A geometric morphometric analysis of wing variations in shape and size of the blue bottle fly, Calliphora vicina (Diptera: Calliphoridae).

A geometric morphometric analysis was performed on the right wing of adult Calliphora vicina (Robineau-Desvoidy) collected across 4 altitudinal levels in Sicily. The objective of this study was to assess differences in shape and centroid size (CS) between females and males and across elevations. The wings analyzed in this study were removed from adults of C. vicina collected with baited traps at 20, 700, 1,153, and 1,552; for this study, 19 landmarks were identified in each wing. The coordinates of the landmarks were aligned and superimposed to prevent variations due to position, orientation, and scale; they were then scaled to the same CS and recentered. CS and Procrustes differences were, respectively, used to assess variations in size and shape. Significant differences were observed in wing shape between males and females but not between all altitudinal levels. Female wings were found to be significantly larger than males (P < 0.01). Wings of flies collected at the highest altitudinal level resulted in significantly larger wings than those collected at lower altitudes (P < 0.001), with CS values ranging from 12.1 to 14.1. Variation in wing shape can impact thermal regulation, and therefore, oxygen content, temperature, atmospheric pressure, and solar radiation can have an effect on an insect's body and activity levels. At high elevations and lower temperatures, larger wings could mean less energy expenditure when flying to increase body temperature.

Transnational comparison of the impact of COVID-19 on medicolegal death investigations and the administration of justice: Early stages of the pandemic.

COVID-19 has had an unprecedented impact on arguably every sector of our criminal justice system. To assess the impact that this global health crisis has had on our medicolegal investigations and administration of justice during the early stages of the pandemic, this research aims to give voice to the lived experiences of medicolegal death investigators (coroners, medical examiners and pathologists). This research involved in-depth interviews and follow-ups with experienced personnel from Canada (3), Italy (1), the United Kingdom (1) and the United States (4). Results suggest that despite facing similar challenges, each individual office has had to develop their own strategies to overcome obstacles during the early stages of the pandemic. These results help identify overlapping areas for constructive policy and procedural changes, including recommendations for workflow adaptations, strategic partnerships and other approaches to best prepare for subsequent health crises.

COVID-19 and British Columbia's volunteer search and rescue workers: risk recognition and risk mitigation.

Background: Early during COVID-19, British Columbia coordinated collaboration between academic researchers, public healthcare systems, and private sector partners to focus research resources on knowledge gaps in a timely manner, avoid duplication, and identify overlooked aspects. At a collaboration symposium, it became evident that BC's volunteer search & rescue (SAR) cadre was overlooked. Objective: Our exploratory project studied volunteer SAR's operational readiness; use and perceived value of information sources; consistency in infection prevention measures among volunteer stations, and with their professional counterparts for comparable first aid medical interventions throughout the pandemic. Methods: We partnered with the 2 organizations that govern BC's volunteer SAR stations. Local station leaders completed a short confidential survey. Guidance documents issued by associations governing voluntary and professional first responders were compared. Results: Survey responses were received from 33 of 109 local stations, spanning all regions of BC. Most remained operationally ready throughout the entire pandemic (12.1% had to stand down at times). Except for 21% lacking eye protection, all had personal protective equipment commensurate with that of healthcare professionals; however, few used this PPE in a manner consistent with professional counterparts. Usage and perceived usefulness of various information sources differed. There was no communication link between the province's infection control experts and 2 volunteer SAR organizations. Conclusions: Search & rescue capability was maintained despite pandemic impacts. Results reveal strengths and opportunities for improvement in the ways volunteers are informed and protected. Infection control experts providing advice for emergency health services professional responders should remember to include their volunteer counterparts.

A bedside to bench study of anti-PD-1, anti-CD40, and anti-CSF1R indicates that more is not necessarily better.

BACKGROUND: Stimulating inflammatory tumor associated macrophages can overcome resistance to PD-(L)1 blockade. We previously conducted a phase I trial of cabiralizumab (anti-CSF1R), sotigalimab (CD40-agonist) and nivolumab. Our current purpose was to study the activity and cellular effects of this three-drug regimen in anti-PD-1-resistant melanoma. METHODS: We employed a Simon's two-stage design and analyzed circulating immune cells from patients treated with this regimen for treatment-related changes. We assessed various dose levels of anti-CSF1R in murine melanoma models and studied the cellular and molecular effects. RESULTS: Thirteen patients were enrolled in the first stage. We observed one (7.7%) confirmed and one (7.7%) unconfirmed partial response, 5 patients had stable disease (38.5%) and 6 disease progression (42.6%). We elected not to proceed to the second stage. CyTOF analysis revealed a reduction in non-classical monocytes. Patients with prolonged stable disease or partial response who remained on study for longer had increased markers of antigen presentation after treatment compared to patients whose disease progressed rapidly. In a murine model, higher anti-CSF1R doses resulted in increased tumor growth and worse survival. Using single-cell RNA-sequencing, we identified a suppressive monocyte/macrophage population in murine tumors exposed to higher doses. CONCLUSIONS: Higher anti-CSF1R doses are inferior to lower doses in a preclinical model, inducing a suppressive macrophage population, and potentially explaining the disappointing results observed in patients. While it is impossible to directly infer human doses from murine studies, careful intra-species evaluation can provide important insight. Cabiralizumab dose optimization is necessary for this patient population with limited treatment options. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03502330.

A standard enteral formula versus an iso-caloric lower carbohydrate/high fat enteral formula in the hospital management of adolescent and young adults admitted with anorexia nervosa: a randomised controlled trial.

BACKGROUND: The nutritional rehabilitation of malnourished patients hospitalised with anorexia nervosa is essential. The provision of adequate nutrition must occur, while simultaneously, minimising the risk of refeeding complications, such as electrolyte, metabolic, and organ dysfunction. The aim of this study was to compare the efficacy and safety of an iso-caloric lower carbohydrate/high fat enteral formula (28% carbohydrate, 56% fat) against a standard enteral formula (54% carbohydrate, 29% fat). METHODS: Patients (aged 15-25 years) hospitalised with anorexia nervosa were recruited into this double blinded randomised controlled trial. An interim analysis was completed at midpoint, when 24 participants, mean age 17.5 years (± 1.1), had been randomly allocated to lower carbohydrate/high fat (n = 14) or standard (n = 10) feeds. RESULTS: At baseline, there was no significant difference in degree of malnutrition, medical instability, history of purging or serum phosphate levels between the two treatment arms. A significantly lower rate of hypophosphatemia developed in patients who received the lower carbohydrate/high fat formula compared to standard formula (5/14 vs 9/10, p = 0.013). The serum phosphate level decreased in both feeds, however it decreased to a larger extent in the standard feed compared to the lower carbohydrate/high fat feed (standard feed 1.11 ± 0.13 mmol/L at baseline vs 0.88 ± 0.12 mmol/L at week 1; lower carbohydrate/high fat feed 1.18 ± 0.19 mmol/L at baseline vs 1.06 ± 0.15 mmol/L at week 1). Overall, serum phosphate levels were significantly higher in the lower carbohydrate/high fat feed compared with standard feed treatment arm at Week 1 (1.06 ± 0.15 mmol/L vs 0.88 ± 0.12 mmol/L, p < 0.001). There was no significant difference in weight gain, number of days to reach medical stability, incidence of hypoglycaemia, or hospital length of stay. CONCLUSIONS: The results of this study indicate that enteral nutrition provided to hospitalised malnourished young people with anorexia nervosa using a lower carbohydrate/high fat formula (28% carbohydrate, 56% fat) seems to provide protection from hypophosphatemia in the first week compared to when using a standard enteral formula. Further research may be required to confirm this finding in other malnourished populations. TRIAL REGISTRATION: ANZCTR, ACTRN12617000342314. Registered 3 March 2017, http://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12617000342314.

Patients hospitalised with anorexia nervosa require nutrition support as part of their treatment, whilst refeeding complications are prevented. Of particular concern, is the reintroduction of carbohydrate to malnourished patients, which has been proposed to cause a surge in insulin levels and disturbance in electrolytes, particularly a decrease in blood phosphate levels. This double-blinded randomised controlled trial measured the occurrence of low phosphate blood levels and other refeeding complications, in adolescent and young adult patients hospitalised with anorexia nervosa. These patients were provided either a lower carbohydrate/high fat feed (28% carbohydrate, 56% fat) or a standard enteral feed (54% carbohydrate, 29% fat). Fewer patients in the lower carbohydrate/high fat feed group (5/14) than standard feed group (9/10) developed a low phosphate level. There was no significant difference in weight gain, number of days to reach medical stability, occurrence of hypoglycaemia, or hospital length of stay.

A Phase I Study of APX005M and Cabiralizumab with or without Nivolumab in Patients with Melanoma, Kidney Cancer, or Non-Small Cell Lung Cancer Resistant to Anti-PD-1/PD-L1.

PURPOSE: PD-1/PD-L1 inhibitors are approved for multiple tumor types. However, resistance poses substantial clinical challenges. PATIENTS AND METHODS: We conducted a phase I trial of CD40 agonist APX005M (sotigalimab) and CSF1R inhibitor cabiralizumab with or without nivolumab using a 3+3 dose-escalation design (NCT03502330). Patients were enrolled from June 2018 to April 2019. Eligibility included patients with biopsy-proven advanced melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC) who progressed on anti-PD-1/PD-L1. APX005M was dose escalated (0.03, 0.1, or 0.3 mg/kg i.v.) with a fixed dose of cabiralizumab with or without nivolumab every 2 weeks until disease progression or intolerable toxicity. RESULTS: Twenty-six patients (12 melanoma, 1 NSCLC, and 13 RCC) were enrolled in six cohorts, 17 on nivolumab-containing regimens. Median duration of follow-up was 21.3 months. The most common treatment-related adverse events were asymptomatic elevations of lactate dehydrogenase (n = 26), creatine kinase (n = 25), aspartate aminotransferase (n = 25), and alanine aminotransferase (n = 19); periorbital edema (n = 17); and fatigue (n = 13). One dose-limiting toxicity (acute respiratory distress syndrome) occurred in cohort 2. The recommended phase 2 dose was APX005M 0.3 mg/kg, cabiralizumab 4 mg/kg, and nivolumab 240 mg every 2 weeks. Median days on treatment were 66 (range, 23-443). Median cycles were 4.5 (range, 2-21). One patient had unconfirmed partial response (4%), 8 stable disease (31%), 16 disease progression (62%), and 1 unevaluable (4%). Pro-inflammatory cytokines were upregulated 4 hours post-infusion. CD40 and MCSF increased after therapy. CONCLUSIONS: This first in-human study of patients with anti-PD-1/PD-L1-resistant tumors treated with dual macrophage-polarizing therapy, with or without nivolumab demonstrated safety and pharmacodynamic activity. Optimization of the dosing frequency and sequence of this combination is warranted.

The Forensic Entomology Case Report-A Global Perspective.

Forensic practitioners analyzing entomological evidence are faced with numerous challenges when presenting their findings to law practitioners, particularly in terms of terminology used to describe insect age, what this means for colonization time of remains, and the limitations to estimates made. Due to varying legal requirements in different countries, there is no standard format for the entomological case report prepared, nor any guidelines as to the sections that are required, optional or unnecessary in a case report. The authors herein propose sections that should be considered when drafting an entomological case report. The criteria under which entomological evidence is analyzed are discussed, as well as the limitations for each criterion. The concept of a global, standardized entomological case report is impossible to achieve due to national legislative differences, but the authors here propose a basic template which can be adapted and changed according to the needs of the practitioner. Furthermore, while the discussion is fairly detailed, capturing all differences between nations could not be accomplished, and those initiating casework for the first time are encouraged to engage other practicing forensic entomologists or professional associations within their own nation or region, to ensure a complete report is generated that meets lab or national requirements, prior to generating a finalized report.

Study protocol for a randomised controlled trial investigating two different refeeding formulations to improve safety and efficacy of hospital management of adolescent and young adults admitted with anorexia nervosa.

INTRODUCTION: Providing effective nutritional rehabilitation to patients hospitalised with anorexia nervosa (AN) is challenging, partly due to conservative recommendations that advocate feeding patients at low energy intakes. An 'underfeeding syndrome' can develop when patients are not provided with adequate nutrition during treatment, whereby malnourished patients fail to restore weight in a timely matter, and even lose weight. Of particular concern, the reintroduction of carbohydrate in a starved patient can increase the risk of developing electrolyte, metabolic and organ dysfunction. The proposed trial assesses the efficacy and safety of a lower carbohydrate enteral formula (28% carbohydrate) against a standard enteral formula (54% carbohydrate), in adolescent and young adult patients (aged 15-25 years), hospitalised with AN. METHODS AND ANALYSIS: The study employs a double-blind randomised controlled trial design. At admission to hospital, malnourished adolescent and young adults with AN will be randomly allocated to commence feeding on a standard enteral feeding formula (1.5 kcal/mL, 54% carbohydrate) or a lower carbohydrate isocaloric enteral feeding formula (1.5 kcal/mL, 28% carbohydrate). Assessments of nutritional intake, weight and biochemistry (phosphate, magnesium, potassium) will be conducted at baseline and during the first 3 weeks of hospital admission. The primary outcome measure will be incidence of hypophosphatemia. Secondary outcomes include weight gain, oedema, other electrolyte distortion, length of hospital admission, admission to the Intensive Care Unit (ICU) and number of days to reach medical stability, using defined parameters. ETHICS AND DISSEMINATION: The protocol was approved by the Western Sydney Local Health District Human Research Ethics Committee and institutional research governance approvals were granted. Written informed consent will be sought prior to study enrolment. Study findings will be widely disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12617000342314); Pre-results.

An audit of the changes in thiamine levels during higher caloric nutritional rehabilitation of adolescent patients hospitalised with a restrictive eating disorder.

BACKGROUND: Routine supplementation of thiamine in patients with restrictive eating disorders prior to initiation of nutritional rehabilitation, is an example of a clinical guideline based on expert opinion rather than evidence-based recommendations. This study investigates whether adolescents hospitalised with a restrictive eating disorder commenced on a higher caloric refeeding regimen, present with or develop thiamine deficiency during their admission. METHODS: An eighteen month retrospective audit of 119 consecutive admissions for nutritional rehabilitation was conducted on patients admitted with an eating disorder in a large tertiary teaching hospital in Western Sydney. Data from paper-based and electronic medical records were collected. Baseline and weekly blood thiamine levels were documented, as well as patient demographic information including admission weight, age, length of stay, percentage median body mass index, weight change throughout admission and caloric prescription. RESULTS: Sixty admissions met inclusion criteria, mean age 17.2 years (SD 1.2); 88% female; BMI 16.8 kg/m2 (SD 1.8) on admission. A linear mixed effects model identified that median thiamine levels increased by 9.2 nmol/L per week (p < 0.001). No patient developed thiamine deficiency during their admission, one patient was admitted with thiamine levels below the normal range at 62 nmol (normal range 67 - 200 nmol/L) which resolved by the second week of admission. In 15 out of 60 patients (25%), thiamine levels were observed to rise above the upper limit. CONCLUSIONS: Nutritional management of 60 malnourished adolescents hospitalised with an eating disorder was conducted safely with the provision of only 10 mg thiamine in a multivitamin daily, and no additional thiamine supplementation. The high caloric refeeding protocol, inclusive of a daily multivitamin, provided adequate thiamine to prevent thiamine deficiency. Further research should examine thiamine requirements in an exclusive severely malnourished population to assess the need for thiamine replacement in the most vulnerable group.

Impact of confinement in vehicle trunks on decomposition and entomological colonization of carcasses.

In order to investigate the impact of confinement in a car trunk on decomposition and insect colonization of carcasses, three freshly killed pig (Sus scrofa domesticus Erxleben) carcasses were placed individually in the trunks of older model cars and deployed in a forested area in the southwestern region of British Columbia, Canada, together with three freshly killed carcasses which were exposed in insect-accessible protective cages in the same forest. Decomposition rate and insect colonization of all carcasses were examined twice a week for four weeks. The exposed carcasses were colonized immediately by Calliphora latifrons Hough and Calliphora vomitoria (L.) followed by Lucilia illustris (Meigen), Phormia regina (Meigen) and Protophormia terraenovae (R.-D.) (Diptera: Calliphoridae). There was a delay of three to six days before the confined carcasses were colonized, first by P. regina, followed by Pr. terraenovae. These species represented the vast majority of blow fly species on the confined carcasses. Despite the delay in colonization, decomposition progressed much more rapidly in two of the confined carcasses in comparison with the exposed carcasses due to the greatly increased temperatures inside the vehicles, with the complete skeletonization of two of the confined carcasses ocurring between nine and 13 days after death. One confined carcass was an anomaly, attracting much fewer insects, supporting fewer larval calliphorids and decomposing much more slowly than other carcasses, despite similarly increased temperatures. It was later discovered that the vehicle in which this carcass was confined had a solid metal fire wall between the passenger area and the trunk, which served to reduce insect access and release of odors. These data may be extremely valuable when analyzing cadavers found inside vehicle trunks.

Effect of arson fires on survivability of entomological evidence on carcasses inside vehicle trunks.

Three vehicles with trunks containing pig (Sus scrofa domesticus Erxleben) carcasses which had been allowed to decompose for 30 days, were set alight in controlled burns to determine whether forensically valuable insect evidence could still be recovered. Each car trunk contained the remains of a carcass, together with its associated carrion insect fauna. An insect collection was performed prior to the fires. Each car was then set alight using a small amount of gasoline as an accelerant, poured onto the driver's seat, lit by a burning stick. The fire was allowed to reach its peak before being extinguished. In all cases, the fires completely destroyed the vehicles. The vehicles were examined the following day and insect evidence was collected. In all cases, large amounts of burned, charred and undamaged insect evidence remained, including identifiable prepuparial 3rd instar larvae, live pupae inside intact puparia and empty puparial cases. As well bones and unburned clothing were also intact. One car did not burn as well as the others with the fire not involving the trunk area as much as in the other cars. Once the fire was extinguished, it was clear that the reason for this was the presence of a steel fire wall, between the passenger compartment and the trunk. This reduced the spread of the fire to the trunk and increased evidence survival. However, in all vehicles, insect evidence survived, which could still be used to estimate the period of insect colonization and thereby infer the minimum elapsed time since death. The evidence was also a clear indicator that the decedent had not died in the fire. After the fire, the carcass remains were still attractive to blow fly adults (Diptera: Calliphoridae). In car fire cases it is important to consider that entomological evidence may still be just as useful in the investigation as in non-burned cases.

Understanding the neural mechanisms of lisdexamfetamine dimesylate (LDX) pharmacotherapy in Binge Eating Disorder (BED): a study protocol.

BACKGROUND: The efficacy and safety of Lisdexamfetamine dimesylate (LDX) in the treatment of moderate to severe binge eating disorder (BED) has been demonstrated in multiple randomised clinical trials. Despite this, little is known about how LDX acts to improve binge eating symptoms. This study aims to provide a comprehensive understanding of the neural mechanisms by which LDX improves symptoms of BED. We hypothesise that LDX will act by normalising connectivity within neural circuits responsible for reward and impulse control, and that this normalisation will correlate with reduced binge eating episodes. METHODS: This is an open-label Phase 4 clinical trial of LDX in adults with moderate to severe BED. Enrolment will include 40 adults with moderate to severe BED aged 18-40 years and Body Mass Index (BMI) of 20-45 kg/m2, and 22 healthy controls matched for age, gender and BMI. Clinical interview and validated scales are used to confirm diagnosis and screen for exclusion criteria, which include comorbid anorexia nervosa or bulimia nervosa, use of psychostimulants within the past 6 months, and current use of antipsychotics or noradrenaline reuptake inhibitors. Baseline assessments include clinical symptoms, multimodal neuroimaging, cognitive assessment of reward sensitivity and behavioural inhibition, and an (optional) genetic sample. A subset of these assessments are repeated after eight weeks of treatment with LDX titrated to either 50 or 70 mg. The primary outcome measures are resting-state intrinsic connectivity and the number of binge eating episodes. Analyses will be applied to resting-state fMRI data to characterise pharmacological effects across the functional connectome, and assess correlations with symptom measure changes. Comparison of neural measures between controls and those with BED post-treatment will also be performed to determine whether LDX normalises brain function. DISCUSSION: First enrolment was in May 2018, and is ongoing. This study is the first comprehensive investigation of the neurobiological changes that occur with LDX treatment in adults with moderate to severe BED. TRIAL REGISTRATION: ACTRN12618000623291, Australian and New Zealand Clinical Trials Registry URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374913&isReview=true. Date of Registration: 20 April 2018.

Predicting Unbound Phenytoin Concentrations: Effects of Albumin Concentration and Kidney Dysfunction.

STUDY OBJECTIVE: Several methods are available to predict unbound (free) phenytoin concentrations in patients with hypoalbuminemia; however, predictive methods have not been evaluated in patients with concurrent hypoalbuminemia and kidney dysfunction or in patients with mild to moderate (estimated glomerular filtration rate [eGFR] 30-90 ml/min/1.73 m2 ) kidney dysfunction alone. Thus the objective was to evaluate the accuracy and precision of predictive methods to estimate free phenytoin concentrations in patients with varying albumin concentrations and/or kidney dysfunction. DESIGN: Retrospective chart review. SETTING: Large academic medical center. PATIENTS: A total of 344 patients with free and total phenytoin, albumin, and serum creatinine concentrations obtained between November 2012 and May 2017. MEASUREMENTS AND MAIN RESULTS: Free phenytoin concentrations were estimated in patients without kidney dysfunction using the Winter-Tozer, Anderson, Kane, and Cheng equations. For the analysis in patients with eGFR lower than 90 ml/min/1.73 m2 , free phenytoin concentrations were estimated using the Shiner-Tozer derivation with adjusted affinity coefficients (C = 0.15, 0.20, 0.25, and 0.30). For both analyses, accuracy of predictive methods was evaluated by P20, the proportion of estimations within 20% of the measured free phenytoin concentration. In 158 patients with normal kidney function/normal albumin concentrations, 73 with normal kidney function/hypoalbuminemia, or 47 with mild kidney dysfunction/normal albumin concentrations, the Anderson method had the highest accuracy (86%, 82%, and 92%, respectively) and highest precision compared with the other methods. In 47 patients with normal albumin concentrations and mild kidney dysfunction or 13 with moderate kidney dysfunction, the free fraction was unchanged, and total phenytoin concentrations accurately reflected free concentrations. In 17 patients with hypoalbuminemia and mild or 17 with moderate kidney dysfunction, the Winter-Tozer (67% and 50%, respectively) and the Anderson (56% and 67%, respectively) methods had the highest accuracy compared with other methods with significantly lower accuracy compared with patients with normal kidney function. In the 14 patients with severe kidney dysfunction and hypoalbuminemia, none of the coefficients had a P20 accuracy greater than 45%. CONCLUSION: In patients with normal albumin concentrations, with or without mild or moderate kidney dysfunction and not receiving a protein-binding displacer, the free fraction of phenytoin is unchanged, and it is not necessary to measure a free phenytoin concentration. Free phenytoin concentrations should be measured directly in patients with hypoalbuminemia and kidney dysfunction.

Long-Term Survival of Patients With Melanoma With Active Brain Metastases Treated With Pembrolizumab on a Phase II Trial.

PURPOSE: Pembrolizumab is active in melanoma, but activity in patients with untreated brain metastasis is less established. We present long-term follow-up of pembrolizumab-treated patients with new or progressing brain metastases treated on a phase II clinical trial ( ClinicalTrials.gov identifier: NCT02085070). PATIENTS AND METHODS: We enrolled 23 patients with melanoma with one or more asymptomatic, untreated 5- to 20-mm brain metastasis not requiring corticosteroids; 70% of patients had prior systemic therapy. Pembrolizumab was administered for up to 24 months. Brain metastasis response, the primary end point, was assessed by modified Response Evaluation Criteria in Solid Tumors (RECIST). Pretreatment tumors were analyzed for T-cell infiltrate and programmed death ligand 1. RESULTS: Six patients (26%) had a brain metastasis response. Eight patients (35%) did not reach a protocol evaluation scan and were unevaluable for brain metastasis response as a result of progression or need for radiation. Brain metastasis and systemic responses were concordant, with all ongoing at 24 months. The median progression-free and overall survival times were 2 and 17 months, respectively. Eleven patients (48%) were alive at 24 months. This included three unevaluable patients. One of these three patients had hemorrhaged, and two had symptoms from perilesional edema requiring radiosurgery, but all three patients remained on commercial pembrolizumab more than 24 months later. None of the 24-month survivors received subsequent BRAF inhibitors. Neurologic adverse events occurred in 65% of patients; all adverse events but one were grade 1 or 2. Three patients had seizures, which were treated with anticonvulsants. Most responders had higher pretreatment tumor CD8 cell density and programmed death ligand 1 expression, whereas all nonresponders did not. CONCLUSION: Pembrolizumab is active in melanoma brain metastases with acceptable toxicity and durable responses. Multidisciplinary care is required to optimally manage patients with brain metastases, including consideration of radiation to large or symptomatic lesions, which were excluded in this trial. Two-year survival was similar to patients without brain metastasis treated with anti-programmed cell death 1 agents. Concordant brain and extracerebral responses support use of pembrolizumab to treat small, asymptomatic brain metastases.

Gallium disrupts bacterial iron metabolism and has therapeutic effects in mice and humans with lung infections.

The lack of new antibiotics is among the most critical challenges facing medicine. The problem is particularly acute for Gram-negative bacteria. An unconventional antibiotic strategy is to target bacterial nutrition and metabolism. The metal gallium can disrupt bacterial iron metabolism because it substitutes for iron when taken up by bacteria. We investigated the antibiotic activity of gallium ex vivo, in a mouse model of airway infection, and in a phase 1 clinical trial in individuals with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa airway infections. Our results show that micromolar concentrations of gallium inhibited P. aeruginosa growth in sputum samples from patients with CF. Ex vivo experiments indicated that gallium inhibited key iron-dependent bacterial enzymes and increased bacterial sensitivity to oxidants. Furthermore, gallium resistance developed slowly, its activity was synergistic with certain antibiotics, and gallium did not diminish the antibacterial activity of host macrophages. Systemic gallium treatment showed antibiotic activity in murine lung infections. In addition, systemic gallium treatment improved lung function in people with CF and chronic P. aeruginosa lung infection in a preliminary phase 1 clinical trial. These findings raise the possibility that human infections could be treated by targeting iron metabolism or other nutritional vulnerabilities of bacterial pathogens.

Anorexia Nervosa, Anxiety, and the Clinical Implications of Rapid Refeeding.

The current study aimed to examine the temporal relationship between anxiety symptoms and weight gain for adolescents with anorexia nervosa over the course of an inpatient admission targeting weight restoration through rapid refeeding. Participants were 31 females presenting to a specialist inpatient unit. Psychometric assessments using standardized procedures were conducted to assess co-morbid anxiety diagnoses, and eating disorder symptom severity at admission and discharge. Study protocols were completed on a weekly basis over the course of their admission and were compared with weekly BMI change. Multiple mixed-effects linear models with random intercepts were used to assess change in weight status and psychological variables. Results indicated a reduction in anxiety over the course of hospitalization; however, there was no evidence to support a relationship between anxiety change and weight restoration. The clinical implications of these results are discussed and directions for future research recommended.

Pharmacokinetic Factors to Consider in the Selection of Antiseizure Drugs for Older Patients with Epilepsy.

The incidence of epilepsy is highest in the older adult age group. Seizures in older adults can be more difficult to diagnose because their presentation is often subtle and can easily be mistaken for other conditions. Fortunately, new-onset epilepsy in the older adult is often pharmaco-responsive, with as many as 80-85% of patients achieving remission, often with monotherapy at modest doses. Many physiological and pathological changes occur with aging that can alter the pharmacokinetics of antiseizure drugs (ASDs). For the majority of the old- and new-generation ASDs, a decrease in dose may be needed to maintain concentrations equivalent to those found in young adults. The risk of drug interactions with ASDs is substantial, as polypharmacy is common. The first-generation ASDs (carbamazepine, phenytoin, phenobarbital, and valproic acid) have the potential to interact with many drugs, but many newer ASDs either do not have significant interactions or are selective inhibitors and inducers of specific hepatic enzymes. The differences in adverse effects between younger and older adults are not just due to dosing and pharmacokinetics. Older adults are more susceptible to the gait, balance, and cognitive effects of ASDs. Overall, the improved tolerability and decreased drug interaction potential of the newer-generation ASDs, such as lamotrigine and levetiracetam, have demonstrated their superiority in the treatment of seizures in older adults and, as such, are clearly favored for new-onset epilepsy in older adults.