Developing a mental toughness program for basic military training.

To build a warfighter from the ground up, training should include not only the core competencies required for job performance in the Fleet but also the mental toughness expected to handle the stress, fatigue, and call for sudden action required of all sailors on duty, regardless of occupation. Recruit Training Command (RTC) has embarked on a program to provide explicit training to recruits on the development of toughness in boot camp. This program is multifaceted, including three pilot programs (two all-male pilots, one integrated/mixed gender pilot) for mental skill training. Recruit divisions were assigned to either mental toughness (MT) condition or active control (AC). The MT group received daily, 10-min guided mindfulness exercises, three "just-in-time" trainings in sports psychology skills, and an on-command focusing exercise. Results varied across the three pilots with the exception of on-time graduation rates, which favored the MT condition in every pilot. Taken together, the three MT pilot studies show possible benefits for performance during boot camp with MT practice, and predictable advantages for graduation rates.

Health Literacy in Surgical Oncology Patients: An Observational Study at a Comprehensive Cancer Center.

BACKGROUND: Low health literacy is associated with increased resource use and poorer outcomes in medical and surgical patients with various diseases. This observational study was designed to determine (1) the prevalence of low health literacy among surgical patients with cancer at an NCI-designated Comprehensive Cancer Center (CCC), and (2) associations between health literacy and clinical outcomes. METHODS: Patients receiving surgery (N=218) for gastrointestinal (60%) or genitourinary cancers (22%) or sarcomas (18%) were recruited during their postsurgical hospitalization. Patients self-reported health literacy using the Brief Health Literacy Screening Tool (BRIEF). Clinical data (length of stay [LoS], postacute care needs, and unplanned presentation for care within 30 days) were abstracted from the electronic medical records 90 days after surgery. Multivariate linear and logistic regressions were used to examine the relationship between health literacy and clinical outcomes, adjusting for potential confounding variables. RESULTS: Of 218 participants, 31 (14%) showed low health literacy (BRIEF score ≤12). In regression analyses including 212 patients with complete data, low health literacy significantly predicted LoS (ß = -1.82; 95% CI, -3.00 to -0.66; P=.002) and postacute care needs (odds ratio [OR], 0.25; 95% CI, 0.07-0.91). However, health literacy was not significantly associated with unplanned presentation for care in the 30 days after surgery (OR, 0.51; 95% CI, 0.20-1.29). CONCLUSIONS: This study demonstrates the prevalence of low health literacy in a surgical cancer population at a high-volume NCI-designated CCC and its association with important clinical outcomes, including hospital LoS and postacute care needs. Universal screening and patient navigation may be 2 approaches to mitigate the impact of low health literacy on postsurgical outcomes.

Meta-analysis of sleep deprivation in the acute treatment of bipolar depression.

BACKGROUND: Sleep deprivation (SD) is an antidepressant intervention with multiple administration formats that has been investigated primarily with uncontrolled clinical trials and qualitative reviews of the literature. The validity and applicability of these findings to the treatment of bipolar depression (BPD) is uncertain. METHODS: A PRISMA-based systematic review of the literature and meta-analysis were conducted to determine the efficacy of SD in the treatment of BPD and to identify moderator variables that influence response rate. RESULTS: From a sample of 15 studies covering 384 patients, the overall, mean response rate to SD was 47.6% (CI 36.0%, 59.5%). This response rate compared post-SD to pre-SD depression scores, and not to a placebo control condition. Of several potential moderating variables examined, the use of adjunctive pharmacotherapy achieved statistical significance with response rates of 59.4% [CI 48.5, 69.5] for patients using adjunctive medication vs 27.4% [CI 17.8, 39.8] for patients not using adjunctive medication. CONCLUSIONS: This meta-analysis of SD in the treatment of BPD found an overall, response rate of almost 50%, reinforcing earlier estimates of efficacy. The use of adjunctive pharmacotherapy had a statistically significant moderating effect on SD response suggesting that clinical practice should routinely pair these interventions. These findings provide a higher level of evidence supporting the use of SD, especially when used with medication, and should inform future management guidelines for the treatment of BPD.

Creutzfeldt-Jakob disease in a man with COVID-19: SARS-CoV-2-accelerated neurodegeneration?

We describe a man whose first manifestations of Creutzfeldt-Jakob disease occurred in tandem with symptomatic onset of coronavirus disease 2019 (COVID-19). Drawing from recent data on prion disease pathogenesis and immune responses to SARS-CoV-2, we hypothesize that the cascade of systemic inflammatory mediators in response to the virus accelerated the pathogenesis of our patient's prion disease. This hypothesis introduces the potential relationship between immune responses to the novel coronavirus and the hastening of preclinical or manifest neurodegenerative disorders. The global prevalence of both COVID-19 and neurodegenerative disorders adds urgency to the study of this potential relationship.

Medicine in the Fourth Dimension.

The importance of circadian biology has rarely been considered in pre-clinical studies, and even more when translating to the bedside. Circadian biology is becoming a critical factor for improving drug efficacy and diminishing drug toxicity. Indeed, there is emerging evidence showing that some drugs are more effective at nighttime than daytime, whereas for others it is the opposite. This suggests that the biology of the target cell will determine how an organ will respond to a drug at a specific time of the day, thus modulating pharmacodynamics. Thus, it is now time that circadian factors become an integral part of translational research.

The Legalization of Medical/Recreational Marijuana: Implications for School Health Drug Education Programs.

BACKGROUND: More than half of US states have legalized medical marijuana. Several states have also legalized it for recreational use. In spite of states' actions, marijuana remains illegal under federal law. It remains to be seen, however, if the Trump administration will enforce federal law in states that have legalized marijuana. For now, it appears the move toward state legalization of marijuana will increase. Because of its legal status, research concerning the medical benefits of marijuana has been limited. METHODS: We reviewed the literature pertaining to medical use and legalization of marijuana. RESULTS: Available research shows that marijuana can benefit some conditions. There are also concerns about harmful effects on both individual and public health and whether legalization will lead to increased marijuana use among youth. Each of these elements has implications for school-based drug education programs. Researchers have shown that the 10 states with the highest rate of past month marijuana use by youth all have legalized recreational and/or medical use of marijuana, whereas none of the 10 states with the lowest rate of past month marijuana use by youth, has legalized marijuana. In the debate over legalization schools can potentially serve as a community resource, providing accurate information concerning marijuana. CONCLUSIONS: Teachers and parents should continue to discourage young people from using marijuana (as well as alcohol, tobacco, and other drugs).

Patterns of depressive symptom remission during the treatment of seasonal affective disorder with cognitive-behavioral therapy or light therapy.

BACKGROUND: To elucidate mechanisms related to remission in winter seasonal affective disorder (SAD), we explored the course of individual depressive symptom offset across two distinct treatment modalities that show comparable outcomes at treatment endpoint: cognitive-behavioral therapy for SAD (CBT-SAD) and light therapy (LT). METHOD: One hundred seventy-seven adults with SAD in a depressive episode were randomized to 6-weeks of CBT-SAD (n = 88) or LT (n = 89). Symptoms were assessed via the 29-item Structured Interview Guide for the Hamilton Rating Scale for Depression-SAD Version (SIGH-SAD) at pretreatment and weekly during treatment. Survival analyses were conducted for the 17 SIGH-SAD items endorsed by more than 40 participants at pretreatment. Within each of the included symptoms, data from participants who endorsed the symptom at pretreatment and who had 3 or fewer weeks missing were included. RESULTS: For most (13/17; 76%) symptoms, CBT-SAD and LT did not differ in time to remission. However, for four symptoms (early insomnia, psychic anxiety, hypersomnia, and social withdrawal), LT led to symptom remission more quickly than CBT-SAD. CONCLUSIONS: Symptom remission progressed comparably across CBT-SAD and LT for most symptoms. Despite the fact that the two treatments led to similar remission rates and improvements at treatment endpoint, for early insomnia, psychic anxiety, hypersomnia, and social withdrawal, LT led to symptom remission faster than CBT-SAD. These results suggest different mechanisms and pathways to the same therapeutic end. Speedier remission of early insomnia and hypersomnia is consistent with the theory that SAD is related to a pathological circadian phase-shift that can be corrected with LT.

Cheaper faster drug development validated by the repositioning of drugs against neglected tropical diseases.

There is an urgent need to make drug discovery cheaper and faster. This will enable the development of treatments for diseases currently neglected for economic reasons, such as tropical and orphan diseases, and generally increase the supply of new drugs. Here, we report the Robot Scientist 'Eve' designed to make drug discovery more economical. A Robot Scientist is a laboratory automation system that uses artificial intelligence (AI) techniques to discover scientific knowledge through cycles of experimentation. Eve integrates and automates library-screening, hit-confirmation, and lead generation through cycles of quantitative structure activity relationship learning and testing. Using econometric modelling we demonstrate that the use of AI to select compounds economically outperforms standard drug screening. For further efficiency Eve uses a standardized form of assay to compute Boolean functions of compound properties. These assays can be quickly and cheaply engineered using synthetic biology, enabling more targets to be assayed for a given budget. Eve has repositioned several drugs against specific targets in parasites that cause tropical diseases. One validated discovery is that the anti-cancer compound TNP-470 is a potent inhibitor of dihydrofolate reductase from the malaria-causing parasite Plasmodium vivax.

Assessing the feasibility of a virtual tumor board program: a case study.

Multidisciplinary tumor boards involve various providers (e.g., oncology physicians, nurses) in patient care. Although many community hospitals have local tumor boards that review all types of cases, numerous providers, particularly in rural areas and smaller institutions, still lack access to tumor boards specializing in a particular type of cancer (e.g., hematologic). Videoconferencing technology can connect providers across geographic locations and institutions; however, virtual tumor board (VTB) programs using this technology are uncommon. In this study, we evaluated the feasibility of a new VTB program at the University of North Carolina (UNC) Lineberger Comprehensive Cancer Center, which connects community-based clinicians to UNC tumor boards representing different cancer types. Methods included observations, interviews, and surveys. Our findings suggest that participants were generally satisfied with the VTB. Cases presented to the VTB were appropriate, sufficient information was available for discussion, and technology problems were uncommon. UNC clinicians viewed the VTB as a service to patients and colleagues and an opportunity for clinical trial recruitment. Community-based clinicians presenting at VTBs valued the discussion, even if it simply confirmed their original treatment plan or did not yield consensus recommendations. Barriers to participation for community-based clinicians included timing of the VTB and lack of reimbursement. To maximize benefits of the VTB, these barriers should be addressed, scheduling and preparation processes optimized, and appropriate measures for evaluating impact identified.

Spin state modulation of iron spin crossover complexes via hydrogen-bonding self-assembly.

Iron complexes derived from 6-diaminotriazyl-2,2'-bipyridines display spin crossover behaviour, and hydrogen bonding-controlled self-assembly with a suitable barbiturate partner can modulate the crossover from mixed low and high spin to high spin. This system is the first to use solution-phase self-assembly of complementary hydrogen-bonding organic species to modulate spin state.

Multiphoton imaging with a direct-diode pumped femtosecond Ti:sapphire laser.

A direct-diode pumped Ti:sapphire femtosecond oscillator is used to perform multiphoton imaging for the first time.

Dietary milk fat globule membrane reduces the incidence of aberrant crypt foci in Fischer-344 rats.

Milk fat globule membrane (MFGM) is a biopolymer composed primarily of membrane proteins and lipids that surround the fat globules in milk. Although it is considered to have potential as a bioactive ingredient, few feeding studies have been conducted to measure its potential benefits. The aim of this investigation was to determine if dietary MFGM confers protection against colon carcinogenesis compared to diets containing corn oil (CO) or anhydrous milk fat (AMF). Male, weanling Fischer-344 rats were randomly assigned to one of three dietary treatments that differed only in the fat source: (1) AIN-76A diet, corn oil; (2) AIN-76A diet, AMF; and (3) AIN-76A diet, 50% MFGM, 50% AMF. Each diet contained 50 g/kg diet of fat. With the exception of the fat source, diets were formulated to be identical in macro and micro nutrient content. Animals were injected with 1,2-dimethylhydrazine once per week at weeks 3 and 4, and fed experimental diets for a total of 13 weeks. Over the course of the study dietary treatment did not affect food consumption, weight gain or body composition. After 13 weeks animals were sacrificed, colons were removed and aberrant crypt foci (ACF) were counted by microscopy. Rats fed the MFGM diet (n = 16) had significantly fewer ACF (20.9 +/- 5.7) compared to rats fed corn oil (n = 17) or AMF (n = 16) diets (31.3 +/- 9.5 and 29.8 +/- 11.4 respectively; P < 0.05). Gene expression analysis of colonic mucosa did not reveal differential expression of candidate colon cancer genes, and the sphingolipid profile of the colonic mucosa was not affected by diet. While there were notable and significant differences in plasma and red blood cell lipids, there was no relationship to the cancer protection. These results support previous findings that dietary sphingolipids are protective against colon carcinogenesis yet extend this finding to MFGM, a milk fat fraction available as a food ingredient.

Delayed administration of glial cell line-derived neurotrophic factor (GDNF) protects retinal ganglion cells in a pig model of acute retinal ischemia.

This study investigates whether intravitreal administration of glial cell line-derived neurotrophic factor (GDNF) enhances survival of NeuN positive retinal cells in a porcine model of retinal ischemia. 16 pigs were subjected to an ischemic insult where intraocular pressure was maintained at 5 mmHg below mean arterial blood pressure for 2 h. The mean IOP during the ischemic insult was 79.5 mmHg (s.e.m. 2.1 mmHg, n = 15). Three days after the insult the pigs received an intravitreal injection of GDNF microspheres or blank microspheres. The pigs were evaluated by way of multifocal electroretinography (mfERG), quantification of NeuN positive cells and evaluation of the degree of retinal perivasculitis and inflammation 6 weeks after the insult. In the post-injection eyes (days 14, 28 and 42), the ratios of the iN1 and the iP2 amplitudes were 0.10 (95% CI: 0.05-0.15) and 0.09 (95% CI: 0.04-0.16) in eyes treated with blank microspheres, and 0.24 (95% CI: 0.18-0.32) and 0.23 (95% CI: 0.15-0.33) in eyes treated with GDNF microspheres. These differences were statistically significant (P < 0.05). The number of NeuN positive cells in the area of the visual streak area was significantly higher in eyes injected with GDNF microspheres compared to eyes injected with blank microspheres. In eyes injected with GDNF microspheres the ganglion cell count was 9.5/field (s.e.m.: 2.1, n = 8), in eyes injected with blank microspheres it was 3.5/field (s.e.m.: 1.2, n = 7). This difference was statistically significant (P < 0.05). There was also a significant difference (P < 0.01) in the degree of perivasculiitis between GDNF treated eyes (median perivasculitis score 1.5) and blank treated eyes (median perivasculitis score 3.0). In conclusion, injection of GDNF microspheres 3 days after an ischemic insult results in functional and morphological rescue of NeuN positive cells in a porcine model of acute ocular ischemia.

Changes in chromatin phenotype predict the response to hormonal deprivation therapy in patients with prostate cancer.

OBJECTIVE: To assess the value of studying chromatin organization using high-resolution digital image analysis to predict the response to hormonal-deprivation therapy (HDT) in patients with prostate cancer, using pretreatment prostate tissues. MATERIALS AND METHODS: A tissue microarray (TMA) was constructed using pretreatment paraffin-embedded tissues from transurethral resection of the prostate (TURP) samples (48 patients, 96 cores). None of the patients had received any treatment for prostate cancer before TURP. The patients' medical records for 5 years after treatment were assessed; patients were divided, based on their prostatic specific antigen (PSA) levels after treatment, into those optimally responsive to HDT (14) and those resistant to HDT (34). The latter were further subclassified based on their nadir PSA level. Imaging comprised a calibrated digital image-analysis system with software for densitometric and texture analysis, the latter being assessed on manually segmented nuclei (> or =30 nuclei/core). RESULTS: Most of the measured digital texture features assessing chromatin density and distribution were significantly different between the prognostic groups (P = 0.001). In the training set, 12 of 14 HDT-responsive and 23 (68%) of HDT-resistant patients were accurately predicted. However, all HDT-resistant patients with a nadir PSA level of >5 ng/mL were accurately predicted. The overall classification sensitivity was 47%, specificity 94% with a positive predictive value of 85%. However, the sensitivity was 100% between patients optimally responsive to HDT and those poorly responsive with a nadir PSA level of >5 ng/mL. CONCLUSION: Quantitative image analysis of chromatin phenotype showed promising value in predicting before treatment the response to HDT in patients diagnosed with prostatic adenocarcinoma. However, further work using larger data sets is required before adapting the technique in routine clinical practice.

Intravitreal injections of GDNF-loaded biodegradable microspheres are neuroprotective in a rat model of glaucoma.

PURPOSE: To evaluate the efficacy of intravitreal injection of GDNF-loaded biodegradable microspheres in promoting the survival of retinal ganglion cells (RGCs) and their axons in a rat model of chronically elevated intraocular pressure (IOP). METHODS: Chronic elevation of IOP was induced in Brown Norway rats through injection of hypertonic saline (1.9 M) into the episcleral veins. After injection, IOP was measured twice a week in rats using topical anesthesia. Poly DL-lactide-co-glycolide (PLGA) microspheres were fabricated using a modified version of the spontaneous emulsification technique. Two and ten percent of volume solutions of microspheres loaded with glial cell line-derived neurotrophic factor (GDNF) were injected into the vitreous cavity of rats with elevated IOP, with injections of blank microspheres and PBS serving as controls. Histological analysis was used to quantify surviving RGCs and axons and provide comparison among different groups. In addition, the thickness of the retinal inner plexiform layer (IPL) and the level of glial fibrillary acidic protein (GFAP) expression within the retina and optic nerve were quantitatively compared. RESULTS: IOP was significantly increased in eyes with episcleral vein injection over untreated eyes (p<0.001) but did not show a significant difference among groups that received intravitreal injections of GDNF microspheres, blank microspheres, or PBS (p=0.1852). The duration of IOP elevation in this experiment was eight weeks. Expression of GDNF and its receptors localizes to the adult rat RGCs. Ten percent of the GDNF microsphere treatment significantly increased RGC survival and axon survival (p<0.001), reduced the loss of retinal IPL thickness (p<0.001), and decreased glial cell activation in the retina and optic nerve (p<0.001) compared with blank microspheres and PBS. In addition, GDNF microsphere treatment moderately reduced cupping of the optic nerve head. CONCLUSIONS: Delivery of GDNF via biodegradable microspheres significantly increased the survival of RGCs and their axons, preserved IPL thickness, and decreased retina and optic nerve glial cell activation in an experimental glaucoma model. This study suggests that GDNF delivered by PLGA microspheres may be useful as a neuroprotective tool in the treatment of glaucomatous optic neuropathy.

Therapies for necrotising fasciitis.

Necrotising fasciitis is a rare but life-threatening infectious disease emergency. Delays in diagnosis and treatment are common, and mortality rates often exceed 30%. Successful management of this disease requires high clinical suspicion and aggressive action. The mainstays of therapy include early and wide surgical debridement, antibiotics and supportive care, with prompt surgical intervention. Adjunctive modalities, such as protein synthesis inhibitors, hyperbaric oxygen and intravenous immunoglobulin, may have a role, but their effectiveness remains unproven. New rapid diagnostic tools are emerging that promise to revolutionize early detection of necrotising fasciitis. Research into the molecular microbiology, especially regarding group A streptococcus, are providing novel insights into the pathogenesis of necrotising soft tissue infections and identifying future targets for rationally designed interventions.

Bright light therapy for winter depression--is phase advancing beneficial?

Bright light is the recommended treatment for winter seasonal affective disorder (SAD). Previously we showed that the antidepressant effect of morning (but not evening) light was greater than placebo after 3 weeks of treatment. Here, we determined if the magnitude and direction of circadian rhythm phase shifts produced by the bright light in the previous study were related to the antidepressant effects. Twenty-six SAD patients from the original sample of 96 had their rectal temperature continuously monitored while they participated in a placebo-controlled parallel design conducted over six winters. After a baseline week, there were three treatments for 4 weeks-morning light, evening light, or morning placebo. Bright light was produced by light boxes (approximately 6000 lux). Placebos were sham negative ion generators. All treatments were 1.5 h in duration. Depression ratings were made weekly by blind raters. Circadian phase shifts were determined from changes in the timing of the core body temperature minimum (Tmin). Morning light advanced and evening light delayed the Tmin by about 1 h. The placebo treatment did not alter circadian phase. As the sleep schedule was held constant, morning light increased and evening light decreased the Tmin to wake interval, or phase angle between circadian rhythms and sleep. Phase advance shifts and increases in the phase angle were only weakly associated with antidepressant response. However, there was an inverted U-shaped function showing that regardless of treatment assignment the greatest antidepressant effects occurred when the phase angle was about 3h, and that patients who moved closer to this phase angle benefited more than those who moved farther from it. However 46% of our sample had a phase angle within 30 min of this 3 h interval at baseline. So it does not appear that an abnormal phase angle can entirely account for the etiology of SAD. A majority (75%) of the responders by strict joint criteria had a phase angle within this range after treatment, so it appears that obtaining the ideal phase relationship may account for some, but not all of the antidepressant response. In any case, regardless of the mechanism for the antidepressant effect of morning light, it can be enhanced when patients sleep at the ideal circadian phase and reduced when they sleep at a more abnormal circadian phase.

Solid-phase extraction and cleanup procedures for determination of acrylamide in fried potato products by liquid chromatography/mass spectrometry.

In response to recent discoveries of acrylamide in heated foods, a solid-phase extraction and cleanup protocol was developed for the determination of acrylamide in fried or baked potato samples by liquid chromatography/mass spectrometry (LC/MS). The analyte was extracted from the matrix by using 2M NaCl, and an aliquot of the initial extract was loaded onto a reversed-phase cartridge. After the analyte was eluted from the cartridge, the eluate was cleaned up on a mixed-mode cation-exchange cartridge. The eluate was then evaporated, and the residue was reconstituted in mobile phase before LC/MS analysis. Recoveries, based on the recovery of an added internal standard, ranged from 96 to 101% with relative standard deviations (RSDs) of 5-11%. The response was linear for a concentration range of 100-2000 ng/g with a coefficient of determination (R2) of 0.992 (n = 25). An interday study showed good accuracy and precision of the method over a 3-day period with a recovery of 98% and an RSD of 9.5% (n = 15). The analyses of 6 potato chip samples showed concentrations of incurred acrylamide ranging from 260 to 1500 ng/g.