Musings on intrinsic cardiomyocyte cell cycle activity and myocardial regeneration.

Although the myocardial renewal rate in the adult mammalian heart is quite low, recent studies have identified genetic variants which can impact the degree of cardiomyocyte cell cycle reentry. Here we use the compound interest law to model the level of regenerative growth over time in mice exhibiting different rates of cardiomyocyte cell cycle reentry following myocardial injury. The modeling suggests that the limited ability of S-phase adult cardiomyocytes to progress through cytokinesis, rather than the ability to reenter the cell cycle per se, is a major contributor to the low levels of intrinsic regenerative growth in the adult myocardium.

Liposomal bupivacaine reduces opioid requirements following Ravitch repair for pectus excavatum.

Background and Aims: The management of post-operative pain after surgical repair of pectus excavatum with the Ravitch procedure is challenging. Although previous studies have compared various methods of pain control in these patients, few have compared different local anesthetics. This retrospective analysis compares the use of bupivacaine to its longer-acting form, liposomal bupivacaine, in patients who had undergone pectus excavatum repair with the Ravitch method. Material and Methods: Eleven patients who received local infiltration with liposomal bupivacaine were matched to 11 patients who received local infiltration utilizing bupivacaine with epinephrine. The primary outcome was total morphine milligram equivalents per kilogram body weight (MME/kg) over the complete length of hospital stay. Secondary outcomes included total cumulative diazepam, acetaminophen, ondansetron, and NSAID dose per kilogram body weight (mg/kg) over the course of the hospital stay, chest tube drainage (ml/kg body weight), number of post-operative hours until the first bowel movement, Haller Index, patient request for magnesium hydroxide, average pain scores from post-operative day 1 to post-operative day 5, and length of hospital stay. Continuous variables were reported as medians with inter-quartile ranges, and categorical values were reported as percentages and frequencies. Results: The total MME/kg [1.7 (1.2-2.4) vs 2.9 (2.0-3.9), P = 0.007] and hydromorphone (mg/kg) [0.1 (0.0-0.2) vs 0.3 (0.1-0.4), P = 0.006] use in the liposomal bupivacaine group versus bupivacaine with epinephrine was significantly reduced over total length of hospital stay. Similarly, there was a reduction in diazepam use in the liposomal bupivacaine group versus the bupivacaine group [0.4 (0.1-0.8) vs 0.6 (0.4-0.7), P = 0.249], but this did not reach statistical significance. The total dose of ondansetron (mg/kg) was not statistically different when comparing the liposomal bupivacaine group to the bupivacaine group [0.3 (0.0-0.5) vs 0.3 (0.2-0.6), P = 0.332]. Interestingly, the total dose of acetaminophen (mg/kg) was statistically increased in the liposomal bupivacaine group compared to the bupivacaine with epinephrine group [172 (138-183) vs 74 (55-111), P = 0.007]. Additionally, the total chest tube drainage (ml/kg) was significantly reduced in the liposomal bupivacaine group [9.3 (7.5-10.6) vs 12.8 (11.3-18.5), P = 0.027]. Finally, the percentage of patients without requests for magnesium hydroxide to promote laxation was significantly higher in the liposomal bupivacaine group than in the bupivacaine group (63.6% vs 18.2%, P = 0.027). Conclusion: The use of liposomal bupivacaine for local infiltration in patients who undergo the Ravitch procedure for pectus repair offers advantages over plain bupivacaine, including reduced opioid consumption and opioid-related side effects. However, more data are needed to understand the significance of these findings.

Cold versus hot snare resection with or without submucosal injection of 6- to 15-mm colorectal polyps: a randomized controlled trial.

BACKGROUND AND AIMS: Cold snare resection of colorectal lesions has been found to be safe and effective for an expanding set of colorectal lesions. In this study, we sought to understand the efficacy of simple cold snare resection and cold EMR versus hot snare resection and hot EMR for colorectal lesions 6 to 15 mm in size. METHODS: At 3 U.S. centers, 235 patients with 286 colorectal lesions 6 to 15 mm in size were randomized to cold snaring, cold EMR, hot snaring, or hot EMR for nonpedunculated colorectal lesions 6 to 15 mm in size. The primary outcome was complete resection determined by 4 biopsy samples from the defect margin and 1 biopsy sample from the center of the resection defect. RESULTS: The overall incomplete resection rate was 2.4% (95% confidence interval [CI], .8%-7.5%). All 7 incompletely removed polyps were 10 to 15 mm in size and removed by hot EMR (n = 4, 6.2%), hot snare (n = 2, 2.2%), or cold EMR (n = 1, 1.8%). Cold snaring had no incomplete resections, required less procedural time than the other methods, and was not associated with serious adverse events. CONCLUSIONS: Cold snaring is a dominant resection technique for nonpedunculated colorectal lesions 6 to 15 mm in size. (Clinical trial registration number: NCT03462706.).

Spinal Anesthesia is Superior to General Anesthesia for Percutaneous Achilles Tenotomy in Infants.

BACKGROUND: Concern about the effects of inhaled, halogenated anesthetics on neurodevelopment of infants has renewed interest in regional anesthesia as an alternative to general anesthesia (GA). Infants undergoing percutaneous Achilles tenotomy (PAT) are well suited for spinal anesthesia (SP). METHODS: Thirty infants (mean age: 2.3 mo) undergoing PAT with SP were compared with 15 infants (mean age: 2.0 mo) undergoing PAT with GA. Data collected included perioperative times, heart rate and blood pressure, and the administration of opioids. RESULTS: Ten of 15 GA (67%) patients received perioperative opioids as opposed to 1 of 30 SP patients (3.3%) (P<0.0001). The time from the start of anesthesia to the start of surgery was shorter in the SP group (8.5 vs. 14 min, P<0.0009). The time from the start of anesthesia to first oral intake was shorter in the SP group (12 vs. 31 min, P<0.0033). The time of first phase recovery (phase 1 post anesthesia care unit) was shorter in the SP group (15.5 vs. 34 min, P<0.0026). Surgery time was not significantly different between the groups (SP: 15.5 min, GA: 15 min, P=0.81). CONCLUSION: Infants undergoing PAT with SP received less opioid, did not require an airway device, did not receive potent inhaled, halogenated hydrocarbon anesthetics, and exhibited faster and qualitatively better postoperative recovery. LEVEL OF EVIDENCE: Level III-case control study.

Elevated Cerebrospinal Fluid Tau Protein Concentrations on Admission Are Associated With Long-term Neurologic and Cognitive Impairment in Ugandan Children With Cerebral Malaria.

BACKGROUND: Elevated concentrations of cerebrospinal fluid (CSF) tau, a marker of axonal injury, have been associated with coma in severe malaria (cerebral malaria [CM]). However, it is unknown whether axonal injury is related to long-term neurologic deficits and cognitive impairment in children with CM. METHODS: Admission CSF tau concentrations were measured in 145 Ugandan children with CM and compared to clinical and laboratory factors and acute and chronic neurologic and cognitive outcomes. RESULTS: Elevated CSF tau concentrations were associated with younger age, increased disease severity (lower glucose and hemoglobin concentrations, malaria retinopathy, acute kidney injury, and prolonged coma duration, all P < .05), and an increased CSF:plasma albumin ratio, a marker of blood-brain barrier breakdown (P < .001). Admission CSF tau concentrations were associated with the presence of neurologic deficits at hospital discharge, and at 6, 12, and 24 months postdischarge (all P ≤ .02). After adjustment for potential confounding factors, elevated log10-transformed CSF tau concentrations correlated with worse cognitive outcome z scores over 2-year follow-up for associative memory (ß coefficient, -0.31 [95% confidence interval [CI], -.53 to -.10]) in children <5 years of age, and for overall cognition (-0.69 [95% CI, -1.19 to -.21]), attention (-0.78 [95% CI, -1.34 to -.23]), and working memory (-1.0 [95% CI, -1.68 to -.31]) in children ≥5 years of age (all P < .006). CONCLUSIONS: Acute axonal injury in children with CM is associated with long-term neurologic deficits and cognitive impairment. CSF tau concentrations at the time of the CM episode may identify children at high risk of long-term neurocognitive impairment.

Relationship of Hippocampal Volume to Amyloid Burden across Diagnostic Stages of Alzheimer's Disease.

AIMS: To assess how hippocampal volume (HV) from volumetric magnetic resonance imaging (vMRI) is related to the amyloid status at different stages of Alzheimer's disease (AD) and its relevance to patient care. METHODS: We evaluated the ability of HV to predict the florbetapir positron emission tomography (PET) amyloid positive/negative status by group in healthy controls (HC, n = 170) and early/late mild cognitive impairment (EMCI, n = 252; LMCI, n = 136), and AD dementia (n = 75) subjects from the Alzheimer's Disease Neuroimaging Initiative Grand Opportunity (ADNI-GO) and ADNI2. Logistic regression analyses, including elastic net classification modeling with 10-fold cross-validation, were used with age and education as covariates. RESULTS: HV predicted amyloid status only in LMCI using either logistic regression [area under the curve (AUC) = 0.71, p < 0.001] or elastic net classification modeling [positive predictive value (PPV) = 72.7%]. In EMCI, age (AUC = 0.70, p < 0.0001) and age and/or education (PPV = 63.1%), but not HV, predicted amyloid status. CONCLUSION: Using clinical neuroimaging, HV predicted amyloid status only in LMCI, suggesting that HV is not a biomarker surrogate for amyloid PET in clinical applications across the full diagnostic spectrum.

Improvement of Pediatric Advanced Airway Management in General Emergency Departments After a Collaborative Intervention Program.

BACKGROUND: In general emergency departments, advanced airway management of pediatric patients who are critically ill has been associated with increased adverse events given the varying exposure to pediatric patients and limited resources. Previous studies have shown significant improvement of simulated pediatric airway management in general emergency departments. The aim of this retrospective study was to determine the effect of an in situ simulation-based collaborative intervention program on the actual care of pediatric airway management in general emergency departments. METHODS: This was a retrospective study of pediatric subjects who were critically ill and required intubation at a diverse set of general emergency departments before referral to the academic medical center. The primary outcome was the quality of clinical care measured by adherence to best practices via a critical action checklist. Secondary outcomes included tracheal intubation associated adverse events and clinical outcomes. RESULTS: A total of 135 pediatric subjects (48 pre- and 87 post-intervention) who were transferred to the academic medical center from 9 general emergency departments between May 2014 and August 2019 were included in the analysis. The use of a cuffed endotracheal tube improved, from 44% to 72% (P = .001), whereas there was no significant change in the appropriate endotracheal tube size. Overall, severe tracheal intubation associated adverse events decreased, from 18.8% to 9.2% (P = .03), and post-intubation cardiac arrest events decreased, from 6.3% to 0% (P = .02). CONCLUSIONS: A simulation-based collaborative intervention program led to improvement in pediatric airway management and subject outcomes in general emergency departments. This model demonstrated the transfer of improvement from a simulated setting to a clinical setting and may be targeted in other clinical settings.

Isha Yoga Practices and Participation in Samyama Program are Associated with Reduced HbA1C and Systemic Inflammation, Improved Lipid Profile, and Short-Term and Sustained Improvement in Mental Health: A Prospective Observational Study of Meditators.

Background: Meditation is gaining recognition as a tool to impact health and well-being. Samyama is an 8-day intensive residential meditation experience conducted by Isha Foundation requiring several months of extensive preparation and vegan diet. The health effects of Samyama have not been previously studied. The objective was to assess physical and emotional well-being before and after Samyama participation by evaluating psychological surveys and objective health biomarkers. Methods: This was an observational study of 632 adults before and after the Isha Samyama retreat. All participants were invited to complete surveys. Controls included household significant others. Surveys were completed at baseline (T1), just before Samyama (T2), immediately after Samyama (T3), and 3 months later (T4) to assess anxiety, depression, mindfulness, joy, vitality, and resilience through validated psychometric scales. Voluntary blood sampling for biomarker analysis was done to assess hemoglobin (Hb), HbA1c, lipid profile, and C-reactive protein (CRP). Primary outcomes were changes in psychometric scores, body weight, and blood biomarkers. Results: Depression and anxiety scores decreased from T1 to T3, with the effect most pronounced in participants with baseline depression or anxiety. Scores at T4 remained below baseline for those with pre-existing depression or anxiety. Vitality, resilience, joy, and mindfulness increased from T1 to T3 (sustained at T4). Body weight decreased by 3% from T1 to T3. Triglycerides (TG) were lower from T2 to T3. Participants had lower HbA1c and HDL at T2, and lower CRP at all timepoints compared with controls. Conclusions: Participation in the Isha Samyama program led to multiple benefits. The 2-month preparation reduced anxiety, and participants maintained lower anxiety levels at 3 months post-retreat. Physical health improved over the course of the program as evidenced by weight loss and improved HbA1C and lipid profile. Practices associated with the Samyama preparation phase and the retreat may serve as an effective way to improve physical and mental health. Future studies may examine their use as an alternative therapy in patients with depression and/or anxiety. Clinical Trial Registration: www.ClinicalTrials.gov, Identifier: 1801728792. Registered retrospectively on 4/17/2020.

Analgesic prescribing for patients who are discharged from an emergency department.

OBJECTIVES: Among patients who arrive at an emergency department (ED) with pain, over half remain in moderate or severe pain at ED discharge. Our objectives were to identify ED physicians' prescribing patterns when discharging patients with common musculoskeletal conditions and to determine if disparities in opioid prescribing exist. DESIGN: Five-year retrospective investigation. SETTING: An urban, academic ED with approximately 100,000 annual visits, where physicians write discharge prescriptions, including over-the-counter medications, using a computerized order entry system. PATIENTS: Adult patients who were discharged home from an ED with fractures (clavicle or long bone fractures) or non-fracture musculoskeletal diagnoses (sprains, strains, sciatica, or back pain). OUTCOME MEASURES: Patient demographics and pain medications prescribed for use at home. RESULTS: The study sample included 13,335 patients with a mean age of 39 years. Half were female; 52% were white; 39% were black; and 7% were Hispanic. Among fracture patients, 77% received an opioid prescription, 2% received a non-opioid prescription, and 21% received no analgesic prescription. The percentages for patients with non-fracture diagnoses were 65% (opioids), 18% (non-opioid analgesics), and 17% (no analgesic). Patients aged 80 years and older were significantly less likely to receive opioid prescriptions. Although prescribing by race for fractures was similar, significantly fewer black and Hispanic patients with non-fracture diagnoses received opioid prescriptions, compared with white patients. CONCLUSIONS: Approximately one fifth of patients in the fracture and non-fracture groups did not receive an analgesic prescription. Age greater than 80 years and minority race/ethnic status were associated with lower rates of opioid prescribing.

Methadone-based Multimodal Analgesia Provides the Best-in-class Acute Surgical Pain Control and Functional Outcomes With Lower Opioid Use Following Major Posterior Fusion Surgery in Adolescents With Idiopathic Scoliosis.

INTRODUCTION: Posterior spinal fusion for idiopathic scoliosis is extremely painful, with no superior single analgesic modality. We introduced a methadone-based multimodal analgesia protocol, aiming to decrease the length of hospital stay (LOS), improve pain control, and decrease the need for additional opioids. METHODS: We analyzed 122 idiopathic scoliosis patients with posterior instrumented spinal fusion. They were matched by age, sex, surgeon, and the number of levels fused before and after the implementation of the new protocol. This analysis included 61 controls (intrathecal morphine, gabapentin, intravenous opioids, and adjuncts) and 61 patients on the new protocol (scheduled methadone, methocarbamol, ketorolac/ibuprofen, acetaminophen, and oxycodone with intravenous opioids as needed). The primary outcome was LOS. Secondary outcomes included pain scores, total opioid use (morphine milligram equivalents), time to a first bowel movement, and postdischarge phone calls. RESULTS: New protocol patients were discharged earlier (median LOS, 2 days) compared with control patients (3 days; P < 0.001). Total inpatient morphine consumption was lower in the protocol group (P < 0.001). Pain scores were higher in the protocol group on the day of surgery, similar on postoperative day (POD) 1, and lower by POD 2 (P = 0.01). The new protocol also reduced the median time to first bowel movement (P < 0.001), and the number of postdischarge pain-related phone calls (P < 0.006). CONCLUSION: Methadone-based multimodal analgesia resulted in significantly lower LOS compared with the conventional regimen. It also provided improved pain control, reduced total opioid consumption, and early bowel movement compared with the control group.

Alzheimer disease brain atrophy subtypes are associated with cognition and rate of decline.

OBJECTIVE: To test the hypothesis that cortical and hippocampal volumes, measured in vivo from volumetric MRI (vMRI) scans, could be used to identify variant subtypes of Alzheimer disease (AD) and to prospectively predict the rate of clinical decline. METHODS: Amyloid-positive participants with AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI) 1 and ADNI2 with baseline MRI scans (n = 229) and 2-year clinical follow-up (n = 100) were included. AD subtypes (hippocampal sparing [HpSpMRI], limbic predominant [LPMRI], typical AD [tADMRI]) were defined according to an algorithm analogous to one recently proposed for tau neuropathology. Relationships between baseline hippocampal volume to cortical volume ratio (HV:CTV) and clinical variables were examined by both continuous regression and categorical models. RESULTS: When participants were divided categorically, the HpSpMRI group showed significantly more AD-like hypometabolism on 18F-fluorodeoxyglucose-PET (p < 0.05) and poorer baseline executive function (p < 0.001). Other baseline clinical measures did not differ across the 3 groups. Participants with HpSpMRI also showed faster subsequent clinical decline than participants with LPMRI on the Alzheimer's Disease Assessment Scale, 13-Item Subscale (ADAS-Cog13), Mini-Mental State Examination (MMSE), and Functional Assessment Questionnaire (all p < 0.05) and tADMRI on the MMSE and Clinical Dementia Rating Sum of Boxes (CDR-SB) (both p < 0.05). Finally, a larger HV:CTV was associated with poorer baseline executive function and a faster slope of decline in CDR-SB, MMSE, and ADAS-Cog13 score (p < 0.05). These associations were driven mostly by the amount of cortical rather than hippocampal atrophy. CONCLUSIONS: AD subtypes with phenotypes consistent with those observed with tau neuropathology can be identified in vivo with vMRI. An increased HV:CTV ratio was predictive of faster clinical decline in participants with AD who were clinically indistinguishable at baseline except for a greater dysexecutive presentation.

Influence of ADH1B polymorphism on alcohol use and its subjective effects in a Jewish population.

Class I alcohol dehydrogenases (ADHs) are the principal enzymes responsible for ethanol metabolism in humans. Genetic polymorphism at the ADH1B locus (old nomenclature ADH2) results in isozymes with quite different catalytic properties. The frequency of the ADH1B*2 allele varies among ethnic groups. ADH1B*2 is most often observed in Asian populations, and has been shown to be protective against alcoholism. The Jewish population has a higher frequency of the ADH1B*2 allele and lower rates of alcohol-related problems as compared to other Caucasian populations. Thus, it would be of interest to determine whether the ADH1B*2 allele is associated with alcohol consumption and its subjective effects in this group. Four groups of Jewish subjects (male and female college-age samples, and male and female general samples) were recruited from the same region of the United States. All subjects completed a questionnaire to delineate alcohol consumption and its subjective consequences. Genotype at the ADH1B locus was determined for each participant. ADH1B*2 allele frequencies were similar for the Jewish college-age and general population samples. Men in both the college-age and general population in the ADH1B*2 group reported more unpleasant reactions following alcohol consumption than men in the ADH1B*1 group. Men in the general population in the ADH1B*2 group drank alcohol less frequently than men who were homozygous ADH1B*1; there was a similar trend among the women. The ADH1B polymorphism is associated with unpleasant reactions after alcohol consumption, and frequency of alcohol consumption in these Jewish samples.

Palliative care for patients with dementia: a national survey.

OBJECTIVES: To determine the extent to which hospice and nonhospice palliative care (PC) programs provide services to patients with dementia and to describe barriers and facilitators to providing nonhospice PC. DESIGN: Telephone and Web-based surveys. SETTING: U.S. hospice and PC programs from the National Hospice and Palliative Care Organization's program list. PARTICIPANTS: Executive directors of 240 hospice programs, 173 programs providing hospice and nonhospice PC, and 13 programs providing nonhospice PC. MEASUREMENTS: A telephone survey of hospice and PC providers followed by an online survey of programs providing nonhospice PC. RESULTS: Ninety-four percent of hospices and 72% of PC programs had served at least one patient with a primary diagnosis of dementia within the past year. Based on 80 responses to the online survey, the most highly rated barriers to providing PC were lack of awareness of PC by families and referring providers, need for respite services, and reimbursement policies. Highly rated needs were family information, assistance with caregiver burden, and behavioral symptoms. Strategies critical for success were an interdisciplinary team, collaboration with community organizations, and alternatives to aggressive end-of-life care. CONCLUSION: Almost all hospices and a majority of nonhospice PC programs serve patients with dementia. Education and policy efforts should focus on education for families and providers, support for caregivers, and reforming reimbursement structures to provide coverage for interdisciplinary PC earlier in the disease, when patients have high needs but are not hospice eligible.

Reliability of reported age at onset for Parkinson's disease.

An individual's age at onset of Parkinson disease (PD) can be collected through a variety of sources, including medical records, family report, and clinical observation. The most common source of PD age at onset information in the research setting is family-report, which is then typically used to classify a subject as juvenile, young, or late age at onset. The reliability of the family-reported age at onset of PD has not been rigorously examined. The present study used data from individuals diagnosed with PD to evaluate the reliability of age at onset information by comparing data obtained from three sources: 1) the subject's medical records, 2) a Family History Questionnaire, and 3) a Subject History Questionnaire. Among the 149 subjects with data for all three age at onset sources, the estimated reliability was R = 0.94. Similar reliability was observed when the sample was stratified based on gender, age at examination, disease duration, first symptom of PD, and years of education. The three measures of age at onset of PD show excellent agreement, strengthening confidence in the reliability of the reported age of clinical onset for PD.