Categorical Shifts Research Articles

Statistical Analysis for Rating Scale in Clinical Trials.

In psychiatry clinical trials, an instrument or questionnaire with rating scale is often used to access safety and efficacy of a test treatment under investigation. Statistical analysis based on the collected rating scale is then performed a determine whether there is an improvement in endpoint change from baseline mean scale. This approach needs on absolute change, however, may not actually reflect the performance of the test treatment under study because the change, which may be considered of clinically importance, may fall within the same category in terms of disease severity such as mild, moderate, and severe. In this case, it is suggested, in addition to absolute change approach, a categorical shift analysis be considered to determine whether the endpoint change from baseline has resulted in an improvement in categorical shift, in terms of disease severity shift e.g., from severe to mild or moderate. In this article, we explore the relationship between absolute change approach and categorical shift analysis based on rating scales for assessment of test treatment under study.

CML-399 CARDINAL: A Phase 1, Multicenter, Open-Label, Dose-Escalation and Dose-Optimization Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of TERN-701 in Chronic Myeloid Leukemia

ObjectiveDespite improvements in outcomes achieved with BCR::ABL1 active-site-targeting tyrosine kinase inhibitors (TKIs) for treatment of chronic-phase (CP) chronic myeloid leukemia (CML), many patients need to switch treatments due to disease progression, intolerance, or resistance. Because active-site TKIs utilize similar mechanisms of action, novel treatment options are needed for patients. TERN-701 is a highly selective, oral, investigational, allosteric BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket. Preclinical data suggest that TERN-701 is highly potent against native BCR::ABL1 and most common BCR::ABL1 mutations, including T315I, acquired with use of second-generation active-site TKIs. CARDINAL (NCT06163430) is an open-label, global, 2-part, phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of TERN-701 in patients with previously treated CP-CML. MethodsEligible patients are ≥18 years old with an Eastern Cooperative Oncology Group performance status of 0–2, a confirmed diagnosis of BCR::ABL1-positive CP-CML, with or without the T315I mutation, and treatment failure/intolerance of ≥1 prior second-generation TKI (dasatinib, nilotinib, or bosutinib). Patients intolerant of asciminib without overt resistance are eligible. Patients with CML in accelerated or blast phase are ineligible. Patients will receive TERN-701 orally once daily in continuous 28-day cycles. Part 1 (dose escalation) has been initiated and will include ≈24–36 patients assigned to sequential dose-escalation cohorts, starting at 160 mg, and optional backfill cohorts; dose escalation will be guided by a Bayesian optimal interval algorithm. Primary endpoints of Part 1 include incidence of dose-limiting toxicities during the first treatment cycle and other measures of safety and tolerability; secondary endpoints include PK and efficacy measures, such as hematologic and molecular responses. Based upon the results of Part 1, ≥2 TERN-701 dose levels will be selected for further evaluation in Part 2. In Part 2 (dose expansion), ≈40 patients will be randomized to one of the selected dose levels. Part 2 primary endpoints will measure efficacy (hematologic response, molecular response, and best categorical shift in BCR::ABL1 transcript levels from baseline); secondary endpoints include safety, tolerability, and PK. The study is being conducted in the US, Europe, Australia, and South Korea.

The effects of variability on context effects and psychometric function slopes in speaking rate normalizationa).

Acoustic context influences speech perception, but contextual variability restricts this influence. Assgari and Stilp [J. Acoust. Soc. Am. 138, 3023-3032 (2015)] demonstrated that when categorizing vowels, variability in who spoke the preceding context sentence on each trial but not the sentence contents diminished the resulting spectral contrast effects (perceptual shifts in categorization stemming from spectral differences between sounds). Yet, how such contextual variability affects temporal contrast effects (TCEs) (also known as speaking rate normalization; categorization shifts stemming from temporal differences) is unknown. Here, stimuli were the same context sentences and conditions (one talker saying one sentence, one talker saying 200 sentences, 200 talkers saying 200 sentences) used in Assgari and Stilp [J. Acoust. Soc. Am. 138, 3023-3032 (2015)], but set to fast or slow speaking rates to encourage perception of target words as "tier" or "deer," respectively. In Experiment 1, sentence variability and talker variability each diminished TCE magnitudes; talker variability also produced shallower psychometric function slopes. In Experiment 2, when speaking rates were matched across the 200-sentences conditions, neither TCE magnitudes nor slopes differed across conditions. In Experiment 3, matching slow and fast rates across all conditions failed to produce equal TCEs and slopes everywhere. Results suggest a complex interplay between acoustic, talker, and sentence variability in shaping TCEs in speech perception.

Vectors of development of energy cooperation between Russia and foreign countries under economic sanctions

The subject of this study is the modern aspects of Russia’s positioning in the global energy space. They are associated with the shift from the previously established liberal world order and the trend towards new polarisation in the world economic system, as well as with the increasing risks of turbulence in world energy markets. In this regard, it is extremely important to assess the real impact of economic sanctions on the nature of relationships and determine promising vectors for the development of energy cooperation between Russia and foreign countries. The research methodology includes analysis and synthesis methods and a historical approach, which are productively used to assess the tactical and strategic actions of our country in the system of international energy cooperation. The scientific novelty of the study lies in the substantiation of theoretical approaches and assessment of the practical implementation of energy cooperation with foreign countries. Those priority interests are considered that determine the economic sovereignty and identity of Russia in the conditions of a gradual but categorical shift of the world community from the previously established imperatives of liberalism and economic globalisation. The article is of an overview nature and describes the key areas of cooperation in the oil and gas and coal industries. Its main provisions may be used for long-term researches related to modernising the strategy of Russia’s foreign economic relations and increasing the level of its foreign economic security in the context of new global challenges.

Surface-to-structure shifts in rational number categories

Experts organize and generalize knowledge in different ways than novices, and conceptual development is often characterized by a surface-to-structure shift in attention and categorization. We explored a surface-to-structure shift in rational number arithmetic. Children and adults sorted arithmetic equations with fractions and whole numbers in three separate studies. In all studies, children were more likely to sort by number type, conceptualizing fraction problems as distinct from whole number problems. In two studies, adults were more likely to sort equations by operation, suggesting integrated rational number categories. Across studies, some older children and adults sorted into highly differentiated categories. Evidence for a surface-to-structure shift in arithmetic categories suggests changes in knowledge organization in addition to content with increasing expertise.

Material category of visual objects computed from specular image structure.

Recognizing materials and their properties visually is vital for successful interactions with our environment, from avoiding slippery floors to handling fragile objects. Yet there is no simple mapping of retinal image intensities to physical properties. Here, we investigated what image information drives material perception by collecting human psychophysical judgements about complex glossy objects. Variations in specular image structure-produced either by manipulating reflectance properties or visual features directly-caused categorical shifts in material appearance, suggesting that specular reflections provide diagnostic information about a wide range of material classes. Perceived material category appeared to mediate cues for surface gloss, providing evidence against a purely feedforward view of neural processing. Our results suggest that the image structure that triggers our perception of surface gloss plays a direct role in visual categorization, and that the perception and neural processing of stimulus properties should be studied in the context of recognition, not in isolation.

Effect of Lumateperone (ITI-007) on Quality of Life and Functional Disability in the Treatment of Bipolar Depression

AbstractIntroductionIn patients with bipolar disorder, depression symptoms are associated with greater reduction in function and quality of life than hypomania/mania symptoms. Lumateperone (LUMA), is an FDA-approved antipsychotic to treat schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder.In a recent phase 3 clinical trial (Study 404, NCT03249376) in people with bipolar depression, LUMA 42 mg monotherapy significantly improved symptoms of depression compared with placebo (PBO). This analysis of Study 404 investigated the effects of LUMA on functional disability and quality of life as measured using the secondary outcome measure, the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF).MethodsPatients (18–75 years) with bipolar I or bipolar II disorder experiencing a major depressive episode (Montgomery-Åsberg Depression Rating Scale [MADRS] Total score ≥20 and Clinical Global Impression Scale-Bipolar Version-Severity [CGI-BP-S] score ≥4) were randomized to LUMA 42 mg or PBO orally, once daily in the evening for 6 weeks. The primary endpoint was the change from baseline to Day 43 in MADRS Total score, analyzed using a mixed-effects model for repeated measures (MMRM) approach in the intent-to-treat population (ITT). This post hoc analysis evaluated the mean change from baseline to Day 43 in the Q-LES-Q-SF individual item scores using an analysis of covariance with last observation carried forward (ANCOVA-LOCF) in the ITT. Categorical shifts in individual items were also analyzed.ResultsThe ITT comprised 376 patients (LUMA 42 mg, 188; PBO, 188). Patients in the LUMA 42 mg group had significantly greater improvement on MADRS Total score change from baseline to Day 43 compared with PBO (least squares mean difference vs PBO [LSMD], −4.585; 95% CI, −6.344 to −2.826; effect size vs PBO [ES], −0.56; P<.0001). LUMA 42 mg treatment significantly improved Q-LES-Q-SF Total score from baseline to Day 43 compared with PBO (LSMD, 2.9; 95% CI, 1.15 to 4.59; P=.001).The Q-LES-Q-SF items with the lowest mean scores at baseline in both groups were mood, leisure time activities, and sexual drive, interest, and/or performance. By Day 43, LUMA 42 mg treatment significantly improved 8 of the 14 items in the Q-LES-Q-SF (P<0.05). Overall life satisfaction also significantly improved with LUMA treatment (P=.0016). The largest improvements with LUMA 42 mg compared with PBO (ES>0.3,) were seen for the ability to function in daily life, family relationships, household activities, leisure time activities, and mood (all LSMD=0.3; all P<.01).ConclusionIn patients with bipolar depression, treatment with LUMA 42 mg compared with PBO significantly improved patient quality of life and functional impairment. These results support LUMA 42 mg as treatment of MDEs associated with bipolar I or bipolar II disorder in adults.FundingIntra-Cellular Therapies, Inc.

Short-term, not long-term, average spectra of preceding sentences bias consonant categorization.

Speech sound perception is influenced by the spectral properties of surrounding sounds. For example, listeners perceive /g/ (lower F3 onset) more often after sounds with prominent high-F3 frequencies and perceive /d/ (higher F3 onset) more often after sounds with prominent low-F3 frequencies. These biases are known as spectral contrast effects (SCEs). Much of this work examined differences between long-term average spectra (LTAS) of preceding sounds and target speech sounds. Post hoc analyses by Stilp and Assgari [(2021) Atten. Percept. Psychophys. 83(6) 2694-2708] revealed that spectra of the last 475 ms of precursor sentences, not the entire LTAS, best predicted biases in consonant categorization. Here, the influences of proximal (last 500 ms) versus distal (before the last 500 ms) portions of precursor sentences on subsequent consonant categorization were compared. Sentences emphasized different frequency regions in each temporal window (e.g., distal low-F3 emphasis, proximal high-F3 emphasis, and vice versa) naturally or via filtering. In both cases, shifts in consonant categorization were produced in accordance with spectral properties of the proximal window. This was replicated when the distal window did not emphasize either frequency region, but the proximal window did. Results endorse closer consideration of patterns of spectral energy over time in preceding sounds, not just their LTAS.

Categorical Improvement in Depressive Symptom Severity: Results From a Randomized Controlled Trial of Cariprazine for Adjunctive Treatment of MDD

AbstractBackgroundPatients with major depressive disorder (MDD) often do not respond to antidepressant (ADT) monotherapy alone and may require adjunctive treatment to provide adequate symptom relief. Cariprazine (CAR) is a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist approved to treat adults with schizophrenia and manic, mixed, or depressive episodes of bipolar I disorder. Post hoc analysis of data from a randomized controlled trial evaluated clinically relevant improvements in depressive symptom severity with adjunctive cariprazine in patients with MDD and inadequate response to ADT monotherapy.MethodsPost hoc analysis evaluated data from a randomized, double-blind, placebo-controlled MDD trial (NCT03738215) in patients treated with CAR (1.5 mg/d or 3 mg/d) + ADT or placebo + ADT; the primary outcome was change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Post hoc analysis evaluated category shifts from baseline to week 6 in MADRS severity (normal <6, mild 7–19, moderate 20–34, severe ≥35). MADRS severity shifts were reported as the percentage of patients with no change or worsened severity, 1 category improvement, ≥1 category improvement, and ≥2 category improvement. Examples of categorical shifts in depressive symptoms at week 6 include change from severe at baseline to moderate (1 category improvement) and change from severe at baseline to mild (2 category improvement).ResultsOf the 751 patients in the intent-to-treat (ITT) population (CAR: 1.5 mg/d=250, 3.0 mg/d=252; placebo=249), baseline MADRS severity was mild in 1.5%, moderate in 64%, and severe in 35%. Fewer CAR + ADT patients compared to placebo + ADT had no change or worsened MADRS severity at week 6 (CAR: 1.5 mg/d=32%, 3.0 mg/d=33%; placebo=42%). Approximately 68% of patients treated with CAR + ADT demonstrated a MADRS severity improvement of 1 category or greater by week 6 (CAR: 1.5 mg/d=68%, 3.0 mg/d=67%; placebo=58%). A greater percentage of patients in the CAR 1.5 mg/d group also had a 2 or greater category improvement versus CAR 3.0 mg/d or placebo 6 (CAR: 1.5 mg/d=28%, 3.0 mg/d=17%; placebo=19%).ConclusionsIn this post hoc analysis, CAR + ADT was associated with a greater proportion of patients with improvements in depressive symptom severity categories compared with placebo + ADT. These results may suggest that CAR + ADT is associated with clinically meaningful depressive symptom improvement in MDD patients.FundingAbbVie

What allows listeners to rapidly adapt to an unfamiliar talker? Evidence from a novel computationally-guided paradigm

Adaptivity in response to talkers with unexpected pronunciations is now understood to be central to speech perception. What mechanisms afford this ability, however, remains unclear. We present first results from a novel paradigm to investigate incremental changes in perception that occur with exposure to an unfamiliar talker. The paradigm is informed by a computational framework and provides high power to detect previously undocumented constraints on adaptive speech perception. L1-US English listeners (N = 122) were randomly assigned to one of three conditions, each corresponding to a different ‘accent’. Accents were identical except that the VOT distributions for /d/ and /t/ were shifted by either + 0msec, + 10msec or + 40msec relative to typical talkers of US English. We find that (1) listeners' categorization functions shifted proportionally with the input; (2) shifts were rapid, leading to significant changes after 48 observations; but (3) adaptation plateaued after 96 observations at only 40% of the shift in categorization that would have been justified by the statistics of the input. Result (2) and (3) together require revision of standard normalization, distributional learning, and exemplar/episodic accounts. We use computational models to show our results follow if listeners adapt by ‘mixing’ talker representations learned from previously experienced input.

Modelling the intensity difference of Spanish alveolar taps with finite mixture models

The production of stops has been documented to vary considerably in several languages. The difference between the minimum intensity during the consonant and the maximum intensity of the surrounding vowels is an acoustic correlate of taps, whose realizations include plosives, approximants, and deletions. We investigated how lexical, phonetic, and predictability-related factors are associated with changes in the intensity difference of Spanish taps. We conducted an acoustic analysis using a force-aligned corpus of conversational Spanish, with ten percent of tokens hand-corrected to evaluate performance. Model checking with generalized linear models indicated that one distribution could not adequately account for the observed data. As such, we analyzed variation in intensity difference using finite mixture models comprising two skew-normal distributions, which provided a substantially better fit. The results of our modelling approach require a more nuanced interpretation than standard linear models. Our model indicates that Spanish tap production is a complex system where some variables, like frequency, are related to categorical shifts between two potential realizations, and other variables are related to gradient intensity changes within each potential realization of the tap. We also find that articulatory factors like speech rate are responsible for larger intensity changes than lexical properties like frequency.

The efficacy of lumateperone on symptoms of depression in bipolar I and bipolar II disorder: Secondary and post hoc analyses

A recent Phase 3, randomized, double-blind, placebo-controlled study established that lumateperone 42-mg monotherapy significantly improved symptoms of depression in patients with bipolar depression. This manuscript reports prespecified secondary and post hoc efficacy analyses. Patients with bipolar I or bipolar II disorder experiencing a major depressive episode were randomized 1:1 to lumateperone 42 mg or placebo, administered orally once daily for 6 weeks. Prespecified analyses evaluated change from baseline to Day 43 in individual Montgomery-Åsberg Depression Rating Scale (MADRS) item scores in the modified intent-to-treat population (mITT) and bipolar I and bipolar II disorder subgroups. Post hoc analyses investigated the MADRS anhedonia factor and categorical shifts in MADRS item scores. In the mITT, there was significant improvement from baseline to Day 43 with lumateperone 42 mg compared with placebo for all 10 MADRS items; most MADRS items significantly improved in subgroups with bipolar I (9 items) and bipolar II disorder (8 items). A significantly higher proportion of patients receiving lumateperone compared with placebo shifted from baseline MADRS item score ≥4 to ≤2 at end of treatment in Reported Sadness, Reduced Sleep, Concentration Difficulties, Lassitude, Inability to Feel, and Pessimistic Thoughts. Lumateperone significantly improved the MADRS anhedonia factor from baseline to Day 43 compared with placebo in the mITT (effect size, −0.47) and subgroups with bipolar I (−0.36) and bipolar II disorder (−0.90). Lumateperone 42 mg treatment significantly improved depression symptoms compared with placebo, with consistent efficacy across a broad range of symptoms in people with bipolar I and bipolar II disorder.

QUAL O IMPACTO DA PANDEMIA DE COVID-19 NA GESTÃO DE PESSOAS E NO TRABALHO? UMA REVISÃO INTEGRATIVA DA LITERATURA

ABSTRACT Considering the pandemic's wide-ranging impacts, this study examined how the literature addressed its effects on work, human resource management (HRM), and organizations. Sixty-four articles published between January 2020 and March 2022 were systematically selected for this bibliographic review. A thematic content analysis was conducted, categorizing the most frequently discussed topics into three argumentative categories: work and workers, HRM, and organizations. These categories revealed convergences, divergences, and gaps in the literature, leading to the conclusion that values such as autonomy, flexibility, and communication were essential across all three categories. Telework emerged as the predominant work modality, requiring profound adaptations to HRM processes. Notably, geographic, socioeconomic, and demographic factors influenced teleworkers' assessments and productivity, warranting further investigation. The pandemic underscored a paradigm shift in recruitment and professional categorization, highlighting the importance of adaptable proficiencies in remote work, encompassing both technical and interpersonal skills, during and after the crisis. Lastly, organizations responded by strengthening flexible and empathetic organizational cultures capable of withstanding the biopsychosocial pressures experienced by workers during the pandemic.

A Quiet Consensus

The respondents to our essay generally agree with us about the endurance of wealthy democracies, but they pose three chief objections: 1) the results reported may be unreliable because our study failed to distinguish breakdowns of less impact from categorical shifts in which autocracy displaces democracy, 2) claims of recent democratic survival are premature because the erosive effects of democratic backsliding are gathering beneath the surface, and 3) even if democratic breakdown remains unlikely in economically developed states, we underestimated the threat that backsliding itself poses to human rights. These points do not shake the essay's basic conclusions, but they prompted valuable extensions. The challenge ahead is to protect democracies genuinely in peril, while not losing valuable time and resources chasing authoritarian ghosts.

Testing the role of primary musical instrument on context effects in music perception

Musicians display numerous perceptual benefits versus nonmusicians, such as better pitch and melody perception (the “musician advantage”). Recently, Shorey et al. (2021 ASA) investigated whether this musician advantage extended to spectral contrast effects (SCEs; categorization shifts produced by acoustic properties of surrounding sounds) in musical instrument recognition. Musicians and nonmusicians listened to a context sound (filtered string quartet passage highlighting frequencies of the horn or saxophone), then categorized a target sound (tone from a six-step series varying from horn to saxophone). Although musicians displayed superior pitch discrimination, their SCEs did not differ from those of nonmusicians. Importantly, separate research has reported that a musician’s instrument of training heavily influences musical perception, potentially improving frequency discrimination and rhythm perception/production. However, in the Shorey et al. study, musicians were recruited without respect to their primary instrument. This follow-up study uses the same methodology as Shorey et al. but recruits only musicians who play horn or saxophone (the instruments used as target sounds) as their primary instrument. It is predicted that horn and saxophone players will display larger SCEs than nonmusicians due to their intimate familiarity with the instrument timbres. Preliminary data are trending in the predicted direction; full results will be discussed.

Analysis of the impact of climate change on grapevines in Turkey using heat unit accumulation-based indices.

Temperature is the most important factor influencing grapevine phenology and yield. Various indices have been developed that deal with the temperature sums that grapevines are exposed to during growth and maturation. With the help of these indices, predictions are made about whether the grapes will grow in a certain region and the quality of the grapevines. In this study, the future impacts of climate change on viticultural conditions in Turkey were projected by using Huglin index (HI), Winkler index (WI), and cool night index (CI). Under the RCP8.5 scenario, HI, WI, and CI indices for the future period of 2022-2050 were calculated for Turkey at 10km spatial resolution with the RegCM4.4 model and compared with the 1972-2000 reference period. As a result of the study, a substantial increase in CI, HI, and WI and at least one level of categorical change were observed in the climatic conditions of the next 30years in Turkey. These categorical shifts in CI, HI, and WI indicate that there may be changes in the geographical pattern of grapevine species grown in Turkey as well as the aroma and quality.

Context effects in perception of vowels differentiated by F1 are not influenced by variability in talkers' mean F1 or F3.

Spectral properties of earlier sounds (context) influence recognition of later sounds (target). Acoustic variability in context stimuli can disrupt this process. When mean fundamental frequencies (f0's) of preceding context sentences were highly variable across trials, shifts in target vowel categorization [due to spectral contrast effects (SCEs)] were smaller than when sentence mean f0's were less variable; when sentences were rearranged to exhibit high or low variability in mean first formant frequencies (F1) in a given block, SCE magnitudes were equivalent [Assgari, Theodore, and Stilp (2019) J. Acoust. Soc. Am. 145(3), 1443-1454]. However, since sentences were originally chosen based on variability in mean f0, stimuli underrepresented the extent to which mean F1 could vary. Here, target vowels (/ɪ/-/ɛ/) were categorized following context sentences that varied substantially in mean F1 (experiment 1) or mean F3 (experiment 2) with variability in mean f0 held constant. In experiment 1, SCE magnitudes were equivalent whether context sentences had high or low variability in mean F1; the same pattern was observed in experiment 2 for new sentences with high or low variability in mean F3. Variability in some acoustic properties (mean f0) can be more perceptually consequential than others (mean F1, mean F3), but these results may be task-dependent.

Alternative prostate cancer grading systems incorporating percent pattern 4/5 (IQ-Gleason) and cribriform architecture (cGrade) improve prediction of outcome after radical prostatectomy

Percentage Gleason pattern 4, invasive cribriform and/or intraductal carcinoma (IC/IDC) and minor pattern 5 are recognized as independent parameters for prostate cancer outcome, but are not incorporated in current grade groups (GGs). Two proof-of-principle studies have proposed alternative grading schemes based on percentage Gleason pattern 4/5 (integrated quantitative Gleason score; IQ-Gleason) and IC/IDC presence (cribriform grade; cGrade). Our objective was to compare the performance of GG, IQ-Gleason and cGrade for predicting biochemical recurrence and metastasis after radical prostatectomy (RP). RP specimens of 1064 patients were pathologically reviewed and graded according to the three schemes. Discriminative power for prediction of biochemical recurrence-free (BCRFS) and metastasis-free (MFS) survival was compared using Harrell’s c-index. The GG distribution at RP was 207 (19.4%) GG1, 472 (44.4%) GG2, 126 (11.8%) GG3, 140 (13.2%) GG4 and 119 (11.2%) GG5. Grading according to 5-tier IQ-Gleason and cGrade systems led to categorical shifts in 49.8% and 29.7% of cases, respectively. Continuous IQ-Gleason had the best performance for predicting BCRFS (c-index 0.743, 95% confidence interval (CI) 0.715–0.771), followed by cGrade (c-index 0.738, 95%CI 0.712–0.759), 5-tier categorical IQ-Gleason (c-index 0.723, 95%CI 0.695–0.750) and GG (c-index 0.718, 95%CI 0.691–0.744). Continuous IQ-Gleason (c-index 0.834, 95%CI 0.802–0.863) and cGrade (c-index 0.834, 95%CI 0.808–0.866) both had better predictive value for MFS than categorical IQ-Gleason (c-index 0.823, 95%CI 0.788–0.857) and GG (c-index 0.806, 95%CI 0.777–0.839). In conclusion, the performance of prostate cancer grading can be improved by alternative grading schemes incorporating percent Gleason pattern 4/5 and IC/IDC.

69. Incidence of metabolic complications among treatment-naïve adults living with HIV-1 randomized to B/F/TAF, DTG/ABC/3TC or DTG+F/TAF after 144 Weeks

BackgroundMetabolic comorbidities including diabetes (DM) and dyslipidemia pose challenges to the long-term care of people with HIV (PWH). Incidence of cardiovascular disease and DM are reported at higher rates in PWH than the general population. Obesity is broadly prevalent in both the general population and PWH, and higher body mass index (BMI) can contribute to metabolic complications. Here we present longer-term follow up on incidence of DM, hypertension (HTN), BMI categorical shifts, and lipid changes over 144 weeks of blinded treatment from two trials of PWH initiating antiretroviral therapy.MethodsWe assessed incidence of metabolic complications in adult PWH in Study 1489: bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) vs dolutegravir/abacavir/ lamivudine (DTG/ABC/3TC) and Study 1490: B/F/TAF vs DTG+F/TAF. Treatment-emergent (TE) metabolic comorbidities were defined by standard MedDRA search lists. CDC-defined BMI categories were compared from baseline (BL) to Week 144. Analyses by sex at birth and race were performed, as well as for lipid changes.ResultsAmong 1,274 total participants, median (range) age was 33 years (18-77), 90% men, 33% black. In study 1489, BL prevalence of DM and HTN was 4.5 and 12.1% with TE DM and HTN in B/F/TAF being 0.7% and 10%, and for DTG/ABC/3TC 1.3% and 6.9%, respectively. In study 1490, BL prevalence of DM and HTN was 6.8 and 18.8% with TE DM and HTN in B/F/TAF being 2.1 and 5.8%, and for DTG+F/TAF 2.3 and 6.5%, respectively. BMI shift from Normal to Obese: B/F/TAF 0%, DTG/ABC/3TC 3.2%, p=0.12 (1489) (Table 1); B/F/TAF 2.5%, DTG+F/TAF 2.9% p=1.00 (1490) (Table 2). Subgroup analyses by gender/race showed similar findings for TE DM, HTN, and BMI changes. Median changes from BL fasted lipids were small (Table 1).Table 1§. Studies 1489 and 1490: Metabolic Outcomes from Baseline to Week 144 Table 2±. Shift Table of BMI Category at Week 144 by Baseline BMI Category – Overall ConclusionThrough over 144 weeks of follow up, PWH randomized to initiate B/F/TAF, DTG/ABC/3TC or DTG+F/TAF had low rates of incident DM or HTN-related AEs, with no statistically significant differences by treatment group. BMI changes/categorical shifts from BL did not significantly differ by regimen, and no clinically significant change or difference by regimen in lipids were observed. While data are limited by three years of follow up, they are strengthened by randomized study design of three widely used initial ART regimens.Disclosures Eric Daar, MD, Bristol-Myers Squibb (Consultant)Gilead Sciences Inc. (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support)Janssen (Consultant, Advisor or Review Panel member, Research Grant or Support)Merck (Consultant, Advisor or Review Panel member, Research Grant or Support)Teva (Consultant, Advisor or Review Panel member)ViiV Healthcare (Consultant, Advisor or Review Panel member, Research Grant or Support) Chloe Orkin, MD, Gilead Sciences Inc. (Grant/Research Support, Scientific Research Study Investigator, Other Financial or Material Support)Janssen (Research Grant or Support, Other Financial or Material Support)Merck (Research Grant or Support, Other Financial or Material Support)ViiV Healthcare (Research Grant or Support, Other Financial or Material Support) Paul Sax, MD, Gilead Sciences (Consultant, Grant/Research Support)Janssen (Consultant)Merck (Consultant, Research Grant or Support)ViiV (Consultant, Research Grant or Support) Jeffrey L. Stephens, MD, Gilead Sciences Inc. (Scientific Research Study Investigator, Research Grant or Support) Ellen Koenig, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Amanda Clarke, MD, Gilead Sciences Inc. (Consultant, Scientific Research Study Investigator, Other Financial or Material Support, Conference attendance sponsorship)ViiV Healthcare (Consultant, Other Financial or Material Support, Conference travel sponsorship) Axel Baumgarten, MD, AbbVie (Advisor or Review Panel member, Speaker’s Bureau)Bristol-Myers Squibb (Advisor or Review Panel member, Speaker's Bureau)Gilead Sciences Inc. (Scientific Research Study Investigator, Advisor or Review Panel member, Speaker's Bureau)Janssen (Speaker’s Bureau)Merck (Advisor or Review Panel member) Cynthia Brinson, MD, Abbvie (Scientific Research Study Investigator)BI (Scientific Research Study Investigator)Gilead Sciences Inc. (Scientific Research Study Investigator, Advisor or Review Panel member, Speaker's Bureau, Personal fees)GSK (Scientific Research Study Investigator)Novo Nordisk (Scientific Research Study Investigator)ViiV Healthcare (Scientific Research Study Investigator, Advisor or Review Panel member, Speaker's Bureau) Moti Ramgopal, MD FIDSA, Abbvie (Scientific Research Study Investigator, Speaker's Bureau)Gilead (Consultant, Scientific Research Study Investigator, Speaker's Bureau)Janssen (Consultant, Scientific Research Study Investigator, Research Grant or Support, Speaker's Bureau)Merck (Consultant, Scientific Research Study Investigator)ViiV (Consultant, Scientific Research Study Investigator, Speaker's Bureau) Hailin Huang, PhD, Gilead Sciences Inc. (Employee, Shareholder) Terry Farrow, MD, Gilead Sciences Inc. (Employee, Shareholder) Jared Baeten, MD, PHD, Gilead Sciences Inc. (Employee, Shareholder) Jason Hindman, PharmD, Gilead Sciences Inc. (Employee, Shareholder) Hal Martin, MD, MPH, Gilead Sciences Inc. (Employee, Shareholder) Kimberly Workowski, MD, Nothing to disclose

Effect of Citrate-Acidified Dialysate on Intact Parathyroid Hormone in Prevalent Hemodialysis Patients: A Matched Retrospective Cohort Study.

BackgroundIt has been proposed that substituting citrate-acidified dialysate (CAD) solutions for acetate-acidified dialysate (AAD) could improve hemodynamics and dialysis tolerance and reduce the requirement for systemic anticoagulation. Citrate chelates ionized calcium, but long-term effects of CAD use during maintenance hemodialysis have not been well studied. While many studies of the effects of CAD on serum calcium and intact parathyroid hormone (iPTH) have been short-term or have been limited by sample size, we aimed to determine if there are any long-term (i.e., 6-month) changes from pre-dialysis iPTH levels when patients are switched from AAD to CAD.MethodsThis retrospective cohort study compared various clinical parameters, including pre-dialysis iPTH and serum calcium as well as single pool Kt/V, from eligible patients who received in-center hemodialysis thrice-weekly in geographically matched CAD (n=3) or AAD clinics (n=12). CAD clinics were defined as clinics converting from AAD to CAD if >85% of the patients were prescribed CAD after implementation of CAD within the clinic.ResultsPre-dialysis iPTH was not significantly different from baseline to 6-month follow-up within either CAD or AAD clinics. Moreover, the mean change from baseline to month 6 in iPTH between patients (n=142) in CAD clinics (−17 pg/mL) and patients (n=671) in AAD clinics (13 pg/mL) was similar (p = 0.24). Likewise, the differences in the mean change in serum calcium concentrations and dialysis adequacy (single pool Kt/V) were not significant between CAD and AAD clinics. For subgroups of patients who were never prescribed cinacalcet or calcium-based phosphate binders, there were no significantly different categorical shifts in iPTH between CAD and AAD clinics.ConclusionSimilar trends in single pool Kt/V, iPTH, and serum calcium levels were observed in clinics that switched from AAD to CAD versus the geographically matched AAD clinics. These results support CAD as a potential alternative to AAD in hemodialysis.