Clinical Features and Therapeutic Outcomes in Men with Advanced Prostate Cancer and DNA Mismatch Repair Gene Mutations

Mismatch repair (MMR) gene mutations are rare in prostate cancer, and their histological and clinical characteristics are largely unknown. We conducted a retrospective study to explore disease characteristics and treatment outcomes of men with metastatic prostate cancer harboring germline and/or somatic MMR mutations detected using clinical-grade genomic assays. Thirteen patients with a deleterious MMR gene mutation were identified. Median age was 64 yr, 75% had grade group 5 (Gleason sum 9 or 10), 23% had intraductal histology, 46% had metastatic disease at initial diagnosis, and 31% had visceral metastases. Most patients (46%) had MSH6 mutations, 73% demonstrated microsatellite instability, and median tumor mutational load was 18/Mb (range, 3–165 mutations/Mb). Surprisingly, responses to standard hormonal therapies were very durable (median progression-free survival [PFS] of 67 mo to initial androgen deprivation and median PFS of 26 mo to abiraterone/enzalutamide). Two of four men receiving PD-1 inhibitors achieved a ≥50% prostate-specific antigen response at 12 wk, with a median PFS duration in these four men of 9 mo. Despite aggressive clinical and pathological features, patients with MMR-mutated advanced prostate cancer appear to have particular sensitivity to hormonal therapies, as well as anecdotal responses to PD-1 inhibitors. Certain histological features (grade group 5, intraductal carcinoma) should prompt evaluation for MMR deficiency. These data are only hypothesis generating.

Fractionating the all-or-nothing definition of goal-directed and habitual decision-making

Goal-directed and habitual decision-making are fundamental processes that support the ongoing adaptive behavior. There is a growing interest in examining their disruption in psychiatric disease, often with a focus on a disease shifting control from one process to the other, usually a shift from goal-directed to habitual control. However, several different experimental procedures can be used to probe whether decision-making is under goal-directed or habitual control, including outcome devaluation and contingency degradation. These different experimental procedures may recruit diverse behavioral and neural processes. Thus, there are potentially many opportunities for these disease phenotypes to manifest as alterations to both goal-directed and habitual controls. In this review, we highlight the examples of behavioral and neural circuit divergence and similarity, and suggest that interpretation based on behavioral processes recruited during testing may leave more room for goal-directed and habitual decision-making to coexist. Furthermore, this may improve our understanding of precisely what the involved neural mechanisms underlying aspects of goal-directed and habitual behavior are, as well as how disease affects behavior and these circuits.     

A cadaveric model for transesophageal echocardiography transducer placement training: A pilot study

BACKGROUND: Transesophageal echocardiography(TEE) is used in the emergency department to guide resuscitation during cardiac arrest. Insertion of a TEE transducer requires manual skill and experience, yet in some residency programs cardiac arrest is uncommon, so some physicians may lack the means to acquire the manual skills to perform TEE in clinical practice. For other infrequently performed procedural skills, simulation models are used. However, there is currently no model that adequately simulates TEE transducer insertion. The aim of this study is to evaluate the feasibility and efficacy of using a cadaveric model to teach TEE transducer placement among novice users.METHODS: A convenience sample of emergency medicine residents was enrolled during a procedure education session using cadavers as tissue models. A pre-session assessment was used to determine prior knowledge and confidence regarding TEE manipulation. Participants subsequently attended a didactic and hands-on education session on TEE placement. All participants practised placing the TEE transducer until they were able to pass a standardized assessment of technical skill(SATS). After the educational session, participants completed a post-session assessment. RESULTS: Twenty-five residents participated in the training session. Mean assessment of knowledge improved from 6.2/10 to 8.7/10(95% confidence interval [CI] of knowledge difference 1.6–3.2, P<0.001) and confidence improved from 1.6/5 to 3.1/5(95% CI of confidence difference 1.1–2.0, P<0.001). There was no relationship between training level and the delta in knowledge or confidence.CONCLUSIONS: In this pilot study, the use of a cadaveric model to teach TEE transducer placement methods among novice users is feasible and improves both TEE manipulation knowledge and confidence levels.     

Determination of vessel cross-sectional area by thresholding in Radon space

The cross-sectional area of a blood vessel determines its resistance, and thus is a regulator of local blood flow. However, the cross-sections of penetrating vessels in the cortex can be non-circular, and dilation and constriction can change the shape of the vessels. We show that observed vessel shape changes can introduce large errors in flux calculations when using a single diameter measurement. Because of these shape changes, typical diameter measurement approaches, such as the full-width at half-maximum (FWHM) that depend on a single diameter axis will generate erroneous results, especially when calculating flux. Here, we present an automated method—thresholding in Radon space (TiRS)—for determining the cross-sectional area of a convex object, such as a penetrating vessel observed with two-photon laser scanning microscopy (2PLSM). The thresholded image is transformed back to image space and contiguous pixels are segmented. The TiRS method is analogous to taking the FWHM across multiple axes and is more robust to noise and shape changes than FWHM and thresholding methods. We demonstrate the superior precision of the TiRS method with in vivo 2PLSM measurements of vessel diameter.     

Antimicrobial treatment options for neurosurgical ventricular shunt infections in children from 1993 to 2012: a systematic review

Purpose

The aim of this systematic review was to review studies that existed from 1993 to 2012 regarding antimicrobial treatment options of paediatric neurosurgical shunt.

Methods

Studies were identified from MEDLINE, Scopus and Cochrane databases using a search strategy that was registered on the PROSPERO database. Studies were included if they had two or more patients, aged less than 18 years, and also specified the organism and antimicrobial treatment that was used.

Results

The search yielded 2,985 articles, and 76 articles were suitable for full review. In the final qualitative analysis, only eight studies were included, involving 86 participants. The most common antimicrobial regimens for Gram-positive infections was intravenous and intrathecal vancomycin (n?=?7), followed by intravenous vancomycin monotherapy.

Conclusion

This systematic review has shown that there are no prospective randomised studies of antimicrobial treatment options for paediatric neurosurgical patients in the last 20 years, and larger prospective studies are urgently required for this serious infection. There is some limited case series showing the benefits of certain antimicrobials such as vancomycin and ceftriaxone, but a larger case series or randomised controlled trial is required, particularly to establish the benefit, if any, of additional intraventricular antimicrobials.     

Correlates of hepatitis B among patients with mental illness in Brazil

Objective

To assess correlates of hepatitis B among adults with mental illness under care in Brazil.

Method

Cross-sectional national multicenter study of 2206 patients with mental illnesses randomly selected from 26 public mental health services. Sociodemographic and behavioral data were obtained from face-to-face interviews and psychiatric diagnoses from medical charts. Serology testing was conducted, and prevalence rate ratios were estimated by log-binomial regression.

Results

The weighted prevalence rates of current hepatitis B virus (HBV) infection (HBsAg +) and previous HBV exposure (anti-HBc +) were 2.0% [95% confidence interval (CI): 1.5%–2.7%] and 17.1% (95% CI: 16.0%–19.0%), respectively. Correlates of HBsAg + included male gender, younger age (18–29 years), unstable place of residence, intellectual disability, main psychiatric diagnosis of dementia, presence of other medical comorbitidy, use of alcohol/drugs during sex, more than one sexual partner and use of cocaine. Correlates of anti-HBc + included male gender, older age (≥ 30 years), black skin color, lower education, unstable place of residence, currently hospitalized, intellectual disability, history of any sexually transmitted disease or syphilis, poor HIV knowledge, history of imprisonment and sexual violence.

Conclusions

Hepatitis B is an important comorbidity among psychiatric patients in Brazil. Screening for HBV, effective prevention and intervention strategies, including universal HBV immunization, should be routine practices in these mental health services.     

Bioreplicated visual features of nanofabricated buprestid beetle decoys evoke stereotypical male mating flights

Recent advances in nanoscale bioreplication processes present the potential for novel basic and applied research into organismal behavioral processes. Insect behavior potentially could be affected by physical features existing at the nanoscale level. We used nano-bioreplicated visual decoys of female emerald ash borer beetles (Agrilus planipennis) to evoke stereotypical mate-finding behavior, whereby males fly to and alight on the decoys as they would on real females. Using an industrially scalable nanomolding process, we replicated and evaluated the importance of two features of the outer cuticular surface of the beetle’s wings: structural interference coloration of the elytra by multilayering of the epicuticle and fine-scale surface features consisting of spicules and spines that scatter light into intense strands. Two types of decoys that lacked one or both of these elements were fabricated, one type nano-bioreplicated and the other 3D-printed with no bioreplicated surface nanostructural elements. Both types were colored with green paint. The light-scattering properties of the nano-bioreplicated surfaces were verified by shining a white laser on the decoys in a dark room and projecting the scattering pattern onto a white surface. Regardless of the coloration mechanism, the nano-bioreplicated decoys evoked the complete attraction and landing sequence of Agrilus males. In contrast, males made brief flying approaches toward the decoys without nanostructured features, but diverted away before alighting on them. The nano-bioreplicated decoys were also electroconductive, a feature used on traps such that beetles alighting onto them were stunned, killed, and collected.Biomimicry of insect visual communication signals has received much recent attention, with growing interest in nanofabrication processes that result in artificially produced structural colors (1) such as those emanating from the ridges on butterfly wing scales (2). The fidelity of the nanoreplication of visual signals with communication value to such organisms has been underexplored, however. Visually induced behavior in arthropods often integrates color and edge-motion detection, with interactions often involving a variety of biotic and abiotic entities, making it difficult to reproduce experimentally (3).Bioreplication of visual signaling structures might be manipulated so as to provide insight into the mechanisms of such signaling processes; however, all currently known examples of bioreplicated nanostructures that have been created to affect behavior involve unicellular movements across particular textured environments (4–7), rather than directed to evoke responses of specialized sensory organs of more complex multicellular organisms. Bioreplicated structures emitting behaviorally effective visual cues also may be useful for such practical purposes as the monitoring and detection of pest species, but the communication efficacy of the bioreplica needs to be validated under field conditions using naturally occurring (i.e., wild) populations.In contrast, biomimicry of chemical signals, such as insect pheromones, has been a burgeoning field for more than half a century. Synthetically reproduced pheromones have been successfully applied under field conditions to manipulate insect behavior for invasive species pest detection, population monitoring of endemic species, and disruption of mating. Thousands of studies have described the essential components of nanoscale levels (nanograms) of semiochemical signals that trigger behavioral responses, such as upwind flight for mating (8), alarm responses (9), and trail following (10). Furthermore, neurophysiological techniques have elucidated how these signals are transduced by peripheral sensory organs (11) and integrated into odor sensations in the higher processing centers of the insect brain (12). In the realm of applied science, these insights have led to trapping protocols for pest population detection, attract-and-kill protocols, and mating disruption (13). Visually attractive features of trapping technologies generally have not been approached with such rigor, however, and are usually optimized by simple manipulations of trap colors without efforts to understand the underlying mechanisms of visual attraction.In an effort to initiate such an approach to manipulation of visual signaling systems, we used an industrially scalable nano-bioreplication technique (14) to produce high-fidelity replicas of the structural features of the cuticle of the hard wing covers (elytra) of an invasive buprestid beetle pest, the emerald ash borer (Agrilus planipennis). This species is a tree-killing pest of Asian origin whose visual signal is emitted by the elytra of a female at rest on an ash leaf in direct sunlight, which triggers attraction of flying males that are patrolling the canopy. Male responses unfold as rapid flights toward the females from heights of up to 2 m, usually terminating with the males alighting directly on the females and attempting to copulate (15). This “paratrooper” descent behavior by flying A. planipennis males in the field can be repeatedly evoked by affixing dead A. planipennis females to ash leaves (15, 16). Furthermore, various other potentially invasive European and North American tree-feeding Agrilus species have been observed performing similar stereotypical inflight descents onto dead beetle decoys affixed to the leaves of preferred host trees (17, 18). Such approaches are often seen to congeneric, heterospecific targets. One such species, the two-spotted oak borer, Agrilus biguttatus, that is similar in size and habits to A. planipennis is known to kill oak trees within its native range in Europe (19), particularly after drought (20) or defoliation events (21).The base colors of many metallic-colored beetles, including buprestid beetles (Fig. 1A), are known to be structurally produced by the repeated alternation of cuticle layers (Fig. 1D) with different refractive indices (22, 23). This periodically multilayered assemblage functions as a quarter-wave Bragg stack reflector in a particular spectral regime (2) and is thus highly effective for creating a color of narrow specificity in sunlight, unlike many naturally occurring pigments. The reflected light is also affected by regular fine-scale topographic features of the surface, including thousands of sharp spicules each emitting green to yellow colors, which are further scattered by numerous spines (Fig. 1 B and C). Many of the physical attributes of the A. planipennis cuticle that produce its attractive visual signal have been replicated by a process that involves the stamping of a polymer quarter-wave Bragg stack reflector with a set of dies cast from the actual elytra of a female A. planipennis (Fig. 2) (14).Open in a separate windowFig. 1.Structural color and surface topography of A. planipennis wings. (A) Optical microscopy showing a dorsal view of the beetle elytron. (B) Higher-magnification optical microscopy showing spines and cilia. (C) Scanning electron micrograph showing a higher-resolution image of the surface topography. (D) Transmission electron micrograph of a cross-section of an elytron, showing four alternating layers of differing refractive indices. (C and D are reprinted with permission from ref. 14.)Open in a separate windowFig. 2.Nano-bioreplicated decoy characteristics. (A) Optical microscopy of the nickel die. (B) Scanning electron micrograph of a nickel die used for bioreplication, showing a similar structure as the A. planipennis surface (Fig. 1), but without the cilia. (C) Optical microscopy of the dorsal view of a nano-bioreplicated A. planipennis decoy that reproduces the surface structure of the beetle and is colored by metallic paint. (A and B are reprinted with permission from ref. 14.)Here we report on direct field observations of A. planipennis and A. biguttatus male behavior toward natural beetle decoys versus three types of synthetic decoys with varying degrees of verisimilitude with respect to the fidelity of bioreplication. These synthetic decoys included: (i) a bioreplicated decoy created by a nanomolding process and colored with a polymer functioning as a Bragg reflector; (ii) another bioreplicated decoy created by a nanomolding process and colored with a metallic green paint; and (iii) a 3D-printed decoy consisting of a smooth polymer surface without a nanomolded bioreplicated surface structure, also colored with green metallic paint. We investigated whether the nanomolding process could create light-scattering patterns similar to those of real decoys by observing light emissions resulting from the application of a white laser to the surfaces of real and synthetic decoys in a dark room. We hypothesized that a sufficient degree of verisimilitude with respect to color and fine-scale topological features of the elytra could be achieved through the bioreplication process to elicit inflight mating approaches and landings similar to those evoked by real beetles. We also incorporated the bioreplicated decoys into a trapping system in which the electroconductive properties of the decoy are used to electrocute male beetles when they approach and alight on the decoys.     

Prevalence of incidental findings in trauma patients detected by computed tomography imaging

Study Objective

The primary intention of spiral computed tomography (SCT) in trauma patients is to identify significant injuries. However, unanticipated information is often discovered. We hypothesize that SCT often identifies clinically significant incidental findings in trauma patients.

Methods

This was a retrospective protocol chart review of consecutive adult trauma patients seen at a level I trauma center. A complete SCT was defined as computed tomography imaging of the head, cervical spine, chest, abdomen, and pelvis, thoracic, and lumbar spine. Incidental findings were classified into 2 categories: type 1, which requires urgent evaluation, and type 2, which requires informing the patient but does not mandate urgent follow-up.

Results

We reviewed 3246 patient charts and 3092 met inclusion criteria. Type 1 findings were reported in 990 (32.0%; 95% confidence interval [CI], 30.4%-33.7%) patients. Type 2 findings were found in 1274 (41.2%; 95% CI, 39.5%-42.9%) patients. Female sex (odds ratio, 1.38; 95% CI, 1.16-1.65) and older age (odds ratio, 2.61; 95% CI, 2.33-2.93) were independently associated with a higher prevalence of type 1 findings. There were 631 incidental findings concerning for neoplasm, which included 196 pulmonary nodules, 99 liver, 36 renal, 23 brain, and 11 breast masses.

Conclusions

A significant number of trauma patients evaluated with SCT are diagnosed with potentially serious incidental findings. For long-term care and medicolegal concerns, physicians need to inform patients of these incidental findings and the need for further evaluation.