A Systematic Review of Female Participation in Randomized Controlled Trials of Post-Stroke Upper Extremity Rehabilitation in Low- to Middle-Income Countries and High-Income Countries and Regions.

INTRODUCTION: Female participation is lower than males in both acute stroke and stroke rehabilitation trials. However, less is known about how female participation differs across countries and regions. This study aimed to assess the percentage of female participants in randomized controlled trials (RCTs) of post-stroke rehabilitation of upper extremity (UE) motor disorders in low-middle-income (LMICs) and high-income countries (HICs) as well as different high-income world regions. METHODS: CINAHL, Embase, PubMed, Scopus, and Web of Science were searched from 1960 to April 1, 2021. Studies were eligible for inclusion if they (1) were RCTs or crossovers published in English; (2) ≥50% of participants were diagnosed with stroke; 3) included adults ≥18 years old; and (4) applied an intervention to the hemiparetic UE as the primary objective of the study. Countries were divided into HICs and LMICs based on their growth national incomes. The HICs were further divided into the three high-income regions of North America, Europe, and Asia and Oceania. Data analysis was performed using SPSS and RStudio v.4.3.1. RESULTS: A total of 1,276 RCTs met inclusion criteria. Of them, 298 RCTs were in LMICs and 978 were in HICs. The percentage of female participants was significantly higher in HICs (39.5%) than LMICs (36.9%). Comparing high-income regions, there was a significant difference in the overall female percentages in favor of RCTs in Europe compared to LMICs but not North America or Asia and Oceania. There was no significant change in the percentage of female participants in all countries and regions over the last 2 decades, with no differences in trends between the groups. CONCLUSIONS: Sufficient female representation in clinical trials is required for the generalizability of results. Despite differences in overall percentage of female participation between countries and regions, females have been underrepresented in both HICs and LMICs with no considerable change over 2 decades.

Beyond the 5-HT2A Receptor: Classic and Nonclassic Targets in Psychedelic Drug Action.

Serotonergic psychedelics, such as psilocybin and LSD, have garnered significant attention in recent years for their potential therapeutic effects and unique mechanisms of action. These compounds exert their primary effects through activating serotonin 5-HT2A receptors, found predominantly in cortical regions. By interacting with these receptors, serotonergic psychedelics induce alterations in perception, cognition, and emotions, leading to the characteristic psychedelic experience. One of the most crucial aspects of serotonergic psychedelics is their ability to promote neuroplasticity, the formation of new neural connections, and rewire neuronal networks. This neuroplasticity is believed to underlie their therapeutic potential for various mental health conditions, including depression, anxiety, and substance use disorders. In this mini-review, we will discuss how the 5-HT2A receptor activation is just one facet of the complex mechanisms of action of serotonergic psychedelics. They also interact with other serotonin receptor subtypes, such as 5-HT1A and 5-HT2C receptors, and with neurotrophin receptors (e.g., tropomyosin receptor kinase B). These interactions contribute to the complexity of their effects on perception, mood, and cognition. Moreover, as psychedelic research advances, there is an increasing interest in developing nonhallucinogenic derivatives of these drugs to create safer and more targeted medications for psychiatric disorders by removing the hallucinogenic properties while retaining the potential therapeutic benefits. These nonhallucinogenic derivatives would offer patients therapeutic advantages without the intense psychedelic experience, potentially reducing the risks of adverse reactions. Finally, we discuss the potential of psychedelics as substrates for post-translational modification of proteins as part of their mechanism of action.

What Came First: Malnutrition or Severe Disease?

A 20-year-old female with depression presented to the emergency department with chronic weight loss, weakness, fatigue, hair loss, rash, palpitations, and 2 weeks of cough. Initial history revealed that she had disordered eating habits with dietary restriction, experienced a 50-pound unintentional weight loss over 2 years despite reported adherence to nutritional supplementation, and had a normal gastrointestinal workup. On examination, she was markedly cachectic with a BMI of 10.3kg/m2 and hypotensive (84/69 mmHg). Her cardiovascular examination revealed a regular rate and rhythm without a murmur. Her breath sounds were diminished in the upper lobes bilaterally. A skin examination showed diffuse hair loss, skin breakdown, and peeling with a tender, erythematous, papular rash over the bilateral ankles, and nonpitting edema. A chest radiograph showed a right upper lobe opacity and lucent lesions in the left proximal humerus. A focused assessment with sonography for trauma examination showed a large pericardial effusion. Chest computed tomography revealed a right upper lobe opacity with an associated cavitation. Though she began improving with rifampin, isoniazid, pyrazinamide, ethambutol, levofloxacin, azithromycin, and nutritional rehabilitation, her clinical course was complicated by an acute worsening nearly 1 month into her hospitalization with persistent high fevers, worsening cough, development of a murmur, and worsening consolidation on chest computed tomography. Adolescent Medicine, Infectious Diseases, Gastroenterology, and Allergy and Immunology were consulted to guide the diagnostic evaluation and management of this patient's complex clinical course.

Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors.

Decreased dendritic spine density in the cortex is a hallmark of several neuropsychiatric diseases, and the ability to promote cortical neuron growth has been hypothesized to underlie the rapid and sustained therapeutic effects of psychedelics. Activation of 5-hydroxytryptamine (serotonin) 2A receptors (5-HT2ARs) is essential for psychedelic-induced cortical plasticity, but it is currently unclear why some 5-HT2AR agonists promote neuroplasticity, whereas others do not. We used molecular and genetic tools to demonstrate that intracellular 5-HT2ARs mediate the plasticity-promoting properties of psychedelics; these results explain why serotonin does not engage similar plasticity mechanisms. This work emphasizes the role of location bias in 5-HT2AR signaling, identifies intracellular 5-HT2ARs as a therapeutic target, and raises the intriguing possibility that serotonin might not be the endogenous ligand for intracellular 5-HT2ARs in the cortex.

5-HT2ARs Mediate Therapeutic Behavioral Effects of Psychedelic Tryptamines.

Psychedelic compounds have displayed antidepressant potential in both humans and rodents. Despite their promise, psychedelics can induce undesired effects that pose safety concerns and limit their clinical scalability. The rational development of optimized psychedelic-related medicines will require a full mechanistic understanding of how these molecules produce therapeutic effects. While the hallucinogenic properties of psychedelics are generally attributed to activation of serotonin 2A receptors (5-HT2ARs), it is currently unclear if these receptors also mediate their antidepressant effects as several nonhallucinogenic analogues of psychedelics with antidepressant-like properties have been developed. Moreover, many psychedelics exhibit promiscuous pharmacology, making it challenging to identify their primary therapeutic target(s). Here, we use a combination of pharmacological and genetic tools to demonstrate that activation of 5-HT2A receptors is essential for tryptamine-based psychedelics to produce antidepressant-like effects in rodents. Our results suggest that psychedelic tryptamines can induce hallucinogenic and therapeutic effects through activation of the same receptor.

A 6-year-old child with a new diagnosis of perinatal human immunodeficiency virus infection.

Perinatal human immunodeficiency virus transmission, while rare in the United States, should be considered in children with a history of recurrent infections, chronic respiratory symptoms and developmental delay. A delayed diagnosis of human immunodeficiency virus in children can lead to significant morbidity and mortality. We present a 6-year-old male who presented for evaluation and management of antibiotic refractory chronic cough and purulent nasal secretions, with a history of recurrent bacterial pneumonias and sinus infections, disseminated varicella zoster, and global developmental delay. He likely had perinatally acquired human immunodeficiency virus. At the time of his human immunodeficiency virus diagnosis, he met the criteria for acquired immunodeficiency syndrome and was ultimately diagnosed with lymphocytic interstitial pneumonia (LIP). Our case illustrates the importance of universal human immunodeficiency virus screening of pregnant women, consideration of human immunodeficiency virus, and the prompt initiation of treatment. We believe this case serves as an important reminder for all medical providers who care for pregnant women and children.

Management of Extensive Central Nervous System Cladophialophora bantiana Infection in a 9-Year-Old Child.

BACKGROUND: Pediatric central nervous system (CNS) phaeohyphomycosis is a rare invasive fungal infection associated with high mortality. METHODS: We describe a child with progressive neurologic symptoms whose ultimate diagnosis was Cladophialophora bantiana -associated CNS phaeohyphomycosis. We discuss her clinical presentation, medical and surgical management and review the current literature. RESULTS: A 9-year-old female presented with acute onset of headaches, ophthalmoplegia and ataxia. Initial infectious work-up was negative, including serial fungal cerebrospinal fluid cultures. Over 2 months, she experienced progressive cognitive and motor declines, and imaging revealed worsening meningitis, ventriculitis and cerebritis. Ultimately, Cladophialophora was detected by plasma metagenomic next-generation sequencing (mNGS). Fourth ventricle fluid sampling confirmed the diagnosis of C. bantiana infection. Given the extent of her disease, complete surgical resection was not feasible. She required multiple surgical debridement procedures and prolonged antifungal therapy, including the instillation of intraventricular amphotericin B. With aggressive surgical and medical management, despite her continued neurologic deficits, she remains alive 3 years after her initial diagnosis. To our knowledge, this is one of a few published pediatric cases of CNS phaeohyphomycosis and the first with the causative pathogen identified by plasma mNGS. CONCLUSION: CNS phaeohyphomycosis is a serious, life-threatening infection. The preferred management includes a combination of surgical resection and antifungal therapy. In cases complicated by refractory ventriculitis, intraventricular antifungal therapy can be considered as adjuvant therapy. Direct sampling of the CNS for pathogen identification and susceptibility testing is the gold standard for diagnosis; however, the use of plasma mNGS may expedite the diagnosis.

Childhood tuberculosis.

PURPOSE OF REVIEW: We discuss the most recent literature to support the identification of children at risk for tuberculosis and optimal testing and treatment strategies. RECENT FINDINGS: The identification and management of children with tuberculosis has increased in complexity due to the recent severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) pandemic, greater use of immunosuppressive agents, and the administration of shorter, rifamycin-containing treatment regimens. Advancements in the diagnosis and treatment of tuberculosis in children include: use of interferon gamma release assays (IGRAs); molecular-based tests; and shorter courses of treatment. While the essential steps to identify and treat children at risk for tuberculosis remain unchanged, providers must be aware of impact of these challenges. SUMMARY: The SARS-CoV-2 pandemic will likely have a negative impact on global tuberculosis control. It is important that countries maintain a comprehensive approach to the identification and management of children at risk for tuberculosis. Increasing evidence supports enhanced utilization of IGRAs and molecular-based testing to improve the diagnosis of tuberculosis in children. Shorter course, rifamycin-based treatment regimens are available to treat children with tuberculosis infection; however, their use is limited in some immunosuppressed children due to drug-drug interactions.

Plasma Metagenomic Sequencing Expedites Diagnosis of Disseminated BCG in an Infant With IKBKB Mutation.

BACKGROUND: Infants with inborn errors of immunity (IEI), born in countries where Bacillus-Calmette-Guerin (BCG) vaccination is recommended at birth, are at risk of developing infectious complications following vaccination. A prompt diagnosis of disseminated BCG infection in these infants is essential, as many will require stem cell transplantation (SCT) for the immunologic cure. In patients with IEI, the mortality risk from disseminated mycobacterial infection is high, both before and following SCT. METHODS: A 7-month-old Qatari infant with an IEI, homozygous IKBKB gene mutation, was evaluated at our institution for SCT. He had a history of recurrent pneumonias, but pretransplant evaluation revealed negative cultures from bronchoalveolar fluid, blood and urine. At 8 months of age, the infant developed skin nodules of unclear etiology, prompting additional evaluation. RESULTS: Given his profound immunosuppression and receipt of broad-spectrum antimicrobials, plasma metagenomic next-generation sequencing (mNGS) was obtained and identified Mycobacterium tuberculosis complex within 72 hours. A skin biopsy was performed, and antimycobacterial therapy was initiated. Mycobacterium bovis-BCG was confirmed from cultures 3 weeks later. Treatment was complicated by elevated serum liver transaminases and aminoglycoside-associated high-frequency hearing loss. The infant completed 14 months of treatment from engraftment. Evaluation for active BCG infection after SCT was negative. CONCLUSION: In an infant with a unique IEI, plasma mNGS provided the first diagnosis of disseminated BCG infection. We believe that early initiation of antimycobacterial treatment improved the infant's clinical outcome. Plasma mNGS testing should be considered as a noninvasive screen for infectious pathogens in children with IEIs before SCT.

Sex-Specific Social Effects on Depression-Related Behavioral Phenotypes in Mice.

Social interaction and empathy play critical roles in determining the emotional well-being of humans. Stress-related depression and anxiety can be exacerbated or mitigated depending on specific social conditions. Although rodents are well known to exhibit emotional contagion and consolation behavior, the effects of group housing on stress-induced phenotypes in both males and females are not well established. Here, we investigated how the presence of stressed or unstressed conspecifics within a cage impact depression-related phenotypes. We housed male and female C57BL/6J mice in same-sex groups and subjected them to either gentle handling (GH) or the daily administration of corticosterone (CORT) for 10 days. The GH and CORT treatment groups were divided into cages of unmixed (GH or CORT) and mixed (GH and CORT) treatments. Depression-related phenotypes were measured using the forced swim test (FST) and sucrose preference test (SPT). We found that mixed housing alters FST behavior in a sex-specific manner. Male mice given chronic corticosterone (CORT) that were housed in the same cage as gently handled animals (GH) exhibited increased immobility, whereas GH females housed with CORT females demonstrated the opposite effect. This study underscores the importance of social housing conditions when evaluating stress-induced behavioral phenotypes and suggests that mixed cages of GH and CORT animals yield the greatest difference between treatment groups. The latter finding has important implications for identifying therapeutics capable of rescuing stress-induced behavioral deficits in the FST.

Variable Diagnostic Performance of Stool Xpert in Pediatric Tuberculosis: A Systematic Review and Meta-analysis.

BACKGROUND: Difficult specimen collection and low bacillary load make microbiological confirmation of tuberculosis (TB) in children challenging. In this study, we conducted a systematic review and meta-analysis to assess the diagnostic accuracy of Xpert on stool for pediatric tuberculosis. METHODS: Our search included studies from 2011 through 2019, and specific search terms were used to retrieve articles from Pubmed, EMBASE, BIOSIS, ClinicalTrials.gov, and Google Scholar. Risk of bias was assessed using the QUADAS 2 tool. The protocol was registered in PROSPERO (CRD42018083637). Summary estimates of sensitivity and specificity were conducted using meta-disc Software assuming a random-effects model. RESULTS: We identified 12 eligible studies, which included data from 2177 children, of whom 295 (13.6%) had bacteriologically confirmed TB on respiratory specimens. The pooled sensitivity of Xpert MTB/RIF on stool specimens compared with bacteriologically confirmed tuberculosis with respiratory specimens was 0.50 (95% CI, 0.44-0.56) with an I 2 of 86%, which was statistically significant (P < .001). The pooled specificity was 0.99 (95% CI, 0.98-0.99; I 2 = 0.0%; P = .44). CONCLUSIONS: Despite the observed heterogeneity, stool may be considered an additional specimen to support diagnosis of pulmonary TB in children, especially in settings where it is impossible to get respiratory samples. Further studies should evaluate its optimization as a diagnostic tool.

An analog of psychedelics restores functional neural circuits disrupted by unpredictable stress.

Psychological stress affects a wide spectrum of brain functions and poses risks for many mental disorders. However, effective therapeutics to alleviate or revert its deleterious effects are lacking. A recently synthesized psychedelic analog tabernanthalog (TBG) has demonstrated anti-addictive and antidepressant potential. Whether TBG can rescue stress-induced affective, sensory, and cognitive deficits, and how it may achieve such effects by modulating neural circuits, remain unknown. Here we show that in mice exposed to unpredictable mild stress (UMS), administration of a single dose of TBG decreases their anxiety level and rescues deficits in sensory processing as well as in cognitive flexibility. Post-stress TBG treatment promotes the regrowth of excitatory neuron dendritic spines lost during UMS, decreases the baseline neuronal activity, and enhances whisking-modulation of neuronal activity in the somatosensory cortex. Moreover, calcium imaging in head-fixed mice performing a whisker-dependent texture discrimination task shows that novel textures elicit responses from a greater proportion of neurons in the somatosensory cortex than do familiar textures. Such differential response is diminished by UMS and is restored by TBG. Together, our study reveals the effects of UMS on cortical neuronal circuit activity patterns and demonstrate that TBG combats the detrimental effects of stress by modulating basal and stimulus-dependent neural activity in cortical networks.

Two Cases of Cronobacter Sakazakii Meningitis in Infants: The Importance Of Early Advanced Brain Imaging and Public Health Reporting.

We report 2 infants hospitalized with Cronobacter sakazakii meningitis. Each infant had exposure to powdered infant formula at home. Both infants survived, but 1 infant had a subdural empyema drained and developed left sensorineural hearing loss. Early advanced brain imaging is recommended in infants with C. sakazakii meningitis. Reporting to state and federal public health officials may help identify outbreaks.

Asking questions of psychedelic microdosing.

A citizen science approach to research has shown that the improvements in mood and cognition associated with psychedelic microdosing are likely due to a placebo effect.

A 16-Year-Old Boy With Cough and Fever in the Era of COVID-19.

A 16-year-old white boy with a history of chronic lung disease of prematurity, cough-variant asthma, and incidental lung nodules presented to the emergency center in spring 2020 with acute onset dry cough, shortness of breath, and fever. An initial history, gathered from his mother because of the patient's respiratory distress, revealed no recent travel. However, his mother is a health care worker at a hospital, and sick contacts included ongoing contact with a friend with cold-like symptoms. He had a variety of animals at home, including a dog, cats, fish, rodents, and reptiles. He had a history of vaping tobacco products >6 months ago. Fever and respiratory symptoms were associated with fatigue, chest tightness, abdominal pain, and myalgias. On examination, he was ill appearing and had tachycardia, tachypnea, borderline hypoxia with an oxygen saturation of 91% on room air, diminished breath sounds at the lung bases, and unremarkable abdominal examination results. A chest radiograph was consistent with the lung examination, revealing bilateral lower lobe hazy infiltrates. He showed initial improvement for 48 hours with antibiotics, intravenous fluid resuscitation, oxygen via nasal cannula, albuterol, and prednisone. Subsequently, he worsened with persistent high fever, increasing respiratory distress with pulmonary findings, and severe persistent epigastric pain, which added a layer of diagnostic complexity. As this patient's clinical course evolved and further history became available, pulmonary medicine and infectious diseases services were consulted to guide diagnostic evaluation and treatment of this patient early in the era of coronavirus disease 2019.

A non-hallucinogenic psychedelic analogue with therapeutic potential.

The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals1. Unlike most medications for the treatment of substance use disorders, anecdotal reports suggest that ibogaine has the potential to treat addiction to various substances, including opiates, alcohol and psychostimulants. The effects of ibogaine-like those of other psychedelic compounds-are long-lasting2, which has been attributed to its ability to modify addiction-related neural circuitry through the activation of neurotrophic factor signalling3,4. However, several safety concerns have hindered the clinical development of ibogaine, including its toxicity, hallucinogenic potential and tendency to induce cardiac arrhythmias. Here we apply the principles of function-oriented synthesis to identify the key structural elements of the potential therapeutic pharmacophore of ibogaine, and we use this information to engineer tabernanthalog-a water-soluble, non-hallucinogenic, non-toxic analogue of ibogaine that can be prepared in a single step. In rodents, tabernanthalog was found to promote structural neural plasticity, reduce alcohol- and heroin-seeking behaviour, and produce antidepressant-like effects. This work demonstrates that, through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant that has therapeutic potential.

Directed Evolution of a Selective and Sensitive Serotonin Sensor via Machine Learning.

Serotonin plays a central role in cognition and is the target of most pharmaceuticals for psychiatric disorders. Existing drugs have limited efficacy; creation of improved versions will require better understanding of serotonergic circuitry, which has been hampered by our inability to monitor serotonin release and transport with high spatial and temporal resolution. We developed and applied a binding-pocket redesign strategy, guided by machine learning, to create a high-performance, soluble, fluorescent serotonin sensor (iSeroSnFR), enabling optical detection of millisecond-scale serotonin transients. We demonstrate that iSeroSnFR can be used to detect serotonin release in freely behaving mice during fear conditioning, social interaction, and sleep/wake transitions. We also developed a robust assay of serotonin transporter function and modulation by drugs. We expect that both machine-learning-guided binding-pocket redesign and iSeroSnFR will have broad utility for the development of other sensors and in vitro and in vivo serotonin detection, respectively.

Identification of Psychoplastogenic N,N-Dimethylaminoisotryptamine (isoDMT) Analogues through Structure-Activity Relationship Studies.

Ketamine, N,N-dimethyltryptamine (DMT), and other psychoplastogens possess enormous potential as neurotherapeutics due to their ability to potently promote neuronal growth. Here, we report the first-ever structure-activity relationship study with the explicit goal of identifying novel psychoplastogens. We have discovered several key features of the psychoplastogenic pharmacophore and used this information to develop N,N-dimethylaminoisotryptamine (isoDMT) psychoplastogens that are easier to synthesize, have improved physicochemical properties, and possess reduced hallucinogenic potential as compared to their DMT counterparts.

Psychedelic Microdosing: Prevalence and Subjective Effects.

Anecdotal reports suggest that the administration of sub-hallucinogenic doses of psychedelic compounds on a chronic, intermittent schedule - a practice known as psychedelic microdosing - is becoming increasingly popular among young adults due to its purported ability to reduce symptoms of depression and anxiety while improving cognitive function and promoting social interaction. Using an anonymous online survey, we collected data from 2347 people to 1) assess the prevalence of psychedelic microdosing and characterize the demographics of microdosers, 2) determine whether microdosers associate the practice with changes in mood, cognitive function, social interaction, or physiology, and 3) investigate frequent motives for discontinuing the practice. Fifty-nine percent of respondents (NT = 2183) reported familiarity with the concept of psychedelic microdosing, with 17% (383 respondents, NT = 2200) having engaged in this practice. Microdosers attributed psychedelic microdosing with improving their mood, decreasing their anxiety, and enhancing their memory, attention, and sociability. The most frequently cited reasons for quitting microdosing (NT = 243) were the risks associated with taking an illegal substance (24.28%) and the difficulty of obtaining psychedelic compounds (22.63%). Overall, our findings suggest that psychedelic microdosing is relatively common and is subjectively associated with a broad spectrum of socio-affective, cognitive, and physical outcomes.