Combined PMM2-CDG and hereditary fructose intolerance in a patient with mild clinical presentation.

We report a patient with an extremely rare, combined diagnosis of PMM2-CDG and hereditary fructose intolerance (HFI). By comparing with other patients, under-galactosylation was identified as a feature of HFI. Fructose/sorbitol/sucrose restriction was initiated right afterwards. The patient is at the mild end of the PMM2-CDG spectrum, raising the question of sorbitol's role in the pathogenesis of PMM2-CDG and whether fructose/sorbitol/sucrose restriction could benefit other PMM2-CDG patients. Additionally, epalrestat, an emerging potential PMM2-CDG therapy, may benefit HFI patients.

Palliative care: An update for internists.

All clinicians should maintain basic skills in general palliative care to help address the needs of patients and families. Because keeping up with the information provided by the growing palliative care literature can be challenging, we conducted a detailed search via Medline for palliative care articles published in 2020 in top peer-reviewed medical journals. Using a consensus-driven process of selection, we reviewed and summarized 11 articles to enhance knowledge of the practice-changing palliative care literature for general internists.

Dilated cardiomyopathy associated with a mutation in the dispatched RND transporter family member 1 gene.

Dilated cardiomyopathy is the most common presentation of cardiomyopathy in children with 20-35% of patients having an identified genetic component. There are more than 30 genes implicated in the pathogenesis of dilated cardiomyopathy. We present the first report of a female infant with dilated cardiomyopathy with a genetic variant in the dispatched RND transporter family member 1 gene.

Reversible Cerebral Vasoconstriction Syndrome and Sickle Cell Disease: A Case Report.

Reversible cerebral vasoconstriction syndrome (RCVS), is rare in the pediatric population and is characterized by severe headaches and other neurologic symptoms. We present a case of RCVS occurring concomitantly with posterior reversible encephalopathy syndrome in an 8-year-old African American child with sickle cell disease (HbSS). Imaging studies including computed tomography, magnetic resonance imaging and cerebral angiography of the brain showed acute hemorrhagic stroke and a beaded appearance of peripheral cerebral vessels. In this report, we focus on the typical features of RCVS and discuss the underlying risk factors that may increase the risk in patients with HbSS disease.

Dextrocardia: When right is wrong!

INTRODUCTION/BACKGROUND: Dextrocardia is a malposition of the heart in the thoracic cavity. Dextrocardia has been known to cause diagnostic dilemmas with atypical presentations in acute coronary syndrome, as well as technical challenges in patients who require interventions such as coronary catheterization, transcutaneous aortic valve replacement, ablation for arrhythmias, or pacemaker/defibrillator placement. Transcription factor Pitx2 has been shown to have a fundamental role during cardio-genesis, and its misexpression has been implicated in arrhythmogenesis and congenital heart diseases including visceral situs inversus. This association between congenital heart diseases and arrythmias is intriguing and need exploring. We aimed to quantify the likelihood of arrhythmias in patients with dextrocardia. MATERIALS AND METHODS: A descriptive, retrospective study was conducted on the National Inpatient Sample (NIS) databases for the year 2016. Patients with dextrocardia and arrhythmias were selected based on appropriate diagnostic codes. We used propensity score-matching to assemble a matched cohort in which adults with dextrocardia and controls balanced on measured baseline characteristics. This was done to reduce the confounding effect of between-group imbalances on outcomes. Complex survey design, weights, and clustering were accounted for during analysis. Multivariate regression analysis was performed to determine the relationship of arrhythmias and length of hospitalization with dextrocardia. RESULTS: The prevalence of arrhythmias in patients with dextrocardia was significantly higher than the control group. Overall, the odds of arrhythmia were higher for patients in the dextrocardia group when compared to a propensity matched control group [adjusted Odds ratio OR 2.60, Confidence Interval (CI) (1.67-4.06), p<0.001]. When looking at only principal/primary diagnosis on admission, the odds of an admitting diagnosis of arrhythmia were significantly higher in the dextrocardia group when compared to the matched cohort [adjusted OR 3.70, CI (1.26-10.89), p 0.02]. The increased odds of arrhythmia in dextrocardia patients were mostly accounted for by the increased odds of atrial fibrillation/atrial flutter [OR 3.06, CI (1.02-9.18), p 0.046] in these patients. No significant difference was found in the odds of other arrhythmias or the length of stay between the two groups. CONCLUSION: In a large inpatient population, patients with dextrocardia were more likely to have arrhythmias especially atrial fibrillation/atrial flutter than patients without dextrocardia. Ours is the first study that investigates the clinical manifestations of molecular and embryologic associations between congenital heart disease and arrhythmias.

Promoting Primary Palliative Care in Severe Chronic Obstructive Pulmonary Disease: Symptom Management and Preparedness Planning.

Chronic obstructive pulmonary disease (COPD) poses challenges not only in symptom management but also in prognostication. Managing COPD requires clinicians to be proficient in the primary palliative care skills of symptom management and communication focused on eliciting goals and preferences. Dyspnea should initially be managed with the combination of long-acting muscarinic antagonists and long-acting ß-agonist inhalers, adding inhaled corticosteroids if symptoms persist. Opioids for the relief of dyspnea are safe when used at appropriate doses. Oxygen is only effective for relieving dyspnea in patients with severe hypoxemia. The relapsing-remitting nature of COPD makes prognostication challenging; however, there are tools to guide clinicians and patients in making plans both with respect to prognosis and symptom burden. Preparedness planning techniques promote detailed culturally appropriate conversations which allow patients and clinicians to consider disease-specific complications and develop goal-concordant treatment plans.

Clinical heterogeneity of mitochondrial NAD kinase deficiency caused by a NADK2 start loss variant.

Mitochondrial NAD kinase deficiency (NADK2D, OMIM #615787) is a rare autosomal recessive disorder of NADPH biosynthesis that can cause hyperlysinemia and dienoyl-CoA reductase deficiency (DECRD, OMIM #616034). NADK2 deficiency has been reported in only three unrelated patients. Two had severe, unremitting disease; one died at 4 months and the other at 5 years of age. The third was a 10 year old female with CNS anomalies, ataxia, and incoordination. In two cases mutations in NADK2 have been demonstrated. Here, we report the fourth known case, a 15 year old female with normal intelligence and a mild clinical and biochemical phenotype presumably without DECRD. Her clinical symptoms, which are now stable, became evident at the age of 9 with the onset of decreased visual acuity, bilateral optic atrophy, nystagmus, episodic lower extremity weakness, peripheral neuropathy, and gait abnormalities. Plasma amino acid levels were within normal limits except for mean lysine and proline levels that were 3.7 and 2.5 times the upper limits of normal. Whole exome sequencing (WES) revealed homozygosity for a g.36241900 A>G p. Met1Val start loss mutation in the primary NADK2 transcript (NM_001085411.1) encoding the 442 amino acid isoform. This presumed hypomorphic mutation has not been previously reported and is absent from the v1000GP, EVS, and ExAC databases. Our patient's normal intelligence and stable disease expands the clinical heterogeneity and the prognosis associated with NADK2 deficiency. Our findings also clarify the mechanism underlying NADK2 deficiency and suggest that this disease should be ruled out in cases of hyperlysinemia, especially those with visual loss, and neurological phenotypes.

Update in Hospital Palliative Care: Symptom Management, Communication, Caregiver Outcomes, and Moral Distress.

BACKGROUND: Updated knowledge of the palliative care (PC) literature is needed to maintain competency and best address the PC needs of hospitalized patients. We critiqued the recent PC literature with the highest potential to impact hospital practice. METHODS: We reviewed articles published between January 2016 and December 2016, which were identified through a handsearch of leading journals and a MEDLINE search. The final 9 articles selected were determined by consensus based on scientific rigor, relevance to hospital medicine, and impact on practice. RESULTS: Key findings include the following: scheduled antipsychotics were inferior to a placebo for nonterminal delirium; a low-dose morphine was superior to a weak opioid for moderate cancer pain; methadone as a coanalgesic improved high-intensity cancer pain; many hospitalized patients on comfort care still receive antimicrobials; video decision aids improved the rates of advance care planning (ACP) and hospice use and decreased costs; standardized, PC-led intervention did not improve psychological outcomes in families of patients with a chronic critical illness; caregivers of patients surviving a prolonged critical illness experienced high and persistent rates of depression; people with non-normative sexuality or gender faced additional stressors with partner loss; and physician trainees experienced significant moral distress with futile treatments. CONCLUSIONS: Recent research provides important guidance for clinicians caring for hospitalized patients with serious illnesses, including symptom management, ACP, moral distress, and outcomes of critical illness.

Ethical Issues in the Design and Implementation of Population Health Programs.

Spurred on by recent health care reforms and the Triple Aim's goals of improving population health outcomes, reducing health care costs, and improving the patient experience of care, emphasis on population health is increasing throughout medicine. Population health has the potential to improve patient care and health outcomes for individual patients. However, specific population health activities may not be in every patient's best interest in every circumstance, which can create ethical tensions for individual physicians and other health care professionals. Because individual medical professionals remain committed primarily to the best interests of individual patients, physicians have a unique role to play in ensuring population health supports this ethical obligation. Using widely recognized principles of medical ethics-nonmaleficence/beneficence, respect for persons, and justice-this article describes the ethical issues that may arise in contemporary population health programs and how to manage them. Attending to these principles will improve the design and implementation of population health programs and help maintain trust in the medical profession.

Secondhand Smoke Exposure Among Community-Dwelling Adult Cancer Survivors in the United States: 1999-2012.

Background: Little is known about the prevalence of secondhand smoke exposure (SHSe) among cancer survivors. We sought to determine the prevalence, trends, and correlates of SHSe among nonsmoking adult cancer survivors in the United States.Methods: Interview and serum cotinine data for nonsmoking adults, age 20 years and older, with a history of cancer (N = 686) were obtained from consecutive two-year cross-sectional cycles of the National Health and Nutrition Examination Survey from 1999 to 2012. SHSe was defined as serum cotinine 0.05-10 ng/mL among nonsmokers. We calculated and trended the prevalence of SHSe among nonsmoking cancer survivors. Multivariable logistic regression was used to examine the associations of SHSe with sociodemographic, smoking, and clinical characteristics. Survey weights were applied in estimating prevalence rates, adjusted ORs, and confidence intervals (CI).Results: The weighted aggregate SHSe and self-reported indoor SHSe prevalence rates over the study period were 28.26% (95% CI: 24.97%-31.55%) and 4.53% (95% CI: 3.48%-5.57%), respectively. SHS exposure declined from 39.61% (95% CI: 27.88%-51.34%) in 1999/2000 to 15.68% (95% CI: 9.38%-21.98%) in 2011/2012 (Ptrend < 0.001). Age ≥ 60 years was protective against SHSe, while being black, having less than high school education, poverty, and a smoking-related cancer history were associated with higher odds of SHSe.Conclusions: Fortunately, SHSe among nonsmoking cancer survivors in the United States is on the decline, although certain subgroups remain disproportionately burdened.Impact: These findings highlight clinical and public health imperatives to target socioeconomically disadvantaged nonsmoking cancer survivors to reduce their SHSe. Cancer Epidemiol Biomarkers Prev; 26(8); 1296-305. ©2017 AACR.

Does adherence to epilepsy quality measures correlate with reduced epilepsy-related adverse hospitalizations? A retrospective experience.

In 2011, the American Academy of Neurology (AAN) established eight epilepsy quality measures (EQMs) for chronic epilepsy treatment to address deficits in quality of care. This study assesses the relationship between adherence to these EQMs and epilepsy-related adverse hospitalizations (ERAHs). A retrospective chart review of 475 new epilepsy clinic patients with an ICD-9 code 345.1-9 between 2010 and 2012 was conducted. Patient demographics, adherence to AAN guidelines, and annual number of ERAHs were assessed. Fisher's exact test was used to assess the relationship between adherence to guidelines (as well as socioeconomic variables) and the presence of one or more ERAH per year. Of the eight measures, only documentation of seizure frequency, but not seizure type, correlated with ERAH (relative risk [RR] 0.343, 95% confidence interval [CI] 0.176-0.673, p = 0.010). Among patients in the intellectually disabled population (n = 70), only review/request of neuroimaging correlated with ERAH (RR 0.128, 95% CI 0.016-1.009, p = 0.004). ERAHs were more likely in African American patients (RR 2.451, 95% CI 1.377-4.348, p = 0.008), Hispanic/Latino patients (RR 4.016, 95% CI 1.721-9.346, p = 0.016), Medicaid patients (RR 2.217, 95% CI 1.258-3.712, p = 0.009), and uninsured patients (RR 2.667, 95% CI 1.332-5.348, p = 0.013). In this retrospective series, adherence to the eight AAN quality measures did not strongly correlate with annual ERAH.

Dendritic spine injury induced by the 8-hydroxy metabolite of efavirenz.

Despite combination antiretroviral therapies (cARTs), a significant proportion of HIV-infected patients develop HIV-associated neurocognitive disorders (HAND). Ongoing viral replication in the central nervous system (CNS) caused by poor brain penetration of cART may contribute to HAND. However, it has also been proposed that the toxic effects of long-term cART may contribute to HAND. A better understanding of the neurotoxic potential of cART is critically needed in light of the use of CNS-penetrating cARTs to contend with the virus reservoir in the brain. The efavirenz (EFV) metabolites 7-hydroxyefavirenz (7-OH-EFV) and 8-hydroxyefavirenz (8-OH-EFV) were synthesized and purified, and their chemical structures were confirmed by mass spectrometry and NMR. The effects of EFV, 7-OH-EFV, and 8-OH-EFV on calcium, dendritic spine morphology, and survival were determined in primary neurons. EFV, 7-OH-EFV, and 8-OH-EFV each induced neuronal damage in a dose-dependent manner. However, 8-OH-EFV was at least an order of magnitude more toxic than EFV or 7-OH-EFV, inducing considerable damage to dendritic spines at a 10 nM concentration. The 8-OH-EFV metabolite evoked calcium flux in neurons, which was mediated primarily by L-type voltage-operated calcium channels (VOCCs). Blockade of L-type VOCCs protected dendritic spines from 8-OH-EFV-induced damage. Concentrations of EFV and 8-OH-EFV in the cerebral spinal fluid of HIV-infected subjects taking EFV were within the range that damaged neurons in culture. These findings demonstrate that the 8-OH metabolite of EFV is a potent neurotoxin and highlight the importance of directly determining the effects of antiretroviral drugs and drug metabolites on neurons and other brain cells.

The human immunodeficiency virus coat protein gp120 promotes forward trafficking and surface clustering of NMDA receptors in membrane microdomains.

Infection by the human immunodeficiency virus (HIV) can result in debilitating neurological syndromes collectively known as HIV-associated neurocognitive disorders. Although the HIV coat protein gp120 has been identified as a potent neurotoxin that enhances NMDA receptor function, the exact mechanisms for this effect are not known. Here we provide evidence that gp120 activates two separate signaling pathways that converge to enhance NMDA-evoked calcium flux by clustering NMDA receptors in modified membrane microdomains. gp120 enlarged and stabilized the structure of lipid microdomains on dendrites by mechanisms that involved a redox-regulated translocation of a sphingomyelin hydrolase (neutral sphingomyelinase-2) to the plasma membrane. A concurrent pathway was activated that accelerated the forward traffic of NMDA receptors by a PKA-dependent phosphorylation of the NR1 C-terminal serine 897 (masks an ER retention signal), followed by a PKC-dependent phosphorylation of serine 896 (important for surface expression). NMDA receptors were preferentially targeted to synapses and clustered in modified membrane microdomains. In these conditions, NMDA receptors were unable to laterally disperse and did not internalize, even in response to strong agonist induction. Focal NMDA-evoked calcium bursts were enhanced by threefold in these regions. Inhibiting membrane modification or NR1 phosphorylation prevented gp120 from accelerating the surface localization of NMDA receptors. Disrupting the structure of membrane microdomains after gp120 treatments restored the ability of NMDA receptors to disperse and internalize. These findings demonstrate that gp120 contributes to synaptic dysfunction in the setting of HIV infection by interfering with NMDA receptor trafficking.