Multicentric reticulohistiocytosis post-COVID-19: a case report.

Background: Multicentric reticulohistiocytosis (MRH) stands as a rare and challenging systemic granulomatous disease characterized by its predilection for skin and joint involvement, confounding clinicians with its infrequent presentation and systemic manifestations. Case Description: This compelling case presentation unravels the intricate complexity of MRH, exemplifying its unique clinical course. Following mild upper respiratory coronavirus disease 2019 (COVID-19) symptoms, the patient manifested purplish-pink papular lesions on both the skin and mucosa, accompanied by debilitating arthralgias. A diagnostic skin biopsy, a pivotal tool in MRH diagnosis, confirmed the presence of this granulomatous disorder, underlining its systemic impact. Strategic therapeutic intervention involving a combination of steroids and methotrexate demonstrated remarkable efficacy, culminating in the resolution of symptoms within 3-month. The absence of malignancy upon thorough screening further amplifies the perplexing nature of MRH. Conclusions: This seminal case not only bridges the realms of rare systemic disorders but also marks the first known instance of MRH emerging post-COVID-19. It underscores the imperative consideration of MRH in analogous scenarios and provides invaluable insights into the nuanced interplay of MRH symptoms, diagnosis, and therapeutic strategies following viral triggers. This comprehensive exploration enriches our scientific understanding, offering nuanced perspectives on the manifestations and intricate dynamics of MRH in the context of post-viral sequelae.

Real-World Treatment Patterns, Clinical Outcomes, and Symptom Burden in Patients With Psoriatic Arthritis Prescribed Ixekizumab in the United States.

OBJECTIVE: The objective of this study was to describe the real-world characteristics and clinical status of patients with psoriatic arthritis (PsA) currently prescribed ixekizumab. METHODS: Data were drawn from the Adelphi PsA Plus Disease Specific Programme (DSP), a cross-sectional survey conducted in the United States between September 2021 and March 2022. Rheumatologists provided data for their next five consulting patients currently receiving ixekizumab, including demographic and clinical characteristics, disease severity, treatment history, reasons for treatment choice, satisfaction with current treatment, and current and historic symptom burden. Patients voluntarily completed questionnaires, providing perceptional data on symptom burden and satisfaction with current treatment. RESULTS: Overall, 68 rheumatologists provided data on 275 patients with PsA, 90 of whom completed the voluntary questionnaire. Patients had been prescribed ixekizumab for a mean of 11.7 (SD 10.6) months. Clinical characteristics, disease severity, and symptom burden of patients with PsA improved significantly from ixekizumab initiation to the most recent consultation, including symptom burden, tender and swollen joint counts, and body surface area affected by psoriasis (all P < 0.001). Both rheumatologists and patients were satisfied with ixekizumab treatment and reported improvements in pain and fatigue. Improvements were noted after more than three months of ixekizumab treatment duration and regardless of whether the patients had prior exposure to an advanced therapy or were treatment naïve. CONCLUSION: Our results indicate that ixekizumab was efficacious in the treatment of PsA in real-world clinical practice, complementing efficacy data from randomized controlled clinical trials. The results of this study may assist rheumatologists and their patients in making informed treatment choices.

In Science Journals.

Highlights from the Science family of journals.

In Science Journals.

Highlights from the Science family of journals.

In Science Journals.

Highlights from the Science family of journals.

Examining the Connectorship Scale: Factor Structure and Correlations With Self-Efficacy and Extraversion.

The Connectorship Scale was designed to assess how leaders connect with their followers and is described to measure eight dimensions: social interactivity, dependability, positive communication, presenting oneself, storytelling ability, belief in networking, tangible introduction, and belief in the importance of online networking. This study explores the scale properties and confirmatory factor analyses (CFA) of the Connectorship Scale and examines how the scale scores correlate with self-efficacy and extraversion based on responses from 454 (52% women) adult business students. The internal consistency estimates suggested that one of the subscales, positive communication, was unreliable; we therefore excluded that subscale from further analyses. A CFA of the seven-factor model suggested good fit once two pairs of error terms were allowed to correlate. Self-efficacy and all facets of extraversion positively correlated with six of the seven connectorship subscales, the exception being the tangible introduction scale. The results raise concern about the positive communication subscale from the Connectorship Scale but do support the use of the other seven subscales for research about engaged and effective leadership.

Long-range inhibitory neurons mediate cortical neurovascular coupling.

To meet the high energy demands of brain function, cerebral blood flow (CBF) parallels changes in neuronal activity by a mechanism known as neurovascular coupling (NVC). However, which neurons play a role in mediating NVC is not well understood. Here, we identify in mice and humans a specific population of cortical GABAergic neurons that co-express neuronal nitric oxide synthase and tachykinin receptor 1 (Tacr1). Through whole-tissue clearing, we demonstrate that Tacr1 neurons extend local and long-range projections across functionally connected cortical areas. We show that whisker stimulation elicited Tacr1 neuron activity in the barrel cortex through feedforward excitatory pathways. Additionally, through optogenetic experiments, we demonstrate that Tacr1 neurons are instrumental in mediating CBF through the relaxation of mural cells in a similar fashion to whisker stimulation. Finally, by electron microscopy, we observe that Tacr1 processes contact astrocytic endfeet. These findings suggest that Tacr1 neurons integrate cortical activity to mediate NVC.

In Science Journals.

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Impact of Age on Cognitive Testing Practice Effects and Cardiorespiratory Responses.

Objective: This study tested the hypothesis that healthy aging attenuates cognitive practice effects and, consequently, limits the familiarity-associated reductions in heart rate (HR) and breathing frequency (BF) responses during retesting. Methods: Twenty-one cognitively normal older and younger adults (65 ± 2 vs. 26 ± 1 years old) participated in the study. Mini-Mental State Examination (MMSE), Digit-Span-Test (DST), Trail Making Test (TMT-B), and California Verbal Learning Test (CVLT-II) were administered twice at 3-week intervals, while HR and BF were monitored by electrocardiography and plethysmography, respectively. Results: Cognitive performances were not affected by the age factor, and the retest factor only affected CVLT-II. HR and BF increased only in the younger adults (p < .01) during cognitive tests; retesting attenuated these responses (retest factor p < .01). Long-delay free-recall in CVLT-II was unchanged in cognitively normal older versus younger adults. Healthy aging did not diminish short-term memory assessed by DST and CVLT-II short-delay or long-delay free-recalls. Conclusions: Only CVLT-II, but not MMSE, DST or TMT-B, demonstrated cognitive retesting practice effects in the younger and older adults. Cognitive testing at 3-week intervals in cognitively normal older and younger subjects revealed divergent cardiorespiratory responses to MMSE, DST, and TMT-B cognitive testing, particularly HR, which increased only in younger adults and to a lesser extent during retesting despite the absence of practice effects.

The functional and anatomical characterization of three spinal output pathways of the anterolateral tract.

The nature of spinal output pathways that convey nociceptive information to the brain has been the subject of controversy. Here, we provide anatomical, molecular, and functional characterizations of two distinct anterolateral pathways: one, ascending in the lateral spinal cord, triggers nociceptive behaviors, and the other one, ascending in the ventral spinal cord, when inhibited, leads to sensorimotor deficits. Moreover, the lateral pathway consists of at least two subtypes. The first is a contralateral pathway that extends to the periaqueductal gray (PAG) and thalamus; the second is a bilateral pathway that projects to the bilateral parabrachial nucleus (PBN). Finally, we present evidence showing that activation of the contralateral pathway is sufficient for defensive behaviors such as running and freezing, whereas the bilateral pathway is sufficient for attending behaviors such as licking and guarding. This work offers insight into the complex organizational logic of the anterolateral system in the mouse.

Capivasertib combines with docetaxel to enhance anti-tumour activity through inhibition of AKT-mediated survival mechanisms in prostate cancer.

BACKGROUND/OBJECTIVE: To explore the anti-tumour activity of combining AKT inhibition and docetaxel in PTEN protein null and WT prostate tumours. METHODS: Mechanisms associated with docetaxel capivasertib treatment activity in prostate cancer were examined using a panel of in vivo tumour models and cell lines. RESULTS: Combining docetaxel and capivasertib had increased activity in PTEN null and WT prostate tumour models in vivo. In vitro short-term docetaxel treatment caused cell cycle arrest in the majority of cells. However, a sub-population of docetaxel-persister cells did not undergo G2/M arrest but upregulated phosphorylation of PI3K/AKT pathway effectors GSK3ß, p70S6K, 4E-BP1, but to a lesser extent AKT. In vivo acute docetaxel treatment induced p70S6K and 4E-BP1 phosphorylation. Treating PTEN null and WT docetaxel-persister cells with capivasertib reduced PI3K/AKT pathway activation and cell cycle progression. In vitro and in vivo it reduced proliferation and increased apoptosis or DNA damage though effects were more marked in PTEN null cells. Docetaxel-persister cells were partly reliant on GSK3ß as a GSK3ß inhibitor AZD2858 reversed capivasertib-induced apoptosis and DNA damage. CONCLUSION: Capivasertib can enhance anti-tumour effects of docetaxel by targeting residual docetaxel-persister cells, independent of PTEN status, to induce apoptosis and DNA damage in part through GSK3ß.

In Science Journals.

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Evaluating the efficacy of biologics with and without methotrexate in the treatment of psoriatic arthritis: a network meta-analysis.

INTRODUCTION: An important consideration in the treatment of patients with psoriatic arthritis (PsA) is whether the addition of methotrexate (MTX) to biologics has greater efficacy than biologic monotherapy with respect to efficacy outcomes in these patients. OBJECTIVES: To conduct a network meta-analysis (NMA) comparing biologics by treatment class with and without MTX for treatment of adults with active PsA. METHODS: A systematic literature review (SLR) identified randomised, double-blinded, controlled trials, and a Bayesian NMA compared biologics with and without MTX by treatment class (tumour necrosis factor inhibitors (TNFi), interleukin-23 inhibitors (IL-23i) and IL-17i). Efficacy outcomes included American College of Rheumatology 20%, 50% and 70% (ACR20, ACR50 and ACR70) improvement response. RESULTS: The SLR initially identified 31 studies, of which 17 met feasibility criteria for the NMA by containing the 'without MTX' subgroup. For ACR20 efficacy (the most robust assessment examined), all active treatments were significantly better than placebo. No statistically significant differences were demonstrated between biologic monotherapy (for all classes examined) and biologics in combination with MTX for ACR20/50. IL-17i were comparable to IL-23i, and IL-17i were significantly better than TNFi for ACR20. Although limited by fewer trials, TNFi, IL-23i and IL-17i were not statistically different for ACR50/70. CONCLUSIONS: Concomitant use of MTX and biologics did not improve ACR efficacy outcomes versus biologic monotherapy. MTX does not appear to be necessary as a background therapy when biologics are used for the achievement of ACR20/50 responses in patients with PsA.

The Suicide Prevention for College Student (SPCS) Gatekeepers Program.

Background: Linking college students with mental health services is critical, especially now, as many students report increased mental health concerns and suicidal ideation in the wake of COVID-19. The Suicide Prevention for College Student (SPCS) Gatekeepers Program provides student education and training to help link those in need with appropriate services. Aims: This study aimed to replicate and extend pilot study results by examining the effects of the training program across a larger, more diverse sample of students. Method: As part of three SAMHSA Mental Health and Training Grants, the program was implemented across three college campuses over three years. Results: At posttest, those who participated in the program demonstrated increased knowledge, suicide prevention self-efficacy, and decreased stigma towards suicide. A follow-up questionnaire revealed that students continued to demonstrate program gains 12 weeks after participating, but there was a slight decline in knowledge and self-efficacy between posttest and follow-up. Limitations: Attrition at follow-up should be addressed in future research, and reliability and validity of measures should be further assessed. Conclusion: This study provides support for the efficacy and generalizability of the SPCS Gatekeepers training program.

Mechanisms maintaining cerebral perfusion during systemic hypotension are impaired in elderly adults.

Postural hypotension abruptly lowers cerebral perfusion, producing unsteadiness which worsens with aging. This study addressed the hypothesis that maintenance of cerebral perfusion weakens in the elderly due to less effective cerebrovascular autoregulation and systemic cardiovascular responses to hypotension. In healthy elderly (n = 13, 68 ± 1 years) and young (n = 13, 26 ± 1 years) adults, systemic hypotension was induced by rapid deflation of bilateral thigh cuffs after 3-min suprasystolic occlusion, while heart rate (HR), mean arterial pressure (MAP), and blood flow velocity of the middle cerebral artery (VMCA) were recorded. VMCA/MAP indexed cerebrovascular conductance (CVC). Durations and rates of recovery of MAP and VMCA from their respective postdeflation nadirs were compared between the groups. Thigh-cuff deflation elicited similar hypotension and cerebral hypoperfusion in the elderly and young adults. However, the time elapsed (TΔ) from cuff deflation to the nadirs of MAP and VMCA, and the time for full recovery (TR) from nadirs to baselines were significantly prolonged in the elderly subjects. The response rates of HR (ΔHR, i.e. cardiac factor), MAP (ΔMAP, i.e. vasomotor factor), and CVC following cuff deflation were significantly slower in the elderly. Collectively, the response rates of the cardiac, vasomotor, and CVC factors largely explained TRVMCA. However, the TRVMCA/ΔMAP slope (-3.0 ± 0.9) was steeper (P = 0.046) than the TRVMCA/ΔHR slope (-1.1 ± 0.4). The TRVMCA/ΔCVC slope (-2.4 ± 0.6) was greater (P = 0.072) than the TRVMCA/ΔHR slope, but did not differ from the TRVMCA/ΔMAP slope (P = 0.52). Both cerebrovascular autoregulatory and systemic mechanisms contributed to cerebral perfusion recovery during systemic hypotension, and the vasomotor factor was predominant over the cardiac factor. Recovery from cerebral hypoperfusion was slower in the elderly adults because of the age-diminished rates of the CVC response and cardiovascular reflex regulation. Systemic vasoconstriction predominated over increased HR for restoring cerebral perfusion after abrupt onset of systemic hypotension.

Identification of a convergent spinal neuron population that encodes itch.

Itch is a protective sensation that drives scratching. Although specific cell types have been proposed to underlie itch, the neural circuit basis for itch remains unclear. Here, we used two-photon Ca2+ imaging of the dorsal horn to visualize the neuronal populations that are activated by itch-inducing agents. We identify a convergent population of spinal neurons that is defined by the expression of GRPR. Moreover, we discover that itch is conveyed to the brain via GRPR-expressing spinal output neurons that target the lateral parabrachial nucleus. Further, we show that nalfurafine, a clinically effective kappa opioid receptor agonist, relieves itch by inhibiting GRPR spinoparabrachial neurons. Finally, we demonstrate that a subset of GRPR spinal neurons show persistent, cell-intrinsic Ca2+ oscillations. These experiments provide the first population-level view of the spinal neurons that respond to pruritic stimuli, pinpoint the output neurons that convey itch to the brain, and identify the cellular target of kappa opioid receptor agonists for the inhibition of itch.

Alleviation of neuropathic pain with neuropeptide Y requires spinal Npy1r interneurons that coexpress Grp.

Neuropeptide Y targets the Y1 receptor (Y1) in the spinal dorsal horn (DH) to produce endogenous and exogenous analgesia. DH interneurons that express Y1 (Y1-INs; encoded by Npy1r) are necessary and sufficient for neuropathic hypersensitivity after peripheral nerve injury. However, as Y1-INs are heterogenous in composition in terms of morphology, neurophysiological characteristics, and gene expression, we hypothesized that a more precisely defined subpopulation mediates neuropathic hypersensitivity. Using fluorescence in situ hybridization, we found that Y1-INs segregate into 3 largely nonoverlapping subpopulations defined by the coexpression of Npy1r with gastrin-releasing peptide (Grp/Npy1r), neuropeptide FF (Npff/Npy1r), and cholecystokinin (Cck/Npy1r) in the superficial DH of mice, nonhuman primates, and humans. Next, we analyzed the functional significance of Grp/Npy1r, Npff/Npy1r, and Cck/Npy1r INs to neuropathic pain using a mouse model of peripheral nerve injury. We found that chemogenetic inhibition of Npff/Npy1r-INs did not change the behavioral signs of neuropathic pain. Further, inhibition of Y1-INs with an intrathecal Y1 agonist, [Leu31, Pro34]-NPY, reduced neuropathic hypersensitivity in mice with conditional deletion of Npy1r from CCK-INs and NPFF-INs but not from GRP-INs. We conclude that Grp/Npy1r-INs are conserved in higher order mammalian species and represent a promising and precise pharmacotherapeutic target for the treatment of neuropathic pain.

In Science Journals.

Highlights from the Science family of journals.

In Science Journals.

Highlights from the Science family of journals.