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The most influential account of phasic dopamine holds that it reports reward prediction errors (RPEs). The RPE-based interpretation of dopamine signaling is, in its original form, probably too simple and fails to explain all the properties of phasic dopamine observed in behaving animals. This Perspective helps to resolve some of the conflicting interpretations of dopamine that currently exist in the literature. We focus on the following three empirical challenges to the RPE theory of dopamine: why does dopamine (1) ramp up as animals approach rewards, (2) respond to sensory and motor features and (3) influence action selection? We argue that the prediction error concept, once it has been suitably modified and generalized based on an analysis of each computational problem, answers each challenge. Nonetheless, there are a number of additional empirical findings that appear to demand fundamentally different theoretical explanations beyond encoding RPE. Therefore, looking forward, we discuss the prospects for a unifying theory that respects the diversity of dopamine signaling and function as well as the complex circuitry that both underlies and responds to dopaminergic transmission.

Despite decades of crime decline, police surveillance has continued to expand through a range of tactics oriented towards policing social disadvantage. Yet, despite attention to the linkages between residential inequality and policing, few studies have accounted for two intertwined structural developments since the turn of the 21stcentury: (1) the shift away from spatially concentrated patterns of racial segregation within urban centers towards sprawling patterns of economic segregation and (2) the turn from reactive policing towards proactive surveillance. Using the case of big data policing, we create a new measure of big data surveillance in metropolitan areas to examine how changes in segregation have affected the expansion of proactive police surveillance. In contrast to theoretical accounts emphasizing the role of police surveillance in governing economic inequality and perpetuating racial segregation, we do not find evidence that racial segregation or income inequality increase big data surveillance. Instead, much of the recent rise in big data policing is explained by increases in sprawling patterns of income segregation. These results provide new insight into the linkages between policing and residential inequality and reveal how changes in metropolitan segregation influence criminal justice surveillance in the era of big data.10.1093/socpro/spac044_video1Video Abstractspac044_video16328836652112

AbstractTransgender youth (TY) often face challenges from home, school, and the child welfare system and even through legislation. Messages both explicit and implicit may lead them to suffering, isolation, and even despair. Aspects of existential counseling and positive psychology may assist in reversing the impact of these while promoting meaning-making and flourishing lives. Features of these two approaches will be integrated and demonstrated with a hypothetical TY to show their potential utility.

Keypoint tracking algorithms can flexibly quantify animal movement from videos obtained in a wide variety of settings. However, it remains unclear how to parse continuous keypoint data into discrete actions. This challenge is particularly acute because keypoint data are susceptible to high-frequency jitter that clustering algorithms can mistake for transitions between actions. Here we present keypoint-MoSeq, a machine learning-based platform for identifying behavioral modules (‘syllables’) from keypoint data without human supervision. Keypoint-MoSeq uses a generative model to distinguish keypoint noise from behavior, enabling it to identify syllables whose boundaries correspond to natural sub-second discontinuities in pose dynamics. Keypoint-MoSeq outperforms commonly used alternative clustering methods at identifying these transitions, at capturing correlations between neural activity and behavior and at classifying either solitary or social behaviors in accordance with human annotations. Keypoint-MoSeq also works in multiple species and generalizes beyond the syllable timescale, identifying fast sniff-aligned movements in mice and a spectrum of oscillatory behaviors in fruit flies. Keypoint-MoSeq, therefore, renders accessible the modular structure of behavior through standard video recordings.

When attempting to deliver specialized rehabilitation therapy interventions, physical therapists (PTs) and occupational therapists (OTs) must account for dynamic and logistical patient factors such as daily wound care, pain, difficulty progressing range of motion with dressings donned, and ongoing surgical interventions. Additionally, they must attain institution-specific productivity standards. Given burn patients often require considerable multidisciplinary interventions, efficiently planning and delivering rehabilitation therapy interventions within productivity expectations may prove difficult. The purpose of this study was to assess the feasibility of integrating rehabilitation therapists, PTs and OTs, into daily burn wound care by investigating therapist productivity and multidisciplinary perceptions of this practice change. The quality improvement project involved 6 rehabilitation therapists (3 PTs and 3 OTs) practicing exclusively in the burn unit within an American Burn Association (ABA)-verified burn center at an urban, tertiary care academic medical center. One rehabilitation therapist was responsible for providing interventions within the burn wound care team 5 days a week. General duties included wound assessment, functional wound dressings, and skilled therapeutic interventions such as manual therapy, therapeutic exercise, and compression interventions. The primary outcome was changes in group productivity and individual therapist productivity, as measured by total billed Current Procedural Terminology (CPT) codes per hour worked, which were tracked 22 weeks preimplementation and 28 weeks postimplementation. Program feasibility and general perceptions were assessed by a qualitative questionnaire. For both the entire group of therapists and each individual rehabilitation therapist, billed CPT codes per hour increased postimplementation, 1.81 vs 1.54 (P= .005) and a matched increase of 0.27/h (P= .003). Of the 23 survey respondents, 96% had a favorable impression of the program and reported it eased staffing demands. All respondents reported improved unit workflow and multidisciplinary communication. The majority of multidisciplinary burn team members actively supported the pilot program and commented on improvements in patient care. Full-time rehabilitation therapy participation in wound care increases therapist productivity and job satisfaction. Future efforts, however, should focus on measuring specific patient outcomes and costs as a result of therapist integration into daily wound care practice.

We report the successful manufacture of several >50 kg batches of a key intermediate via a Birch reduction that utilized liquified ammonia as well as lithium metal. With an eye toward continued scalability, we explored two alternative procedures to obtain the same intermediate: (1) an electrochemical reduction performed using continuous flow technology and (2) a ketalization approach that proceeds with olefin migration to give the target molecule. Both options were explored in detail and then demonstrated on a ≥100 g scale to assess the overall robustness. Ultimately, the olefin migration route appeared to be more promising and was demonstrated on a >1 kg scale to show the potential to avoid several unattractive aspects of the Birch reduction for future scale-up needs.

IMPORTANCE: Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD). OBJECTIVE: To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment. DESIGN, SETTING, AND PARTICIPANTS: From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed. INTERVENTIONS: In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks. MAIN OUTCOMES AND MEASURES: Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3–like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL. RESULTS: Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] β = −242.43 [48.04] pg/mL; P < .001); reduced plasma GFAP level at year 1 (mean [SD] β = −0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] β = −0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] β = −0.06 [0.02] ng/mL; P < .001); and increased CSF sTREM2 level at year 2 (mean [SD] β = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] β = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] β = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo. CONCLUSIONS AND RELEVANCE: This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04623242

Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations1,2. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants3. More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS4. Here we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumour activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumour versus normal tissues. Treated tumours exhibited waves of apoptosis along with sustained proliferative arrest, whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumours identified Myccopy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.

Background: Preventing or delaying the onset of psychosis requires identification of those at risk for developing psychosis. For predictive purposes, the prodrome – a constellation of symptoms which may occur before the onset of psychosis – has been increasingly recognized as having utility. However, it is unclear what proportion of patients experience a prodrome or how this varies based on the multiple definitions used. Methods: We conducted a systematic review and meta-analysis of studies of patients with psychosis with the objective of determining the proportion of patients who experienced a prodrome prior to psychosis onset. Inclusion criteria included a consistent prodrome definition and reporting the proportion of patients who experienced a prodrome. We excluded studies of only patients with a prodrome or solely substance-induced psychosis, qualitative studies without prevalence data, conference abstracts, and case reports/case series. We searched Ovid MEDLINE, Embase (Ovid), APA PsycInfo (Ovid), Web of Science Core Collection (Clarivate), Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, APA PsycBooks (Ovid), ProQuest Dissertation & Thesis, on March 3, 2021. Studies were assessed for quality using the Critical Appraisal Checklist for Prevalence Studies. Narrative synthesis and proportion meta-analysis were used to estimate prodrome prevalence. I2and predictive interval were used to assess heterogeneity. Subgroup analyses were used to probe sources of heterogeneity. (PROSPERO ID: CRD42021239797). Results: Seventy-one articles were included, representing 13,774 patients. Studies varied significantly in terms of methodology and prodrome definition used. The random effects proportion meta-analysis estimate for prodrome prevalence was 78.3% (95% CI = 72.8–83.2); heterogeneity was high (I297.98% [95% CI = 97.71–98.22]); and the prediction interval was wide (95% PI = 0.411–0.936). There were no meaningful differences in prevalence between grouped prodrome definitions, and subgroup analyses failed to reveal a consistent source of heterogeneity. Conclusions: This is the first meta-analysis on the prevalence of a prodrome prior to the onset of first episode psychosis. The majority of patients (78.3%) were found to have experienced a prodrome prior to psychosis onset. However, findings are highly heterogenous across study and no definitive source of heterogeneity was found despite extensive subgroup analyses. As most studies were retrospective in nature, recall bias likely affects these results. While the large majority of patients with psychosis experience a prodrome in some form, it is unclear if the remainder of patients experience no prodrome, or if ascertainment methods employed in the studies were not sensitive to their experiences. Given widespread investment in indicated prevention of psychosis through prospective identification and intervention during the prodrome, a resolution of this question as well as a consensus definition of the prodrome is much needed in order to effectively direct and organize services, and may be accomplished through novel, densely sampled and phenotyped prospective cohort studies that aim for representative sampling across multiple settings.

Studies focusing on pharmacotherapy interventions to aid patients after thermal injury are a minor focus in burn injury-centered studies and published across a wide array of journals, which challenges those with limited resources to keep their knowledge current. This review is a renewal of previous years’ work to facilitate extraction and review of the most recent pharmacotherapy-centric studies in patients with thermal and inhalation injury. Twenty-three geographically dispersed, board-certified pharmacists participated in the review. A Medical Subject Heading-based, filtered search returned 2336 manuscripts over the previous 2-year period. After manual review, 98 (4%) manuscripts were determined to have a potential impact on current pharmacotherapy practice. The top 10 scored manuscripts are discussed. Only 17% of those reviewed were assessed to likely have little effect on current practice. The overall impact of the current cohort was higher than previous editions of this review, which is encouraging. There remains a need for investment in well-designed, high-impact, pharmacotherapy-pertinent research for patients sustaining thermal or inhalation injuries.

Nanoporous materials have attracted great attention for gas storage, but achieving high volumetric storage capacity remains a challenge. Here, by using neutron powder diffraction, volumetric gas adsorption, inelastic neutron scattering and first-principles calculations, we investigate a magnesium borohydride framework that has small pores and a partially negatively charged non-flat interior for hydrogen and nitrogen uptake. Hydrogen and nitrogen occupy distinctly different adsorption sites in the pores, with very different limiting capacities of 2.33 H2and 0.66 N2per Mg(BH4)2. Molecular hydrogen is packed extremely densely, with about twice the density of liquid hydrogen (144 g H2per litre of pore volume). We found a penta-dihydrogen cluster where H2molecules in one position have rotational freedom, whereas H2molecules in another position have a well-defined orientation and a directional interaction with the framework. This study reveals that densely packed hydrogen can be stabilized in small-pore materials at ambient pressures.

After the active shooting incident in Columbine, Colorado, the police response to these events changed. Rather than have the first responding officers secure the perimeter and wait for a special weapons and tactics team, police officers have been trained to move quickly to engage and neutralize a shooter. The expectation is that an officer will prioritize the lives of victims over their own. This approach is contrary to the police culture of surviving dangerous encounters. This article presents a discussion of terror management theory as a possible explanation for why some officers may fail to perform according to contemporary expectations, and why some officers may willingly place themselves in positions in which their lives are threatened. This examination is followed by a discussion of policy and research implications.

Despite the greater sensitivity and specificity of disease-specific patient-reported outcome measures (PROM) to detect clinical change, only recently have such instruments been developed for pulmonary hypertension (PH), specifically pulmonary arterial hypertension (PAH) and chronic thromboembolic disease (CTEPH). Although these valuable tools are now being incorporated into clinical studies of PH, they have not yet reached widespread integration into routine clinical care.

Pregnancies with a complete hydatidiform mole and co‐existing fetus (CMCF) are rare, but increasingly common due to the rising prevalence of assisted reproductive technology. They are frequently associated with adverse obstetric outcomes, providing women with the challenge of pregnancy termination or continuing the pregnancy at the risk of maternal‐fetal morbidity and fetal mortality. This report demonstrates two cases of CMCF pregnancy with excellent maternal‐fetal outcomes, including spontaneous resolution of the molar tissue antenatally. It is helpful in counselling women who are diagnosed with this rare and frequently morbid condition in considering how to proceed with their pregnancy.

Graphical abstract:

Continuous attractors are an emergent property of neural population dynamics that have been hypothesized to encode continuous variables such as head direction and eye position1–4. In mammals, direct evidence of neural implementation of a continuous attractor has been hindered by the challenge of targeting perturbations to specific neurons within contributing ensembles2,3. Dynamical systems modelling has revealed that neurons in the hypothalamus exhibit approximate line-attractor dynamics in male mice during aggressive encounters5. We have previously hypothesized that these dynamics may encode the variable intensity and persistence of an aggressive internal state. Here we report that these neurons also showed line-attractor dynamics in head-fixed mice observing aggression6. This allowed us to identify and manipulate line-attractor-contributing neurons using two-photon calcium imaging and holographic optogenetic perturbations. On-manifold perturbations yielded integration of optogenetic stimulation pulses and persistent activity that drove the system along the line attractor, while transient off-manifold perturbations were followed by rapid relaxation back into the attractor. Furthermore, single-cell stimulation and imaging revealed selective functional connectivity among attractor-contributing neurons. Notably, individual differences among mice in line-attractor stability were correlated with the degree of functional connectivity among attractor-contributing neurons. Mechanistic recurrent neural network modelling indicated that dense subnetwork connectivity and slow neurotransmission7best recapitulate our empirical findings. Our work bridges circuit and manifold levels3, providing causal evidence of continuous attractor dynamics encoding an affective internal state in the mammalian hypothalamus.

Females exhibit complex, dynamic behaviours during mating with variable sexual receptivity depending on hormonal status1–4. However, how their brains encode the dynamics of mating and receptivity remains largely unknown. The ventromedial hypothalamus, ventrolateral subdivision contains oestrogen receptor type 1-positive neurons that control mating receptivity in female mice5,6. Here, unsupervised dynamical system analysis of calcium imaging data from these neurons during mating uncovered a dimension with slow ramping activity, generating a line attractor in neural state space. Neural perturbations in behaving females demonstrated relaxation of population activity back into the attractor. During mating, population activity integrated male cues to ramp up along this attractor, peaking just before ejaculation. Activity in the attractor dimension was positively correlated with the degree of receptivity. Longitudinal imaging revealed that attractor dynamics appear and disappear across the oestrus cycle and are hormone dependent. These observations suggest that a hypothalamic line attractor encodes a persistent, escalating state of female sexual arousal or drive during mating. They also demonstrate that attractors can be reversibly modulated by hormonal status, on a timescale of days.

ParaView is one of the most prominent software tools for scientific visualization used by scientists around the world. Color is a primary conduit to visually map data to its representation and, thus, enable investigation and interpretation of the data. Colormap selection has a significant impact on the data revealed; its design and selection is a critical aspect of scientific data visualization. A common choice for a user is the program’s default colormap, so careful consideration of this default is consequential. Although the current default colormap in ParaView, a succession of hues from cool blue to warm red, has served the community well, research shows that more nuanced colormap configurations increase discriminability while maintaining other critical metrics. These findings inspire us to revisit and update the default colors in ParaView. Here we present a new ParaView default colormap, the criteria and methods of development, and example visualizations and analytic metrics.

Background/Objectives: Anti-VEGF treatment response in DMO has been measured by changes in the central subfield thickness (CST) and best visual acuity (BVA) outcomes at 3 months after initial treatment, termed early or limited early response (ER/LER). This study correlates LER with 12-month BVA, CST, and retinal fluid volumes quantified by a machine learning algorithm on optical coherence tomography (OCT). Subjects/Methods: The study included treatment naïve DMO patients ≥ 18 years with OCT scans at baseline (M0), M3, M6, and M12. The 220 patients were categorized as limited early responders (LER) if they had ≤ 10% CST reduction and/or < 5 ETDRS letter gain at M3. BVA, CST, and subretinal (SRF), intraretinal (IRF), and total retinal (TRF) fluid volumes quantified by a machine learning algorithm were compared between groups and across time. Results: At M12, the anatomic LER (aLER), defined solely by CST, had significantly worse BVA and CST versus the anatomic ER (aER) group (p< 0.001). Retinal fluid M12 outcomes did not significantly vary between all LER and ER groups. No significant BVA, CST, TRF, and IRF variance across time for LER was found (p> 0.1). Conclusions: BVA and CST M12 outcomes vary by aLER/aER status indicating that CST may be a strong predictor of treatment outcomes, while retinal fluid volumes were not predicted by LER status.

Reactions that enable carbon–nitrogen, carbon–oxygen and carbon–carbon bond formation lie at the heart of synthetic chemistry. However, substrate prefunctionalization is often needed to effect such transformations without forcing reaction conditions. The development of direct coupling methods for abundant feedstock chemicals is therefore highly desirable for the rapid construction of complex molecular scaffolds. Here we report a copper-mediated, net-oxidative decarboxylative coupling of carboxylic acids with diverse nucleophiles under visible-light irradiation. Preliminary mechanistic studies suggest that the relevant chromophore in this reaction is a Cu(ii) carboxylate species assembled in situ. We propose that visible-light excitation to a ligand-to-metal charge transfer (LMCT) state results in a radical decarboxylation process that initiates the oxidative cross-coupling. The reaction is applicable to a wide variety of coupling partners, including complex drug molecules, suggesting that this strategy for cross-nucleophile coupling would facilitate rapid compound library synthesis for the discovery of new pharmaceutical agents.

Background and objective: Anti-vascular endothelial growth factor (VEGF) injections are often administered less frequently in real-world treatment of diabetic macular oedema (DMO) than what was studied in clinical trials. This study aims to characterise real-world DMO treatment patterns and the effect of treatment intervals on patient outcomes. Study design/patients and methods: This was a retrospective study of 291 patients with DMO treated with anti-VEGF therapy. 12- and 24-month best visual acuity (BVA) and central subfield thickness (CST) were compared between injection interval groups, which were determined by averaging the two most recent injection intervals. Multiple linear regressions were performed to identify factors associated with injection interval, BVA, and CST. Results: 48.8% of patients received injections less than or equal to every 8 weeks (≤ q8w), 27.5% between every 8 to 12 weeks (q8–12w), and 23.7% greater than every 12 weeks (> q12w). Baseline CST was similar (p= 0.32), but BVA differed significantly in q8–12w patients (p= 0.0095). BVA and CST at 12 months were similar, but q8–12w patients experienced greater 12-month BVA improvement (7.36 ± 12.4 letters) than > q12w patients (1.26 ± 12.3 letters; p= 0.0056). 24-month BVA and CST changes were similar between groups (p= 0.30 and 0.87). Baseline BVA, HbA1c, and sex were associated with 12-month BVA, and baseline BVA and CST were associated with 12-month CST. Conclusion: Many patients experienced improvements in BVA and CST over 12 months of treatment despite receiving less frequent anti-VEGF therapy than recommended in the pivotal trials. The present study showed that extended treatment intervals with bevacizumab were effective in preserving vision of many individuals with high baseline BVA.

Undifferentiated intestinal stem cells (ISCs) are crucial for maintaining homeostasis and resolving injury. Lgr5+ cells in the crypt base constantly divide, pushing daughter cells upward along the crypt axis where they differentiate into specialized cell types. Coordinated execution of complex transcriptional programs is necessary to allow for the maintenance of undifferentiated stem cells while permitting differentiation of the wide array of intestinal cells necessary for homeostasis. Previously, members of the myeloid translocation gene (MTG) family have been identified as transcriptional co-repressors that regulate stem cell maintenance and differentiation programs in multiple organ systems, including the intestine. One MTG family member, myeloid translocation gene related 1 (MTGR1), has been recognized as a crucial regulator of secretory cell differentiation and response to injury. However, whether MTGR1 contributes to the function of ISCs has not yet been examined. Here, using Mtgr1−/−mice, we have assessed the effects of MTGR1 loss specifically in ISC biology. Interestingly, loss of MTGR1 increased the total number of cells expressing Lgr5, the canonical marker of cycling ISCs, suggesting higher overall stem cell numbers. However, expanded transcriptomic and functional analyses revealed deficiencies in Mtgr1-null ISCs, including deregulated ISC-associated transcriptional programs. Ex vivo, intestinal organoids established from Mtgr1-null mice were unable to survive and expand due to aberrant differentiation and loss of stem and proliferative cells. Together, these results indicate that the role of MTGR1 in intestinal differentiation is likely stem cell intrinsic and identify a novel role for MTGR1 in maintaining ISC function.

Choline is an essential nutrient that the human body needs in vast quantities for cell membrane synthesis, epigenetic modification and neurotransmission. The brain has a particularly high demand for choline, but how it enters the brain remains unknown1–3. The major facilitator superfamily transporter FLVCR1 (also known as MFSD7B or SLC49A1) was recently determined to be a choline transporter but is not highly expressed at the blood–brain barrier, whereas the related protein FLVCR2 (also known as MFSD7C or SLC49A2) is expressed in endothelial cells at the blood–brain barrier4–7. Previous studies have shown that mutations in human Flvcr2cause cerebral vascular abnormalities, hydrocephalus and embryonic lethality, but the physiological role of FLVCR2 is unknown4,5. Here we demonstrate both in vivo and in vitro that FLVCR2 is a BBB choline transporter and is responsible for the majority of choline uptake into the brain. We also determine the structures of choline-bound FLVCR2 in both inward-facing and outward-facing states using cryo-electron microscopy. These results reveal how the brain obtains choline and provide molecular-level insights into how FLVCR2 binds choline in an aromatic cage and mediates its uptake. Our work could provide a novel framework for the targeted delivery of therapeutic agents into the brain.

Subtle alterations in white matter microstructure are observed in youth at clinical high risk (CHR) for psychosis. However, the timing of these changes and their relationships to the emergence of psychosis remain unclear. Here, we track the evolution of white matter abnormalities in a large, longitudinal cohort of CHR individuals comprising the North American Prodrome Longitudinal Study (NAPLS-3). Multi-shell diffusion magnetic resonance imaging data were collected across multiple timepoints (1–5 over 1 year) in 286 subjects (aged 12–32 years): 25 CHR individuals who transitioned to psychosis (CHR-P; 61 scans), 205 CHR subjects with unknown transition outcome after the 1-year follow-up period (CHR-U; 596 scans), and 56 healthy controls (195 scans). Linear mixed effects models were fitted to infer the impact of age and illness-onset on variation in the fractional anisotropy of cellular tissue (FAT) and the volume fraction of extracellular free water (FW). Baseline measures of white matter microstructure did not differentiate between HC, CHR-U and CHR-P individuals. However, age trajectories differed between the three groups in line with a developmental effect: CHR-P and CHR-U groups displayed higher FATin adolescence, and 4% lower FATby 30 years of age compared to controls. Furthermore, older CHR-P subjects (20+ years) displayed 4% higher FW in the forceps major (p< 0.05). Prospective analysis in CHR-P did not reveal a significant impact of illness onset on regional FATor FW, suggesting that transition to psychosis is not marked by dramatic change in white matter microstructure. Instead, clinical high risk for psychosis—regardless of transition outcome—is characterized by subtle age-related white matter changes that occur in tandem with development.

Histone acetylation is a dynamic modification regulated by the opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Deacetylation of histone tails results in chromatin tightening, and therefore, HDACs are generally regarded as transcriptional repressors. Counterintuitively, simultaneous deletion of Hdac1and Hdac2in embryonic stem cells (ESCs) reduces expression of the pluripotency-associated transcription factors Pou5f1, Sox2, and Nanog(PSN). By shaping global histone acetylation patterns, HDACs indirectly regulate the activity of acetyl-lysine readers, such as the transcriptional activator BRD4. Here, we use inhibitors of HDACs and BRD4 (LBH589 and JQ1, respectively) in combination with precision nuclear run-on and sequencing (PRO-seq) to examine their roles in defining the ESC transcriptome. Both LBH589 and JQ1 cause a marked reduction in the pluripotent gene network. However, although JQ1 treatment induces widespread transcriptional pausing, HDAC inhibition causes a reduction in both paused and elongating polymerase, suggesting an overall reduction in polymerase recruitment. Using enhancer RNA (eRNA) expression to measure enhancer activity, we find that LBH589-sensitive eRNAs are preferentially associated with superenhancers and PSN binding sites. These findings suggest that HDAC activity is required to maintain pluripotency by regulating the PSN enhancer network via the recruitment of RNA polymerase II.

Macular edema secondary to retinal vein occlusion (RVO) is a sight-threatening condition. Previous studies showed that early responders (ERs) who respond well to anti-VEGF injections within 3 months of treatment have better outcomes, as measured by best visual acuity (BVA) and central subfield thickness (CST) at 12 months postinjection initiation compared with limited early responders (LERs). This study analyzed whether ER eyes continue to respond better than LER eyes over longer periods. This study also aimed to identify baseline comorbidities associated with response status.

Secondary pharmacology screening of investigational small-molecule drugs for potentially adverse off-target activities has become standard practice in pharmaceutical research and development, and regulatory agencies are increasingly requesting data on activity against targets with recognized adverse effect relationships. However, the screening strategies and target panels used by pharmaceutical companies may vary substantially. To help identify commonalities and differences, as well as to highlight opportunities for further optimization of secondary pharmacology assessment, we conducted a broad-ranging survey across 18 companies under the auspices of the DruSafe leadership group of the International Consortium for Innovation and Quality in Pharmaceutical Development. Based on our analysis of this survey and discussions and additional research within the group, we present here an overview of the current state of the art in secondary pharmacology screening. We discuss best practices, including additional safety-associated targets not covered by most current screening panels, and present approaches for interpreting and reporting off-target activities. We also provide an assessment of the safety impact of secondary pharmacology screening, and a perspective on opportunities and challenges in this rapidly developing field.

The elimination of large genomic regions has been enabled by the advent of site-specific nucleases. However, as the intended deletions get larger, the efficiency of successful engineering decreases to a point where it is not feasible to retrieve edited cells due to the rarity of on-target events. To address this issue, we developed a system called molecular alteration of chromosomes with engineered tandem elements (MACHETE). MACHETE is a CRISPR–Cas9-based system involving two stages: the initial insertion of a bicistronic positive/negative selection cassette to the locus of interest. This is followed by the introduction of single-guide RNAs flanking the knockin cassette to engineer the intended deletion, where only cells that have lost the locus survive the negative selection. In contrast to other approaches optimizing the activity of sequence-specific nucleases, MACHETE selects for the deletion event itself, thus greatly enriching for cells with the engineered alteration. The procedure routinely takes 4–6 weeks from design to selection of polyclonal populations bearing the deletion of interest. We have successfully deployed MACHETE to engineer deletions of up to 45 Mb, as well as the rapid creation of allelic series to map the relevant activities within a locus. This protocol details the design and step-by-step procedure to engineer megabase-sized deletions in cells of interest, with potential application for cancer genetics, transcriptional regulation, genome architecture and beyond.

Pyoderma gangrenosum is a rare dermatologic disorder that disrupts the skin barrier, requiring immunosuppressive therapy. We successfully used cefiderocol for the treatment of an extensively drug-resistant Pseudomonas aeruginosabacteremia, and presumed osteomyelitis in a patient with severe pyoderma gangrenosum and associated immunosuppressive therapy while being medically optimized for skin grafting. We obtained bone and skin/subcutaneous tissue while the patient was on cefiderocol under an institutional review board-approved biologic waste recovery protocol. Cefiderocol concentrations in bone and skin/subcutaneous tissue were 13.9 and 35.9 mcg/g, respectively. The patient recovered from bacteremia and underwent autografting without further complications. Cefiderocol at approved dosing of 2 g IV (3-hour infusion) every 8 hours resulted in bone and skin/subcutaneous tissue concentrations adequate to treat extensively drug-resistant Gram-negative bacteria that remain susceptible to cefiderocol.

Purpose: The Polish economy has undergone major challenges and changes over the past few decades. The country's trade flows, in particular, have become more firmly tied to the country’s Western neighbors as they have grown in volume. This study examines Poland's trade balances in ten Standard International Trade Classification (SITC) sectors versus the United States of America, first testing for and isolating structural breaks in each time series. These breaks are then included in a set of the cointegration models to examine their macroeconomic determinants. Design/methodology/approach: Linear and nonlinear and nonlinear autoregressive distributed lag models, both with and without dummies corresponding to structural breaks, are estimated. Findings: One key finding is that incorporating these breaks reduces the significance of the real exchange rate in the model, supporting the hypothesis that this variable already incorporates important information. It also results in weaker evidence for cointegration of all variables in certain sectors. Research limitations/implications: This study looks only at one pair of countries, without any third-country effects. Originality/value: An important country pair's trade relations is examined; in addition, the real exchange rate is shown to incorporate economic information that results in structural changes in the economy. The paper extends the existing literature by conducting an analysis of Poland's trade balances with the USA, which have not been studied in such a context so far. A strong point is a broad methodology that lets compare the results the authors obtained with different kinds of models, both linear and nonlinear ones, with and without structural breaks.

Purpose: The present study examines the risk of citizens encountering police use of intermediate and deadly force, as opposed to using physical force, given a set of individual, situational and neighborhood variables. Design/methodology/approach: The study uses data from 2003 to 2016 in the Dallas Open Data Portal. Two-level multinomial logistic regression is used to analyze the data. Findings: The effects of citizen race differ across the types of police force. Overall, citizen race plays no significant role in the officer's decision to shoot firearms at citizens. However, there is evidence of intra-racial disparity in officer-involved shootings (OISs) between Hispanic citizens and officers. African American citizens are disproportionately exposed to display-but-don't shoot incidents, while Hispanic citizens have a lower risk of encountering police use of intermediate weapons. Originality/value: The study helps to understand how citizen and officer race influence and interact across various types of police force. Implications of the results are offered in relation to relevant literature.

An ethnoracial minority density (EMD) effect in studies of psychotic spectrum disorders has been observed, whereby the risk of psychosis in ethnoracial minority group individuals is inversely related to the proportion of minorities in their area of residence. The authors investigated the relationships among area-level EMD during childhood, cortical thickness (CT), and social engagement (SE) in clinical high risk for psychosis (CHR-P) youth. Data were collected as part of the North American Prodrome Longitudinal Study. Participants included 244 ethnoracial minoritized (predominantly Hispanic, Asian and Black) CHR-P youth and ethnoracial minoritized healthy controls. Among youth at CHR-P (n= 164), lower levels of EMD during childhood were associated with reduced CT in the right fusiform gyrus (adjusted β = 0.54; 95% CI 0.17 to 0.91) and right insula (adjusted β = 0.40; 95% CI 0.05 to 0.74). The associations between EMD and CT were significantly moderated by SE: among youth with lower SE (SE at or below the median, n= 122), lower levels of EMD were significantly associated with reduced right fusiform gyrus CT (adjusted β = 0.72; 95% CI 0.29 to 1.14) and reduced right insula CT (adjusted β = 0.57; 95% CI 0.18 to 0.97). However, among those with greater SE (n= 42), the associations between EMD and right insula and fusiform gyrus CT were not significant. We found evidence that lower levels of ethnic density during childhood were associated with reduced cortical thickness in regional brain regions, but this association may be buffered by greater levels of social engagement.

Augmented renal clearance (ARC) is defined by supraphysiologic renal function and is associated with drug failure due to subtherapeutic drug exposure. Burn patients are cited as being at high risk for ARC, yet rates of ARC have not been well described. This retrospective study described the prevalence and incidence of ARC, and compared 12-hour urine collection values (CrCl-12) vs. common estimates of renal function in assessed patients at an American Burn Association-verified burn center. All thermally injured burn patients with a CrCl-12 result were included. ARC was defined as a CrCl-12 >130 ml/min. Cockcroft-Gault, modification of diet in renal disease (MDRD), and CKD-EPI-2021 estimates were calculated. Over 13 months, 163 CrCl-12 results were collected in 68 patients at a median of 9 days from admission with an average value of 160 ml/min. The median total body surface area (total body surface area [TBSA]%) was 17.25%. ARC prevalence was 70.6% with an incidence of 66.3% in all CrCl-12 assessments. Those with ARC were less likely to have heart failure, P= .007. Age, TBSA%, and trauma were not different between those with or without ARC. ARC incidences in those with TBSAs of ≥20%, <20%, or <10%, were 70.5%, 58.6%, and 76.7%, respectively. Agreement of Cockcroft-Gault, MDRD, and CKD-EPI-2021 to CrCl-12 was moderate to weak and frequently failed to identify ARC. ARC is common in burn patients, regardless of TBSA%. Widely accepted estimations of renal function may be incorrect resulting in under-dosing of medications. Additional research is required to identify burn patients at greatest risk for ARC and subsequent dosing strategies to maintain pharmacologic efficacy without unduetoxicity.

Study Design Retrospective Cohort.Objective The aim of this study was to develop a clinical tool to pre-operatively risk-stratify patients undergoing spine surgery based on their likelihood to have high postoperative analgesic requirements.Methods A total of 1199 consecutive patients undergoing elective spine surgery over a 2-year period at a single center were included. Patients not requiring inpatient admission, those who received epidural analgesia, those who had two surgeries at separate sites under one anesthesia event, and those with a length of stay greater than 10 days were excluded. The remaining 860 patients were divided into a derivation and validation cohort. Pre-operative factors were collected by review of the electronic medical record. Total postoperative inpatient opioid intake requirements were converted into morphine milligram equivalents to standardize postoperative analgesic requirements.Results The postoperative analgesic intake needs (PAIN) score was developed after the following predictor variables were identified: age, race, history of depression/anxiety, smoking status, active pre-operative benzodiazepine use and pre-operative opioid use, and surgical type. Patients were risk-stratified based on their score with the high-risk group being more likely to have high opioid consumption postoperatively compared to the moderate and low-risk groups in both the derivation and validation cohorts.Conclusion The PAIN Score is a pre-operative clinical tool for patients undergoing spine surgery to risk stratify them based on their likelihood for high analgesic requirements. The information can be used to individualize a multi-modal analgesic regimen rather than utilizing a “one-size fits all” approach.