Two-Drug Regimens Dolutegravir/Lamivudine and Dolutegravir/Rilpivirine Are Effective with Few Discontinuations in US Real-World Settings: Results from the TANDEM Study.

INTRODUCTION: Dolutegravir/lamivudine (DTG/3TC) and dolutegravir/rilpivirine (DTG/RPV) are fixed-dose, complete, single-tablet, two-drug regimens (2DRs) indicated for HIV-1. DTG/3TC is approved for antiretroviral therapy (ART)-naive people with HIV-1 and virologically suppressed individuals to replace current ART; DTG/RPV is indicated for virologically suppressed individuals as a switch option. Virologic efficacy and effectiveness of these DTG-based 2DRs have been demonstrated in phase 3 clinical trials and real-world cohorts, primarily from Europe. This study characterized real-world use of DTG-based 2DRs for HIV-1 treatment in the USA. METHODS: TANDEM was a retrospective medical chart review across 24 US sites. Individuals aged ≥ 18 years who initiated DTG/3TC or DTG/RPV before September 30, 2020, with ≥ 6 months of follow-up were included. One cohort included ART-naive people who initiated DTG/3TC (n = 126), and two other cohorts included virologically suppressed (HIV-1 RNA < 50 copies/mL) people on stable ART regimens for ≥ 3 months before switch to either DTG/3TC (n = 192) or DTG/RPV (n = 151). Clinical characteristics, treatment history, and outcomes are described. RESULTS: Virologically suppressed individuals were older than those who were ART-naive, and the ART-naive cohort had higher proportions of individuals assigned male at birth and of Hispanic ethnicity. The most common healthcare provider-reported reason for choosing a DTG-based 2DR was avoidance of long-term toxicities (25-33% across cohorts), followed by simplification/streamlining of treatment. Among ART-naive people on DTG/3TC, 94% achieved virologic suppression after initiation, and 83% maintained suppression at last follow-up; discontinuation rate was < 1%. Among cohorts who switched to DTG-based 2DRs, 96% maintained virologic suppression on DTG/3TC and 93% on DTG/RPV; 2% on DTG/3TC and 3% on DTG/RPV discontinued. CONCLUSION: Motivation for selecting DTG-based 2DRs was primarily driven by a desire to avoid or manage toxicities and simplify treatment. Results demonstrate that DTG/3TC and DTG/RPV are effective in real-world settings, with few discontinuations, reflecting data from clinical trials.

Immersive Technology for Cognitive-Motor Training in Parkinson's Disease.

Background: Parkinson's disease (PD) is a neurodegenerative disease in which the progressive loss of dopaminergic neurons (DA) leads to initially sporadic and eventually widespread damage of the nervous system resulting in significant musculoskeletal and cognitive deterioration. Loss of motor function alongside increasing cognitive impairment is part of the natural disease progression. Gait is often considered an automatic activity; however, walking is the result of a delicate balance of multiple systems which maintain the body's center of mass over an ever-changing base of support. It is a complex motor behavior that requires components of attention and memory to prevent falls and injury. In addition, evidence points to the critical role of salient visual information to gait adaptability. There is a growing understanding that treatment for PD needs to address movement as it occurs naturally and walking needs to be practiced in more complex environments than traditional therapy has provided. Methods: In this single-blinded randomized-controlled pilot study, an immersive treadmill training was piloted to determine feasibility and preliminary efficacy on gait and cognition in people with PD. Eighteen participants with Hoehn and Yahr stages I-III PD were randomized to either an intervention or a waitlist control group. Following baseline data collection, the intervention group trained for 30 min, three times/week for 4 weeks on a split belt treadmill combined with a first-person immersive video game targeting visuospatial skills and working memory. Assessment was repeated after 4 weeks of training for the experimental group and 1-month after baseline for the control group. Primary motor outcomes were captured with the APDM Opal sensors during 6 MWT, TUG, and TUG Cognitive. Secondary outcomes of cognition were measured with the Montreal Cognitive Assessment (MoCA), Verbal Fluency (Fruit, Vegetable, and Animal) and the Symbol Digit Modality Test (SDMT). Within subject differences were calculated using the Wilcoxon Signed Ranked Test and between subject comparisons were analyzed using the Mann Whitney U-test. Results: This novel treadmill training program was well-tolerated with all participants in the intervention group completing 4 weeks of training three times a week without any adverse effects. After immersive cognitive motor training, the experimental group made clinically relevant improvements in gait speed and walking distance during the 6 MWT while members of the control group showed no change or decreased gait speed and walking distance over the 1-month trial. In addition, the experimental group demonstrated significant improvement for the TUG Cognitive (p = 0.05) and those changes were greater than the control group (between group p = 0.040). The experimental group also improved scores on MoCA (p = 0.007) and SDMT (p = 0.01) cognitive outcome measures while the control group did not. Conclusion: The use of immersive gaming technology to engage specific areas of cognition related to gait is feasible in PD. The treadmill training program paired with a customized interactive video game improved walking velocity in addition to non-significant but consistent improvements in other gait measures and cognitive performance in participants with early to mid-stage PD.

Influence of aging and gadolinium exposure on T1, T2, and T2*-relaxation in healthy women with an increased risk of breast cancer with and without prior exposure to gadoterate meglumine at 3.0-T brain MR imaging.

OBJECTIVES: We examined the effects of aging and of gadolinium-based contrast agent (GBCA) exposure on MRI measurements in brain nuclei of healthy women. METHODS: This prospective, IRB-approved single-center case-control study enrolled 100 healthy participants of our high-risk screening center for hereditary breast cancer, who had received at least six doses of macrocyclic GBCA (exposed group) or were newly entering the program (GBCA-naïve group). The cutoff "at least six doses" was chosen to be able to include a sufficient number of highly exposed participants. All participants underwent unenhanced 3.0-T brain MRI including quantitative T1, T2, and R2* mapping and T1- and T2-weighted imaging. The relaxation times/signal intensities were derived from region of interest measurements in the brain nuclei performed by a radiologist and a neuroradiologist, both board certified. Statistical analysis was based on descriptive evaluations and uni-/multivariable analyses. RESULTS: The participants (exposed group: 49, control group: 51) were aged 42 ± 9 years. In a multivariable model, age had a clear impact on R2* (p < 0.001-0.012), T2 (p = 0.003-0.048), and T1 relaxation times/signal intensities (p < 0.004-0.046) for the majority of deep brain nuclei, mostly affecting the substantia nigra, globus pallidus (GP), nucleus ruber, thalamus, and dentate nucleus (DN). The effect of prior GBCA administration on T1 relaxation times was statistically significant for the DN, GP, and pons (p = 0.019-0.037). CONCLUSIONS: In a homogeneous group of young to middle-aged healthy females aging had an effect on T2 and R2* relaxation times and former GBCA applications influenced the measured T1 relaxation times. KEY POINTS: The quantitative T1, T2, and R2* relaxation times measured in women at high risk of developing breast cancer showed characteristic bandwidth for all brain nuclei examined at 3.0-T MRI. The effect of participant age had a comparatively strong impact on R2*, T2, and T1 relaxation times for the majority of brain nuclei examined. The effect of prior GBCA administrations on T1 relaxation times rates was comparatively less pronounced, yielding statistically significant results for the dentate nucleus, globus pallidus, and pons. Healthy women with and without previous GBCA-enhanced breast MRI exhibited age-related T2* and T2 relaxation alterations at 3.0 T-brain MRI. T1 relaxation alterations due to prior GBCA administration were comparatively less pronounced.

Possibility to discriminate benign from malignant breast lesions detected on dual-layer spectral CT-evaluation.

OBJECTIVES: Intramammary mass lesions are reportedly present in up to 5.8% of all contrast enhanced CT-examinations of the female chest. We aimed to assess whether their biological relevance can be estimated using spectral CT-datasets. METHODS: In this bicentric retrospective study patients with breast masses visualized on spectral CT-examinations from 07/2017 to 06/2019 were included. Lesions were characterized as malignant or benign based on histology and/or a stable follow-up of >2 years. Conventional CT-images, iodine density-maps, virtual monoenergetic-images (40 keV, 100 keV) and Zeffective-maps were evaluated by two independent readers. Statistical analysis derived from the Regions of interest (ROIs) was done by calculating the Areas under the Receiver operating characteristic (ROC) curve (AUC) and Youden-indices. RESULTS: 106 breast masses (malignant/benign: 81/25, 76.4%/23.6%) were included. The mean AUCs of the variables "iodine content" (reader 1/2:0.97;0.98), "monoenergetic curve-slope" (0.97;0.96) and "Zeffective" (0.98;0.98) measured in the target lesions (TL) showed superior results compared to those derived from the variable "density" (0.92;0.93) (p < 0.001). The ratios "TL to aorta" calculated for the variables "iodine content", "monoenergetic curve-slope" and "Zeffective" showed superior results compared to normal breast tissue and muscle (p < 0.001). The optimal cutpoint for the "iodine content" in the TL was 0.7-0.9 mg/ml (sensitivity 96.6%, specificity 91.7%). The best diagnostic results were achieved by normalizing the iodine content in the TL to that in the aorta (optimal cutpoint 0.1, sensitivity 95.5%, 98.9%, specificity 91.7%). CONCLUSIONS: Our preliminary results suggest that spectral CT-datasets might allow to estimate the biological dignity of breast masses detected on clinically indicated chest-examinations.

Single cell derived mRNA signals across human kidney tumors.

Tumor cells may share some patterns of gene expression with their cell of origin, providing clues into the differentiation state and origin of cancer. Here, we study the differentiation state and cellular origin of 1300 childhood and adult kidney tumors. Using single cell mRNA reference maps of normal tissues, we quantify reference "cellular signals" in each tumor. Quantifying global differentiation, we find that childhood tumors exhibit fetal cellular signals, replacing the presumption of "fetalness" with a quantitative measure of immaturity. By contrast, in adult cancers our assessment refutes the suggestion of dedifferentiation towards a fetal state in most cases. We find an intimate connection between developmental mesenchymal populations and childhood renal tumors. We demonstrate the diagnostic potential of our approach with a case study of a cryptic renal tumor. Our findings provide a cellular definition of human renal tumors through an approach that is broadly applicable to human cancer.

Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell.

Neuroblastoma is a childhood cancer that resembles developmental stages of the neural crest. It is not established what developmental processes neuroblastoma cancer cells represent. Here, we sought to reveal the phenotype of neuroblastoma cancer cells by comparing cancer (n = 19,723) with normal fetal adrenal single-cell transcriptomes (n = 57,972). Our principal finding was that the neuroblastoma cancer cell resembled fetal sympathoblasts, but no other fetal adrenal cell type. The sympathoblastic state was a universal feature of neuroblastoma cells, transcending cell cluster diversity, individual patients, and clinical phenotypes. We substantiated our findings in 650 neuroblastoma bulk transcriptomes and by integrating canonical features of the neuroblastoma genome with transcriptional signals. Overall, our observations indicate that a pan-neuroblastoma cancer cell state exists, which may be attractive for novel immunotherapeutic and targeted avenues.

A Multicentric Comparison of Apparent Diffusion Coefficient Mapping and the Kaiser Score in the Assessment of Breast Lesions.

MATERIALS AND METHODS: In this multicentric study, individual patient data from 3 different centers were analyzed. Consecutive patients receiving standardized multiparametric breast magnetic resonance imaging for standard nonscreening indications were included. At each center, 2 experienced radiologists with more than 5 years of experience retrospectively interpreted the examinations in consensus and applied the KS to every histologically verified lesion. The corresponding mean ADC of each lesion was measured using a Wielema type 4 region of interest. According to established methods, the KS and ADC were combined, yielding the KS+ score. Diagnostic accuracy was evaluated by the area under the receiver operating characteristics curve (AUROC) and compared between the KS, ADC, and KS+ (DeLong test). Likewise, the potential to help avoid unnecessary biopsies was compared between the KS, ADC, and KS+ based on established high sensitivity thresholds (McNemar test). RESULTS: A total of 450 lesions in 414 patients (mean age, 51.5 years; interquartile range, 42-60.8 years) were included, with 219 lesions being malignant (48.7%; 95% confidence interval [CI], 44%-53.4%). The performance of the KS (AUROC, 0.915; CI, 0.886-0.939) was significantly better than that of the ADC (AUROC, 0.848; CI, 0.811-0.880; P < 0.001). The largest difference between these parameters was observed when assessing subcentimeter lesions (AUROC, 0.909 for KS; CI, 0.849-0.950 vs 0.811 for ADC; CI, 0.737-0.871; P = 0.02).The use of the KS+ (AUROC, 0.918; CI, 0.889-0.942) improved the performance slightly, but without any significant difference relative to a single KS or ADC reading (P = 0.64).When applying high sensitivity thresholds for avoiding unnecessary biopsies, the KS and ADC achieved equal sensitivity (97.7% for both; cutoff values, >4 for KS and ≤1.4 × 10-3 mm2/s for ADC). However, the rate of potentially avoidable biopsies was higher when using the KS (specificity: 65.4% for KS vs 32.9% for ADC; P < 0.0001). The KS was superior to the KS+ in avoiding unnecessary biopsies. CONCLUSIONS: Both the KS and ADC may be used to distinguish benign from malignant breast lesions. However, KS proved superior in this task including, most of all, when assessing small lesions less than 1 cm. Using the KS may avoid twice as many unnecessary biopsies, and the combination of both the KS and ADS does not improve diagnostic performance.

Surface Perturbation Training to Prevent Falls in Older Adults: A Highly Pragmatic, Randomized Controlled Trial.

BACKGROUND: Falls are the leading cause of injuries among older adults, and trips and slips are major contributors to falls. OBJECTIVE: The authors sought to compare the effectiveness of adding a component of surface perturbation training to usual gait/balance training for reducing falls and fall-related injury in high-risk older adults referred to physical therapy. DESIGN: This was a multi-center, pragmatic, randomized, comparative effectiveness trial. SETTING: Treatment took place within 8 outpatient physical therapy clinics. PATIENTS: This study included 506 patients 65+ years of age at high fall risk referred for gait/balance training. INTERVENTION: This trial evaluated surface perturbation treadmill training integrated into usual multimodal exercise-based balance training at the therapist's discretion versus usual multimodal exercise-based balance training alone. MEASUREMENTS: Falls and injurious falls were assessed with a prospective daily fall diary, which was reviewed via telephone interview every 3 months for 1 year.A total of 211/253 (83%) patients randomized to perturbation training and 210/253 (83%) randomized to usual treatment provided data at 3-month follow-up. At 3 months, the perturbation training group had a significantly reduced chance of fall-related injury (5.7% versus 13.3%; relative risk 0.43) but no significant reduction in the risk of any fall (28% versus 37%, relative risk 0.78) compared with usual treatment. Time to first injurious fall showed reduced hazard in the first 3 months but no significant reduction when viewed over the entire first year. LIMITATIONS: The limitations of this trial included lack of blinding and variable application of interventions across patients based on pragmatic study design. CONCLUSION: The addition of some surface perturbation training to usual physical therapy significantly reduced injurious falls up to 3 months posttreatment. Further study is warranted to determine the optimal frequency, dose, progression, and duration of surface perturbation aimed at training postural responses for this population.

Residual glandular tissue (RGT) in BRCA1/2 germline mutation carriers with unilateral and bilateral prophylactic mastectomies.

BACKGROUND: Prophylactic mastectomy (PME) is increasingly performed in women carrying deleterious BRCA1 and BRCA2 germline mutations. The oncologic risk resulting from residual fibroglandular tissue (RGT) is unknown. METHODS: All women who had received a mastectomy and at least one postoperative breast MRI, between 2006 and 2016 were extracted from the register of the Center for Hereditary Breast and Ovarian Cancer Cologne (CHBOC). The index MRI was evaluated in terms of basic clinical data and the morphological criteria of RGT. The RGT volume was measured in diameter and was semi-automatically evaluated using software. RESULTS: We identified 169 women carrying BRCA1/2 mutations who underwent prophylactic and curative mastectomy: a total of 338 breasts. RGT was found in 128 of the 338 breasts (37.9%). 68 of the 128 breasts (53.1%) were related to bilateral PME, 37 (28.9%) to unilateral PME and 23 (18.0%) to curative mastectomy. RGT was predominantly unifocal and located in the retroareolar breast region. RGT was observed more often after bilateral PME (p < 0.0001). In this subgroup, the nipple-sparing mastectomy dominated (108 of 136, 79.4%), in contrast to 23 standard mastectomies (23 of 94, 24.5%) in the subgroup of curative mastectomy (23%). There was a trend towards higher amounts of RGT in surgical units with fewer mastectomies performed. During follow-up, two breast cancers were detected after bilateral and unilateral PME, respectively. CONCLUSIONS: Our results suggest that the indication for surgery and in particular the selected surgical procedure affect the surgical outcome with respect to RGT. Oncological safety should not be neglected, especially in the high-risk group of BRCA1/2 mutation carriers.

Brain abnormalities in patients with hyperimmunoglobulin E syndrome.

OBJECTIVES: Hyperimmunoglobulin E syndrome is a multisystem disorder with abnormalities of the immunologic, connective tissue, and skeletal tissue systems. Central nervous system abnormalities have not been considered a feature of hyperimmunoglobulin E syndrome. We aimed to determine whether central nervous system abnormalities detected on brain MRI exist in hyperimmunoglobulin E syndrome and to characterize any identified abnormalities. PATIENTS AND METHODS: Fifty patients aged from 3 to 52 years (mean: 24 years) with established diagnoses of hyperimmunoglobulin E syndrome had MRI of the brain as part of an hyperimmunoglobulin E syndrome natural history protocol. Abnormalities were described, measured, counted, and mapped. Patient charts were reviewed for neurologic findings and blood pressure measurements. RESULTS: Focal brain lesions exhibiting high signal intensities on flow-attenuated inversion recovery and on T2-weighted techniques were found in 35 of the 50 patients. The focal hyperintensities were predominantly in the white matter of the cerebral hemispheres, and the number ranged from 2 to >50. The hyperintensities occurred more frequently in adults than in children, and no association with elevated blood pressure was found. Five patients had lacunar infarctions. Chiari type 1 malformations were found in 9 of 50 patients. Two patients had infectious complications presenting on MRI as cerebritis in 1 patient and as a hemorrhagic infarct in the other; both were found on autopsy to be fungal. Neurologic abnormalities were present in 1 patient with a lacunar infarction, the 2 patients with infectious complications, and in 1 patient with a subarachnoid hemorrhage secondary to a berry aneurysm. CONCLUSIONS: Central nervous system abnormalities are common in hyperimmunoglobulin E syndrome. Focal T2 hyperintensities, not appreciated previously, represent a prominent feature of this rare disease that may assist in diagnosis. The etiology and clinical implications of these abnormalities remain to be investigated.

Level of response to alcohol and brain response during visual working memory.

OBJECTIVE: This study examined neural correlates of the low level of response to alcohol using functional magnetic resonance imaging (FMRI) during a challenging visual working memory task. METHOD: Participants were healthy adolescents (N = 35) with a range of drinking patterns recruited from local high schools. After a minimum 5 days of abstinence from alcohol and other drugs, FMRI, neuropsychological testing and the Self-Rating of the Effects of Alcohol were administered. RESULTS: Self-report of initial level of response to alcohol was significantly predicted by FMRI blood oxygen level dependent (BOLD) response to the visual working memory task in the right prefrontal and bilateral anterior cingulate region (12% of unique variance, p < .05) and right cerebellum and parahippocampal gyrus (17% of unique variance, p < .01), above and beyond effects accounted for by drinks consumed per month, age, gender and ethnicity. CONCLUSIONS: Young people who report having needed more alcohol to achieve specific effects during early drinking experiences show higher levels of brain response during visual working memory, perhaps suggesting less capacity to adjust cognitive processing to contextual demands.