: Of the 593 cases with videos available for review, 515 (87%) were performed with a standard geometry Macintosh video laryngoscope. First-attempt success was not significantly different when the screen was viewed (195/207; 94% [95%CI 91-97]) compared to when the screen was not viewed (284/301; 94% [95%CI 92-97]). The median first-attempt duration was longer when the screen was viewed compared to when the screen was not viewed (45 versus 33 s; median difference 12 s [95%CI 10-15 s]). CONCLUSION: In this study of orotracheal intubations performed by emergency physicians with Macintosh-style VL, the first-attempt success rate was high. The success rate was similar whether or not the intubating physician chose to view the video screen.

Renal replacement therapy in patients with acute respiratory distress syndrome: a single-center retrospective study.

BACKGROUND: Patients with acute respiratory distress syndrome (ARDS) who develop acute kidney injury have increased mortality and frequently require renal replacement therapy (RRT). The optimal timing for initiation of RRT after onset of ARDS to improve survival is not known. METHODS: We retrospectively reviewed clinical data on patients admitted to our health system over a 2-year period. Individual charts were carefully reviewed to ascertain that patients met the Berlin criteria for ARDS and to categorize RRT utilization. The Kaplan-Meier analysis was conducted to compare early (£48 hours postintubation) versus late (>48 hours postintubation) initiation of RRT. Associations between RRT initiation and mortality were evaluated using Cox proportional hazards regression. RESULTS: A total of 75 patients were identified with ARDS, 95% of whom received RRT. Mortality of patients who required RRT was 56%. The main indications for RRT initiation were fluid overload (75%), metabolic acidosis (64%), and hyperkalemia (33%). The Kaplan-Meier analysis comparing early initiation of RRT to late initiation of RRT showed no survival benefit. Cox proportional hazard models testing the association between timing of RRT initiation with survival and adjusting for sex, race, ethnicity, and Acute Physiology and Chronic Health Evaluation II score did not reach statistical significance (HR=0.94, 95% CI=0.48-1.86). CONCLUSION: Timing of RRT initiation was not associated with a survival benefit. Prospective study in the utilization and outcomes of RRT in ARDS could assist in optimizing its usage in this population.

Association of aeroallergen sensitization and atopic disease in the Sonoran Desert.

BACKGROUND: Numerous aeroallergens have been associated with the development of asthma, including Alternaria, house-dust mite, and pet dander. Tucson, Arizona, is located in the Sonoran Desert, which has the highest diversity of vegetation of any desert in the world. Given the unique pollen profile in this region, we sought to identify the most common aeroallergens associated with rhinitis and asthma diagnosis in the local adult population. OBJECTIVE: To identify the prevalence of aeroallergen sensitivity in the Tucson adult population and to identify which aeroallergens are associated with a diagnosis of asthma. METHODS: We conducted a retrospective electronic chart review of 226 consecutive adult patients who underwent aeroallergen skin-prick testing for rhinitis at The University of Arizona Adult Allergy and Immunology Clinic over the course of 1 year. All the subjects were tested to a standard panel of tree, grass, weed, mold, house-dust mite, animal dander, cockroach, and feather extracts. Asthma was diagnosed by using the Expert Panel Report 3 guidelines. RESULTS: Skin testing results were most commonly positive to mesquite (54%), Bermuda (48%), palo verde (47%), olive tree (43%), and chenopodium (43%). Compared with the subjects without asthma, those subjects with asthma were more often sensitized to molds (odds ratio [OR] 2.25 [95% confidence interval {CI}, 1.22-4.14]; p = 0.005), including Alternaria alternata (OR 2.58 [95% CI, 1.23-5.39]; p = 0.011), and cat hair and/or pelt (OR 2.13 [95% CI, 1.24-3.69]; p = 0.006). CONCLUSION: Regional pollens contributed significantly to allergic disease in this unique climate. Sensitization to Alternaria and other nonregional aeroallergens were related to asthma, which supported the current practice of testing and treating patients for allergy to both locally significant and ubiquitous aeroallergens.

DNA binding and unwinding by Hel308 helicase requires dual functions of a winged helix domain.

Hel308 helicases promote genome stability linked to DNA replication in archaea, and have homologues in metazoans. In the crystal structure of archaeal Hel308 bound to a tailed DNA duplex, core helicase domains encircle single-stranded DNA (ssDNA) in a "ratchet" for directional translocation. A winged helix domain (WHD) is also present, but its function is mysterious. We investigated the WHD in full-length Hel308, identifying that mutations in a solvent exposed α-helix resulted in reduced DNA binding and unwinding activities. When isolated from the rest of Hel308, the WHD protein alone bound to duplex DNA but not ssDNA, and DNA binding by WHD protein was abolished by the same mutations as were analyzed in full-length Hel308. Isolated WHD from a human Hel308 homologue (HelQ) also bound to duplex DNA. By disrupting the interface between the Hel308 WHD and a RecA-like domain, a topology typical of Ski2 helicases, we show that this is crucial for ATPase and helicase activities. The data suggest a model in which the WHD promotes activity of Hel308 directly, through binding to duplex DNA that is distinct from ssDNA binding by core helicase, and indirectly through interaction with the RecA-like domain. We propose how the WHD may contribute to ssDNA translocation, resulting in DNA helicase activity or in removal of other DNA bound proteins by "reeling" ssDNA.

The Bougie and First-Pass Success in the Emergency Department.

STUDY OBJECTIVE: The bougie may improve first-pass intubation success in operating room patients. We seek to determine whether bougie use is associated with emergency department (ED) first-pass intubation success. METHODS: We studied consecutive adult ED intubations at an urban, academic medical center during 2013. Intubation events were identified by motion-activated video recording. We determined the association between bougie use and first-pass intubation success, adjusting for neuromuscular blockade, video laryngoscopy, abnormal airway anatomy, and whether the patient was placed in the sniffing position or the head was lifted off the bed during intubation. RESULTS: Intubation with a Macintosh blade was attempted in 543 cases; a bougie was used on the majority of initial attempts (80%; n=435). First-pass success was greater with than without bougie use (95% versus 86%; absolute difference 9% [95% confidence interval {CI} 2% to 16%]). The median first-attempt duration was higher with than without bougie (40 versus 27 seconds; difference 14 seconds [95% CI 11 to 16 seconds]). Bougie use was independently associated with greater first-pass success (adjusted odds ratio 2.83 [95% CI 1.35 to 5.92]). CONCLUSION: Bougie was associated with increased first-pass intubation success. Bougie use may be helpful in ED intubation.

The Double Mandibular Osteotomy for Vascular and Tumor Surgery of the Parapharyngeal Space.

PURPOSE: The purposes of this study are to describe our experience using a double mandibular osteotomy for access to the parapharyngeal space in vascular and tumor surgery and to report on the outcomes and complications of this procedure. PATIENTS AND METHODS: We designed and implemented a case series to review the medical records of all patients treated with a double mandibular osteotomy for parapharyngeal space access from 1994 to 2016. Patient demographic characteristics, indications for the procedure, outcomes, and complications were recorded. RESULTS: A total of 17 patients underwent a double mandibular osteotomy procedure for access to the parapharyngeal space during the study period. There were 7 men (41%) and 10 women (59%) comprising the cohort. The average age was 57 years (range, 29 to 75 years). The follow-up period ranged from 6 to 98 months (mean, 40 months), and 7 patients (41%) were tobacco users at the time of surgery. The most common indication was high internal carotid artery stenosis (n = 6) followed by carotid body paraganglioma (n = 3). Average blood loss was 186 mL, and there were no deaths during the study period. Eight postoperative complications were noted in 7 patients (41%). No procedures were aborted or compromised because of inadequate parapharyngeal space access. All patients showed clinical and radiographic signs of healing of the osteotomy sites. CONCLUSION: The double mandibular osteotomy provides adequate access to the parapharyngeal space for effective tumor removal and high carotid surgical intervention with acceptable patient morbidity and complications.

An Update on Inpatient Hypertension Management.

Hypertension is highly prevalent affecting nearly one third of the US adult population. Though generally approached as an outpatient disorder, elevated blood pressure is observed in a majority of hospitalized patients. The spectrum of hypertensive disease ranges from patients with hypertensive emergency including markedly elevated blood pressure and associated end-organ damage to asymptomatic patients with minimally elevated pressures of unclear significance. It is important to note that current evidence-based hypertension guidelines do not specifically address inpatient hypertension. This narrative review focuses primarily on best practices for diagnosing and managing nonemergent hypertension in the inpatient setting. We describe examples of common hypertensive syndromes, provide suggestions for optimal post-acute management, and point to evidence-based or consensus guidelines where available. In addition, we describe a practical approach to managing asymptomatic elevated blood pressure observed in the inpatient setting. Finally, arranging effective care transitions to ensure optimal ongoing hypertension management is appropriate in all cases.

Impact of elevated cardiac biomarkers on mortality after vascular surgery procedures.

Concurrent cardiac disease is an important cause of morbidity and mortality in vascular surgical patients. Increasingly, cardiac biomarkers are used to identify cardiac injury in these high-risk patients. This review provides data demonstrating that perioperative troponin elevation correlates with poor short- and long-term outcomes for vascular surgical patients. In addition, the data demonstrate that patients with high circulating troponin levels fair worse than those with lower levels. Early identification of patients with cardiac injury using biomarkers allows timely diagnosis, risk stratification, and aggressive medical therapy for vascular surgical patients.

A systematic review of early postpartum medroxyprogesterone receipt and early breastfeeding cessation: evaluating the methodological rigor of the evidence.

BACKGROUND: Breastfeeding has numerous maternal and infant benefits. Progesterone contraception after birth is frequently recommended, but because a decrease in progesterone is required to initiate lactation, early postpartum progesterone contraception use could inhibit lactation. The purpose of this article is to critically evaluate the scientific basis for conflicting clinical recommendations related to postpartum medroxyprogesterone use among breastfeeding women. METHODS: Relevant peer-reviewed literature was identified through a comprehensive search of PubMed through December 2010. The search was restricted to clinical trials, randomized clinical trials, or comparative studies written in English and conducted among humans. The studies included in this review addressed the effect of medroxyprogesterone administration at <6 weeks postpartum on breastfeeding exclusivity and/or duration and measured breastfeeding outcomes at ≥ 6 weeks postpartum. RESULTS: Of the 20 articles identified, only three studies satisfied the inclusion criteria. However, all three studies were of low-quality methodological rigor, and none accounted for potential confounders. CONCLUSION: Current evidence is methodologically weak and provides an inadequate basis for inference about a possible causal relationship between early postpartum medroxyprogesterone use and poor breastfeeding outcomes. However, given the presence of a strong biological model describing the potential deleterious effect of postpartum medroxyprogesterone use on lactation, further research that improves on current literature is warranted. Meanwhile, we recommend that potential breastfeeding risks associated with early (<6 weeks) postpartum medroxyprogesterone use be disclosed to allow for a fully informed consent and decision-making process.