USP50 suppresses alternative RecQ helicase use and deleterious DNA2 activity during replication.

Mammalian DNA replication relies on various DNA helicase and nuclease activities to ensure accurate genetic duplication, but how different helicase and nuclease activities are properly directed remains unclear. Here, we identify the ubiquitin-specific protease, USP50, as a chromatin-associated protein required to promote ongoing replication, fork restart, telomere maintenance, cellular survival following hydroxyurea or pyridostatin treatment, and suppression of DNA breaks near GC-rich sequences. We find that USP50 supports proper WRN-FEN1 localisation at or near stalled replication forks. Nascent DNA in cells lacking USP50 shows increased association of the DNA2 nuclease and RECQL4 and RECQL5 helicases and replication defects in cells lacking USP50, or FEN1 are driven by these proteins. Consequently, suppression of DNA2 or RECQL4/5 improves USP50-depleted cell resistance to agents inducing replicative stress and restores telomere stability. These data define an unexpected regulatory protein that promotes the balance of helicase and nuclease use at ongoing and stalled replication forks.

Outcomes of distal femoral replacement versus internal fixation for metastatic bone diseases of the distal femur.

Background: In clinical practice, internal fixation (IF) is a commonly utilized technique for metastatic bone disease (MBD) to the distal femur. Additionally, distal femoral reconstruction (DFR) has shown to be an effective surgical technique for primary tumors and MBD in the distal femur. The existing body of research comparing these methods has not focused on MBD or pathological fractures and thus does not guide surgical approach in the case of distal femoral MBD. Methods: A multi-institutional retrospective review of musculoskeletal oncology patients treated surgically with IF (n = 29) or DFR (n = 34) for distal femoral MBD between 2005 and 2023. Overall survival, revision risk, and functional status were assessed. Results: 5-year patient overall survival was 47.9 % (CI, 29.5-77.6 %) and 46.6 % (CI, 31.5-68.8 %), for DFR and IF, respectively (p = 0.91). After competing risk analysis, the 5-year risk of implant revision for DFR was 18 % (95 % CI: 5.1-37 %) and 11 % for IF (95 % CI: 2.4-28 %) (p = 0.3). DFR had longer operative times (p = 0.002), higher blood loss (p < 0.001), and greater postoperative (p = 0.006) complications than IF. In addition, patients undergoing DFR had more distal lesions than patients who received IF (p = 0.003). Conclusion: Despite similar overall survival and revision rates, IF may be preferable for patients due to its shorter operative time and lower rates of complication than DFR. However, specific anatomic location in the distal femur must be considered prior to deciding which procedure is optimal.

Osteochondral Allograft Reaming Significantly Affects Chondrocyte Viability.

BACKGROUND: Chondrocyte viability is associated with the clinical success of osteochondral allograft (OCA) transplantation. PURPOSE: To investigate the effect of distal femoral OCA plug harvest and recipient site preparation on regional cell viability using traditional handheld saline irrigation versus saline submersion. STUDY DESIGN: Controlled laboratory study. METHODS: For each of 13 femoral hemicondyles, 4 cartilage samples were harvested: (1) 5-mm control cartilage, (2) 15-mm OCA donor plug harvested with a powered coring reamer and concurrent handheld saline irrigation ("traditional"), (3) 15-mm OCA donor plug harvested while submerged under normal saline ("submerged"), and (4) 5-mm cartilage from the peripheral rim of a recipient socket created with a 15-mm cannulated counterbore reamer to a total depth of 7 mm with concurrent handheld saline irrigation ("recipient"). The 15 mm-diameter plugs were divided into the central 5 mm and the peripheral 5 mm (2 edges) for comparisons. Samples were stained using calcein and ethidium, and live/dead cell percentages were calculated and compared across groups. RESULTS: Compared with the submerged group, the traditional group had significantly lower percentages of live cells across the whole plug (71.54% ± 4.82% vs 61.42% ± 4.98%, respectively; P = .003), at the center of the plug (72.76% ± 5.87% vs 62.30% ± 6.11%, respectively; P = .005), and at the periphery of the plug (70.93% ± 4.51% vs 60.91% ± 4.75%, respectively; P = .003). The traditional group had significantly fewer live cells in all plug regions compared with the control group (77.51% ± 9.23%; P < .0001). There were no significant differences in cell viability between the control and submerged groups (whole: P = .590; center: P = .713; periphery: P = .799). There were no differences between the central and peripheral 5-mm plug regions for the traditional (62.30% ± 6.11% vs 60.91% ± 4.75%, respectively; P = .108) and submerged (72.76% ± 5.87% vs 70.93% ± 4.51%, respectively; P = .061) groups. The recipient group (61.10% ± 5.02%) had significantly lower cell viability compared with the control group (P < .0001) and the periphery of the submerged group (P = .009) but was equivalent to the periphery of the traditional group (P = .990). CONCLUSION: There was a significant amount of chondrocyte death induced by OCA donor plug harvesting using a powered coring reamer with traditional handheld saline irrigation, which was mitigated by harvesting the plug while the allograft was submerged under saline. CLINICAL RELEVANCE: Mitigating this thermally induced damage by harvesting the OCA plug while the allograft was submerged in saline maintained chondrocyte viability throughout the plug and may help to improve the integration and survival of OCAs.

PMS2 has both pro-mutagenic and anti-mutagenic effects on repeat instability in the Repeat Expansion Diseases.

Genome Wide Association studies (GWAS) have implicated PMS2 as a modifier of somatic expansion in Huntington's disease (HD), one of >45 known Repeat Expansion Diseases (REDs). PMS2 is a subunit of the MutLα complex, a major component of the mismatch repair (MMR) system, a repair pathway that is involved in the generation of expansions in many different REDs. However, while MLH3, a subunit of a second MutL complex, MutLγ, is required for all expansions, PMS2 has been shown to protect against expansion in some model systems but to drive expansion in others. To better understand PMS2's behavior, we have compared the effect of the loss of PMS2 in different tissues of an HD mouse model (CAG/CTG repeats) and a mouse model for the Fragile X-related disorders (FXDs), disorders that result from a CGG/CCG repeat expansion. Mice heterozygous for Pms2 show increased expansions in most expansion-prone tissues in both disease models. However, in Pms2 null mice expansions of both repeats increased in some tissues but decreased in others. Thus, the previously reported differences in the effects of PMS2 in different model systems do not reflect fundamentally different roles played by PMS2 in different REDs, but rather the paradoxical effects of PMS2 in different cellular contexts. These findings have important implications not only for the mechanism of expansion and the development of therapeutic approaches to reduce the pathology generated by repeat expansion, but also for our understanding of normal MMR.

Status of zoonotic disease research in refugees, asylum seekers and internally displaced people, globally: A scoping review of forty clinically important zoonotic pathogens.

BACKGROUND: At the end of 2022, there were over 108 million forcibly displaced people globally, including refugees, asylum seekers (AS) and internally displaced people (IDPs). Forced migration increases the risk of infectious disease transmission, and zoonotic pathogens account for 61% of emerging and re-emerging infectious diseases. Zoonoses create a high burden of disease and have the potential to cause large-scale outbreaks. This scoping review aimed to assess the state of research on a range of clinically relevant zoonotic pathogens in displaced populations in order to identify the gaps in literature and guide future research. METHODOLOGY / PRINCIPAL FINDINGS: Literature was systematically searched to identify original research related to 40 selected zoonotic pathogens of interest in refugees, AS and IDPs. We included only peer-reviewed original research in English, with no publication date restrictions. Demographic data, migration pathways, health factors, associated outbreaks, predictive factors and preventative measures were extracted and synthesized. We identified 4,295 articles, of which 347 were included; dates of publications ranged from 1937 to 2022. Refugees were the most common population investigated (75%). Migration pathways of displaced populations increased over time towards a more complex web, involving migration in dual directions. The most frequent pathogen investigated was Schistosoma spp. (n = 99 articles). Disease outbreaks were reported in 46 publications (13.3%), with viruses being the most commonly reported pathogen type. Limited access to hygiene/sanitation, crowding and refugee status were the most commonly discussed predictors of infection. Vaccination/prophylaxis drug administration, surveillance/screening and improved hygiene/sanitation were the most commonly discussed preventative measures. CONCLUSIONS / SIGNIFICANCE: The current research on zoonoses in displaced populations displays gaps in the spectrum of pathogens studied, as well as in the (sub)populations investigated. Future studies should be more inclusive of One Health approaches to adequately investigate the impact of zoonotic pathogens and identify transmission pathways as a basis for designing interventions for displaced populations.

USP50 suppresses alternative RecQ helicase use and deleterious DNA2 activity during replication.

Mammalian DNA replication employs several RecQ DNA helicases to orchestrate the faithful duplication of genetic information. Helicase function is often coupled to the activity of specific nucleases, but how helicase and nuclease activities are co-directed is unclear. Here we identify the inactive ubiquitin-specific protease, USP50, as a ubiquitin-binding and chromatin-associated protein required for ongoing replication, fork restart, telomere maintenance and cellular survival during replicative stress. USP50 supports WRN:FEN1 at stalled replication forks, suppresses MUS81-dependent fork collapse and restricts double-strand DNA breaks at GC-rich sequences. Surprisingly we find that cells depleted for USP50 and recovering from a replication block exhibit increased DNA2 and RECQL4 foci and that the defects in ongoing replication, poor fork restart and increased fork collapse seen in these cells are mediated by DNA2, RECQL4 and RECQL5. These data define a novel ubiquitin-dependent pathway that promotes the balance of helicase: nuclease use at ongoing and stalled replication forks.

Outcomes of surgical treatment with patterns of bacterial culture and antimicrobial susceptibility testing in cases of cervical abscessation in dogs: 82 cases (2018-2021).

OBJECTIVE: The objective of this study was to summarize the presentation, diagnosis, and outcome for dogs surgically treated for chronic cervical abscessation following suspected or reported cervical or oropharyngeal trauma, as well as to report on culture results and antimicrobial susceptibility patterns. RESULTS: Eighty-two dogs were identified by retrospective review. Successful surgical outcome was achieved in 92.7% of dogs. Abscess recurrence was confirmed or suspected in 6/82 (7.3%) cases, and surgical intervention for abscess recurrence was performed in 4/82 (4.9%) cases. Foreign material was identified at surgery in 5/82 (6%) cases. Incisional healing complications were noted in 9/82 (10.9%) cases and required additional surgery in 5/82 (6%) cases. Twenty-three (28%) dogs had negative culture results. The results of antimicrobial sensitivity testing led to a change in antimicrobial treatment in only 9% of cases.Surgically treated cervical abscessation carries a good prognosis with a low incidence of recurrence in this cohort (in contrast to previous reports), despite low frequency of foreign body removal or identification of the underlying cause of the abscess. Excision of chronic inflammatory tissue may not be necessary for a successful outcome, contrary to previous recommendations. Multi-pathogen infections and anaerobic infections are commonly encountered.

The contribution of white matter pathology, hypoperfusion, lesion load, and stroke recurrence to language deficits following acute subcortical left hemisphere stroke.

Aphasia, the loss of language ability following damage to the brain, is among the most disabling and common consequences of stroke. Subcortical stroke, occurring in the basal ganglia, thalamus, and/or deep white matter can result in aphasia, often characterized by word fluency, motor speech output, or sentence generation impairments. The link between greater lesion volume and acute aphasia is well documented, but the independent contributions of lesion location, cortical hypoperfusion, prior stroke, and white matter degeneration (leukoaraiosis) remain unclear, particularly in subcortical aphasia. Thus, we aimed to disentangle the contributions of each factor on language impairments in left hemisphere acute subcortical stroke survivors. Eighty patients with acute ischemic left hemisphere subcortical stroke (less than 10 days post-onset) participated. We manually traced acute lesions on diffusion-weighted scans and prior lesions on T2-weighted scans. Leukoaraiosis was rated on T2-weighted scans using the Fazekas et al. (1987) scale. Fluid-attenuated inversion recovery (FLAIR) scans were evaluated for hyperintense vessels in each vascular territory, providing an indirect measure of hypoperfusion in lieu of perfusion-weighted imaging. We found that language performance was negatively correlated with acute/total lesion volumes and greater damage to substructures of the deep white matter and basal ganglia. We conducted a LASSO regression that included all variables for which we found significant univariate relationships to language performance, plus nuisance regressors. Only total lesion volume was a significant predictor of global language impairment severity. Further examination of three participants with severe language impairments suggests that their deficits result from impairment in domain-general, rather than linguistic, processes. Given the variability in language deficits and imaging markers associated with such deficits, it seems likely that subcortical aphasia is a heterogeneous clinical syndrome with distinct causes across individuals.

An Analysis of Right Hemisphere Stroke Discourse in the Modern Cookie Theft Picture.

PURPOSE: Adults with right hemisphere damage demonstrate differences in connected speech compared to controls, but systematic, quantitative methods to capture these differences are lacking. The current study aimed to (a) investigate if measures using the Modern Cookie Theft picture description would identify discourse differences in acute right hemisphere stroke, and (b) examine if discourse differences were associated with documented cognitive impairment. METHOD: Eighty-four participants completed the Modern Cookie Theft picture description within 5 days of right hemisphere stroke. Descriptions were analyzed for multiple microlinguistic characteristics. Medical charts were retrospectively reviewed for documented presence of cognitive impairment. RESULTS: Individuals with acute right hemisphere stroke produced fewer content units, total syllables, and lower left-right content unit ratios compared to controls, indicating a paucity of informativeness. Presence of cognitive impairment was associated with fewer content units produced. CONCLUSIONS: Multiple measures of microlinguistic discourse characteristics differentiated adults with right hemisphere stroke from controls, highlighting variations in both the quantity and quality of connected speech. Findings continue to underscore the contribution and correlation between cognitive skills and discourse performance. Future work is needed to assess the relationship between particular cognitive domains and discourse production as well as to investigate longitudinal changes to discourse production during stroke recovery. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.20778541.

Enhanced Imaging and Language Assessments for Primary Progressive Aphasia.

BACKGROUND AND OBJECTIVES: It is widely agreed that primary progressive aphasia (PPA) is a clinical syndrome with at least 3 distinct variants that differ in phenotype, areas of atrophy, and most common underlying neurodegenerative disease. The distinction between logopenic variant PPA (lvPPA) and other variants is important for prognosis and medical management. However, differentiating logopenic from nonfluent agrammatic variant can be difficult. We aimed to identify a novel behavioral assessment that (1) distinguishes logopenic from the other variants with a high degree of accuracy and (2) correlates with left superior temporal-inferior parietal atrophy (previously shown to be associated with this variant). The location of atrophy was measured using a novel, clinically useful imaging analysis. METHODS: In this observational cohort study of 227 individuals with PPA, participants were administered sentence reading and repetition subtests from a standard battery. A subset of 41 participants were administered enhanced reading and repetition subtests with 5 longer sentences, of which 13 had brain imaging. Ratios of word-level and sentence-level accuracy in reading:repetition were calculated. We used one-way analysis of variance (ANOVA) to determine whether either or both ratios of reading:repetition independently discriminated between variants and t test to determine whether the ratios distinguished between nonfluent and logopenic variants. We identified receiver operating characteristics and Pearson correlations between the reading:repetition ratios and ratio of left:right superior temporal-inferior parietal volume. RESULTS: The sentence reading:repetition ratio using the new stimuli significantly differed across the 3 variants (p < 0.00001) and differed between nonfluent and logopenic variants (t(27) = 4.1; p = 0.0003). The area under the curve for distinguishing logopenic from other variants was 0.85 (0.71-0.99), and the diagnostic accuracy was 87.5%. The sentence reading:repetition ratio correlated with left:right superior temporal-inferior parietal volume (r = 0.69; p = 0.0087), but not with left:right volume of regions of interest associated with other variants. DISCUSSION: Results provide an efficient and reliable clinical assessment, and a novel imaging analysis, to distinguish the clinical syndrome of logopenic variant from other variants of PPA. Results also support the proposal that lvPPA reflects a defect in phonological short-term memory caused by atrophy in the superior temporal-inferior parietal cortex. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that the sentence reading:repetition ratio distinguished logopenic PPA from other PPA variants.

Dysfunctional Tissue Correlates of Unrelated Naming Errors in Acute Left Hemisphere Stroke.

Most naming error lesion-symptom mapping (LSM) studies have focused on semantic and/or phonological errors. Anomic individuals also produce unrelated word errors, which may be linked to semantic or modality-independent lexical deficits. To investigate the neural underpinnings of rarely-studied unrelated errors, we conducted LSM analyses in 100 individuals hospitalized with a left hemisphere stroke who completed imaging protocols and language assessments. We used least absolute shrinkage and selection operator regression to capture relationships between naming errors and dysfunctional brain tissue metrics (regional damage or hypoperfusion in vascular territories) in two groups: participants with and without impaired single-word auditory comprehension. Hypoperfusion-particularly within the parietal lobe-was an important error predictor, especially for the unimpaired group. In both groups, higher unrelated error proportions were associated with primarily ventral stream damage, the language route critical for processing meaning. Nonetheless, brain metrics implicated in unrelated errors were distinct from semantic error correlates.

Transcranial Direct Current Stimulation Paired With Verb Network Strengthening Treatment Improves Verb Naming in Primary Progressive Aphasia: A Case Series.

PURPOSE: There are few evidence-based treatments for language deficits in primary progressive aphasia (PPA). PPA treatments are often adopted from the poststroke aphasia literature. The poststroke aphasia literature has shown promising results using Verb Network Strengthening Treatment (VNeST), a behavioral therapy that focuses on improving naming by producing verbs and their arguments in phrases and sentences. Emerging research in poststroke aphasia and PPA has shown promising results pairing behavioral language therapy with transcranial direct current stimulation (tDCS). METHOD: This study used a double-blind, within-subjects, sham-controlled crossover design to study the effect of anodal tDCS applied to left inferior frontal gyrus (IFG) plus VNeST versus VNeST plus sham stimulation in two individuals with nonfluent variant PPA and one individual with logopenic variant PPA. Participants received two phases of treatment, each with 15 1-hr sessions of VNeST. One phase paired VNeST with tDCS stimulation, and one with sham. For each phase, language testing was conducted at baseline, and at 1 week and 8 weeks posttreatment conclusion. For each participant, treatment efficacy was evaluated for each treatment phase by comparing the mean change in accuracy between baseline and the follow-up time points for naming trained verbs (primary outcome measure), untrained verbs, and nouns on the Object and Action Naming Battery. Mean change from baseline was also directly compared between tDCS and sham phases at each time point. RESULTS: Results revealed a different pattern of outcomes for each of the participants. A tDCS advantage was not found for trained verbs for any participant. Two participants with nonfluent variant PPA had a tDCS advantage for generalization to naming of untrained verbs, which was apparent at 1 week and 8 weeks posttreatment. One participant with nonfluent variant also showed evidence of generalization to sentence production in the tDCS phase. CONCLUSION: VNeST plus anodal tDCS stimulation of left IFG shows promising results for improving naming in PPA.

Simultaneous Hemodynamic and Structural Imaging of Ischemic Stroke With Magnetic Resonance Fingerprinting Arterial Spin Labeling.

BACKGROUND: Perfusion and structural imaging play an important role in ischemic stroke. Magnetic resonance fingerprinting (MRF) arterial spin labeling (ASL) is a novel noninvasive method of ASL perfusion that allows simultaneous estimation of cerebral blood flow (CBF), bolus arrival time (BAT), and tissue T1 map in a single scan of <4 minutes. Here, we evaluated the utility of MRF-ASL in patients with ischemic stroke in terms of detecting hemodynamic and structural damage and predicting neurological deficits and disability. METHODS: A total of 34 patients were scanned on 3T magnetic resonance imaging. MRF-ASL, standard single-delay pseudo-continuous ASL, T2-weighted, and diffusion magnetic resonance imaging were performed. Regions of interest of lesion and contralateral normal tissues were manually delineated. CBF (with 2 different compartmental models), BAT, and tissue T1 parameters were quantified. Cross-sectional linear regression analyses were performed to examine the relationship between MRF-ASL parameters and National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale. Receiver operating characteristic analyses were performed to determine the utility of MRF-ASL in the classification of stroke lesion voxels. RESULTS: MRF-ASL derived parameters revealed a significant difference between stroke lesion and contralateral normal regions of interest, in that lesion regions manifested a lower CBF1-compartment (P<0.001), lower CBF2-compartment (P<0.001), longer BAT (P=0.002), and longer T1 (P<0.001) compared with normal regions of interest. NIHSS scores at acute stage revealed a strong association with lesion-normal differences in CBF1-compartment,diff (ß=-0.11, P=0.008), CBF2-compartment,diff (ß=-0.16, P=0.003), and T1,diff (ß=0.008, P=0.001). MRF-ASL parameters were also predictive of NIHSS score and modified Rankin Scale scale measured at a later stage, although the degree of the associations was weaker. These associations tended to be even stronger when the MRF-ASL data were acquired at the acute/subacute stage. Compared with standard pseudo-continuous ASL, the multiparametric capability of MRF-ASL yielded higher area under curve values in the receiver operating characteristic analyses of stroke voxel classifications. CONCLUSIONS: MRF-ASL may provide a new approach for quantitative hemodynamic and structural imaging in ischemic stroke.

Disruptions of the Human Connectome Associated With Hemispatial Neglect.

BACKGROUND AND OBJECTIVES: Hemispatial neglect is a heterogeneous and complex disorder that can be classified by frame of reference for "left" vs "right," including viewer-centered neglect (VCN, affecting the contralesional side of the view), stimulus-centered neglect (SCN, affecting the contralesional side of the stimulus, irrespective of its location with respect to the viewer), or both. We investigated the effect of acute stroke lesions on the connectivity of neural networks that underlie VCN or SCN. METHODS: A total of 174 patients within 48 hours of acute right hemispheric infarct underwent a detailed hemispatial neglect assessment that included oral reading, scene copy, line cancellation, gap detection, horizontal line bisection tests, and MRI. Each patient's connectivity map was generated. We performed a linear association analysis between network connectivity strength and continuous measures of neglect to identify lesion-induced disconnections associated with the presence or severity of VCN and SCN. Results were corrected for multiple comparisons. RESULTS: About 42% of the participants with right hemisphere stroke had at least one type of neglect. The presence of any type of neglect was associated with lesions to tracts connecting the right inferior parietal cortex, orbitofrontal cortex, and right thalamus to other right-hemispheric structures. VCN only was strongly associated with tracts connecting the right putamen to other brain regions and tracts connecting right frontal regions with other brain regions. The presence of both types of neglect was most strongly associated with tracts connecting the right inferior and superior parietal cortex to other brain regions and those connecting left or right mesial temporal cortex to other brain regions. DISCUSSION: Our study provides new evidence for the specific white matter tracts where disruption can cause hemispatial neglect in a relatively large number of participants and homogeneous time after onset. We obtained MRI and behavioral testing acutely, before the opportunity for rehabilitation or substantial recovery. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that damage to specific white matter tracts identified on MRI are associated with the presence of neglect following right hemispheric stroke.

Hyperintense vessels on imaging account for neurological function independent of lesion volume in acute ischemic stroke.

In acute ischemic stroke, reported relationships between lesion metrics and behavior have largely focused on lesion volume and location. However, hypoperfusion has been shown to correlate with deficits in the acute stage. Hypoperfusion is typically identified using perfusion imaging in clinical settings, which requires contrast. Unfortunately, contrast is contraindicated for some individuals. An alternative method has been proposed to identify hypoperfusion using hyperintense vessels on fluid-attenuated inversion recovery (FLAIR) imaging. This study aimed to validate the clinical importance of considering hypoperfusion when accounting for behavior in acute stroke and demonstrate the clinical utility of scoring the presence of hyperintense vessels to quantify it. One hundred and fifty-three participants with acute ischemic stroke completed a battery of commonly-used neurological and behavioral measures. Clinical MRIs were used to determine lesion volume and to score the presence of hyperintense vessels seen on FLAIR images to estimate severity of hypoperfusion in six different vascular regions. National Institutes of Health Stroke Scale (NIHSS) scores, naming accuracy (left hemisphere strokes), and language content produced during picture description were examined in relation to lesion volume, hypoperfusion, and demographic variables using correlational analyses and multivariable linear regression. Results showed that lesion volume and hypoperfusion, in addition to demographic variables, were independently associated with performance on NIHSS, naming, and content production. Specifically, hypoperfusion in the frontal lobe independently correlated with NIHSS scores, while hypoperfusion in parietal areas independently correlated with naming accuracy and content production. These results correspond to previous reports associating hypoperfusion with function, confirming that hypoperfusion is an important consideration-beyond lesion volume-when accounting for behavior in acute ischemic stroke. Quantifying hypoperfusion using FLAIR hyperintense vessels can be an essential clinical tool when other methods of identifying hypoperfusion are unavailable or time prohibitive.

Health trends, inequalities and opportunities in South Africa's provinces, 1990-2019: findings from the Global Burden of Disease 2019 Study.

BACKGROUND: Over the last 30 years, South Africa has experienced four 'colliding epidemics' of HIV and tuberculosis, chronic illness and mental health, injury and violence, and maternal, neonatal, and child mortality, which have had substantial effects on health and well-being. Using data from the 2019 Global Burden of Diseases, Injuries and Risk Factors Study (GBD 2019), we evaluated national and provincial health trends and progress towards important Sustainable Development Goal targets from 1990 to 2019. METHODS: We analysed GBD 2019 estimates of mortality, non-fatal health loss, summary health measures and risk factor burden, comparing trends over 1990-2007 and 2007-2019. Additionally, we decomposed changes in life expectancy by cause of death and assessed healthcare system performance. RESULTS: Across the nine provinces, inequalities in mortality and life expectancy increased over 1990-2007, largely due to differences in HIV/AIDS, then decreased over 2007-2019. Demographic change and increases in non-communicable diseases nearly doubled the number of years lived with disability between 1990 and 2019. From 1990 to 2019, risk factor burdens generally shifted from communicable and nutritional disease risks to non-communicable disease and injury risks; unsafe sex remained the top risk factor. Despite widespread improvements in healthcare system performance, the greatest gains were generally in economically advantaged provinces. CONCLUSIONS: Reductions in HIV/AIDS and related conditions have led to improved health since 2007, though most provinces still lag in key areas. To achieve health targets, provincial governments should enhance health investments and exchange of knowledge, resources and best practices alongside populations that have been left behind, especially following the COVID-19 pandemic.

Longitudinal decline in spoken word recognition and object knowledge in primary progressive aphasia.

ABSTRACT: The premise of this study is that spoken word recognition and object knowledge are impaired in semantic variant primary progressive aphasia (PPA) (svPPA) and are spared in logopenic variant (lvPPA) and nonfluent agrammatic primary progressive aphasia (nfaPPA) at disease onset. Over time, however, there may be heterogeneity in these abilities in lvPPA and nfaPPA. We hypothesized that individuals with svPPA would demonstrate poorer performance on baseline spoken word recognition and object knowledge than those with lvPPA and nfaPPA) as documented in the literature, but that rates of decline over time on spoken word recognition and object knowledge would be similar in all 3 PPA variants because these become less distinguishable with disease progression.The aim of this study was to investigate longitudinal patterns of decline in spoken word recognition and object knowledge across PPA variants.Ninety-five individuals with PPA completed the Semantic Word Picture Matching and Semantic Associates tests at baseline to establish expected performance in these areas. Thirty-five individuals completed follow-up testing.The distributions of trichotomized mean rates of decline in object knowledge were similar for lvPPA and svPPA (P = .05). There were weak negative correlations between symptom duration and baseline scores on Semantic Word Picture Matching (r[37] = -0.399, P = .01), and baseline scores on Semantic Associates (r[37] = -0.394, P = .01) in lvPPA.Degradation of spoken word recognition and object knowledge occurs over time in lvPPA. Further investigation of the receptive language deficits in PPA is warranted to characterize language changes that lessen the distinctions between PPA variants with disease progression.

How are social stressors at work related to well-being and health? A systematic review and meta-analysis.

BACKGROUND: Social relationships are crucial for well-being and health, and considerable research has established social stressors as a risk for well-being and health. However, researchers have used many different constructs, and it is unclear if these are actually different or reflect a single overarching construct. Distinct patterns of associations with health/well-being would indicate separate constructs, similar patterns would indicate a common core construct, and remaining differences could be attributed to situational characteristics such as frequency or intensity. The current meta-analysis therefore investigated to what extent different social stressors show distinct (versus similar) patterns of associations with well-being and health. METHODS: We meta-analysed 557 studies and investigated correlations between social stressors and outcomes in terms of health and well-being (e.g. burnout), attitudes (e.g. job satisfaction), and behaviour (e.g. counterproductive work behaviour). Moderator analyses were performed to determine if there were differences in associations depending on the nature of the stressor, the outcome, or both. To be included, studies had to be published in peer-reviewed journals in English or German; participants had to be employed at least 50% of a full-time equivalent (FTE). RESULTS: The overall relation between social stressors and health/well-being was of medium size (r = -.30, p < .001). Type of social stressor and outcome category acted as moderators, with moderating effects being larger for outcomes than for stressors. The strongest effects emerged for job satisfaction, burnout, commitment, and counterproductive work behaviour. Type of stressor yielded a significant moderation, but differences in effect sizes for different stressors were rather small overall. Rather small effects were obtained for physical violence and sexual mistreatment, which is likely due to a restricted range because of rare occurrence and/or underreporting of such intense stressors. CONCLUSIONS: We propose integrating diverse social stressor constructs under the term "relational devaluation" and considering situational factors such as intensity or frequency to account for the remaining variance. Practical implications underscore the importance for supervisors to recognize relational devaluation in its many different forms and to avoid or minimize it as far as possible in order to prevent negative health-related outcomes for employees.

Effects of a topical treatment with spleen tyrosine kinase inhibitor in healthy subjects and patients with cold urticaria or chronic spontaneous urticaria: Results of a phase 1a/b randomised double-blind placebo-controlled study.

AIMS: To explore the safety, tolerability, pharmacokinetics and pharmacodynamics (PD) of GSK2646264 using skin challenge models. METHODS: Healthy volunteers (HV) with a positive allergen skin prick test received GSK2646264 (0.5% or 1% ww) and placebo creams on up to 10% body surface area (BSA). Cold (ColdU) or chronic spontaneous (CSU) urticaria patients received 1% GSK2646264 or placebo on up to 10% BSA. PD assessments included weal characteristics after skin allergen challenge, critical temperature threshold (CTT) in ColdU patients and defined area urticaria activity score in CSU patients. RESULTS: Thirty-four patients were randomised (17 HV, 12 ColdU, 5 CSU). Topical application of GSK2646264 and placebo was well tolerated. Systemic pharmacokinetics (AUC [0-24] h*ng/mL) was similar between HVs (Geomean 97.9 [%CV 37]) and ColdU patients (Geomean 68.2 [%CV 14; 3.5% BSA] or 167 [%CV 120; 10% BSA]). Whilst in HVs a similar reduction in skin allergen challenge weal area was observed following 3 applications of GSK2646264 and placebo, a trend towards a greater reduction was seen in ColdU with GSK2646264 compared to placebo. A clinically meaningful reduction in CTT, in ColdU patients treated with GSK2646264, was observed in 4 of 9 patients, who demonstrated either a complete inhibition of ColdU to ≤4°C (n = 2) or partial response (reduction by >4°C, n = 2). Due to the small number of CSU patients recruited, no meaningful conclusions could be drawn from the defined area urticaria activity score PD endpoint. CONCLUSION: This Phase 1/1b study confirms that GSK2646264 cream applied topically penetrates the skin and some reduction in CTT was observed. (NCT02424799).