Male sexual and reproductive health in multiple sclerosis: a scoping review.

BACKGROUND: Multiple sclerosis (MS) is a chronic neuroinflammatory disease with highest incidence during the period of optimal reproductive health. This scoping review aimed to identify and summarize available data on sexual/reproductive health in males with MS (MwMS). METHODS: This review was based on PRISMA extension for Scoping Review. PubMed database was searched for keyword "multiple sclerosis" alongside keywords "sexual health", "reproductive health", "family planning", "male fertility", "male infertility", "sexual dysfunction", and "erectile dysfunction", iteratively using the "AND" logical operator. Descriptive analysis was performed on the included articles. RESULTS: Thirty-four studies were included, and four topics emerged: sexual dysfunction, erectile dysfunction, fertility, and family planning. Sexual dysfunction is common in MwMS (35-72%), yet only a minority of MwMS discuss their sexual health with their treatment teams. Both MS disability and depression were associated with sexual dysfunction in MwMS, with erectile dysfunction and decreased libido as the most prevalent aspects of sexual dysfunction. Positively, phosphodiesterase-5 inhibitors appear effective for treating erectile dysfunction and improving sexual quality of life in MwMS. There may also be a relationship between MS and male infertility, though changes in sexual behavior may underlie this association. Finally, a prominent knowledge gap was observed for disease-modifying therapy use and family planning in MwMS. CONCLUSION: Sexual dysfunction is common, impacted by MS severity, and associates with decreased quality of life in MwMS. Communication barriers regarding sexual and reproductive health appear to exist between MwMS and providers, as do literature gaps related to MS therapeutics and sexual/reproductive health.

Ischemic cerebrovascular complications with initial presentation of genetic atypical hemolytic uremic syndrome.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare disease, with scarce reports of neurologic manifestations in the acute setting. Ischemic cortical infarcts concurrently with aHUS presentation have not been described in adult patients. CASE DESCRIPTION: A 46-year-old male presented with acutely declining mental status and progressive weakness, in the setting of longstanding hypertension and known type B aortic dissection. Urgent neuroimaging showed bilateral multifocal multiterritorial ischemic infarcts, concerning for an embolic source or hypercoagulable state. Systemic workup was notable for microangiopathic hemolytic anemia and acute kidney injury. Empiric plasmapheresis was initiated for presumed thrombotic thrombocytopenic purpura. Broad workup did not support such a diagnosis, and kidney biopsy showed findings compatible with aHUS. Additional blood testing showed increased complement pathway activity. Shiga toxin was negative, and overall clinical picture fit with aHUS as diagnosis. Treatment with complement inhibitor was started and patient gradually recovered. Genetic testing confirmed a pertinent pathogenic mutation, CFHR1 homozygous deletion. CONCLUSION: Acute multifocal multiterritorial ischemic infarcts and systemic thrombotic microangiopathy may be a manifestation of aHUS, and with associated genetic mutation, even in adult population.

Predictors for the development of neurological immune-related adverse events of immune checkpoint inhibitors and impact on mortality.

BACKGROUND AND PURPOSE: Little is known about risk factors for developing neurological immunological adverse events (neuro-irAEs) from immune checkpoint inhibitors (ICIs). We report the incidence, predictors for development, impact on mortality of neuro-irAEs, and impact of ICIs on pre-existing neurological conditions in a large clinical cohort. METHODS: Patients who received ICIs between January 2011 and December 2018 were identified from a tertiary cancer center registry. Descriptive statistics were used to summarize patient, cancer, and treatment data. Odds ratios from univariable and multivariable logistic regression models were calculated to identify potential predictors for developing a neuro-irAE. Impact of neuro-irAEs on overall survival was estimated by Kaplan-Meier and Cox proportional hazard models. RESULTS: Overall frequency of neurological irAEs was 2.3%. Peripheral nervous system complications were most frequent (53.6%). Melanoma, younger age, prior chemotherapy, prior resection, CTLA-4 ICIs exposure, and combination PD-1 and CTLA-4 ICIs exposure had significantly higher odds for developing a neuro-irAE (p < 0.05) in univariate but not multivariate models. Those with a neuro-irAE were less likely to die at 3 years compared to those without a neuro-irAE (69% vs. 55%, p = 0.004) in univariate but not multivariate model. Flare of pre-existing neurological condition after exposure to ICIs was present (15.4%, 2 of 13 patients) but manageable. One patient was rechallenged with ICIs without recurrent flare. CONCLUSIONS: Neuro-irAEs are not associated with increase in overall mortality. Potential predictors for the development of neuro-irAEs are younger age, melanoma, prior chemotherapy and resection, CTLA-4, or combination ICIs exposure.

Pediatric anti-NMDA-receptor autoimmune encephalitis in siblings: Developmental, Electrophysiologic, and Genetic Implications.

BACKGROUND: Anti-NMDAR encephalitis is a leading cause of autoimmune encephalitis in children. Untreated disease can lead to long-term neurological disability. CASE REPORT: We present siblings with pediatric-onset anti-NMDAR encephalitis. One was treated early, while the other's diagnosis and treatment were delayed by several years. Developmental, electrophysiologic, and genetic implications are discussed. CONCLUSION: Anti-NMDAR encephalitis is a severely debilitating disease that often requires prompt initiation and early escalation in treatment. Delayed treatment may lead to irreversible neurological sequalae. Further studies exploring associations between timing and tier of treatment initiation and longitudinal outcomes are needed.

Pearls & Oy-sters: Hemorrhagic Myelitis Following SARS-CoV-2 Infection.

Hemorrhage in the setting of myelitis is rarely seen in clinical practice. We report a series of 3 women aged 26, 43, and 44 years, who presented with acute hemorrhagic myelitis within 4 weeks of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Two required intensive care, and 1 had severe disease with multiorgan failure. Serial MRI of the spine demonstrated T2-weighted hyperintensity with T1-weighted postcontrast enhancement in the medulla and cervical spine (patient 1) and thoracic spine (patients 2 and 3). Hemorrhage was identified on precontrast T1-weighted, susceptibility-weighted, and gradient echo sequences. Distinct from typical inflammatory or demyelinating myelitis, clinical recovery was poor in all cases, with residual quadriplegia or paraplegia, despite immunosuppression. These cases highlight that although hemorrhagic myelitis is rare, it can occur as a post/parainfectious complication of SARS-CoV-2 infection.

Nanotechnology in Stroke: New Trails with Smaller Scales.

Stroke is a leading cause of death, long-term disability, and socioeconomic costs, highlighting the urgent need for effective treatment. During acute phase, intravenous administration of recombinant tissue plasminogen activator (tPA), a thrombolytic agent, and endovascular thrombectomy (EVT), a mechanical intervention to retrieve clots, are the only FDA-approved treatments to re-establish cerebral blood flow. Due to a short therapeutic time window and high potential risk of cerebral hemorrhage, a limited number of acute stroke patients benefit from tPA treatment. EVT can be performed within an extended time window, but such intervention is performed only in patients with occlusion in a larger, anatomically more proximal vasculature and is carried out at specialty centers. Regardless of the method, in case of successful recanalization, ischemia-reperfusion injury represents an additional challenge. Further, tPA disrupts the blood-brain barrier integrity and is neurotoxic, aggravating reperfusion injury. Nanoparticle-based approaches have the potential to circumvent some of the above issues and develop a thrombolytic agent that can be administered safely beyond the time window for tPA treatment. Different attributes of nanoparticles are also being explored to develop a multifunctional thrombolytic agent that, in addition to a thrombolytic agent, can contain therapeutics such as an anti-inflammatory, antioxidant, neuro/vasoprotective, or imaging agent, i.e., a theragnostic agent. The focus of this review is to highlight these advances as they relate to cerebrovascular conditions to improve clinical outcomes in stroke patients.

New diagnosis of multiple sclerosis in the setting of mRNA COVID-19 vaccine exposure.

BACKGROUND: Multiple sclerosis (MS) with onset in the setting of acute SARS-CoV-2 virus infection has been reported, and reactivation of MS following non-mRNA COVID-19 vaccination has been noted, but there have only been three reports of newly diagnosed MS following exposure to mRNA COVID-19 vaccine. The association cannot be determined to be causal, as latent central nervous system demyelinating disease may unmask itself in the setting of an infection or a systemic inflammatory response. We report a series of 5 cases of newly diagnosed MS following recent exposure to mRNA COVID-19 vaccines. Latency from vaccination to initial presentation varied. Neurological manifestations and clinical course appeared to be typical for MS including response to high dose steroids in 4 cases and additional need for plasmapheresis in one case. CONCLUSION: Acute neurological deficits in the setting of recent mRNA COVID-19 vaccine administration may represent new onset multiple sclerosis.

Circadian changes in Alzheimer's disease: Neurobiology, clinical problems, and therapeutic opportunities.

The understanding of Alzheimer's disease (AD) pathophysiology is an active area of research, and the traditional focus on hippocampus, amyloid and tau protein, and memory impairment has been expanded with components like neuroinflammation, insulin resistance, and circadian rhythm alterations. The bidirectional vicious cycle of neuroinflammation and neurodegeneration on a molecular level may cause functional deficits already long before the appearance of overt clinical symptoms. Located at the crossroads of metabolic, circadian, and hormonal signaling, the hypothalamus has been identified as another brain region affected by AD pathophysiology. Current findings on hypothalamic dysfunction open a broader horizon for studying AD pathogenesis and offer new opportunities for diagnosis and therapy. While treatments with cholinomimetics and memantine form a first line of pharmacological treatment, additional innovative research is pursued toward the development of antiinflammatory, growth factor, or antidiabetic types of medication. Following recent epidemiological data showing associations of AD incidence with modern societal and "life-style"-related risk factors, also nonpharmacological interventions, including sleep optimization, are being developed and some have been shown to be beneficial. Circadian aspects in AD are relevant from a pathophysiological standpoint, but they can also have an important role in pharmacologic and nonpharmacologic interventions, and appropriate timing of sleep, meals, and medication may boost therapeutic efficacy.

Assessment of Cardiovascular Risk in Transgender Patients Presenting for Gender-Affirming Care.

BACKGROUND: The transgender population is rapidly growing in the United States and abroad. Transgender men and women are marginalized as a result of their transgender status, with resultant health repercussions. This and other factors such as increased substance use, mental health disorders, violence, and chronic stress may place transgender individuals at higher risk for cardiovascular disease. Additionally, many transgender patients pursue gender-affirming hormone therapy, which has been linked to increased rates of some cardiovascular events such as metabolic syndrome, venous thromboembolism, and stroke. Despite the likelihood of elevated cardiovascular risk in this population, there is a paucity of published data about the cardiovascular risk of this population. METHODS: We present baseline cardiovascular data from a transgender population at a large tertiary care center prior to the initiation of hormone therapy. RESULTS: The described transgender population had much higher rates of mental health disorders and substance use than the general population. Furthermore, there were high rates of undiagnosed and untreated comorbidities, such as hypertension and dyslipidemia, that increase risk for cardiovascular disease. Baseline risk assessment using the ASCVD (Atherosclerotic Cardiovascular Disease) and QRISK3 calculators showed higher-than-expected cardiovascular risk, particularly given the young age of our patient population. CONCLUSIONS: Transgender individuals are at high baseline cardiovascular risk. These data help fill some important knowledge gaps in this patient subgroup, and provide us with much-needed data to help guide our management and counseling of individuals seeking this type of care.

Vladimir Sertic: forgotten pioneer of virology and bacteriophage therapy.

Vladimir Sertic was a pioneer of bacteriophage research in the period between the two world wars. He was born and educated in Croatia, where he made his initial discoveries, and joined Félix d'Herelle's Laboratoire du Bactériophage in Paris in 1928. Original documents and a box with hundreds of sealed bacteriophages samples were kept in Sertic's Zagreb home for decades. Following Vladimir's death, his sister passed this archival material to Professor Zdravko Lackovic in 1989. Some years later, these artefacts were opened and studied. Additionally, we conducted a literature search using the term 'Vladimir Sertic' in the databases PubMed and Google Scholar. After a detailed examination of these data, we established a chronology of his work and compiled a list of his scientific publications. A complete bibliography, with the exception of those publications already cited here, is provided as an appendix. Sertic's key contributions included the exploration of the properties of phage lysins, the devising of a uniform bacteriophage classification system and, in collaboration with his protégé, Nikolai Boulgakov, the isolation of numerous bacteriophage strains, including the famous φX174. Finally it was Sertic's pioneering work in Zagreb that offered confirmation that phages are live agents.

Acute Carotid Stent Thrombosis in an Ultrarapid Clopidogrel Metabolizer: Case Report and Literature Review.

INTRODUCTION: Carotid angioplasty and stenting (CAS) represents an effective procedure for treating carotid artery disease. The acute in-stent thrombosis is an extremely rare complication of CAS especially when it occurs postprocedurally during the first 24 hours. Improper antiplatelet therapy or poor response to antiplatelet medications is known to be associated with a higher risk of in-stent thrombosis during early postprocedural period following a successful intervention. MATERIAL AND METHODS: A patient who experienced acute carotid in-stent thrombosis in early postprocedural period is described. He had been taking dual antiplatelet therapy for 2 weeks before undergoing a successful CAS. Moreover, pharmacogenetics studies showed the patient to be a clopidogrel ultrarapid metabolizer, which theoretically confers hyperresponsivity to medication. Alongside the report itself, a brief literature review of relevant sources pertinent to the case has been conducted. RESULTS: According to the available literature, this is the first case report describing an ultrarapid clopidogrel metabolizer who underwent an uneventful CAS but experienced acute carotid in-stent thrombosis in early postprocedural period. A rescue procedure included an endovascular intervention consisting of thrombectomy and local alteplase application, followed by postprocedural administration of intravenous eptifibatide. At discharge, patient's dual antiplatelet therapy included ticagrelor instead of clopidogrel. CONCLUSION: Acute carotid in-stent thrombosis is a highly unexpected complication of CAS and can occur despite ultrarapid clopidogrel metabolism trait.

Emergent Rescue Extracranial-Intracranial Bypass for Acute Carotid Stent Thrombosis Report.

BACKGROUND: Acute stent thrombosis is a rare adverse event following endovascular treatment of carotid artery. Experience on the topic is scarce, making the therapeutic approach a clinical challenge. In cases of intraprocedural acute carotid stent thrombosis, thromboaspiration, thrombectomy, and thrombolysis have been used as successful modalities for achieving recanalization. CASE DESCRIPTION: We describe a case of carotid artery dissection treated endovascularly and complicated by intraprocedural stent thrombosis, which was ultimately managed by emergent extracranial-intracranial bypass with radial artery graft connecting the external carotid artery to the ipsilateral middle cerebral artery. CONCLUSIONS: Neurosurgical management may represent a rescue option for otherwise unmanageable acute carotid stent thrombosis.

Low-Dose Naltrexone (LDN)-Review of Therapeutic Utilization.

Naltrexone and naloxone are classical opioid antagonists. In substantially lower than standard doses, they exert different pharmacodynamics. Low-dose naltrexone (LDN), considered in a daily dose of 1 to 5 mg, has been shown to reduce glial inflammatory response by modulating Toll-like receptor 4 signaling in addition to systemically upregulating endogenous opioid signaling by transient opioid-receptor blockade. Clinical reports of LDN have demonstrated possible benefits in diseases such as fibromyalgia, Crohn's disease, multiple sclerosis, complex-regional pain syndrome, Hailey-Hailey disease, and cancer. In a dosing range at less than 1 µg per day, oral naltrexone or intravenous naloxone potentiate opioid analgesia by acting on filamin A, a scaffolding protein involved in µ-opioid receptor signaling. This dose is termed ultra low-dose naltrexone/naloxone (ULDN). It has been of use in postoperative control of analgesia by reducing the need for the total amount of opioids following surgery, as well as ameliorating certain side-effects of opioid-related treatment. A dosing range between 1 µg and 1 mg comprises very low-dose naltrexone (VLDN), which has primarily been used as an experimental adjunct treatment for boosting tolerability of opioid-weaning methadone taper. In general, all of the low-dose features regarding naltrexone and naloxone have been only recently and still scarcely scientifically evaluated. This review aims to present an overview of the current knowledge on these topics and summarize the key findings published in peer-review sources. The existing potential of LDN, VLDN, and ULDN for various areas of biomedicine has still not been thoroughly and comprehensively addressed.

Circadian Rhythm and Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder with a growing epidemiological importance characterized by significant disease burden. Sleep-related pathological symptomatology often accompanies AD. The etiology and pathogenesis of disrupted circadian rhythm and AD share common factors, which also opens the perspective of viewing them as a mutually dependent process. This article focuses on the bi-directional relationship between these processes, discussing the pathophysiological links and clinical aspects. Common mechanisms linking both processes include neuroinflammation, neurodegeneration, and circadian rhythm desynchronization. Timely recognition of sleep-specific symptoms as components of AD could lead to an earlier and correct diagnosis with an opportunity of offering treatments at an earlier stage. Likewise, proper sleep hygiene and related treatments ought to be one of the priorities in the management of the patient population affected by AD. This narrative review brings a comprehensive approach to clearly demonstrate the underlying complexities linking AD and circadian rhythm disruption. Most clinical data are based on interventions including melatonin, but larger-scale research is still scarce. Following a pathophysiological reasoning backed by evidence gained from AD models, novel anti-inflammatory treatments and those targeting metabolic alterations in AD might prove useful for normalizing a disrupted circadian rhythm. By restoring it, benefits would be conferred for immunological, metabolic, and behavioral function in an affected individual. On the other hand, a balanced circadian rhythm should provide greater resilience to AD pathogenesis.

Psychoneuroimmunological approach to gastrointestinal related pain.

BACKGROUND AND PURPOSE (AIMS): Psychoneuroimmunology is both a theoretical and practical field of medicine in which human biology and psychology are considered an interconnected unity. Through such a framework it is possible to elucidate complex syndromes in gastrointestinal related pain, particularly chronic non-malignant. The aim is to provide insight into pathophysiological mechanisms and suggest treatment modalities according to a comprehensive paradigm. The article also presents novel findings that may guide clinicians to recognize new targets or scientists to find new research topics. METHODS: A literature search of 'PubMed' and 'Google Scholar' databases was performed. Search terms included: 'Visceral pain', 'Psychoneuroimmunology', 'Psychoneuroimmunology and pain', 'Pain in GI system', 'GI related pain', 'Pain and microbiota', 'Enteric nervous system', 'Enteric nervous system and inflammation', 'CNS and pain', 'Inflammation and pain in GI tract', 'Neurogastroenterology', 'Neuroendocrinology', 'Immune system in GI pain'. After searching and reading sources deemed recent and relevant, a narrative review was written with a tendency to discriminate the peripheral, intermediate, and central pathophysiological mechanisms or treatment targets. RESULTS: Recent evidence point out the importance of considering the brain-gut axis as the main connector of the central and peripheral phenomena encountered in patients suffering from chronic non-malignant gastrointestinal related pain. This axis is also a prime clinical target with multiple components to be addressed in order for therapy to be more effective. Patients suffering from inflammatory bowel disease or functional gastrointestinal disorders represent groups that could benefit most from the proposed approach. CONCLUSIONS (BASED ON OUR FINDINGS): Rather than proceeding with established allopathic single-target central or peripheral treatments, by non-invasively modulating the brain-gut axis components such as the psychological and neuroendocrinological status, microbiota, enteric nervous system, or immune cells (e.g. glial or mast cells), a favourable clinical outcome in various chronic gastrointestinal related pain syndromes may be achieved. Clinical tools are readily available in forms of psychotherapy, prebiotics, probiotics, nutritional advice, and off-label drugs. An example of the latter is low-dose naltrexone, a compound which opens the perspective of targeting glial cells to reduce neuroinflammation and ultimately pain. IMPLICATIONS (OUR OPINION ON WHAT OUR FINDINGS MEAN): Current findings from basic science provide sound mechanistic evidence and once entering clinical practice should yield more effective outcomes for patients. In addition to well-established pharmacotherapy comprised notably of anti-inflammatories, antibiotics, and proton-pump inhibitors, valid treatment strategies may contain other options. These disease modulating add-ons include probiotics, prebiotics, food supplements with anti-inflammatory properties, various forms of psychotherapy, and low-dose naltrexone as a glial modulator that attenuates neuroinflammation. Clearly, a broader and still under exploited set of evidence-based tools is available for clinical use.