Repeatability and reliability of GABA measurements with magnetic resonance spectroscopy in healthy young adults.

PURPOSE: Gamma-aminobutyric acid (GABA) abnormalities have been implicated in a range of neuropsychiatric disorders. Despite substantial interest in probing GABA in vivo, human imaging studies relying on magnetic resonance spectroscopy (MRS) have generally been hindered by technical challenges, including GABA's relatively low concentration and spectral overlap with other metabolites. Although past studies have shown moderate-to-strong test-retest repeatability and reliability of GABA within certain brain regions, many of these studies have been limited by small sample sizes. METHODS: GABA+ (macromolecular-contaminated) test-retest reliability and repeatability were assessed via a Meshcher-Garwood point resolved spectroscopy (MEGA-PRESS) MRS sequence in the rostral anterior cingulate cortex (rACC; n = 21) and dorsolateral prefrontal cortex (dlPFC; n = 20) in healthy young adults. Data were collected on a 3T scanner (Siemens Prisma, Siemens Healthcare, Erlangen, Germany) and GABA+ results were reported in reference to both total creatine (GABA+/tCr) and water (GABA+/water). RESULTS: Results showed strong test-retest repeatability (mean GABA+/tCr coefficient of variation [CV] = 4.6%; mean GABA+/water CV = 4.0%) and reliability (GABA+/tCr intraclass correlation coefficient [ICC] = 0.77; GABA+/water ICC = 0.87) in the dlPFC. The rACC showed acceptable (but comparatively lower) repeatability (mean GABA+/tCr CV = 8.0%; mean GABA+/water CV = 7.5%), yet low-moderate reliability (GABA+/tCr ICC = 0.40; GABA+/water ICC = 0.44). CONCLUSION: The present study found excellent GABA+ MRS repeatability and reliability in the dlPFC. The rACC showed inferior results, possibly because of a combination of shimming impedance and measurement error. These data suggest that MEGA-PRESS can be utilized to reliably distinguish participants based on dlPFC GABA+ levels, whereas the mixed results in the rACC merit further investigation.

Gatekeepers' perceptions of the quality and availability of services for breast and cervical cancer patients in the English-speaking Windward Islands: an exploratory investigation.

PURPOSE: Although extensive screening services for breast and cervical cancers are available in the Caribbean, these cancers continue to be the leading causes of cancer death among women in this region. The purpose of this study was to determine the quality and availability of breast and cervical cancer treatment care and support services from the perspective of the gatekeepers who provide care for the patients in the Windward Islands of Dominica, Grenada, St Lucia, and St. Vincent. METHODS: A qualitative research design using semi-structured, in-depth interviews was used to gather data from gatekeepers who provided oncology prevention and care services to patients for at least one year. Data were collected on availability and quality of cancer care and treatment services and coded using the themes obtained via thematic analysis of the data. RESULTS: Twenty-three current providers participated in the study (Dominica, 5; Grenada, 7; St. Lucia, 5; St. Vincent and the Grenadines, 6). The participants' years of work experience ranged from 2 to 45 years. The codes encompassed a range of social ecological factors that influence breast and cervical cancer screening and treatment in the Windward Islands. The emergent themes were availability of resources, cost of care, and social support. CONCLUSION: The findings of this study emphasize the varying social determinants of health that affect breast and cervical cancer prevention and treatment. It also highlights the disparities in availability of treatment within the wider Caribbean. It is necessary to broaden the perspective on health from a purely biomedical paradigm to a social perspective.

Knowledge and Awareness Among Patients with Chronic Kidney Disease Stage 3.

Knowledge is a prerequisite for changing behavior, and is useful for improving outcomes and reducing mortality rates in patients diagnosed with chronic kidney disease (CKD). The purpose of this article is to describe baseline CKD knowledge and awareness obtained as part of a larger study testing the feasibility of a self-management intervention. Thirty patients were recruited who had CKD Stage 3 with coexisting diabetes and hypertension. Fifty-four percent of the sample were unaware of their CKD diagnosis. Participants had a moderate amount of CKD knowledge. This study suggests the need to increase knowledge in patients with CKD Stage 3 to aid in slowing disease progression.

Association of Lower Rostral Anterior Cingulate GABA+ and Dysregulated Cortisol Stress Response With Altered Functional Connectivity in Young Adults With Lifetime Depression: A Multimodal Imaging Investigation of Trait and State Effects.

OBJECTIVE: Preclinical work suggests that excess glucocorticoids and reduced cortical γ-aminobutyric acid (GABA) may affect sex-dependent differences in brain regions implicated in stress regulation and depressive phenotypes. The authors sought to address a critical gap in knowledge, namely, how stress circuitry is functionally affected by glucocorticoids and GABA in current or remitted major depressive disorder (MDD). METHODS: Multimodal imaging data were collected from 130 young adults (ages 18-25), of whom 44 had current MDD, 42 had remitted MDD, and 44 were healthy comparison subjects. GABA+ (γ-aminobutyric acid and macromolecules) was assessed using magnetic resonance spectroscopy, and task-related functional MRI data were collected under acute stress and analyzed using data-driven network modeling. RESULTS: Across modalities, trait-related abnormalities emerged. Relative to healthy comparison subjects, both clinical groups were characterized by lower rostral anterior cingulate cortex (rACC) GABA+ and frontoparietal network amplitude but higher amplitude in salience and stress-related networks. For the remitted MDD group, differences from the healthy comparison group emerged in the context of elevated cortisol levels, whereas the MDD group had lower cortisol levels than the healthy comparison group. In the comparison group, frontoparietal and stress-related network connectivity was positively associated with cortisol level (highlighting putative top-down regulation of stress), but the opposite relationship emerged in the MDD and remitted MDD groups. Finally, rACC GABA+ was associated with stress-induced changes in connectivity between overlapping default mode and salience networks. CONCLUSIONS: Lifetime MDD was characterized by reduced rACC GABA+ as well as dysregulated cortisol-related interactions between top-down control (frontoparietal) and threat (task-related) networks. These findings warrant further investigation of the role of GABA in the vulnerability to and treatment of MDD.

Effects of GABA, Sex, and Stress on Reward Learning in Current and Remitted Major Depression.

BACKGROUND: Neurocognitive factors including aberrant reward learning, blunted GABA (gamma-aminobutyric acid), and potentiated stress sensitivity have been linked to anhedonia, a hallmark depressive symptom, possibly in a sex-dependent manner. However, previous research has not investigated the putative associations among these factors or the extent to which they represent trait- or state-based vulnerabilities for depression. METHODS: Young adults with current major depressive disorder (MDD) (n = 44), remitted MDD (n = 42), and healthy control participants (HCs) (n = 44), stratified by sex assigned at birth, underwent magnetic resonance spectroscopy to assess macromolecular contaminated GABA (GABA+) and then a reward learning task before and after acute stress. We assessed changes in reward learning after stress and associations with GABA+. RESULTS: Results revealed blunted baseline reward learning in participants with remitted MDD versus participants with current MDD and HCs but, surprisingly, no differences between participants with current MDD and HCs. Reward learning was reduced following acute stress regardless of depressive history. GABA+ in the rostral anterior cingulate cortex, but not the dorsolateral prefrontal cortex, was associated with reduced baseline reward learning only in female participants. GABA+ did not predict stress-related changes in reward learning. CONCLUSIONS: To our knowledge, this is the first study to investigate associations among GABA, reward learning, and stress reactivity in current versus past depression. Hypothesized depression-related differences in reward learning did not emerge, precluding claims about state versus trait vulnerabilities. However, our finding that blunted GABA was associated with greater reward learning in female participants provides novel insights into sex-selective associations between the frontal GABAergic inhibitory system and reward processing.

Neural response to stress differs by sex in young adulthood.

Increase in stress-related disorders in women begins post-puberty and persists throughout the lifespan. To characterize sex differences in stress response in early adulthood, we used functional magnetic resonance imaging while participants underwent a stress task in conjunction with serum cortisol levels and questionnaires assessing anxiety and mood. Forty-two healthy subjects aged 18-25 years participated (21M, 21F). Interaction of stress and sex in brain activation and connectivity were examined. Results demonstrated significant sex differences in brain activity with women exhibiting increased activation in regions that inhibit arousal compared to men during the stress paradigm. Women had increased connectivity among stress circuitry regions and default mode network, whereas men had increased connectivity between stress and cognitive control regions. In a subset of subjects (13F, 17M), we obtained gamma-aminobutyric acid (GABA) magnetic resonance spectroscopy in rostral anterior cingulate cortex (rostral ACC) and dorsolateral prefrotal cortex (dlPFC) and conducted exploratory analyses to relate GABA measurements with sex differences in brain activation and connectivity. Prefrontal GABA levels were negatively associated with inferior temporal gyrus activation in men and women and with ventromedial prefrontal cortex activation in men. Despite sex differences in neural response, we found similar subjective ratings of anxiety and mood, cortisol levels, and GABA levels between sexes, suggesting sex differences in brain activity result in similar behavioral responses among the sexes. These results help establish sex differences in healthy brain activity from which we can better understand sex differences underlying stress-associated illnesses.

Woman-to-woman: Feasibility of a lay health advisor program for cervical cancer education in Grenada, W.I.

Objective: The aim of this study was to evaluate the impact of Woman- to-Woman, a lay health advisor (LHA)-led educational intervention on cervical cancer and human papillomavirus (HPV) knowledge in a cohort of at-risk Grenadian women. Methods: LHAs from high-risk parishes were trained in the administration of the intervention and administered the program to 78 local women. Participants completed a pre- and post-knowledge test and a session evaluation. LHAs participated in a process evaluation focus group. Results: Sixty-eight percent (68%) of participants obtained higher knowledge scores following the educational intervention. The difference between the pre- and post-test scores was statistically significant (p = 0.05). Almost 94% agreed that they were taught new and useful information by credible, community informed and responsive LHAs. Ninety percent (90%) indicated great satisfaction and high motivation to recommend to others. LHAs reported on the intervention and their community interactions. Conclusions: Results demonstrate that a LHA-led educational intervention significantly improved participants' knowledge of cervical cancer, HPV, Papanicolaou test and vaccination against HPV. Innovations: Researchers trancreated an evidenced based intervention originally designed for Latina women for Grenadian women. There is no evidence in the literature of previous LHA- cervical cancer education studies conducted in Grenada nor the Caribbean.

Use of Stability Modeling to Support Accelerated Vaccine Development and Supply.

Stability assessment of pharmaceuticals in specific storage and shipment conditions is a key requirement to ensure that safe and efficacious products are administered to patients. This is particularly relevant for vaccines, with numerous vaccines strictly requiring cold storage to remain stable. When stability evaluation is exclusively based on real-time data, it may represent a bottleneck for rapid and effective vaccine access. Stability modeling for vaccines represents a key resource to predict stability based on accelerated stability studies; nevertheless, this approach is not fully exploited for these kinds of products. This is likely because of the complexity and diversity of vaccines, as well as the limited availability of dedicated guidelines or illustrative case studies. This article reports a cross-company perspective on stability modeling for vaccines. Several examples, based on the direct experience of the contributors, demonstrate that modeling approaches can be highly valuable to predict vaccines' shelf life and behavior during shipment or manipulation. It is demonstrated that modeling methodologies need to be tailored to the nature of the vaccine, the available prior knowledge, and the monitored attributes. Considering that the well-established strategies reported in ICH or WHO guidelines are not always broadly applicable to vaccines, this article represents an important source of information for vaccine researchers and manufacturers, setting the grounds for further discussion within the vaccine industry and with regulators.

Clinical Guidance to Optimize Work Participation After Injury or Illness: The Role of Physical Therapists.

Work rehabilitation refers to the process of assisting workers to remain at work or return to work (RTW) in a safe and productive manner, while limiting the negative impact of restricted work, unemployment, and work disability. The primary purpose of this clinical practice guideline (CPG) is to systematically review available scientific evidence and provide a set of evidence-based recommendations for effective physical therapy evaluation, treatment, and management of individuals experiencing limitations in the ability to participate in work following injury or illness. J Orthop Sports Phys Ther 2021;51(8):CPG1-CPG102. doi:10.2519/jospt.2021.0303.

Reductions in rostral anterior cingulate GABA are associated with stress circuitry in females with major depression: a multimodal imaging investigation.

The interplay between cortical and limbic regions in stress circuitry calls for a neural systems approach to investigations of acute stress responses in major depressive disorder (MDD). Advances in multimodal imaging allow inferences between regional neurotransmitter function and activation in circuits linked to MDD, which could inform treatment development. The current study investigated the role of the inhibitory neurotransmitter GABA in stress circuitry in females with current and remitted MDD. Multimodal imaging data were analyzed from 49 young female adults across three groups (current MDD, remitted MDD (rMDD), and healthy controls). GABA was assessed at baseline using magnetic resonance spectroscopy, and functional MRI data were collected before, during, and after an acute stressor and analyzed using a network modeling approach. The MDD group showed an overall lower cortisol response than the rMDD group and lower rostral anterior cingulate cortex (ACC) GABA than healthy controls. Across groups, stress decreased activation in the frontoparietal network (FPN) but increased activation in the default mode network (DMN) and a network encompassing the ventromedial prefrontal cortex-striatum-anterior cingulate cortex (vmPFC-Str-ACC). Relative to controls, the MDD and rMDD groups were characterized by decreased FPN and salience network (SN) activation overall. Rostral ACC GABA was positively associated with connectivity between an overlapping limbic network (Temporal-Insula-Amygdala) and two other circuits (FPN and DMN). Collectively, these findings indicate that reduced GABA in females with MDD was associated with connectivity differences within and across key networks implicated in depression. GABAergic treatments for MDD might alleviate stress circuitry abnormalities in females.

Type of job, personal factors, and disease status are important contextual factors when measuring worker productivity in people with arthritis: a Delphi study.

Purpose: Arthritis is associated with lost wages, work disability, and decreased productivity. There is a lack of knowledge regarding contextual factors that influence worker productivity to inform rehabilitation. Our study aims to identify the essential contextual factors that need to be considered when measuring worker productivity outcomes in people with arthritis.Materials and methods: A three-round international Delphi survey was performed. Round 1 (N = 50) elicited a comprehensive list of contextual factors. In Round 2 (N = 27), participants ranked their top ten factors from the list in Round 1. In Round 3 (N = 27), participants ranked their top five factors and their suggested outcome measures.Results: The key contextual factors identified in the Delphi are (1) type of job (e.g., level of physical demand, manual vs. sedentary), (2) personal factors (e.g., attitude, self-esteem, personal satisfaction, motivation), (3) disease state, (4) financial need, (5) societal incentive (e.g., insurance, government support, return to work transition programs), and (6) age.Conclusion: Future clinical trials in arthritis measuring worker productivity should consider the type of job (physical demands), personal factors, and disease state (as related to physical function). Contextual factors are not well investigated in the area but are crucial to developing the appropriate rehabilitation interventions.Implications for rehabilitationThis study identifies key contextual factors affecting worker productivity in people with arthritis: type of job, personal factors, disease state, financial need, societal incentive, and age.To facilitate proper interpretation of patient outcomes, rehabilitation professionals should consider contextual factors alongside their standard assessment tools.These findings provide a framework in designing rehabilitation programs and clinical trials on worker productivity in arthritis.

Impact of adrenal hormones, reproductive aging, and major depression on memory circuitry decline in early midlife.

Dehydroepiandrosterone-sulfate (DHEAS) is an adrenal androgen that is, in part, aromatized to estradiol. It continues to be produced after menopause and provides estrogenicity after depletion of ovarian hormones. Estradiol depletion contributes to memory circuitry changes over menopause, including changes in hippocampal (HIPP) and dorsolateral- and ventrolateral-prefrontal cortex (DLPFC; VLPFC) function. Further, major depressive disorder (MDD) patients have, in general, lower levels of estradiol and lower DHEAS than healthy controls, thus potentially a higher risk of adverse menopausal outcomes. We investigated whether higher DHEAS levels after menopause is associated with better memory circuitry function, especially in women with MDD. 212 adults (ages 45-55, 50% women) underwent clinical and fMRI testing. Participants performed a working memory (WM) N-back task and an episodic memory verbal encoding (VE) task during fMRI scanning. DHEAS levels were significantly associated with memory circuitry function, specifically in MDD postmenopausal women. On the WM task, lower DHEAS levels were associated with increased HIPP activity. On the VE task, lower DHEAS levels were associated with decreased activity in the HIPP and VLPFC. In contrast, there was no association between DHEAS levels and memory circuitry function in MDD pre/perimenopausal women, men, and non-MDD participants regardless of sex and reproductive status. In fact, MDD postmenopausal women with higher levels of DHEAS were similar to MDD pre/perimenopausal women and men. Thus, memory circuitry deficits associated with MDD and a lower ability of the adrenal gland to produce DHEAS after menopause may contribute to a lower ability to maintain intact memory function with age.

Arch height index measurement system: establishment of reliability and normative values.

BACKGROUND: The purposes of this study were 1) to determine the intrarater and interrater reliability of the arch height index measurement system device, 2) to establish population normative values for the arch height index in recreational runners, and 3) to compare arch height index values between the right and left feet and between genders. METHODS: Eleven subjects were used to establish intrarater and interrater reliability of the arch height index measurement system. This system was then used to measure the arch height index of 100 recreational runners. RESULTS: Measurements taken with the arch height index measurement system device exhibited high intrarater and interrater reliability. The mean +/- SD arch height index of the recreational runners was 0.340 +/- 0.030. Men had larger feet than women, but the arch height index between genders was similar. CONCLUSIONS: The arch height index measurement system device is reliable to use between testers while simplifying the measurement procedure for recording the arch height index. The arch height index may be helpful in identifying potential structural factors that predispose individuals to lower-extremity injuries.

TWEAK is an endothelial cell growth and chemotactic factor that also potentiates FGF-2 and VEGF-A mitogenic activity.

OBJECTIVE: TWEAK, a member of the tumor necrosis factor superfamily, binds to the Fn14 receptor and stimulates angiogenesis in vivo. In this study, we investigated Fn14 gene expression in human endothelial cells (ECs) and examined the effect of TWEAK, added either alone or in combination with fibroblast growth factor-2 (FGF-2) or vascular endothelial growth factor-A (VEGF-A), on EC proliferation, migration, and survival in vitro. We also determined whether a soluble Fn14-Fc fusion protein could inhibit TWEAK biologic activity on ECs and investigated TWEAK signal transduction in ECs. METHODS AND RESULTS: We found that both FGF-2 and VEGF-A could induce Fn14 mRNA expression in ECs. TWEAK was a mitogen for ECs, and this proliferative activity could be inhibited by an Fn14-Fc decoy receptor. Furthermore, TWEAK treatment activated several intracellular signaling pathways in ECs and potentiated FGF-2--and VEGF-A--stimulated EC proliferation. TWEAK also had EC chemotactic activity, but it did not promote EC survival. CONCLUSIONS: These results indicate that TWEAK is an EC growth and migration factor but not a survival factor. TWEAK can also enhance both FGF-2 and VEGF-A mitogenic activity on ECs. Thus, TWEAK may act alone as well as in combination with FGF-2 or VEGF-A to regulate pathological angiogenesis.

Validation of clinical examination versus magnetic resonance imaging and arthroscopy for the detection of rotator cuff lesions.

Limited evidence exists regarding the validity of clinical examination for the detection of shoulder pathology. We therefore wished to establish the sensitivity, specificity, positive predictive value and negative predictive value of clinical tests and magnetic resonance imaging (MRI) in the diagnosis of rotator cuff disorders against findings at arthroscopy. Using recognised tests for specific shoulder lesions, 117 patients with shoulder symptoms awaiting surgery were examined in a standard manner. The diagnoses were categorised and compared with abnormalities found on MRI and at surgery. Results were cross-tabulated to determine the above parameters. Ninety-four patients formed the study group with a mean age of 51 years. The median duration of symptoms was 45 weeks. For clinical examination, sensitivity and specificity to detect a tear or rupture of supraspinatus were 30 % (16/54) and 38 % (15/40) and, for the detection of any pathology, were 94 % (67/71) and 22 % (5/23), respectively, compared with arthroscopy. Correspondingly, the sensitivity of MRI compared with arthroscopy to detect a tear or rupture of supraspinatus was 90 % (28/31) with a specificity of 70 % (46/53), whereas for the detection of any abnormality, the sensitivity was 92 % (65/71) with a specificity of 48 % (11/23). The sensitivity of detecting any rotator cuff abnormality is high when examination and MRI is compared with arthroscopy with the specificity being greater with MRI than examination. In patients with shoulder symptoms severe enough to consider surgery, clinical assessment followed by specific imaging may help define the pathology in order to direct appropriate management.

The Fn14 cytoplasmic tail binds tumour-necrosis-factor-receptor-associated factors 1, 2, 3 and 5 and mediates nuclear factor-kappaB activation.

Fn14 is a growth-factor-inducible immediate-early-response gene encoding a 102-amino-acid type I transmembrane protein. The human Fn14 protein was recently identified as a cell-surface receptor for the tumour necrosis factor (TNF) superfamily member named TWEAK (TNF-like weak inducer of apoptosis). In the present paper, we report that the human TWEAK extracellular domain can also bind the murine Fn14 protein. Furthermore, site-specific mutagenesis and directed yeast two-hybrid interaction assays revealed that the TNFR-associated factor (TRAF) 1, 2, 3 and 5 adaptor molecules bind the murine Fn14 cytoplasmic tail at an overlapping, but non-identical, amino acid sequence motif. We also found that TWEAK treatment of quiescent NIH 3T3 cells stimulates inhibitory kappaBalpha phosphorylation and transcriptional activation of a nuclear factor-kappaB (NF-kappaB) enhancer/luciferase reporter construct. Fn14 overexpression in transiently transfected NIH 3T3 cells also promotes NF-kappaB activation, and this cellular response requires an intact TRAF binding site. These results indicate that Fn14 is a functional TWEAK receptor that can associate with four distinct TRAF family members and stimulate the NF-kappaB transcription factor signalling pathway.