Systemic therapy for hormone receptor-positive/human epidermal growth factor receptor 2-negative early stage and metastatic breast cancer

Hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer is defined by the presence of the estrogen receptor and/or the progesterone receptor and the absence of HER2 gene amplification. HR-positive/HER2-negative breast cancer accounts for 65%–70% of all breast cancers, and incidence increases with increasing age. Treatment varies by stage, and endocrine therapy is the mainstay of treatment in both early stage and late-stage disease. Combinations with cyclin-dependent kinase 4/6 inhibitors have reduced distant recurrence in the early stage setting and improved overall survival in the metastatic setting. Chemotherapy is used based on stage and tumor biology in the early stage setting and after endocrine resistance for advanced disease. New therapies, including novel endocrine agents and antibody-drug conjugates, are now changing the treatment landscape. With the availability of new treatment options, it is important to define the optimal sequence of treatment to maximize clinical benefit while minimizing toxicity. In this review, the authors first discuss the pathologic and molecular features of HR-positive/HER2-negative breast cancer and mechanisms of endocrine resistance. Then, they discuss current and emerging therapies for both early stage and metastatic HR-positive/HER2-negative breast cancer, including treatment algorithms based on current data.     

A Model for the Origin of Motion Direction Selectivity in Visual Cortex

Motion perception is a vital part of our sensory repertoire in that it contributes to navigation, awareness of moving objects, and communication. Motion sense in carnivores and primates originates with primary visual cortical neurons selective for motion direction. More than 60 years after the discovery of these neurons, there is still no consensus on the mechanism underlying direction selectivity. This paper describes a model of the cat''s visual system in which direction selectivity results from the well-documented orientation selectivity of inhibitory neurons: inhomogeneities in the orientation preference map for inhibitory neurons leads to spatially asymmetric inhibition, and thus to direction selectivity. Stimulation of the model with a drifting grating shows that direction selectivity results from the relative timing of excitatory and inhibitory inputs to a neuron. Using a stationary contrast-reversing grating reveals that the inhibitory input is spatially displaced in the preferred direction relative to the excitatory input, and that this asymmetry leads to the timing difference. More generally, the model yields physiologically realistic estimates of the direction selectivity index, and it reproduces the critical finding with contrast-reversing gratings that response phase advances with grating spatial phase. It is concluded that a model based on intracortical inhibition can account well for the known properties of direction selectivity in carnivores and primates.SIGNIFICANCE STATEMENT Motion perception is vital for navigation, communication, and the awareness of moving objects. Motion sense depends on cortical neurons that are selective for motion direction, and this paper describes a model for the physiological mechanism underlying cortical direction selectivity. The essence of the model is that intracortical inhibition of a direction-selective cell is spatially inhomogeneous and therefore depends on whether a stimulus generates inhibition before or after reaching the cell''s receptive field: the response is weaker in the former than in the latter case. If the model is correct, it will contribute to the understanding of motion processing in carnivores and primates.     

Student perspective on outcomes and process – Recommendations for implementing competency-based medical education

Purpose: Competency-based medical education (CBME) seeks to prepare undergraduate and postgraduate trainees for clinical practice. Its major emphasis is on outcomes, but questions about how best to reach these remain. One key issue is the need to integrate what matters most to students when setting educational goals: this is crucial if we are to design curricula that trainees understand and engage with, and that promote successful achievement of competencies.

Method: We interviewed medical students in years 4 and 6 of a 6-year medical degree and used thematic analysis to understand their main educational priorities and how these fit with the aims of CBME.

Results: Two major themes emerged: features of content and process. For content, students wanted clear guidance on what constitutes competence, finding broad outcome statements abstract and difficult to understand as novices. They also attach critical importance to features of process such as being welcomed, included in clinical teams and being known personally – these promote motivation, understanding, and professional development.

Conclusions: We present recommendations for those designing CBME curricula to emphasize the student perspective: what kind of guidance on outcomes is required, and features of process that must not be neglected if competence is to be achieved.     

Prelimbic cortex is a common brain area activated during cue‐induced reinstatement of cocaine and heroin seeking in a polydrug self‐administration rat model

Many preclinical studies examined cue‐induced relapse to heroin and cocaine seeking in animal models, but most of these studies examined only one drug at a time. In human addicts, however, polydrug use of cocaine and heroin is common. We used a polydrug self‐administration relapse model in rats to determine similarities and differences in brain areas activated during cue‐induced reinstatement of heroin and cocaine seeking. We trained rats to lever press for cocaine (1.0 mg/kg per infusion, 3‐hr/day, 18 day) or heroin (0.03 mg/kg per infusion) on alternating days (9 day for each drug); drug infusions were paired with either intermittent or continuous light cue. Next, the rats underwent extinction training followed by tests for cue‐induced reinstatement where they were exposed to either heroin‐ or cocaine‐associated cues. We observed cue‐selective reinstatement of drug seeking: the heroin cue selectively reinstated heroin seeking and the cocaine cue selectively reinstated cocaine seeking. We used Fos immunohistochemistry to assess cue‐induced neuronal activation in different subregions of the medial prefrontal cortex, dorsal striatum, nucleus accumbens, and amygdala. Fos expression results indicated that only the prelimbic cortex (PL) was activated by both heroin and cocaine cues; in contrast, no significant cue‐induced neuronal activation was observed in other brain areas. RNA in situ hybridization indicated that the proportion of glutamatergic and GABAergic markers in PL Fos‐expressing cells was similar for the heroin and cocaine cue‐activated neurons. Overall, the results indicate that PL may be a common brain area involved in both heroin and cocaine seeking during polydrug use.     

Cryptosporidiosis among solid organ transplant recipient attendees at a summer camp

We report a cluster of pediatric cryptosporidiosis infections among solid organ transplant recipients at a summer camp in Georgia, USA. A retrospective cohort study was conducted to investigate the risk factors for infection. A total of 118 campers attended the camp during July 23‐28, 2017. The overall attack rate among campers during the outbreak was 11% (13/118). Sanger‐based amplicon sequencing of stool specimens from 7 (80%) campers identified Cryptosporidium hominis as the suspected etiologic agent. All infected campers were heart or kidney transplant recipients receiving immunosuppressive therapy. The median reported symptom duration was 12 days (range 6‐18 days) and 9 (69.2%) were hospitalized for at least one night (median length of stay 5 days, range 2‐16 days). There were no deaths or acute rejection events attributed to infection. The results of the epidemiologic and environmental investigation suggest a recreational pool as the presumed source, although there was no direct evidence to support this. Many long‐term interventions were implemented, and there have been no further outbreaks at the camp in the following two years. This outbreak demonstrates that cryptosporidiosis may be associated with notable burden in pediatric transplant recipients, and illustrates the challenges associated with source identification and containment.