Pragya Shrestha

The gastropod molluskAplysiais an important model for cellular and molecular neurobiological studies, particularly for investigations of molecular mechanisms of learning and memory. We developed an optimized assembly pipeline to generate an improvedAplysianervous system transcriptome. This improved transcriptome enabled us to explore the evolution of cognitive capacity at the molecular level. Were there evolutionary expansions of neuronal genes between this relatively simple gastropodAplysia(20,000 neurons) andOctopus(500 million neurons), the invertebrate with the most elaborate neuronal circuitry and greatest behavioral complexity? Are the tremendous advances in cognitive power in vertebrates explained by expansion of the synaptic proteome that resulted from multiple rounds of whole genome duplication in this clade? Overall, the complement of genes linked to neuronal function is similar betweenOctopusandAplysia.As expected, a number of synaptic scaffold proteins have more isoforms in humans than inAplysiaorOctopus. However, several scaffold families present in mollusks and other protostomes are absent in vertebrates, including the Fifes, Lev10s, SOLs, and a NETO family. Thus, whereas vertebrates have more scaffold isoforms from select families, invertebrates have additional scaffold protein families not found in vertebrates. This analysis provides insights into the evolution of the synaptic proteome. Both synaptic proteins and synaptic plasticity evolved gradually, yet the last deuterostome-protostome common ancestor already possessed an elaborate suite of genes associated with synaptic function, and critical for synaptic plasticity.

Rationale: Clinical decision support (CDS) tools leveraging electronic health records (EHRs) have been an approach for addressing challenges in asthma care but remain under-studied through clinical trials. Objectives: To assess the effectiveness and efficiency of Asthma-Guidance and Prediction System (A-GPS), an Artificial Intelligence (AI)-assisted CDS tool, in optimizing asthma management through a randomized clinical trial (RCT). Methods: This was a single-center pragmatic RCT with a stratified randomization design conducted for one year in the primary care pediatric practice of the Mayo Clinic, MN. Children (<18 years) diagnosed with asthma receiving care at the study site were enrolled along with their 42 primary care providers. Study subjects were stratified into three strata (based on asthma severity, asthma care status, and asthma diagnosis) and were blinded to the assigned groups. Measurements: Intervention was a quarterly A-GPS report to clinicians including relevant clinical information for asthma management from EHRs and machine learning-based prediction for risk of asthma exacerbation (AE). Primary endpoint was the occurrence of AE within 1 year and secondary outcomes included time required for clinicians to review EHRs for asthma management. Main results: Out of 555 participants invited to the study, 184 consented for the study and were randomized (90 in intervention and 94 in control group). Median age of 184 participants was 8.5 years. While the proportion of children with AE in both groups decreased from the baseline (P = 0.042), there was no difference in AE frequency between the two groups (12% for the intervention group vs. 15% for the control group, Odds Ratio: 0.82; 95%CI 0.374–1.96; P = 0.626) during the study period. For the secondary end points, A-GPS intervention, however, significantly reduced time for reviewing EHRs for asthma management of each participant (median: 3.5 min, IQR: 2–5), compared to usual care without A-GPS (median: 11.3 min, IQR: 6.3–15); p<0.001). Mean health care costs with 95%CI of children during the trial (compared to before the trial) in the intervention group were lower than those in the control group (-$1,036 [-$2177, $44] for the intervention group vs. +$80 [-$841, $1000] for the control group), though there was no significant difference (p = 0.12). Among those who experienced the first AE during the study period (n = 25), those in the intervention group had timelier follow up by the clinical care team compared to those in the control group but no significant difference was found (HR = 1.93; 95% CI: 0.82–1.45, P = 0.10). There was no difference in the proportion of duration when patients had well-controlled asthma during the study period between the intervention and the control groups. Conclusions: While A-GPS-based intervention showed similar reduction in AE events to usual care, it might reduce clinicians’ burden for EHRs review resulting in efficient asthma management. A larger RCT is needed for further studying the findings. Trial registration: ClinicalTrials.gov Identifier: NCT02865967.

Introduction Mycophenolate Mofetil (MMF), although a widely used immunosuppressant; an increasing concern of MMF induced Primary Central Nervous System Lymphoma (PCNSL) are being reported. Timely diagnosis and management of MMF induced PCNSL can play a vital role in improved outcomes. Case Presentation Eighty-one-year-old female with history of Eosinophilic Granulomatosis with Polyangiitis (EGPA) presented with word finding difficulty, right-hand weakness and right foot clumsiness. EGPA had been stable with MMF for 6 years. Physical examination revealed weakened right-hand grip, positive right-sided dysdiadokokinesia and right foot drop. MRI-brain identified three enhancing solid lesions - in right parietal, left insular and left mid brain extending into the left thalamus. Brain biopsy revealed a focally dense lymphoid infiltrate with CD20 positive B cells, with large atypical cells resembling Hodgkin Reed-Sternberg cells. With concern for immunosuppression related PCNSL, MMF was stopped. Patient was treated with 8 weeks of rituximab therapy for its least toxic profile and concomitant benefit in EGPA. On a 2 month follow up MRI-brain, near total resolution of the intracranial lesion was observed. Patient still had some residual right lower extremity incoordination, however, strength and speech normalized with resolution of dysdiadokokinesia. Patient was advised to discontinue MMF indefinitely and remains on low dose prednisone daily. Conclusion MMF is an inhibitor of Inosine Monophosphate Dehydrogenase which prevents T- and B-cell proliferation. PCNSL is a potential complication of chronic immunosuppression with this medication. Discontinuation of the drug along with immunosuppressive therapies have been the effective therapeutic options till date.

Obstructive sleep apnea (OSA) has been described as a risk factor for cardiac arrhythmias. Its association with atrial fibrillation has been established. However, relationships with other arrhythmias and conduction disorders have not been fully studied. We used the National Inpatient Sample database from 2009 to 2011 to explore the relationship between OSA and arrhythmias and conduction disorders. The presence of diagnosis was determined based on the International Classification of Disease-9 (ICD-9) codes. Univariate and multivariate logistic regressions were used to establish mortality risks among all groups. Multivariate logistic regression showed increased mortality in patients with OSA in comparison to patients without OSA and patients across all categories of arrhythmias and conduction disorders. One significant finding was the increased association of cardiac arrest in patients with OSA versus patients without OSA (OR: 95.72; CI: 89.13-105.81, p < 0.001). OSA is significantly associated with non-atrial fibrillation arrhythmias, conduction disorders, and sudden cardiac arrest. Awareness regarding this association is important for early screening for OSA in obese patients to prevent cardiovascular morbidity and mortality. The use of continuous positive airway pressure (CPAP) might be beneficial against all kinds of arrhythmias and sudden cardiac death.

IgG4-related sclerosing cholangitis (IgG4-SC) is one of the most common extra-pancreatic manifestation of IgG4-related disease (IgG4-RD) and is clinically distinct from primary sclerosing cholangitis (PSC). IgG4-RD is an increasingly recognized immune-mediated fibroinflammatory systemic disease, mostly affecting middle-aged and older male populations that can affect multiple organs. The presence of extra-biliary clinical manifestations of IgG4-RD, such as parotid and lacrimal swelling, lymphadenopathy, autoimmune pancreatitis, and retroperitoneal fibrosis, if present could provide important clues to diagnosis. High serum IgG4 levels, characteristic radiological (e.g., sausage-shaped pancreas or periaortitis) or biopsy findings (high percentage of IgG4+ plasma cells, lymphoplasmacytic infiltrate, storiform fibrosis, or obliterative phlebitis) in the setting of these features is diagnostic of this disease process. However, isolated IgG4-SC might be a diagnostic challenge, and the distinction is important as management of this disorder is vastly different from other causes of cholangitis such as PSC. Systemic corticosteroid therapy is the mainstay of therapy.

Although Hyper-IgE Syndrome (HIES) is a rare immunodeficiency disorder, presenting symptoms may be as common as lung and skin infections. Symptoms are usually nonspecific such as recurrent abscesses, folliculitis, and pneumonias along with skeletal abnormalities. Careful history of susceptibility to skin and lung infections, thorough family history, and findings on physical exam can guide towards the diagnosis of this often-eluded condition. Early optimization of therapy with prophylactic antibiotics can prevent recurrent infections and future complications and improve quality of life and longevity of survival. We present a case of a young female with Hyper-IgE Syndrome with a novel mutation in STAT 3 gene who initially presented with long standing history of intractable skin abscesses being managed as Hidradenitis Suppurativa.