Complementary insights into corticostriatal synapse loss and cognition in Huntington's disease.

In a recent study, Wilton and colleagues link activation of the classical complement pathway with corticostriatal synapse loss and cognitive decline in Huntington's disease.1.

Not according to plan: Cognitive failures in marksmanship due to effects of expertise, unknown environments, and the likelihood of shooting unintended targets.

Shooting errors have multi-faceted causes with contributing factors that include sensorimotor activity and cognitive failures. Empirical investigations often assess mental errors through threat identification, yet other cognitive failures could contribute to poor outcomes. The current study explored several possible sources of cognitive failures unrelated to threat identification with live fire exercises. Experiment 1 examined a national shooting competition to compare marksmanship accuracy, expertise, and planning in the likelihood of hitting no-shoot or unintended targets. Experts demonstrated an inverse speed/accuracy trade-off and fired upon fewer no-shoot targets than lesser skilled shooters, yet overall, greater opportunity to plan produced more no-shoot errors, thereby demonstrating an increase in cognitive errors. Experiment 2 replicated and extended this finding under conditions accounting for target type, location, and number. These findings further dissociate the roles of marksmanship and cognition in shooting errors while suggesting that marksmanship evaluations should be re-designed to better incorporate cognitive variables.

Don't Shoot Me: Potential Consequences of Force-on-Force Training Modulate the Human Stress Response.

ABSTRACT: Jensen, AE, Bernards, JR, Hamilton, JA, Markwald, RR, Kelly, KR, and Biggs, AT. Do not shoot me: potential consequences of force-on-force training modulate the human stress response. J Strength Cond Res 37(9): 1761-1769, 2023-Close-quarters combat (CQC) engagements trigger the "fight-or-flight" response, activating the sympathetic nervous system and hypothalamic-pituitary-adrenal axis in response to perceived threats. However, it has yet to be shown if a force-on-force (FoF) CQC training environment will lead to adaptations in the physiological stress response or performance. United States Marines and Army infantry personnel participated in a 15-day CQC training program. The CQC program focused heavily on FoF training with the use of nonlethal training ammunition (NLTA). Data collections occurred on training days 1 and 15, during a simulated FoF-hostage rescue (HR) scenario and photorealistic target drill. For the FoF-HR, subjects were instructed to clear the shoot house, rescue the hostage, and only shoot hostile threat(s) with NLTA. The photorealistic target drills were similar, but replaced the role players in the FoF-HR with paper targets. Salivary alpha-amylase (sAA) and salivary cortisol were obtained immediately before entering and exiting the shoot house. Time to completion significantly decreased, between days 1 and 15, for both the FoF-HR and the photorealistic drills by 67.7 and 54.4%, respectively ( p < 0.05). Analyses revealed that the change in sAA, nonsignificantly, doubled from day 1 to 15 during FoF-HR ( p > 0.05), whereas the change in sAA decreased during the photorealistic drills across days ( p < 0.05). Cortisol was significantly higher during the FoF-HR in comparison to the photorealistic drills ( p < 0.05). These data suggest that potential consequences of FoF training heighten the stress response in conjunction with enhanced performance.

Moving Beyond the Neck and Arm: The Pain Experience of People With Degenerative Cervical Myelopathy Who Have Pain.

STUDY DESIGN: Cross-sectional internet survey of people living with degenerative cervical myelopathy. OBJECTIVE: The purpose of this study was to quantify pain distribution, severity, and interference in persons with degenerative cervical myelopathy. METHODS: Eighty-two participants with degenerative cervical myelopathy were recruited for this internet survey. This survey utilized the Michigan Body Map and brief pain inventory (BPI) to assess anatomical distribution and severity of pain as well as the patient derived modified Japanese Orthopedic Association scale (p-mJOA) for myelopathic severity and SF-36 for measures of health-related quality of life. Internal consistency was evaluated with Cronbach's alpha. Pearson's correlations were assessed with p-mJOA and SF-36. Multivariate analysis of variance was used to determine if history of prior surgery or concomitant pain diagnosis impacted experience of pain. RESULTS: Michigan body map distribution and brief pain inventory severity and interference were correlated with p-mJOA and SF-36 scores (p < 0.05). Pain was moderate to severe in 78% of participants. Pain was commonly widespread. Pain scales were sufficiently internally consistent (α > 0.9). History of surgery or other pain diagnosis did not impact experience of pain in myelopathy. CONCLUSIONS: Pain is commonly identifiable in large areas of the body, is frequently moderate to severe in intensity and impacts quality of life and severity of myelopathy in a cohort of individuals with myelopathy who have pain.

Polyglutamine diseases.

Polyglutamine diseases are a collection of nine CAG trinucleotide expansion disorders, presenting with a spectrum of neurological and clinical phenotypes. Recent human, mouse and cell studies of Huntington's disease have highlighted the role of DNA repair genes in somatic expansion of the CAG repeat region, modifying disease pathogenesis. Incomplete splicing of the HTT gene has also been shown to occur in humans, with the resulting exon 1 fragment most probably contributing to the Huntington's disease phenotype. In the spinocerebellar ataxias, studies have converged on transcriptional dysregulation of ion channels as a key disease modifier. In addition, advances have been made in understanding how increased levels of toxic, polyglutamine-expanded proteins can arise in the spinocerebellar ataxias through post-transcriptional and -translational modifications and autophagic mechanisms. Recent studies in spinal and bulbar muscular atrophy implicate similar pathogenic pathways to the more common polyglutamine diseases, highlighting autophagy stimulation as a potential therapeutic target. Finally, the therapeutic use of antisense oligonucleotides in several polyglutamine diseases has shown preclinical benefits and serves as potential future therapies in humans.

FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington's disease.

CAG repeat expansion in the HTT gene drives Huntington's disease (HD) pathogenesis and is modulated by DNA damage repair pathways. In this context, the interaction between FAN1, a DNA-structure-specific nuclease, and MLH1, member of the DNA mismatch repair pathway (MMR), is not defined. Here, we identify a highly conserved SPYF motif at the N terminus of FAN1 that binds to MLH1. Our data support a model where FAN1 has two distinct functions to stabilize CAG repeats. On one hand, it binds MLH1 to restrict its recruitment by MSH3, thus inhibiting the assembly of a functional MMR complex that would otherwise promote CAG repeat expansion. On the other hand, it promotes accurate repair via its nuclease activity. These data highlight a potential avenue for HD therapeutics in attenuating somatic expansion.

Perception during use of force and the likelihood of firing upon an unarmed person.

Stress can impact perception, especially during use-of-force. Research efforts can thus advance both theory and practice by examining how perception during use-of-force might drive behavior. The current study explored the relationship between perceptual judgments and performance during novel close-combat training. Analyses included perceptual judgments from close-combat assessments conducted pre-training and post-training that required realistic use-of-force decisions in addition to an artificially construed stress-inoculation event used as a training exercise. Participants demonstrated significant reductions in situational awareness while under direct fire, which correlated to increased physiological stress. The initial likelihood of firing upon an unarmed person predicted the perceptual shortcomings of later stress-inoculation training. Subsequently, likelihood of firing upon an unarmed person was reduced following the stress-inoculation training. These preliminary findings have several implications for low or zero-cost solutions that might help trainers identify individuals who are underprepared for field responsibilities.

How unintentional cues can bias threat assessments during shoot/don't-shoot simulations.

OBJECTIVE: Identify whether contextual information may unintentionally alter decision-making during lethal force training. BACKGROUND: Lethal force decisions inherently involve a threat assessment, where an individual learns to identify a threat and use force commensurate to the situation. This decision is ultimately subject to numerous cognitive influences, particularly during training where artificial factors may bias decision-making. METHOD: Participants made threat assessments for tasks that presented hostile stimuli (pointing guns) and non-hostile stimuli (holding cell phones). Experiment 1 identified issues in target design by applying scoring rings as cues to targets, whereas Experiment 2 used bullet holes to assess cues due to target reuse. Experiment 3 applied these cues equally to hostile and non-hostile stimuli to prevent a predictive relationship from forming. RESULTS: Significant cueing effects were observed in both Experiments 1 and 2. For Experiment 3, response times were not impacted by the invalid cues as participants could no longer reliably use the cue to distinguish between hostile and non-hostile stimuli. CONCLUSION: Stimulus-related factors can unintentionally create predictive relationships during lethal force training. These predictive factors are problematic because they allow participants to make threat assessments during training in a way that would never be realistic in the field. APPLICATION: Modifications should be made to hostile and non-hostile targets in equal measure to avoid creating an unintentionally predictive relationship that identifies hostile targets. In practice, scoring rings and bullet holes should be added to non-hostile stimuli to better parallel hostile stimuli.

Improving Antibody-Tubulysin Conjugates through Linker Chemistry and Site-Specific Conjugation.

Tubulysins have emerged in recent years as a compelling drug class for delivery to tumor cells via antibodies. The ability of this drug class to exert bystander activity while retaining potency against multidrug-resistant cell lines differentiates them from other microtubule-disrupting agents. Tubulysin M, a synthetic analogue, has proven to be active and well tolerated as an antibody-drug conjugate (ADC) payload, but has the liability of being susceptible to acetate hydrolysis at the C11 position, leading to attenuated potency. In this work, we examine the ability of the drug-linker and conjugation site to preserve acetate stability. Our findings show that, in contrast to a more conventional protease-cleavable dipeptide linker, the ß-glucuronidase-cleavable glucuronide linker protects against acetate hydrolysis and improves ADC activity in vivo. In addition, site-specific conjugation can positively impact both acetate stability and in vivo activity. Together, these findings provide the basis for a highly optimized delivery strategy for tubulysin M.

Structure-activity relationships of tubulysin analogues.

The tubulysins are an emerging antibody-drug conjugate (ADC) payload that maintain potent anti-proliferative activity against cells that exhibit the multi-drug resistant (MDR) phenotype. These drugs possess a C-11 acetate known to be hydrolytically unstable in plasma, and loss of the acetate significantly attenuates cytotoxicity. Structure-activity relationship studies were undertaken to identify stable C-11 tubulysin analogues that maintain affinity for tubulin and potent cytotoxicity. After identifying several C-11 alkoxy analogues that possess comparable biological activity to tubulysin M with significantly improved plasma stability, additional analogues of both the Ile residue and N-terminal position were synthesized. These studies revealed that minor changes within the tubulin binding site of tubulysin can profoundly alter the activity of this chemotype, particularly against MDR-positive cell types.

Effect of seasonal variation on the peak presentation of slipped capital femoral epiphysis. A comparison of children in Johannesburg, South Africa and London, UK.

Variation exists in the peak presentation of slipped capital femoral epiphysis (SCFE). The objective of this study was to compare two cohorts of children (South Africa and the UK) and explore similarities and differences regarding demographic and epidemiological features, incidence and seasonal variation in peak presentation. Patients presenting with SCFE at one of two hospitals were included in the study. A retrospective cohort was collected from hospital records. The following factors were recorded: duration of symptoms, chronicity, stability, seasonality, severity and prophylactic pinning. A total of 137 patients were included in the study - 70 patients (80 hips) from South Africa and 67 patients (73 hips) from the UK. Both sites recorded more than 50% incidence of a chronic slip. There was higher delay to presentation in the UK compared with South Africa (90 vs 60 days, P = 0.0262). The UK population were more skeletally mature (32.8% open triradiate cartilage) compared with the South Africa population (64.9% open triradiate cartilage). In both populations, the most common season of symptom onset was summer. In the UK, the most common season of symptom presentation was in autumn compared with summer in South Africa. This study found significant differences in the two countries, including a more skeletally mature population in the UK. Both cohorts showed seasonal variation in peak incidence, but there was more seasonal variation in peak incidence in the UK - in the summer for onset of symptoms and autumn months for time of presentation.

Glucuronide-Linked Antibody-Tubulysin Conjugates Display Activity in MDR+ and Heterogeneous Tumor Models.

Although antibody-drug conjugates (ADCs) find increasing applications in cancer treatment, de novo or treatment-emergent resistance mechanisms may impair clinical benefit. Two resistance mechanisms that emerge under prolonged exposure include upregulation of transporter proteins that confer multidrug resistance (MDR+) and loss of cognate antigen expression. New technologies that circumvent these resistance mechanisms may serve to extend the utility of next-generation ADCs. Recently, we developed the quaternary ammonium linker system to expand the scope of conjugatable payloads to include tertiary amines and applied the linker to tubulysins, a highly potent class of tubulin binders that maintain activity in MDR+ cell lines. In this work, tubulysin M, which contains an unstable acetate susceptible to enzymatic hydrolysis, and two stabilized tubulysin analogues were prepared as quaternary ammonium-linked glucuronide-linkers and assessed as ADC payloads in preclinical models. The conjugates were potent across a panel of cancer cell lines and active in tumor xenografts, including those displaying the MDR+ phenotype. The ADCs also demonstrated potent bystander activity in a coculture model comprised of a mixture of antigen-positive and -negative cell lines, and in an antigen-heterogeneous tumor model. Thus, the glucuronide-tubulysin drug-linkers represent a promising ADC payload class, combining conjugate potency in the presence of the MDR+ phenotype and robust activity in models of tumor heterogeneity in a structure-dependent manner. Mol Cancer Ther; 17(8); 1752-60. ©2018 AACR.

Optimization of a PEGylated Glucuronide-Monomethylauristatin E Linker for Antibody-Drug Conjugates.

The emergence of antibody-drug conjugates (ADC), such as brentuximab vedotin and ado-trastuzumab emtansine, has led to increased efforts to identify new payloads and develop improved drug-linker technologies. Most antibody payloads impart significant hydrophobicity to the ADC, resulting in accelerated plasma clearance and suboptimal in vivo activity, particularly for conjugates with high drug-to-antibody ratios (DAR). We recently reported on the incorporation of a discrete PEG24 polymer as a side chain in a ß-glucuronidase-cleavable monomethylauristatin E (MMAE) linker to provide homogeneous DAR 8 conjugates with decreased plasma clearance and increased antitumor activity in xenograft models relative to a non-PEGylated control. In this work, we optimized the drug-linker by minimizing the size of the PEG side chain and incorporating a self-stabilizing maleimide to prevent payload de-conjugation in vivo Multiple PEG-glucuronide-MMAE linkers were prepared with PEG size up to 24 ethylene oxide units, and homogeneous DAR 8 ADCs were evaluated. A clear relationship was observed between PEG length and conjugate pharmacology when tested in vivo Longer PEG chains resulted in slower clearance, with a threshold length of PEG8 beyond which clearance was not impacted. Conjugates bearing PEG of sufficient length to minimize plasma clearance provided a wider therapeutic window relative to faster clearing conjugates bearing shorter PEGs. A lead PEGylated glucuronide-MMAE linker was identified incorporating a self-stabilizing maleimide and a PEG12 side chain emerged from these efforts, enabling highly potent, homogeneous DAR 8 conjugates and is under consideration for future ADC programs. Mol Cancer Ther; 16(1); 116-23. ©2016 AACR.

Development of Novel Quaternary Ammonium Linkers for Antibody-Drug Conjugates.

A quaternary ammonium-based drug-linker has been developed to expand the scope of antibody-drug conjugate (ADC) payloads to include tertiary amines, a functional group commonly present in biologically active compounds. The linker strategy was exemplified with a ß-glucuronidase-cleavable auristatin E construct. The drug-linker was found to efficiently release free auristatin E (AE) in the presence of ß-glucuronidase and provide ADCs that were highly stable in plasma. Anti-CD30 conjugates comprised of the glucuronide-AE linker were potent and immunologically specific in vitro and in vivo, displaying pharmacologic properties comparable with a carbamate-linked glucuronide-monomethylauristatin E control. The quaternary ammonium linker was then applied to a tubulysin antimitotic drug that contained an N-terminal tertiary amine that was important for activity. A glucuronide-tubulysin quaternary ammonium linker was synthesized and evaluated as an ADC payload, in which the resulting conjugates were found to be potent and immunologically specific in vitro, and displayed a high level of activity in a Hodgkin lymphoma xenograft. Furthermore, the results were superior to those obtained with a related tubulysin derivative containing a secondary amine N-terminus for conjugation using previously known linker technology. The quaternary ammonium linker represents a significant advance in linker technology, enabling stable conjugation of payloads with tertiary amine residues. Mol Cancer Ther; 15(5); 938-45. ©2016 AACR.

Simulation in the early management of gastroschisis.

AIM: Our aim was to design, create, and validate a simulator model and simulation scenario for the early management of gastroschisis. METHODS: Candidates of varying surgical experience had 1 attempt on an abdominal wall defect simulator and were scored for 4 different aspects: resuscitation of the neonate, application of a silo by both a global rating scale and a procedure-specific checklist, and nontechnical skills (scored by Non-Technical Skills scale). Surgical trainees subsequently received a focused teaching module on the resuscitative management and the surgical decision-making process, including bowel protection methods. Trainees then had a second attempt, which was objectively analyzed for improvement. RESULTS: Candidates attempted the simulation and were assessed, looking for construct validity. There was a statistically significant difference between candidate experience levels for all aspects of the simulation (resuscitation, global rating scale, procedure-specific checklist, and nontechnical skills) calculated using analysis of variance. Feedback forms gave us face validity, with a mean adjusted score of 8.3/10 for realism. After teaching the module, there was a statistically significant improvement (P < 0.05) of 20% for technical skills and 10% for nontechnical skills, which is comparable with similar controlled studies. CONCLUSIONS: We showed that creating and running a simulation scenario for the early management of gastroschisis is a feasible and useful tool for training and assessment. The simulation may also be able to discriminate between experience levels and could be used as a teaching aid to improve a surgeon's technical and nontechnical skills.

The aging physician with cognitive impairment: approaches to oversight, prevention, and remediation.

There are many important unanswered issues regarding the occurrence of cognitive impairment in physicians, such as detection of deficits, remediation efforts, policy implications for safe medical practice, and the need to safeguard quality patient care. The authors review existing literature on these complex issues and derive heuristic formulations regarding how to help manage the professional needs of the aging physician with dementia. To ensure safe standards of medical care while also protecting the needs of physicians and their families, state regulatory or licensing agencies in collaboration with state medical associations and academic medical centers should generate evaluation guidelines to assure continued high levels of functioning. The authors also raise the question of whether age should be considered as a risk factor that merits special screening for adequate functioning. Either age-related screening for cognitive impairment should be initiated or rigorous evaluation after lapses in standard of care should be the norm regardless of age. Ultimately, competence rather than mandatory retirement due to age per se should be the deciding factor regarding whether physicians should be able to continue their practice. Finally, the authors issue a call for an expert consensus panel to convene to make recommendations concerning aging physicians with cognitive impairment who are at risk for medical errors.

Olanzapine in cocaine dependence: a double-blind, placebo-controlled trial.

Preclinical and uncontrolled human studies have suggested the possible efficacy of second-generation antipsychotics, particularly olanzapine, in treating cocaine dependence. We conducted a randomized, double-blind, placebo-controlled trial in which 48 cocaine-dependent subjects received olanzapine or identical-appearing placebo for 16 weeks. The primary outcome measure was the proportion of cocaine-negative weekly urine screens during treatment. Secondary measures included scores on a Craving Questionnaire, Addiction Severity Index subscales, and extrapyramidal symptom scales. Olanzapine and placebo did not differ on any outcome measure. Both olanzapine and placebo subjects frequently reported side effects, but no unexpected ones. We conclude that olanzapine appears ineffective for cocaine dependence.

When anxiety symptoms masquerade as medical symptoms: what medical specialists know about panic disorder and available psychological treatments.

Under-recognition of somatic symptoms associated with panic in primary care settings results in unnecessary and costly diagnostic procedures and inappropriate referrals to cardiologists, gastroenterologists, and neurologists. In the current study specialists' knowledge regarding the nature and treatment of panic were examined. One-hundred and fourteen specialists completed a questionnaire assessing their knowledge about panic attacks, including their perceptions of psychologists' role in treating panic. Respondents answered 51% of knowledge items correctly. Although most knew the definition of a panic attack, they knew less about clinical features of panic and its treatment. Specifically, whereas 97.4% believed medication effectively relieves panic symptoms, only 32.5% knew that cognitive-behavioral therapy (CBT) is a first-line treatment. Only 6% reported knowing how to implement CBT, and only 56.1% recognized that psychologists could effectively treat panic. These findings demonstrate significant gaps in specialists' knowledge about panic and the need to enhance physician knowledge about panic attacks and their treatment.

Treating comorbid panic disorder in veterans with posttraumatic stress disorder.

This study compares the effectiveness of panic control treatment (PCT) with that of a psychoeducational supportive treatment (PE-SUP) in treating panic disorder among a veteran sample with a primary diagnosis of chronic posttraumatic stress disorder (PTSD). Thirty-five patients randomized to receive 10 individual sessions of either PCT or PE-SUP underwent assessments at pretreatment, at 1-week posttreatment, and at a 3-month follow-up. Intent-to-treat analyses of covariance showed that PCT participants significantly improved on panic severity at posttreatment and panic fear at the 3-month follow-up. The PCT group also showed significant reductions in anxiety sensitivity at posttreatment and follow-up compared with that of the PE-SUP group. A significantly higher proportion of persons (63%) in the PCT group was panic free by the follow-up period compared with that of the PE-SUP group (19%). Patient self-report and clinician ratings showed no changes in general anxiety, depression, and PTSD symptoms in either group. These findings indicated that PCT was superior to an active control therapy in reducing the frequency, severity, and distress associated with panic disorder and suggested that brief cognitive-behavioral therapy for panic is effective for persons with chronic PTSD.