Long COVID Brain Fog Treatment: Findings from a Pilot Randomized Controlled Trial of Constraint-Induced Cognitive Therapy.

Purpose: Long COVID brain fog is often disabling. Yet, no empirically-supported treatments exist. This study's objectives were to evaluate feasibility and efficacy, provisionally, of a new rehabilitation approach, Constraint-Induced Cognitive Therapy (CICT), for post-COVID-19 cognitive sequelae. Design: Sixteen community-residents ≥ 3-months post-COVID-19 infection with mild cognitive impairment and dysfunction in instrumental activities of daily living (IADL) were enrolled. Participants were randomized to Immediate-CICT or treatment-as-usual (TAU) with crossover to CICT. CICT combined behavior change techniques modified from Constraint-Induced Movement Therapy with Speed of Processing Training, a computerized cognitive-training program. CICT was deemed feasible if (a) ≥80% of participants completed treatment, (b) the same found treatment highly satisfying and at most moderately difficult, and (c) <2 study-related, serious adverse-events occurred. The primary outcome was IADL performance in daily life (Canadian Occupational Performance Measure). Employment status and brain fog (Mental Clutter Scale) were also assessed. Results: Fourteen completed Immediate-CICT ( n =7) or TAU ( n =7); two withdrew from TAU before their second testing session. Completers were [ M (S D )]: 10 (7) months post-COVID; 51 (13) years old; 10 females, 4 males; 1 African American, 13 European American. All the feasibility benchmarks were met. Immediate-CICT, relative to TAU, produced very large improvements in IADL performance ( M =3.7 points, p<.001, d =2.6) and brain fog ( M =-4 points, p<.001, d =-2.9). Four of five non-retired Immediate-CICT participants returned-to-work post-treatment; no TAU participants did, p =.048. Conclusions: CICT has promise for reducing brain fog, improving IADL, and promoting returning-to-work in adults with Long COVID. Findings warrant a large-scale RCT with an active-comparison group. IMPACT: Brain fog in adults with Long COVID is often associated with dysfunction in everyday activities and unemployment. Yet, there are no empirically supported treatments targeting cognition in this population. Findings from this small-scale, pilot randomized controlled trial (RCT) suggest that a novel intervention, i.e., Constraint-Induced Cognitive Therapy, is a feasible cognitive rehabilitation method in adults with Long COVID cognitive sequelae with promise of (a) improving performance of cognition-based tasks in daily life and (b) promoting return-to-work. Further studies with larger sample sizes are warranted.Speed of Processing Training (SOPT) has been shown to increase processing speed in older adults without neurological disorders but has not been applied to adults with brain fog due to Long COVID, in whom slowing of cognitive processing speed is common. The results of this pilot RCT suggest that SOPT, in conjunction with behavior change techniques, may increase cognitive processing speed in this brain-injured population.

"Safety Is Elusive:" A Critical Discourses Analysis of Newspapers' Reporting of Domestic Violence During the Coronavirus Pandemic.

The COVID-19 pandemic exacerbated incidences of domestic violence (DV). The framing of DV within media sources contributes to the public's understanding of DV. Using critical discourse analysis (CDA), this paper explores representations of safety within newspapers' reporting of DV during the pandemic. The sample included newspaper articles (n = 31) from U.S. newspapers. The analysis involved multiple rounds of coding and employing "structured questions." These articles depicted limited courses of action for DV survivors and represented safety as unattainable. Safety was constructed in four ways: homes are unsafe, social services are overburdened, government failures, and the elusiveness of safety. These discursive formations provide insight regarding "idealized" social responses to DV.

Do people with epilepsy want to participate in an exercise intervention randomized controlled trial? - Results of a brief survey and its preliminary application.

Our goal was to survey people with epilepsy (PWE) about their interest in and factors that may influence willingness and ability to participate in an exercise randomized controlled trial (RCT). A brief survey was administered to 100 PWE asking if they would take part in a hypothetical 6-week exercise intervention RCT. Follow-up questions queried reasons for and against participation and why participation would be difficult. Sixty-nine percent of respondents indicated willingness to participate. The top reason for participation was "to improve overall health with exercise" (n = 49). The top reason for why participation would be difficult was they "do not have a reliable source of transportation" (n = 27). The top reason for not participating was "not interested in research participation" (n = 19). Preliminary results were used to budget for transportation in a prospective RCT (NCT04959019). Of the first 27 PWE enrolled (63 % female; 44 % African American/Black), six (50 % female; 50 % African American/Black) have used the transportation service. The majority of PWE surveyed were interested in participating in an exercise RCT, but some indicated barriers. Accommodating transportation in an ongoing RCT has facilitated recruitment of PWE who would otherwise not be able to participate. Barriers to participation should be accounted for when designing studies.

Catheterization Without Supination-A Series of 36 Prone Position Internal Jugular Vein Cannulations.

Describe the clinical characteristics and outcomes of 32 critically ill patients who underwent central venous cannulation of the internal jugular vein while in prone position. DESIGN: Retrospective cohort analysis. SETTING: Single tertiary-care urban academic safety-net hospital. PATIENTS/SUBJECTS: Patients requiring mechanical ventilation and prone positioning for severe acute respiratory distress syndrome from March 1, 2020, through March 31, 2021. INTERVENTIONS: Internal jugular vein cannulation while in the prone position. MEASUREMENTS AND MAIN RESULTS: The technique used for venous access, procedural complications, patient demographics, and clinical outcomes are described. Thirty-six prone internal jugular vein cannulations for 32 hemodialysis catheters and four central venous catheters were successfully performed in 32 patients. One immediate and one delayed pneumothorax occurred. Inhospital mortality was 88%. CONCLUSIONS: In the largest series to date, cannulation of the internal jugular vein with the patient in prone position is feasible but associated with a 6% risk of pneumothorax. Severity of illness in patients intolerant of supine positioning results in high inhospital mortality.

Patient-Identified Markers of Quality Care: Improving HIV Service Delivery for Older African Americans.

BACKGROUND: Over 50% of new AIDS/HIV diagnoses are older adults and disproportionately African American people. Longstanding health inequities, driven by the enduring nature of systemic racism, pose challenges to obtaining optimal HIV services. Patient experiences and identities shape the health care experience, yet patient voices are often minimized, including their assessment of quality HIV care. Understanding these markers of care, including facilitators of and barriers to care and engagement, may help enhance the patient voice, potentially improving service delivery and eradicating HIV healthcare disparities. METHOD: Using a convergent mixed method design, our study identifies patient-identified markers of quality care among older African Americans (N = 35). Measurements of global stress, HIV stigma, and engagement in care were collected, and in-depth qualitative interviews explored the symbols of quality care as well as facilitators of and barriers to care. RESULTS: We identified widespread participant awareness and recognition of quality care, the detection of facilitators and barriers across individual, clinic, and community levels. Facilitators of care include diet, health, relationships, community support, and compassionate HIV care. Barriers to care include health comorbidities, economic, food, and housing insecurity, lack of transportation, and structural racism. CONCLUSION: Our findings illuminate how the prominence of barriers to care often uproot facilitators of care, creating impediments to HIV service delivery as patients transition through the HIV care continuum. We offer implications for practice and policy, as well as recommendations for reducing structural barriers to care by enhancing the patient voice and for aligning services toward compassionate and inclusive care.

School-Based Mental Health Practitioners: A Resource Guide for Educational Leaders.

School-based mental health practitioners can offer enhanced support to schools and students; yet their training, roles, and expertise vary. The roles of these professionals are often conflated, misunderstood, or marginalized in their utility throughout the school system. The purpose of this manuscript is to enhance the capacity of educational leaders to make informed hiring, contracting, and role assignment decisions that best fit school and student needs regarding school mental health services. We clarify the landscape of two distinct groups of qualified school mental health professionals-those who are education certified and those who are independently licensed; each group represents professionals from multiple disciplines. We illuminate similarities and differences of these professionals and juxtapose the utility of traditional mental health versus school-based mental health. We then discuss the similarities and differences of qualified school mental health professionals described within the context of traditional and school-based mental health preparation and service delivery. We conclude by contributing three resources for educational leaders to support the process of engaging school-based mental health practitioners. First, we offer a planning guide to understand state variations in certification requirements across professionals. Second, we provide a hiring guide primer that summarizes education requirements and delineates role orientations for school mental health practitioners. Third, we provide an interview guide to help clarify a candidate's experience and skills useful to contemporary school needs. We conclude by offering recommendations for educational leaders to become more effective consumers of school-based mental health services. Supplementary Information: The online version contains supplementary material available at 10.1007/s12310-022-09530-5.

Social-ecological factors associated with having a regular healthcare provider among lesbian, gay, bisexual and transgender persons in Jamaica.

Lesbian, gay, bisexual, and transgender (LGBT) people experience a multitude of barriers to healthcare access, particularly in highly stigmatising contexts, such as Jamaica. Access to a regular healthcare source can contribute to uptake of health knowledge and services. Yet social-ecological factors associated with access to a regular healthcare provider among LGBT persons in Jamaica are underexplored. We conducted a cross-sectional survey with LGBT persons in Jamaica to examine socio-demographic and social-ecological factors associated with having a regular healthcare provider. Nearly half (43.6%) of 911 participants reported having a regular healthcare provider. In multivariate analyses, socio-demographic factors (higher age; identifying as a cisgender sexual minority man or woman compared to a transgender woman) were associated with higher odds of having a regular healthcare provider. Socio-demographic (living in Ocho Rios or Montego Bay compared to Kingston), stigma/discrimination (a bad past healthcare experience), and structural factors (insufficient money for housing; reporting medication costs as a barrier; no health insurance) were associated with decreased odds of having a regular healthcare provider. Findings support a multi-level approach to understanding and addressing barriers to having a regular healthcare provider among LGBT people in Jamaica.

Real-World Experience of Vismodegib in Advanced Basal Cell Carcinoma at a Canadian Cancer Center.

BACKGROUND: Vismodegib is a novel Hedgehog pathway inhibitor that has revolutionized the treatment of patients with advanced basal cell carcinoma (BCC) who are poor candidates for surgery or radiation. Few studies have explored the use of vismodegib to facilitate further surgery or radiotherapy, and the optimal treatment duration to balance outcomes with adverse effects. OBJECTIVES: To characterize the disease response, progression, and recurrence outcomes of BCC patients, and to report the impact of subsequent therapies. METHODS: We performed a retrospective study of 46 adult patients with advanced basal cell carcinoma (aBCC), including both locally advanced (laBCC) and metastatic (mBCC) disease, treated with vismodegib at a single center from 2012 to 2019. RESULTS: Thirty-six had laBCC, and 10 had mBCC. Treatment was given over a mean of 21.9 months. Twenty-three (50%) had a complete response (CR), and 19 (41.3%) achieved partial response (PR). Median time to maximal response was 5.3 months. Eleven (23.9%) had resected disease at median 17.2 months, and 11 patients (23.9%) received radiotherapy. Thirty-two (69.6%) experienced progressive disease after achievement of CR or PR. Among 17 CR patients, who stopped treatment, 14 (82.3%) experienced subsequent relapse; 6 (85%) attained a repeat response. Twenty (43.5%) discontinued treatment at least once due to adverse effects. CONCLUSIONS: With a response rate of 91%, London Regional Cancer Center's (LRCP)'s experience with vismodegib supports its effectiveness in treatment of aBCC. Moreover, a significant number of patients treated with vismodegib became amenable to surgery or radiotherapy. Toxicity remained an important factor that limited treatment duration.

"We Are Saving Their Bodies and Destroying Their Souls.": Family Caregivers' Experiences of Formal Care Setting Visitation Restrictions during the COVID-19 Pandemic.

This study aims to explore the experiences of family caregivers during the COVID-19 pandemic-imposed visitation restrictions at formal care settings (FCS) such as assisted living centers and traditional nursing homes. Participants (N = 512) were recruited from an international caregiving social media site that was developed at the beginning of the COVID-19 pandemic. Descriptive data was collected on the family caregivers, the care recipient and facility. Respondents also provided a single feeling word describing their experience and an open-ended question allowed for further exploration. Caregivers were predominantly daughters (n = 375). The most common reported feeling words were sadness (n = 200), trauma (n = 108), anger (n = 65), frustration (n = 56), helplessness (n = 50), and anxiety (n = 36). Thematic analysis revealed four overarching themes: 1) isolation 2) rapid decline 3) inhumane care and 4) lack of oversight. This study highlights the importance of addressing the mental, emotional and physical needs of both care recipient and family caregiver during this challenging time. Caregiver visitation policy reform that includes the care recipient and family caregiver is also discussed.

TGF-ß and IL-15 Synergize through MAPK Pathways to Drive the Conversion of Human NK Cells to an Innate Lymphoid Cell 1-like Phenotype.

Circulating NK cells are known to convert to a type 1 innate lymphoid cell (ILC1)-like phenotype in response to TGF-ß exposure. However, the precise cellular changes defining this process as well as the downstream signaling pathways guiding it remain poorly defined, particularly in humans. We used mass cytometry by time-of-flight (CyTOF) to model this phenotypic shift in vitro and identify a synergistic activity of TGF-ß and IL-15 in this cellular conversion. CyTOF profiling identified substantial heterogeneity in the propensity of NK cells to adopt an ILC1-like phenotype in culture, characterized by the step-wise acquisition of various markers, including CD69, CD9, CD103, and CD49a. Activating and inhibitory receptors, including NKG2A, NKG2D, KIR2DL1, KIR3DL1, NKp30, NKp44, and NKp46, were all found to be upregulated exclusively on the cellular subsets that converted most readily in response to TGF-ß. An assessment of downstream TGF-ß signaling identified TAK1-mediated activation of p38 MAPK as the critical pathway driving conversion. IL-15 enhanced TGF-ß-mediated conversion through Ras:RAC1 signaling as well as via the activation of MEK/ERK. Interestingly, the adoption of an ILC1-like phenotype was independent of the effect of IL-15 or TGF-ß on mTOR, as the culture of NK cells in the presence of mTOR inhibitors, such as rapamycin or torin1, had minimal impact on the degree of conversion. In conclusion, we have used in vitro human culture systems and CyTOF to define the conversion of circulating NK cells to an ILC1-like phenotype and have clarified the pathways responsible for this process.

Spontaneous Embedding of DNA Mismatches Within the RNA:DNA Hybrid of CRISPR-Cas9.

CRISPR-Cas9 is the forefront technology for editing the genome. In this system, the Cas9 protein is programmed with guide RNAs to process DNA sequences that match the guide RNA forming an RNA:DNA hybrid structure. However, the binding of DNA sequences that do not fully match the guide RNA can limit the applicability of CRISPR-Cas9 for genome editing, resulting in the so-called off-target effects. Here, molecular dynamics is used to probe the effect of DNA base pair mismatches within the RNA:DNA hybrid in CRISPR-Cas9. Molecular simulations revealed that the presence of mismatched pairs in the DNA at distal sites with respect to the Protospacer Adjacent Motif (PAM) recognition sequence induces an extended opening of the RNA:DNA hybrid, leading to novel interactions established by the unwound nucleic acids and the protein counterpart. On the contrary, mismatched pairs upstream of the RNA:DNA hybrid are rapidly incorporated within the heteroduplex, with minor effect on the protein-nucleic acid interactions. As a result, mismatched pairs at PAM distal ends interfere with the activation of the catalytic HNH domain, while mismatches fully embedded in the RNA:DNA do not affect the HNH dynamics and enable its activation to cleave the DNA. These findings provide a mechanistic understanding to the intriguing experimental evidence that PAM distal mismatches hamper a proper function of HNH, explaining also why mismatches within the heteroduplex are much more tolerated. This constitutes a step forward in understanding off-target effects in CRISPR-Cas9, which encourages novel structure-based engineering efforts aimed at preventing the onset of off-target effects.

NMR and computational methods for molecular resolution of allosteric pathways in enzyme complexes.

Allostery is a ubiquitous biological mechanism in which a distant binding site is coupled to and drastically alters the function of a catalytic site in a protein. Allostery provides a high level of spatial and temporal control of the integrity and activity of biomolecular assembles composed of proteins, nucleic acids, or small molecules. Understanding the physical forces that drive allosteric coupling is critical to harnessing this process for use in bioengineering, de novo protein design, and drug discovery. Current microscopic models of allostery highlight the importance of energetics, structural rearrangements, and conformational fluctuations, and in this review, we discuss the synergistic use of solution NMR spectroscopy and computational methods to probe these phenomena in allosteric systems, particularly protein-nucleic acid complexes. This combination of experimental and theoretical techniques facilitates an unparalleled detection of subtle changes to structural and dynamic equilibria in biomolecules with atomic resolution, and we provide a detailed discussion of specialized NMR experiments as well as the complementary methods that provide valuable insight into allosteric pathways in silico. Lastly, we highlight two case studies to demonstrate the adaptability of this approach to enzymes of varying size and mechanistic complexity.

Nuclear motion in the σ-bound regime of metal-H2 complexes: [Mg(H2)(n=1-6)]²âº.

The dynamic, quantum structure of [Mg(H2)(n=1-6)](2+)complexes is investigated via ab initio path integral molecular dynamics simulations. These complexes represent the strong, σ-complex regime of metal-H2 interactions and are representative of bonding motifs found in metal-organic frameworks. Significant nuclear motion within the coordination sphere is observed, even though the ligands remain largely intact. Quantum effects are found to be important in the H-H and metal-H2 stretch coordinates, but the remaining motion in the molecule is well represented by classical simulations. Nearly free rotation of the dihydrogen moiety is observed in all complexes. Statistical averages and distributions of structural parameters are found to deviate nontrivially from the same parameters in static, equilibrium structures.