The role of the lateral septum in neuropsychiatric disease.

The lateral septum (LS) is a structure in the midline of the brain that is interconnected with areas associated with stress and feeding. This review highlights the role of the LS in anxiety, depression, and eating disorders and their comorbidity. There is a prevailing view that the LS is anxiolytic. This review finds that the LS is both anxiolytic and anxiogenic. Furthermore, the LS can promote and inhibit feeding. Given these shared roles, the LS represents a common site for the comorbidity of neuropsychiatric disorders, and therefore a potential pharmacological target. This is crucial since currently available treatments are not always effective. Corticotrophin-releasing factor 2 antagonists are potential drugs for the treatment of anxiety and anorexia and require further research. Furthermore, other drugs currently in trials for binge eating, such as alpha-adrenergic agonists, may in fact promote food intake. It is hoped that the advancements in chemo- and optogenetic techniques will allow future studies to profile the specific neural connections of the LS and their function. This information could facilitate our understanding of the underlying mechanisms, and therefore pharmacological targets, of these psychiatric conditions.

Antiplatelet Use in Ischemic Stroke.

OBJECTIVE: A literature review of antiplatelet agents for primary and secondary stroke prevention, including mechanism of action, cost, and reasons for lack of benefit. DATA SOURCES: Articles were gathered from MEDLINE, Cochrane Reviews, and PubMed databases (1980-2021). Abstracts from scientific meetings were considered. Search terms included ischemic stroke, aspirin, clopidogrel, dipyridamole, ticagrelor, cilostazol, prasugrel, glycoprotein IIb/IIIa inhibitors. STUDY SELECTION AND DATA EXTRACTION: English-language original and review articles were evaluated. Guidelines from multiple countries were reviewed. Articles were evaluated independently by 2 authors. DATA SYNTHESIS: An abundance of evidence supports aspirin and clopidogrel use for secondary stroke prevention. In the acute phase (first 21 days postinitial stroke), these medications have higher efficacy for preventing further stroke when combined, but long-term combination therapy is associated with higher hemorrhage rates. Antiplatelet treatment failure is influenced by poor adherence and genetic polymorphisms. Antiplatelet agents such as cilostazol may provide extra benefit over clopidogrel and aspirin, in certain racial groups, but further research in more diverse ethnic populations is needed. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This review presents the data available on the use of different antiplatelet agents poststroke. Dual therapy, recurrence after initiation of secondary preventative therapy, and areas for future research are discussed. CONCLUSIONS: Although good evidence exists for the use of certain antiplatelet agents postischemic stroke, there are considerable opportunities for future research to investigate personalized therapies. These include screening patients for platelet polymorphisms that confer antiplatelet resistance and for randomized trials including more racially diverse populations.

Difficult Conversations in Cancer Care: Lessons from a Student-Led Initiative.

With the rising global burden of cancer, healthcare professionals will inevitably be involved directly or indirectly in the care of cancer patients. Although medical education has recently evolved to emphasise the biopsychosocial model, current training regarding difficult communication skills and breaking bad news remains inadequate. Our aim was to utilise a novel method of teaching communication skills through public engagement. This was achieved by setting up a local network of cancer patients who were willing to share their stories to aid student learning. A group of medical students from years one to four interviewed a total of 48 cancer patients about their illness experiences. Student reflections were collated, producing three common themes: (1) knowing what to say, (2) seeing the person in the patient, and (3) understanding the consequences of poor communication. The experiences allowed students to develop their communication skills, learn from patient experiences, and reflect on their future practice. Patient stories, including art, drawings, and poems, were collated in the form of a book and disseminated to promote further learning. We hope our reflections and public engagement initiative will identify key areas of difficult communication, enhance learning, and prepare students for meaningful and often difficult conversation in cancer care. Similar principles could be used in other areas of medical education to allow students to develop safe and effective interpersonal skills.

Familial and sporadic idiopathic pulmonary fibrosis: making the diagnosis from peripheral blood.

BACKGROUND: Peripheral blood biomarkers might improve diagnostic accuracy for idiopathic pulmonary fibrosis (IPF). RESULTS: Gene expression profiles were obtained from 89 patients with IPF and 26 normal controls. Samples were stratified according to severity of disease based on pulmonary function. The stratified dataset was split into subsets; two-thirds of the samples were selected to comprise the training set, while one-third was reserved for the validation set. Bayesian probit regression was used on the training set to develop a gene expression model for IPF versus normal. The gene expression model was tested by using it on the validation set to perform class prediction. Unsupervised clustering failed to discriminate between samples of different severity. Therefore, samples of all severities were included in the training and validation sets, in equal proportions. A gene signature model was developed from the training set. The model was built in an iterative fashion with the number of gene features selected to minimize the misclassification error in cross validation. The final model was based on the top 108 discriminating genes in the training set. The signature was successfully applied to the validation set, ROC area under the curve = 0.893, p < 0.0001. Using the optimal threshold (0.74) accurate class predictions were made for 77% of the test cases with sensitivity = 0.70, specificity = 1.00. CONCLUSIONS: By using Bayesian probit regression to develop a model, we show that it is entirely possible to make a diagnosis of IPF from the peripheral blood with gene signatures.

A Retrospective Cohort Study Assessing the Impact of Statin Therapy on Hospital Length of Stay and Inpatient Mortality in COVID-19 Patients.

Background: Coronaviruses, known for their crown-like appearance, cause mild gastrointestinal and respiratory diseases. Some cause outbreaks of respiratory diseases, most recently, SARS-CoV-2, the coronavirus disease 2019 (COVID-19). Individuals with COVID-19 are reported to be in both arterial and venous prothrombotic states. In addition to a lipid-lowering effect, statin also has an anti-inflammatory effect, which addresses one of the underlying causes of thrombosis. An in-silico study revealed that statins could directly interact with the main protease enzyme of SARS-CoV-2 and prevent infectivity. Due to these pleiotropic properties, statins may positively impact the outcome of hospitalized patients with COVID-19 infections. Methods: A total of 26 445 acute COVID-19-infected patients were included in this study. Patients were stratified based on home statin use status: no statins, high-intensity statins (atorvastatin 40-80 mg daily and rosuvastatin 20-40 mg daily), and low-to-moderate intensity statins (all other statins). A multivariate generalized linear model and logistic regression were used to predict the hospital length of stay and inpatient mortality, respectively. Results: The hospital length of stay was compared between low-intensity and high-intensity statin use against no statin therapy. The length of stay was 3.88 days (95% CI, 3.56-4.20; P < .0001) longer among patients with low-dose statin therapy compared to patients without. The length of stay was 4.77 days (95% CI, 4.42-5.13; P <.0001) longer among patients with high-intensity statin therapy than those without. The odds of in-hospital mortality decreased by 24% (OR, 0.76; 95% CI, 0.76-0.97) among those with high-dose statin therapy compared to patients without (P = .02). There was no statistical significance between the low-dose statin group and the no statin group for inpatient mortality. Conclusion: Hospitalized COVID-19 patients on statin therapy, regardless of intensity, are more likely to have a longer length of stay. There may be a mortality benefit in using high-intensity statin in acute COVID-19-infected patients. The results of this study are insufficient to recommend statin therapy for inpatient COVID-19 treatment. However, patients with significant cardiovascular comorbidities, where statins are indicated, should be on these medications, especially amidst the COVID-19 pandemic. Randomized controlled trials are needed to assess the potential in-hospital benefit of statin therapy on COVID-19 patients.

The role of PKMζ in the maintenance of long-term memory: a review.

Long-term memories are thought to be stored in neurones and synapses that undergo physical changes, such as long-term potentiation (LTP), and these changes can be maintained for long periods of time. A candidate enzyme for the maintenance of LTP is protein kinase M zeta (PKMζ), a constitutively active protein kinase C isoform that is elevated during LTP and long-term memory maintenance. This paper reviews the evidence and controversies surrounding the role of PKMζ in the maintenance of long-term memory. PKMζ maintains synaptic potentiation by preventing AMPA receptor endocytosis and promoting stabilisation of dendritic spine growth. Inhibition of PKMζ, with zeta-inhibitory peptide (ZIP), can reverse LTP and impair established long-term memories. However, a deficit of memory retrieval cannot be ruled out. Furthermore, ZIP, and in high enough doses the control peptide scrambled ZIP, was recently shown to be neurotoxic, which may explain some of the effects of ZIP on memory impairment. PKMζ knockout mice show normal learning and memory. However, this is likely due to compensation by protein-kinase C iota/lambda (PKCι/λ), which is normally responsible for induction of LTP. It is not clear how, or if, this compensatory mechanism is activated under normal conditions. Future research should utilise inducible PKMζ knockdown in adult rodents to investigate whether PKMζ maintains memory in specific parts of the brain, or if it represents a global memory maintenance molecule. These insights may inform future therapeutic targets for disorders of memory loss.

Dermatomyositis Flare With Immune Checkpoint Inhibitor Therapy for Melanoma.

Immune checkpoint inhibitor (ICI) medications have seen expanded use in the management of numerous malignancies. These therapies encompass a unique spectrum of immune-related adverse events (irAEs). Rheumatological irAEs from ICIs have been described in various case reports; however, limited literature exists regarding the treatment of patients with pre-existing myositis. We describe a case of myositis flare after initiation of nivolumab for metastatic melanoma in a patient who had previously achieved remission of dermatomyositis.

Perplexing Rash: Challenges to Diagnosis and Management of Mycosis Fungoides.

Mycosis fungoides is the most ubiquitous form of cutaneous T-cell lymphoma. Diagnosis is arduous, as early phases often resemble common inflammatory dermatoses. The principal histologic features of MF include medium to large-sized cerebriform mononuclear cells in single or small clusters in the epidermis. Treatment modalities are prodigious and relapses are common. The authors present a case of a 69-year-old man with mycosis fungoides, followed by a review of diagnostic modalities and phototherapeutic interventions for patients with this condition. According to literature reports, monochromatic excimer light therapy is the most advantageous and well-tolerated phototherapy modality for patients with early patch stage mycosis fungoides.

HIV-1 Group O Genotypes and Phenotypes: Relationship to Fitness and Susceptibility to Antiretroviral Drugs.

Despite only 30,000 group O HIV-1 infections, a similar genetic diversity is observed among the O subgroups H (head) and T (tail) (previously described as subtypes A, B) as in the 9 group M subtypes (A-K). Group O isolates bearing a cysteine at reverse transcriptase (RT) position 181, predominantly the H strains are intrinsically resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs). However, their susceptibility to newer antiretroviral drugs such as etravirine, maraviroc, raltegravir (RAL), and elvitegravir (EVG) remains relatively unknown. We tested a large collection of HIV-1 group O strains for their susceptibility to four classes of antiretroviral drugs namely nucleoside RT, non-nucleoside RT, integrase, and entry inhibitors knowing in advance the intrinsic resistance to NNRTIs. Drug target regions were sequenced to determine various polymorphisms and were phylogenetically analyzed. Replication kinetics and fitness assays were performed in U87-CD4(+)CCR5 and CXCR4 cells and peripheral blood mononuclear cells. With all antiretroviral drugs, group O HIV-1 showed higher variability in IC50 values than group M HIV-1. The mean IC50 values for entry and nucleoside reverse transcriptase inhibitor (NRTI) were similar for group O and M HIV-1 isolates. Despite similar susceptibility to maraviroc, the various phenotypic algorithms failed to predict CXCR4 usage based on the V3 Env sequences of group O HIV-1 isolates. Decreased sensitivity of group O HIV-1 to integrase or NNRTIs had no relation to replicative fitness. Group O HIV-1 isolates were 10-fold less sensitive to EVG inhibition than group M HIV-1. These findings suggest that in regions where HIV-1 group O is endemic, first line treatment regimens combining two NRTIs with RAL may provide more sustained virologic responses than the standard regimens involving an NNRTI or protease inhibitors.