Reclaiming Agency in Care Decisions and Barriers From the Perspectives of Individuals With Acquired Brain Injury and Their Family Members.

BACKGROUND: The ability to self-advocate or have a say in one's care is integral to personalised care after acquired brain injury (ABI). This study aimed to understand what constitutes self-advocacy and associated barriers and facilitators throughout hospital transitions and into the community. METHOD: Qualitative methodology was employed with semistructured interviews conducted with 12 people with ABI and 13 family members. Interviews were conducted at predischarge (in-person or via telephone) and 4 months postdischarge (via telephone) from the brain injury rehabilitation unit of a tertiary hospital. Data were thematically analysed using a hybrid deductive-inductive approach. RESULTS: Self-advocacy reflects the process of reclaiming agency or people's efforts to exert influence over care decisions after ABI. Agency varies along a continuum, often beginning with impaired processing of the self or environment (loss of agency) before individuals start to understand and question their care (emerging agency) and ultimately plan and direct their ongoing and future care (striving for agency). This process may vary across individuals and contexts. Barriers to self-advocacy for individuals with ABI include neurocognitive deficits that limit capacity and desire for control over decisions, unfamiliar and highly structured environments and lack of family support. Facilitators include neurocognitive recovery, growing desire to self-advocate and scaffolded support from family and clinicians. CONCLUSION: Self-advocacy after ABI entails a process of reclaiming agency whereby individuals seek to understand, question and direct their ongoing care. This is facilitated by neurocognitive recovery, growing capacity and desire and scaffolded supports. Research evaluating approaches for embedding self-advocacy skills early in brain injury rehabilitation is recommended. PATIENT OR PUBLIC CONTRIBUTION: Two caregivers with lived experience of supporting a family member with ABI were involved in the design and conduct of this study and contributed to and provided feedback on the manuscript.

On-road driving remediation following acquired brain injury: a randomized controlled trial.

OBJECTIVE: To investigate the relationship between on-road driving remediation and achieving fitness to drive following acquired brain injury. DESIGN: Randomized controlled trial. SETTING: Tertiary hospital outpatient driver assessment and rehabilitation service, Australia. PARTICIPANTS: Thirty-five participants (54.3% male), aged 18-65 years, 41 days-20 years post-acquired brain injury (including stroke, aneurysm, traumatic brain injury) recommended for on-road driving remediation following occupational therapy driver assessment were randomly assigned to intervention (n = 18) and waitlist control (n = 17) groups. INTERVENTION: Intervention group received on-road driving remediation delivered by a qualified driving instructor in a dual-control vehicle. The waitlist control group completed a 6 week period of no driving-related remediation. MAIN MEASURE: Fitness to drive rated following the conduct of an on-road occupational therapy driver assessment with a qualified driving instructor where outcome assessors were blinded to group allocation. RESULTS: The intervention group were significantly more likely to achieve a fit to drive recommendation than no driving specific intervention (p = 0.003). CONCLUSION: Following comprehensive assessment, individualized on-road driving remediation programs devised by an occupational therapist with advanced training in driver assessment and rehabilitation and delivered by a qualified driving instructor are significantly associated with achieving fitness to drive after acquired brain injury.

Cortico-striatal networking deficits associated with advanced HIV disease and cocaine use.

Cocaine use is disproportionately prevalent in people with HIV (PWH) and is known to potentiate HIV neuropathogenesis. As both HIV and cocaine have well-documented cortico-striatal effects, PWH who use cocaine and have a history of immunosuppression may exhibit greater FC deficits compared to PWH without these conditions. However, research investigating the legacy effects of HIV immunosuppression (i.e., a history of AIDS) on cortico-striatal functional connectivity (FC) in adults with and without cocaine use is sparse. Resting-state functional magnetic resonance imaging (fMRI) and neuropsychological assessment data from 273 adults were analyzed to examine FC in relation to HIV disease: HIV-negative (n = 104), HIV-positive with nadir CD4 ≥ 200 (n = 96), HIV-positive with nadir CD4 < 200 (AIDS; n = 73), and cocaine use (83 COC and 190 NON). Using independent component analysis/dual regression, FC was assessed between the basal ganglia network (BGN) and five cortical networks: dorsal attention network (DAN), default mode network, left executive network, right executive network, and salience network. There were significant interaction effects such that AIDS-related BGN-DAN FC deficits emerged in COC but not in NON participants. Independent of HIV, cocaine effects emerged in FC between the BGN and executive networks. Disruption of BGN-DAN FC in AIDS/COC participants is consistent with cocaine potentiation of neuro-inflammation and may be indicative of legacy HIV immunosuppressive effects. The current study bolsters previous findings linking HIV and cocaine use with cortico-striatal networking deficits. Future research should consider the effects of the duration of HIV immunosuppression and early treatment initiation.

Additive cortical gray matter deficits in people living with HIV who use cocaine.

Cocaine use, which is disproportionately common in people living with HIV (PWH), is known to have neurotoxic effects that may exacerbate HIV neuropathogenesis. While both cocaine use and HIV disease are independently associated with deficits in gray matter (GM) volume, the additive effect of cocaine use to HIV disease on GM volume has not been explored. Here, we investigated subcortical and cortical brain volume differences between four groups of individuals with and without HIV disease and/or cocaine use. Participants also completed a comprehensive neuropsychological testing battery, and HIV disease characteristics were recorded. Within subcortical regions, cocaine use was independently associated with higher volume in the dorsal striatum and pallidum, while HIV disease was associated with lower volume in the nucleus accumbens and thalamus. For cortical regions, there was an additive effect of cocaine use on HIV disease in parietal and occipital lobe volume with PWH who used cocaine displaying the lowest GM volume. Within regions that differed between groups, higher neurocognitive function was positively associated with thalamic, nucleus accumbens, dorsal striatum, and occipital lobe volume. For regions that showed a significant main effect of HIV disease, lower nadir CD4 + T cell count was associated with lower nucleus accumbens and occipital lobe volume. Lower current CD4 + T cell count was associated with lower occipital lobe volume. These results suggest that PWH who use cocaine are at greater risk for cortical atrophy than cocaine use or HIV disease alone.

Neuroimaging and immunological features of neurocognitive function related to substance use in people with HIV.

This study sought to identify neuroimaging and immunological factors associated with substance use and that contribute to neurocognitive impairment (NCI) in people with HIV (PWH). We performed cross-sectional immunological phenotyping, neuroimaging, and neurocognitive testing on virally suppressed PWH in four substance groups: cocaine only users (COC), marijuana only users (MJ), dual users (Dual), and Non-users. Participants completed substance use assessments, multimodal MRI brain scan, neuropsychological testing, and blood and CSF sampling. We employed a two-stage analysis of 305 possible biomarkers of cognitive function associated with substance use. Feature reduction (Kruskal Wallis p-value < 0.05) identified 53 biomarkers associated with substance use (22 MRI and 31 immunological) for model inclusion along with clinical and demographic variables. We employed eXtreme Gradient Boosting (XGBoost) with these markers to predict cognitive function (global T-score). SHapley Additive exPlanations (SHAP) values were calculated to rank features for impact on model output and NCI. Participants were 110 PWH with sustained HIV viral suppression (33 MJ, 12 COC, 22 Dual, and 43 Non-users). The ten highest ranking biomarkers for predicting global T-score were 4 neuroimaging biomarkers including functional connectivity, gray matter volume, and white matter integrity; 5 soluble biomarkers (plasma glycine, alanine, lyso-phosphatidylcholine (lysoPC) aC17.0, hydroxy-sphingomyelin (SM.OH) C14.1, and phosphatidylcholinediacyl (PC aa) C28.1); and 1 clinical variable (nadir CD4 count). The results of our machine learning model suggest that substance use may indirectly contribute to NCI in PWH through both metabolomic and neuropathological mechanisms.

Cocaine Use Prediction With Tensor-Based Machine Learning on Multimodal MRI Connectome Data.

This letter considers the use of machine learning algorithms for predicting cocaine use based on magnetic resonance imaging (MRI) connectomic data. The study used functional MRI (fMRI) and diffusion MRI (dMRI) data collected from 275 individuals, which was then parcellated into 246 regions of interest (ROIs) using the Brainnetome atlas. After data preprocessing, the data sets were transformed into tensor form. We developed a tensor-based unsupervised machine learning algorithm to reduce the size of the data tensor from 275 (individuals) × 2 (fMRI and dMRI) × 246 (ROIs) × 246 (ROIs) to 275 (individuals) × 2 (fMRI and dMRI) × 6 (clusters) × 6 (clusters). This was achieved by applying the high-order Lloyd algorithm to group the ROI data into six clusters. Features were extracted from the reduced tensor and combined with demographic features (age, gender, race, and HIV status). The resulting data set was used to train a Catboost model using subsampling and nested cross-validation techniques, which achieved a prediction accuracy of 0.857 for identifying cocaine users. The model was also compared with other models, and the feature importance of the model was presented. Overall, this study highlights the potential for using tensor-based machine learning algorithms to predict cocaine use based on MRI connectomic data and presents a promising approach for identifying individuals at risk of substance abuse.

Identification and rescue of a tRNA wobble inosine deficiency causing intellectual disability disorder.

The deamination of adenosine to inosine at the wobble position of tRNA is an essential post-transcriptional RNA modification required for wobble decoding in bacteria and eukaryotes. In humans, the wobble inosine modification is catalyzed by the heterodimeric ADAT2/3 complex. Here, we describe novel pathogenic ADAT3 variants impairing adenosine deaminase activity through a distinct mechanism that can be corrected through expression of the heterodimeric ADAT2 subunit. The variants were identified in a family in which all three siblings exhibit intellectual disability linked to biallelic variants in the ADAT3 locus. The biallelic ADAT3 variants result in a missense variant converting alanine to valine at a conserved residue or the introduction of a premature stop codon in the deaminase domain. Fibroblast cells derived from two ID-affected individuals exhibit a reduction in tRNA wobble inosine levels and severely diminished adenosine tRNA deaminase activity. Notably, the ADAT3 variants exhibit impaired interaction with the ADAT2 subunit and alterations in ADAT2-dependent nuclear localization. Based upon these findings, we find that tRNA adenosine deaminase activity and wobble inosine modification can be rescued in patient cells by overexpression of the ADAT2 catalytic subunit. These results uncover a key role for the inactive ADAT3 deaminase domain in proper assembly with ADAT2 and demonstrate that ADAT2/3 nuclear import is required for maintaining proper levels of the wobble inosine modification in tRNA.

Bursal Acromial Reconstruction (BAR) Using an Acellular Dermal Allograft for Massive, Irreparable Posterosuperior Rotator Cuff Tears: A Dynamic Biomechanical Investigation.

PURPOSE: To investigate the effect of bursal acromial reconstruction (BAR) using an acellular dermal allograft on glenohumeral joint kinematics including maximum abduction angle, glenohumeral superior translation, cumulative deltoid force, and subacromial contact pressure. METHODS: In this dynamic biomechanical cadaveric shoulder study, 8 fresh-frozen cadaveric shoulders (age 53.4 ± 14.2 years, mean ± standard deviation) were tested using a dynamic shoulder testing system. Maximum abduction angle (MAA), glenohumeral superior translation (ghST), maximum cumulative deltoid force (cDF), and subacromial peak contact pressure (sCP) were compared across 3 conditions: (1) intact shoulder; (2) massive retracted irreparable posterosuperior rotator cuff tear (psRCT) according to Patte III; and (3) BAR. Additionally, humeral head containment was measured using contact pressure. RESULTS: Compared with the simulated psRCT, BAR significantly increased mean MAA and significantly decreased ghST (P < .001, respectively) and cDF (P = .017) Additionally, BAR was found to significantly decrease sCP compared with psRCT (P = .024). CONCLUSION: In a dynamic biomechanical cadaveric shoulder simulator, resurfacing the undersurface of the acromion using the BAR technique leads to significantly improved ghST, MAA, cDF, and sCP compared with the irreparable rotator cuff tear. CLINICAL RELEVANCE: With the BAR technique, native humeral containment may be restored, which can potentially delay progressive subacromial and glenoidal abrasive wear and improve overall shoulder function. As such, the proposed BAR technique can be considered as a technically feasible and potentially cost- and timesaving procedure, as no bone anchors are needed, glenoidal or humeral side graft ruptures can be avoided, and postoperative rehabilitation can be started immediately. However, future clinical studies are needed.

Increased Glenohumeral Joint Loads Due to a Supraspinatus Tear Can Be Reversed With Rotator Cuff Repair: A Biomechanical Investigation.

PURPOSE: To evaluate the effect of an isolated full-thickness supraspinatus (SSP) tear on glenohumeral kinematics and contact mechanics, as well as to quantify improvement following rotator cuff repair (RCR). METHODS: Ten fresh-frozen cadaveric shoulders (mean age: 63.1 ± 4.6 years) were tested using a dynamic shoulder simulator. A pressure-mapping sensor was placed between the humeral head and the glenoid. Each specimen underwent the following three conditions: 1) native, 2) isolated full-thickness SSP tear, and 3) RCR. Maximum abduction angle (MAA) and superior humeral head migration (SHM) were measured using 3D motion tracking software. Cumulative deltoid force (CDF) and glenohumeral contact mechanics, including contact area (GCA) and contact pressure (GCP), were assessed at the resting position, as well as at 15°, 30°, 45°, and 60° of glenohumeral abduction. RESULTS: Compared to native, the SSP tear resulted in a significant decrease in MAA (Δ-8.3°; P < .001) along with a SHM of 6.4 ± 3.8 mm, while significantly increasing CDF (Δ20.5 N; P = .008), GCP (Δ63.1 kPa; P < .001), and peak GCP (Δ278.6 kPa; P < .001), as well as decreasing GCA (Δ-45.8 mm2; P < .001) at each degree of abduction. RCR reduced SHM to 1.2 ± 2.5 mm, while restoring native MAA, CDF (Δ1.8 N), GCA (Δ4.5 mm2), GCP (Δ-4.5 kPa) and peak GCP (Δ19.9 kPa) at each degree of abduction (P > .999, respectively). CONCLUSION: In a dynamic biomechanical cadaveric model, increased glenohumeral joint loads due to a full-thickness SSP tear can be reversed with RCR. More specifically, RCR restored native glenohumeral contact area and contact pressure, while preventing superior humeral head migration and decreasing compensatory deltoid forces. CLINICAL RELEVANCE: These time 0 observations indicate that undergoing rotator cuff repair may prevent the development of degenerative changes by significantly reducing glenohumeral joint loads and ensuring sufficiently stable joint kinematics.

Structural and Functional Brain Abnormalities in Human Immunodeficiency Virus Disease Revealed by Multimodal Magnetic Resonance Imaging Fusion: Association With Cognitive Function.

BACKGROUND: Human immunodeficiency virus (HIV)-associated neurocognitive impairment remains a prevalent comorbidity that impacts daily functioning and increases morbidity. While HIV infection is known to cause widespread disruptions in the brain, different magnetic resonance imaging (MRI) modalities have not been effectively integrated. In this study, we applied 3-way supervised fusion to investigate how structural and functional coalterations affect cognitive function. METHODS: Participants (59 people living with HIV and 58 without HIV) completed comprehensive neuropsychological testing and multimodal MRI scanning to acquire high-resolution anatomical, diffusion-weighted, and resting-state functional images. Preprocessed data were reduced using voxel-based morphometry, probabilistic tractography, and regional homogeneity, respectively. We applied multimodal canonical correlation analysis with reference plus joint independent component analysis using global cognitive functioning as the reference. RESULTS: Compared with controls, participants living with HIV had lower global cognitive functioning. One joint component was both group discriminating and correlated with cognitive function. This component included the following covarying regions: fractional anisotropy in the corpus callosum, short and long association fiber tracts, and corticopontine fibers; gray matter volume in the thalamus, prefrontal cortex, precuneus, posterior parietal regions, and occipital lobe; and functional connectivity in frontoparietal and visual processing regions. Component loadings for fractional anisotropy also correlated with immunosuppression. CONCLUSIONS: These results suggest that coalterations in brain structure and function can distinguish people with and without HIV and may drive cognitive impairment. As MRI becomes more commonplace in HIV care, multimodal fusion may provide neural biomarkers to support diagnosis and treatment of cognitive impairment.

Human immunodeficiency virus-related decreases in corpus callosal integrity and corresponding increases in functional connectivity.

People living with human immunodeficiency virus (PLWH) often have neurocognitive impairment. However, findings on HIV-related differences in brain network function underlying these impairments are inconsistent. One principle frequently absent from these reports is that brain function is largely emergent from brain structure. PLWH commonly have degraded white matter; we hypothesized that functional communities connected by degraded white matter tracts would show abnormal functional connectivity. We measured white matter integrity in 69 PLWH and 67 controls using fractional anisotropy (FA) in 24 intracerebral white matter tracts. Then, among tracts with degraded FA, we identified gray matter regions connected to these tracts and measured their functional connectivity during rest. Finally, we identified cognitive impairment related to these structural and functional connectivity systems. We found HIV-related decreased FA in the corpus callosum body (CCb), which coordinates activity between the left and right hemispheres, and corresponding increases in functional connectivity. Finally, we found that individuals with impaired cognitive functioning have lower CCb FA and higher CCb functional connectivity. This result clarifies the functional relevance of the corpus callosum in HIV and provides a framework in which abnormal brain function can be understood in the context of abnormal brain structure, which may both contribute to cognitive impairment.

Brain multimodal co-alterations related to delay discounting: a multimodal MRI fusion analysis in persons with and without cocaine use disorder.

BACKGROUND: Delay discounting has been proposed as a behavioral marker of substance use disorders. Innovative analytic approaches that integrate information from multiple neuroimaging modalities can provide new insights into the complex effects of drug use on the brain. This study implemented a supervised multimodal fusion approach to reveal neural networks associated with delay discounting that distinguish persons with and without cocaine use disorder (CUD). METHODS: Adults with (n = 35) and without (n = 37) CUD completed a magnetic resonance imaging (MRI) scan to acquire high-resolution anatomical, resting-state functional, and diffusion-weighted images. Pre-computed features from each data modality included whole-brain voxel-wise maps for gray matter volume, fractional anisotropy, and regional homogeneity, respectively. With delay discounting as the reference, multimodal canonical component analysis plus joint independent component analysis was used to identify co-alterations in brain structure and function. RESULTS: The sample was 58% male and 78% African-American. As expected, participants with CUD had higher delay discounting compared to those without CUD. One joint component was identified that correlated with delay discounting across all modalities, involving regions in the thalamus, dorsal striatum, frontopolar cortex, occipital lobe, and corpus callosum. The components were negatively correlated with delay discounting, such that weaker loadings were associated with higher discounting. The component loadings were lower in persons with CUD, meaning the component was expressed less strongly. CONCLUSIONS: Our findings reveal structural and functional co-alterations linked to delay discounting, particularly in brain regions involved in reward salience, executive control, and visual attention and connecting white matter tracts. Importantly, these multimodal networks were weaker in persons with CUD, indicating less cognitive control that may contribute to impulsive behaviors.

Machine learning prediction of neurocognitive impairment among people with HIV using clinical and multimodal magnetic resonance imaging data.

Diagnosis of HIV-associated neurocognitive impairment (NCI) continues to be a clinical challenge. The purpose of this study was to develop a prediction model for NCI among people with HIV using clinical- and magnetic resonance imaging (MRI)-derived features. The sample included 101 adults with chronic HIV disease. NCI was determined using a standardized neuropsychological testing battery comprised of seven domains. MRI features included gray matter volume from high-resolution anatomical scans and white matter integrity from diffusion-weighted imaging. Clinical features included demographics, substance use, and routine laboratory tests. Least Absolute Shrinkage and Selection Operator Logistic regression was used to perform variable selection on MRI features. These features were subsequently used to train a support vector machine (SVM) to predict NCI. Three different classification tasks were performed: one used only clinical features; a second used only selected MRI features; a third used both clinical and selected MRI features. Model performance was evaluated by area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity with a tenfold cross-validation. The SVM classifier that combined selected MRI with clinical features outperformed the model using clinical features or MRI features alone (AUC: 0.83 vs. 0.62 vs. 0.79; accuracy: 0.80 vs. 0.65 vs. 0.72; sensitivity: 0.86 vs. 0.85 vs. 0.86; specificity: 0.71 vs. 0.37 vs. 0.52). Our results provide preliminary evidence that combining clinical and MRI features can increase accuracy in predicting NCI and could be developed as a potential tool for NCI diagnosis in HIV clinical practice.

Stable suppression of skeletal muscle fructose-1,6-bisphosphatase during ground squirrel hibernation: Potential implications of reversible acetylation as a regulatory mechanism.

Mammalian hibernation is a period that involves substantial metabolic change in order to promote survival in harsh conditions, with animals typically relying on non-carbohydrate fuel stores during long bouts of torpor. However, the use and maintenance of carbohydrate fuel stores remains important during periods of arousal from torpor as well as when exiting hibernation. Gluconeogenesis plays a key role in maintaining glucose stores; however, little is known about this process within the muscles of hibernating mammals. Here, we used 13-lined ground squirrels (Ictidomys tridecemlineatus) as our model for mammalian hibernation, and showed that skeletal muscle fructose-1,6-bisphosphatase (FBPase; EC 3.1.3.11), the rate-limiting enzyme for the gluconeogenic pathway, was suppressed during torpor as compared to the euthermic control. A physical assessment of partially purified FBPase via exposure to increasing concentrations of the denaturant urea indicated that FBPase from the two conditions were structurally distinct. Western blot analysis suggests that the kinetic and physical differences between euthermic and torpid FBPase may be derived from differential acetylation, whereby increased acetylation of the torpid enzyme makes FBPase more rigid and less active. This study increases our understanding of skeletal muscle carbohydrate metabolism during mammalian hibernation and sets forth a potentially novel mechanism for the regulation of FBPase during environmental stress.

Modified base-binding EVE and DCD domains: striking diversity of genomic contexts in prokaryotes and predicted involvement in a variety of cellular processes.

BACKGROUND: DNA and RNA of all cellular life forms and many viruses contain an expansive repertoire of modified bases. The modified bases play diverse biological roles that include both regulation of transcription and translation, and protection against restriction endonucleases and antibiotics. Modified bases are often recognized by dedicated protein domains. However, the elaborate networks of interactions and processes mediated by modified bases are far from being completely understood. RESULTS: We present a comprehensive census and classification of EVE domains that belong to the PUA/ASCH domain superfamily and bind various modified bases in DNA and RNA. We employ the "guilt by association" approach to make functional inferences from comparative analysis of bacterial and archaeal genomes, based on the distribution and associations of EVE domains in (predicted) operons and functional networks of genes. Prokaryotes encode two classes of EVE domain proteins, slow-evolving and fast-evolving ones. Slow-evolving EVE domains in α-proteobacteria are embedded in conserved operons, potentially involved in coupling between translation and respiration, cytochrome c biogenesis in particular, via binding 5-methylcytosine in tRNAs. In ß- and γ-proteobacteria, the conserved associations implicate the EVE domains in the coordination of cell division, biofilm formation, and global transcriptional regulation by non-coding 6S small RNAs, which are potentially modified and bound by the EVE domains. In eukaryotes, the EVE domain-containing THYN1-like proteins have been reported to inhibit PCD and regulate the cell cycle, potentially, via binding 5-methylcytosine and its derivatives in DNA and/or RNA. We hypothesize that the link between PCD and cytochrome c was inherited from the α-proteobacterial and proto-mitochondrial endosymbiont and, unexpectedly, could involve modified base recognition by EVE domains. Fast-evolving EVE domains are typically embedded in defense contexts, including toxin-antitoxin modules and type IV restriction systems, suggesting roles in the recognition of modified bases in invading DNA molecules and targeting them for restriction. We additionally identified EVE-like prokaryotic Development and Cell Death (DCD) domains that are also implicated in defense functions including PCD. This function was inherited by eukaryotes, but in animals, the DCD proteins apparently were displaced by the extended Tudor family proteins, whose partnership with Piwi-related Argonautes became the centerpiece of the Piwi-interacting RNA (piRNA) system. CONCLUSIONS: Recognition of modified bases in DNA and RNA by EVE-like domains appears to be an important, but until now, under-appreciated, common denominator in a variety of processes including PCD, cell cycle control, antivirus immunity, stress response, and germline development in animals.

A new approach to superior capsular reconstruction with hamstring allograft for irreparable posterosuperior rotator cuff tears: a dynamic biomechanical evaluation.

BACKGROUND: Superior capsular reconstruction (SCR) treatment of massive, symptomatic, irreparable rotator cuff tears (RCTs) has become a more recently used procedure. However, there is a lack of consensus surrounding optimal graft choice for the SCR technique, and current dermal grafts have increased cost and are technically challenging because of a need for multiple implants. The purpose of this study was to biomechanically investigate a biological lower-cost alternative as a support for the superior capsule reconstruction concept: an isolated semitendinosus tendon (STT) allograft and a combination graft with the long head of the biceps tendon (LHBT) in an established massive posterosuperior RCT cadaver model. METHODS: Ten fresh-frozen cadaveric shoulders (53.3 ± 12.4 years: range: 26-65) were tested on an established dynamic shoulder simulator using dynamic muscle loading. Cumulative deltoid forces, maximum abduction angle, and superior humeral head translation were compared across 4 testing conditions: (1) intact state, (2) massively retracted (Patte III), irreparable posterosuperior RCT, (3) SCR repair using an STT allograft, and (4) SCR repair using a combined STT-LHBT repair. RESULTS: Intact shoulders required a mean deltoid force of 154.2 ± 20.41 N to achieve maximum glenohumeral abduction (55.3° ± 2.3°). Compared with native shoulders, the maximum abduction angle decreased following a massively retracted posterosuperior RCT by 52% (28.3° ± 8.4°; P < .001), whereas the cumulative deltoid forces increased by 48% (205.3 ± 40.9 N; P = .001). The STT repair and the STT-LHBT repair improved shoulder function compared with the tear state, with a mean maximum abduction angle of 30.6° ± 9.0° and 31.8° ± 7.7° and a mean deltoid force of 205.3 ± 40.9 N and 201.0 ± 34.0 N, respectively, but this was not statistically significant (P > .05). The STT-LHBT repair significantly improved the range of motion with respect to the tear state (P = .04). CONCLUSIONS: In a dynamic shoulder simulator model, both the STT and the STT-LHBT repair techniques improved glenohumeral joint kinematics in an amount similar to previously reported "traditional" SCR techniques for treatment of an irreparable posterosuperior RCT.

Neural sensitivity to risk in adults with co-occurring HIV infection and cocaine use disorder.

Persons with co-occurring HIV infection and cocaine use disorder tend to engage in riskier decision-making. However, the neural correlates of sensitivity to risk are not well-characterized in this population. The purpose of this study was to examine the neural interaction effects of HIV infection and cocaine use disorder to sensitivity to risk. The sample included 79 adults who differed on HIV status and cocaine use disorder. During functional magnetic resonance imaging (fMRI), participants completed a Wheel of Fortune (WoF) task that assessed neural activation in response to variations of monetary risk (i.e., lower probability of winning a larger reward). Across groups, neural activation to increasing risk was in cortical and subcortical regions similar to previous investigations using the WoF in nondrug-using populations. Our analyses showed that there was a synergistic effect between HIV infection and cocaine use in the left precuneus/posterior cingulate cortex and hippocampus, and right postcentral gyrus, lateral occipital cortex, cerebellum, and posterior parietal cortex. HIV+ individuals with cocaine use disorder displayed neural hyperactivation to increasing risk that was not observed in the other groups. These results support a synergistic effect of co-occurring HIV infection and cocaine dependence in neural processing of risk probability that may reflect compensation. Future studies can further investigate and validate how neural activation to increasing risk is associated with risk-taking behavior.

Synergistic effects of marijuana abuse and HIV infection on neural activation during a cognitive interference task.

Marijuana use, which is disproportionately prevalent among human immunodeficiency virus (HIV)-infected persons, can alter activity in fronto-parietal regions during cognitively demanding tasks. While HIV is also associated with altered neural activation, it is not known how marijuana may further affect brain function in this population. Our study examined the independent and additive effects of HIV infection and regular marijuana use on neural activation during a cognitive interference task. The sample included 93 adults who differed on marijuana (MJ) and HIV statuses (20 MJ+/HIV+, 19 MJ+/HIV-, 29 MJ-/HIV+, 25 MJ-/HIV-). Participants completed a counting Stroop task during a functional magnetic resonance imaging scan. Main and interactive effects on neural activation during interference versus neutral blocks were examined using a mixed-effects analysis. The sample showed the expected Stroop effect for both speed and accuracy. There were main effects of MJ in the right and left inferior parietal lobules, with the left cluster extending into the posterior middle temporal gyrus and a main effect of HIV in the dorsal anterior cingulate cortex. There was an interaction in the left fronto-insular cortex, such that the MJ+/HIV+ group had the largest increase in activation compared with other groups. Among MJ+, signal change in this cluster correlated positively with cumulative years of regular marijuana use. These results suggest that comorbid HIV and marijuana use is associated with complex neural alterations in multiple brain regions during cognitive interference. Follow-up research is needed to determine how marijuana-related characteristics may moderate HIV neurologic disease and impact real-world functioning.

GBStools: A Statistical Method for Estimating Allelic Dropout in Reduced Representation Sequencing Data.

Reduced representation sequencing methods such as genotyping-by-sequencing (GBS) enable low-cost measurement of genetic variation without the need for a reference genome assembly. These methods are widely used in genetic mapping and population genetics studies, especially with non-model organisms. Variant calling error rates, however, are higher in GBS than in standard sequencing, in particular due to restriction site polymorphisms, and few computational tools exist that specifically model and correct these errors. We developed a statistical method to remove errors caused by restriction site polymorphisms, implemented in the software package GBStools. We evaluated it in several simulated data sets, varying in number of samples, mean coverage and population mutation rate, and in two empirical human data sets (N = 8 and N = 63 samples). In our simulations, GBStools improved genotype accuracy more than commonly used filters such as Hardy-Weinberg equilibrium p-values. GBStools is most effective at removing genotype errors in data sets over 100 samples when coverage is 40X or higher, and the improvement is most pronounced in species with high genomic diversity. We also demonstrate the utility of GBS and GBStools for human population genetic inference in Argentine populations and reveal widely varying individual ancestry proportions and an excess of singletons, consistent with recent population growth.

Evaluating the Effects of Platelet-Rich Plasma and Amniotic Viscous Fluid on Inflammatory Markers in a Human Coculture Model for Osteoarthritis.

PURPOSE: To assess the anti-inflammatory effects of platelet-rich plasma (PRP) and amniotic viscous fluid using a human coculture system of cartilage and synovial tissue from osteoarthritic patients. METHODS: A coculture system was created using cartilage and synovium from 3 patients undergoing total knee arthroplasty. To induce inflammation, interleukin-1ß was added to each coculture. Biologic agents tested included 2 PRP concentrations (PRPL and PRPH) and 2 different samples of amniotic viscous fluid (Amnion and Flograft). Amnion was also tested with PRP to check for any additive effects. Quantitative polymerase chain reaction was used to measure gene expression of factors involved in osteoarthritis, including disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), tissue inhibitor of metalloproteinases 1 (TIMP-1), vascular endothelial growth factor (VEGF), aggrecan, type 1 collagen, and nitric oxide, at 0, 24, 48, and 72 hours. A synthetic nonsteroidal medication, Ketorolac, was used for baseline comparison to the biologic agents. RESULTS: When comparing from time 0, both Amnion and Flograft resulted in significant decreases of ADAMTS-5 and TIMP-1 gene expression in cartilage and synovium for up to 72 hours. Both amniotic preparations increased collagen-1 gene expression in cartilage and decreased VEGF expression in synovium. Amnion was not found to have any effect on nitric oxide concentration at any time point (P > .05), as opposed to both PRP concentrations (P < .05). All biologic agents showed differences in gene expression similar to Ketorolac in ADAMTS-5, TIMP-1, and VEGF expression. CONCLUSION: This study found that amniotic fluid had anti-inflammatory effects mostly similar to those of both PRPH and PRPL; however, no significant additive effects in reducing inflammatory gene expression were found when combining biologic agents. CLINICAL RELEVANCE: PRP and amniotic fluid may provide alternative treatment options to delay the progression of the disease without the systemic and intra-articular side effects of corticosteroids.