EATING AND GLYCEMIC CONTROL AMONG CRITICALLY ILL PATIENTS RECEIVING CONTINUOUS INTRAVENOUS INSULIN.

Objective: Consensus guidelines recommend that intensive care unit (ICU) patients with blood glucose (BG) levels >180 mg/dL receive continuous intravenous insulin (CII). The effectiveness of CII at controlling BG levels among patients who are eating relative to those who are eating nothing by mouth (nil per os; NPO) has not been described. Methods: We conducted a retrospective cohort study of 260 adult patients (156 eating, 104 NPO) admitted to an ICU between January 1, 2014, and December 31, 2014, who received CII. Patients were excluded for a diagnosis of diabetic ketoacidosis or hyperglycemic hyperosmolar nonketotic syndrome, admission to an obstetrics service, or receiving continuous enteral or parenteral nutrition. Results: Among 22 baseline characteristics, the proportion of patients receiving glucocorticoid treatment (GCTx) (17.3% eating, 37.5% NPO; P<.001) and APACHE II score (15.0 ± 7.5 eating, 17.9 ± 7.9 NPO; P = .004) were significantly different between eating and NPO patients. There was no significant difference in the primary outcome of patient-day weighted mean BG overall (153 ± 8 mg/dL eating, 156 ± 7 mg/dL NPO; P = .73), or day-by-day BG (P = .37) adjusted for GCTx and APACHE score. Surprisingly, there was a significant difference in the distribution of BG values, with eating patients having a higher percentage of BG readings in the recommended range of 140 to 180 mg/dL. However, eating patients showed greater glucose variability (coefficient of variation 23.1 ± 1.0 eating, 21.2 ± 1.0 NPO; P = .034). Conclusion: Eating may not adversely affect BG levels of ICU patients receiving CII. Whether or not prandial insulin improves glycemic control in this setting should be studied. Abbreviations: BG = blood glucose; CII = continuous insulin infusion; CV = coefficient of variation; HbA1c = hemoglobin A1c; ICU = intensive care unit; NPO = nil per os; PDWMBG = patient day weighted mean blood glucose.

Mechanism governing heme synthesis reveals a GATA factor/heme circuit that controls differentiation.

Metal ion-containing macromolecules have fundamental roles in essentially all biological processes throughout the evolutionary tree. For example, iron-containing heme is a cofactor in enzyme catalysis and electron transfer and an essential hemoglobin constituent. To meet the intense demand for hemoglobin assembly in red blood cells, the cell type-specific factor GATA-1 activates transcription of Alas2, encoding the rate-limiting enzyme in heme biosynthesis, 5-aminolevulinic acid synthase-2 (ALAS-2). Using genetic editing to unravel mechanisms governing heme biosynthesis, we discovered a GATA factor- and heme-dependent circuit that establishes the erythroid cell transcriptome. CRISPR/Cas9-mediated ablation of two Alas2 intronic cis elements strongly reduces GATA-1-induced Alas2 transcription, heme biosynthesis, and surprisingly, GATA-1 regulation of other vital constituents of the erythroid cell transcriptome. Bypassing ALAS-2 function in Alas2 cis element-mutant cells by providing its catalytic product 5-aminolevulinic acid rescues heme biosynthesis and the GATA-1-dependent genetic network. Heme amplifies GATA-1 function by downregulating the heme-sensing transcriptional repressor Bach1 and via a Bach1-insensitive mechanism. Through this dual mechanism, heme and a master regulator collaborate to orchestrate a cell type-specific transcriptional program that promotes cellular differentiation.

Trafficking of the EGFR ligand Spitz regulates its signaling activity in polarized tissues.

Epidermal growth factor receptor (EGFR) ligands undergo a complex series of processing events during their maturation to active signaling proteins. Like its mammalian homologs, the predominant Drosophila EGFR ligand Spitz is produced as a transmembrane pro-protein. In the secretory pathway, Spitz is cleaved within its transmembrane domain to release the extracellular signaling domain. This domain is modified with an N-terminal palmitate group that tethers it to the plasma membrane. We found that the pro-protein can reach the cell surface in the absence of proteolysis, but that it fails to activate the EGFR. To address why the transmembrane pro-protein is inactive, whereas membrane association through the palmitate group promotes activity, we generated a panel of chimeric constructs containing the Spitz extracellular region fused to exogenous transmembrane proteins. Although the orientation of the EGF domain and its distance from the plasma membrane varies in these chimeras, they are all active in vivo. Thus, tethering Spitz to the membrane via a transmembrane domain at either terminus does not prevent activity. Conversely, removing the N-terminal palmitate group from the C-terminally tethered pro-protein does not render it active. Furthermore, we show that the Spitz transmembrane pro-protein can activate the EGFR in a tissue culture assay, indicating that its failure to signal in vivo is not due to structural features. In polarized imaginal disc cells, unprocessed Spitz pro-protein localizes to apical puncta, whereas the active chimeric Spitz constructs are basolaterally localized. Taken together, our data support the model that localized trafficking of the pro-protein restricts its ability to activate the receptor in polarized tissues.

Auditory hallucinations associated with migraine: Case series and literature review.

OBJECTIVE: The objective of this review is to describe auditory hallucinations (paracusias) associated with migraine attacks to yield insights into their clinical significance and pathogenesis. BACKGROUND: Isolated observations have documented rare associations of migraine with auditory hallucinations. Unlike visual, somatosensory, language, motor, and brainstem symptoms, paracusias with acute headache attacks are not a recognized aura symptom by the International Headache Society, and no systematic review has addressed this association. METHODS: We retrospectively studied patients experiencing paracusias associated with migraine at our center and in the literature. RESULTS: We encountered 12 patients (our center = 5, literature = 7), 58% were female, and 75% had typical migraine aura. Hallucinations most commonly featured voices (58%), 75% experienced them during headache, and the duration was most often <1 hour (67%). No patients described visual aura evolving to paracusias. Most patients (50%) had either a current or previous psychiatric disorder, most commonly depression (67%). The course of headache and paracusias were universally congruent, including improvement with headache prophylaxis (58%). CONCLUSION: Paracusias uncommonly co-occur with migraine and usually feature human voices. Their timing and high prevalence in patients with depression may suggest that paracusias are not necessarily a form of migraine aura, though could be a migraine trait symptom. Alternative mechanisms include perfusion changes in primary auditory cortex, serotonin-related ictal perceptual changes, or a release phenomenon in the setting of phonophobia with avoidance of a noisy environment.

A population-based description of atrial fibrillation in the emergency department, 2002 to 2010.

STUDY OBJECTIVE: We aimed to describe the demographics, care, and outcomes of patients with atrial fibrillation in the emergency department (ED), as well as temporal changes over time. METHODS: In this retrospective cohort study, we used a province-wide database to identify all adult patients who were treated in a nonpediatric ED in the province of Ontario with a primary diagnosis of atrial fibrillation, April 2002 to March 2010. We determined the frequency and rate of ED visits and assessed patient demographics, ED care, and outcomes, both overall and by year. RESULTS: During the 8-year study period, 113,786 patients made 143,003 ED visits for atrial fibrillation, accounting for 0.5% of all ED visits. The annual number of ED visits increased from 15,931 to 20,168 (29.4%; 95% confidence interval [CI] 28.7% to 30.1%) between 2002 and 2010, whereas the crude rate increased from 172 per 100,000 to 195 per 100,000 persons. Median age was 72.0 years (Interquartile range 61.0 to 80.0 years) and 50.8% were women, which did not change significantly during the study period. The percentage of index ED visits with a physician billing for cardioversion increased from 6.3% (95% CI 5.9% to 6.7%) to 11.8% (95% CI 11.3% to 12.3%). Although the percentage of patients with a CHADS2 score greater than or equal to 2 increased from 49.3% (95% CI 48.4% to 50.2%) to 53.6% (95% CI 52.9% to 54.4%) and high-acuity ED triage scores increased from 41.1% (95% CI 40.2% to 42.0%) to 62.5% (95% CI 61.7% to 63.2%), hospital admissions decreased from 48.1% (95% CI 47.3% to 49.0%) to 38.4% (95% CI 37.6% to 39.2%). Thirty-day mortality was 3.3% (95% CI 3.2% to 3.4%) and showed a slight downward trend during the study period (P=.05), whereas subsequent hospitalizations within 30 days for atrial fibrillation or stroke (2.8%; 95% CI 2.7% to 2.9%) and repeated ED visits (7.3%; 95% CI 7.1% to 7.4%) remained unchanged. CONCLUSION: The number of ED visits for atrial fibrillation increased markedly during an 8-year period. Although it appears that slightly higher-risk patients are being treated in the province's EDs, fewer patients are being admitted to the hospital, and mortality rates have not increased.

Hospital Readmission Risk and Risk Factors of People with a Primary or Secondary Discharge Diagnosis of Diabetes.

Hospital readmission among people with diabetes is common and costly. A better understanding of the differences between people requiring hospitalization primarily for diabetes (primary discharge diagnosis, 1°DCDx) or another condition (secondary discharge diagnosis, 2°DCDx) may translate into more effective ways to prevent readmissions. This retrospective cohort study compared readmission risk and risk factors between 8054 hospitalized adults with a 1°DCDx or 2°DCDx. The primary outcome was all-cause hospital readmission within 30 days of discharge. The readmission rate was higher in patients with a 1°DCDx than in patients with a 2°DCDx (22.2% vs. 16.2%, p < 0.01). Several independent risk factors for readmission were common to both groups including outpatient follow up, length of stay, employment status, anemia, and lack of insurance. C-statistics for the multivariable models of readmission were not significantly different (0.837 vs. 0.822, p = 0.15). Readmission risk of people with a 1°DCDx was higher than that of people with a 2°DCDx of diabetes. Some risk factors were shared between the two groups, while others were unique. Inpatient diabetes consultation may be more effective at lowering readmission risk among people with a 1°DCDx. These models may perform well to predict readmission risk.

New York City jails: COVID discharge policy, data transparency, and reform.

During the early stages of the COVID-19 pandemic in 2020, Mayor Bill de Blasio ordered the release of individuals incarcerated in New York City jails who were at high risk of contracting the disease and at low risk of committing criminal reoffense. Using public information, we construct and analyze a database of nearly 350,000 incarceration episodes in the city jail system from 2014-2020, paying special attention to what happened during the week of March 23-29, 2020, immediately following the mayor's order. In concordance with de Blasio's stated policy, we find that being discharged during this focus week is associated with a lower probability of readmission as compared to being discharged during the same calendar week in previous years. Furthermore, comparing the individuals discharged during the focus week of 2020 to those discharged during the same calendar week in previous years, we find that the former group was, on average, slightly older than the latter group, although the difference is not large. Additionally, the individuals in the former group had spent substantially longer in jail than those in the latter group. With the release of long-serving individuals demonstrated to be feasible, we also examine how the jail population would have looked over the past six years had caps in incarceration been in place. With a cap of one year, the system would experience a 15% decrease in incarceration. With a cap of 100 days, the reduction would be over 50%. Because our results are only as accurate as New York City's public-facing jail data, we discuss numerous challenges with this data and suggest improvements related to the incarcerated individual's age, gender, race, and more. Finally, we discuss the policy implications of our work, highlight some opportunities and challenges posed by incarceration caps, and suggest key areas for reform. One such reform might involve identifying and discharging low-risk individuals sooner in general, which might be feasible given the de Blasio administration's actions during the early stages of COVID-19.

OCCULT PRIMARY HYPERPARATHYROIDISM: A CASE REPORT AND REVIEW OF PARATHYROID ULTRASONOGRAPHY.

OBJECTIVE: To discuss the diagnosis and management of occult primary hyperparathyroidism. METHODS: We present the biochemical and radiologic evaluation, treatment, and outcome of a woman with occult primary hyperparathyroidism which presented as an unusual neck mass on ultrasound. We also present a relevant literature review. RESULTS: A 52-year-old female presented with Hashimoto thyroiditis and a 1.2-cm, hypoechoic oval nodule in the left upper lateral portion of the thyroid. She returned a decade later with a 2.2-cm, hypervascular mass on ultrasound. Parathyroid hormone was mildly elevated at 90 pg/mL (reference range is 15 to 65 pg/mL), but she had persistently normal levels of total serum calcium at 9.9 mg/dL (reference range is 8.7 to 10.3 mg/dL), phosphorus at 3.5 mg/dL (reference range is 2.1 to 4.5 mg/dL), and albumin at 4.4 g/dL (reference range is 3.6 to 4.8 g/dL). She had elevated ionized calcium of 5.9 mg/dL (reference range is 4.5 to 5.6 mg/dL). Computed tomography with contrast of the neck revealed an enhancing oval lesion abutting the superior pole of the left thyroid with attenuation characteristics similar though slightly different from the thyroid. 99mTc-Sestamibi scan showed increased uptake posterior to the superior aspect of the left thyroid. Bone densitometry showed osteoporosis of the left distal radius and osteopenia of the left femoral neck. Minimally invasive radio-guided parathyroidectomy was performed with normalization of parathyroid hormone. Pathology confirmed a 1.715-g parathyroid adenoma. CONCLUSION: Despite normal total calcium levels, clinically significant primary hyperparathyroidism may present as a large adenoma which could appear as a hypervascular neck mass on ultrasound. A high index of suspicion based on ultrasound features and measurement of ionized calcium may be helpful in diagnosing occult, but clinically relevant primary hyperparathyroidism.

Drosophila spermatid individualization is sensitive to temperature and fatty acid metabolism.

Fatty acids are precursors of potent lipid signaling molecules. They are stored in membrane phospholipids and released by phospholipase A2 (PLA2). Lysophospholipid acyltransferases (ATs) oppose PLA2 by re-esterifying fatty acids into phospholipids, in a biochemical pathway known as the Lands Cycle. Drosophila Lands Cycle ATs oys and nes, as well as 7 predicted PLA2 genes, are expressed in the male reproductive tract. Oys and Nes are required for spermatid individualization. Individualization, which occurs after terminal differentiation, invests each spermatid in its own plasma membrane and removes the bulk of the cytoplasmic contents. We developed a quantitative assay to measure individualization defects. We demonstrate that individualization is sensitive to temperature and age but not to diet. Mutation of the cyclooxygenase Pxt, which metabolizes fatty acids to prostaglandins, also leads to individualization defects. In contrast, modulating phospholipid levels by mutation of the phosphatidylcholine lipase Swiss cheese (Sws) or the ethanolamine kinase Easily shocked (Eas) does not perturb individualization, nor does Sws overexpression. Our results suggest that fatty acid derived signals such as prostaglandins, whose abundance is regulated by the Lands Cycle, are important regulators of spermatogenesis.

Vertebral artery dissection presenting as a Brown-Séquard syndrome: a case report.

INTRODUCTION: Vertebral artery dissection has become increasingly recognized as an important cause of stroke. It usually presents with posterior headache or neck pain followed within hours or days by signs of posterior circulation stroke. To the best of our knowledge, the clinical presentation of a Brown-Séquard syndrome with a vertebral artery dissection has been reported only once before. CASE PRESENTATION: An otherwise healthy 35-year-old man presented with acute left-sided weakness. He had experienced left-sided posterior neck pain after a 4-hour flight 4 weeks previously. Physical examination was consistent with a left Brown-Séquard syndrome. Magnetic resonance angiography showed evidence of left vertebral artery dissection. He improved after therapy with anticoagulants. CONCLUSION: We report a case of an unusual presentation of a relatively uncommon condition. This diagnosis should be considered early in relatively young patients with stroke-like symptoms or unexplained neck pain, because missing a dissection can result in adverse outcomes.