Tob Regulates the Timing of Sleep Onset at Night in Drosophila.

Sleep is regulated by homeostatic sleep drive and the circadian clock. While tremendous progress has been made in elucidating the molecular components of the core circadian oscillator, the output mechanisms by which this robust oscillator generates rhythmic sleep behavior remain poorly understood. At the cellular level, growing evidence suggests that subcircuits in the master circadian pacemaker suprachiasmatic nucleus (SCN) in mammals and in the clock network in Drosophila regulate distinct aspects of sleep. Thus, to identify novel molecules regulating the circadian timing of sleep, we conducted a large-scale screen of mouse SCN-enriched genes in Drosophila Here, we show that Tob (Transducer of ERB-B2) regulates the timing of sleep onset at night in female fruit flies. Knockdown of Tob pan-neuronally, either constitutively or conditionally, advances sleep onset at night. We show that Tob is specifically required in "evening neurons" (the LNds and the fifth s-LNv) of the clock network for proper timing of sleep onset. Tob levels cycle in a clock-dependent manner in these neurons. Silencing of these "evening" clock neurons results in an advanced sleep onset at night, similar to that seen with Tob knockdown. Finally, sharp intracellular recordings demonstrate that the amplitude and kinetics of LNd postsynaptic potentials (PSPs) cycle between day and night, and this cycling is attenuated with Tob knockdown in these cells. Our data suggest that Tob acts as a clock output molecule in a subset of clock neurons to potentiate their activity in the evening and enable the proper timing of sleep onset at night.

The effect of dipeptidyl peptidase-4 inhibitor on incidence and clinical course in bullous pemphigoid patients in a tertiary medical center.

Several studies have reported an association between dipeptidyl peptidase 4 inhibitor (DPP4i), a commonly prescribed second-line oral antihyperglycemic drug, and bullous pemphigoid (BP). However, the benefits of DPP4i withdrawal in patients with BP remain controversial. This study primarily aimed to evaluate the clinical severity of DPP4i-associated BP by comparing it to those without Type 2 diabetes mellitus (DM). The secondary objective was to determine whether cessation of DPP4i is necessary for all patients with BP. This retrospective case-control study included 83 patients. The participants were divided into three groups according to their diabetic status and the status of discontinuance or continuance of DPP4i. The 12-month follow-up of the monthly dosage of systemic steroids per body weight (kg) and the percentage of systemic steroid off-therapy in these participants were recorded since the diagnosis of BP. Compared to patients with BP without DM, the 1st, 3rd, and 12th systemic prednisolone doses were significantly lower in the DPP4i group (p = 0.01684, 0.02559, and 0.009336, respectively). The 12th systemic prednisolone dose was significantly lower in patients who discontinued DPP4i (p = 0.0338). Nevertheless, several spontaneous remissions with systemic steroid off-therapy were also noted in the DPP4i-continuance group within 12 months of follow-up. This article supports the favorable impact of DPP4i withdrawal in patients with BP and shows that DPP4i may incite or aggravate BP, resulting in a milder disease course.

Case Report: Unilateral Cranial Nerve VI Palsy Secondary to Intracranial Hypotension.

SIGNIFICANCE: Intracranial hypotension is a condition that occurs from a cerebrospinal fluid leak. Various visual symptoms have been associated with this condition. Cranial nerve VI (CN VI) palsies are the most common ocular manifestation, as the abducens nerve is prone to injury because of its intracranial anatomical course. PURPOSE: This case report presents a CN VI palsy secondary to intracranial hypotension from ventriculoperitoneal shunt overfiltration. Diagnosis, treatment, and management considerations are discussed. No identifiable health information was included in this case report. CASE REPORT: A 70-year-old White man was referred to the eye clinic for evaluation of binocular horizontal diplopia. The patient had a recent history of a left ventriculoperitoneal shunt for a persistent cerebrospinal fluid leak after complex mastoid surgery. The patient was also symptomatic for positional headaches, which improved in a recumbent position. He was diagnosed with a left CN VI palsy secondary to intracranial hypotension from a ventriculoperitoneal shunt overfiltration. The patient was followed up by neurosurgery for shunt adjustments to resolve the overfiltration. Binocular horizontal diplopia was managed conservatively with Fresnel prism. CONCLUSIONS: Intracranial hypotension should be considered in patients presenting with cranial nerve palsies and positional headaches. Obtaining neuroimaging and comanaging with neurology or neurosurgery are advised to make prompt diagnosis and treatment. Careful clinical monitoring and conservative diplopia therapy are recommended as visual symptoms improve upon resolution of the cerebrospinal fluid leak.

Assessment of ethanol exposure from hand sanitizer use and potential for developmental toxicity in nursing infants.

Ingestion of ethanol during pregnancy is known to have detrimental effects on the fetus. Although the potential developmental effects of maternal ethanol intake during lactation are less well characterized, public health guidelines recommend avoidance of alcohol or, if alcohol is consumed, to allow for 1-2 h to pass before nursing. A proposal to classify ethanol as potentially harmful to breast-fed children warrants an investigation of the potential adverse neurodevelopmental effects of low-dose ethanol exposure during lactation. There currently are no studies that have examined neurodevelopmental outcomes from lactational exposure to ethanol from the use of topical products that contain ethanol, such as alcohol-based hand sanitizers (ABHS). Furthermore, the epidemiological literature of lactational ethanol exposures from maternal alcohol consumption is limited in design, provides equivocal evidence of neurological effects in infants, and is insufficient to characterize a dose-response relationship for developmental effects. Toxicological studies that observed neurodevelopmental effects in pups from ethanol via lactation did so at exceedingly high doses that also caused maternal toxicity. In this investigation, blood ethanol concentrations (BECs) of breastfeeding women following typical-to-intense ABHS use were computationally predicted and compared to health benchmarks to quantify the risk for developmental outcomes. Margins of 2.2 to 1000 exist between BECs associated with ABHS use compared to BECs associated with neurotoxicity adverse effect levels in the toxicology literature or oral ethanol intake per public health guidelines. Neurodevelopmental effects are not likely to occur in infants due to ABHS use by breastfeeding women, even when ABHSs are used at intense frequencies.

Healthcare personnel experiences implementing carbapenem-resistant Enterobacterales infection control measures at a ventilator-capable skilled nursing facility-A qualitative analysis.

OBJECTIVE: Ventilator-capable skilled nursing facilities (vSNFs) are critical to the epidemiology and control of antibiotic-resistant organisms. During an infection prevention intervention to control carbapenem-resistant Enterobacterales (CRE), we conducted a qualitative study to characterize vSNF healthcare personnel beliefs and experiences regarding infection control measures. DESIGN: A qualitative study involving semistructured interviews. SETTING: One vSNF in the Chicago, Illinois, metropolitan region. PARTICIPANTS: The study included 17 healthcare personnel representing management, nursing, and nursing assistants. METHODS: We used face-to-face, semistructured interviews to measure healthcare personnel experiences with infection control measures at the midpoint of a 2-year quality improvement project. RESULTS: Healthcare personnel characterized their facility as a home-like environment, yet they recognized that it is a setting where germs were 'invisible' and potentially 'threatening.' Healthcare personnel described elaborate self-protection measures to avoid acquisition or transfer of germs to their own household. Healthcare personnel were motivated to implement infection control measures to protect residents, but many identified structural barriers such as understaffing and time constraints, and some reported persistent preference for soap and water. CONCLUSIONS: Healthcare personnel in vSNFs, from management to frontline staff, understood germ theory and the significance of multidrug-resistant organism transmission. However, their ability to implement infection control measures was hampered by resource limitations and mixed beliefs regarding the effectiveness of infection control measures. Self-protection from acquiring multidrug-resistant organisms was a strong motivator for healthcare personnel both outside and inside the workplace, and it could explain variation in adherence to infection control measures such as a higher hand hygiene adherence after resident care than before resident care.

Fungal Endocarditis With Severe Vegetations of the Aortic Valve and Septic Emboli Secondary to Total Parenteral Nutrition.

Fungal endocarditis is a rare but serious complication of fungemia. It is most commonly caused by Candida species. Risk factors include prosthetic heart valves, injection drug use, and indwelling central venous catheters. In comparison to bacterial endocarditis, fungal endocarditis is more commonly associated with arterial embolization, likely due to the larger size of vegetations. Unfortunately, diagnosis is often delayed, contributing to significant morbidity and mortality. Relapses are common, and extended treatment is often warranted. Antifungal agents and valve replacement are the recommended treatments. However, in-hospital mortality remains at 36%. For these reasons, it is critical to have a high index of suspicion and not delay appropriate therapy.

Persistent SARS-CoV-2 infectivity greater than 50 days in a case series of allogeneic peripheral blood stem cell transplant recipients.

The coronavirus disease 19 (COVID-19) pandemic has infected tens of millions across the world, but there is a significant gap in our understanding about COVID-19 in the hematopoietic stem transplant (HSCT) recipient population. Prolonged viral shedding is frequently observed with severe acute respiratory syndrome coronavirus-2 (SARSCoV-2), but studies suggest viral loads decline 10 days after symptom onset. Current CDC guidance suggests that severely ill and immunocompromised hosts are no longer infectious after 20 days from symptom onset. Cycle threshold (Ct) values are inversely proportional to the viral load and are used to detect SARS-CoV-2 RNA concentration. Specimens with reverse transcriptase PCR (RT-PCR) Ct values > 33-34 have been associated with inability to culture virus, and have been used as a surrogate for diminished infectivity. We report two cases of  allogeneic peripheral blood stem cell transplant (PBSCT) recipients who had prolonged durations of infectivity with SARSCov-2, based on culture positivity and persistently low Ct values for greater than 50 days.

Episodic, severe abdominal pain due to isolated jejunal Crohn's disease.

Small bowel Crohn's disease can present with episodic, relapsing, and remitting symptoms and delays in the diagnosis are common. We present a case of a young woman with three years of intermittent abdominal pain and nausea with negative previous evaluations. On presentation, inflammatory markers were elevated, and repeat imaging showed jejunal inflammation, with histopathological examination showing non-caseating granulomas of the small bowel consistent with Crohn's disease. This case highlights the importance of gastroenterologist recognizing the alarm signs in a patient with unexplained symptoms and adds to the literature on the clinical presentation of a rare diagnosis of isolated jejunal Crohn's disease.

Early Tocilizumab Dosing Is Associated With Improved Survival in Critically Ill Patients Infected With Severe Acute Respiratory Syndrome Coronavirus-2.

To identify the most efficacious timing for tocilizumab administration in critically ill patients infected with severe acute respiratory syndrome coronavirus-2. DESIGN: Observational multicenter cohort study. SETTING: A total of 23 acute care hospitals in four states. PATIENTS: One-hundred eighteen patients admitted between March 13, 2020, and April 16, 2020. Eighty-one patients received tocilizumab, and 37 were untreated and served as a control group. MEASUREMENTS AND MAIN RESULTS: The main outcome was mortality and was analyzed by timing of tocilizumab dosing. Early dosing was defined as a tocilizumab dose administered prior to or within 1 day of intubation. Late dosing was defined as a dose administered greater than 1 day after intubation. A control group that was treated only with standard of care, and without tocilizumab, was used for comparison. Early tocilizumab therapy was associated with a statistically significant decrease in mortality as compared to patients who were untreated (p = 0.003). Dosing tocilizumab late was associated with an increased mortality compared with the untreated group (p = 0.006). CONCLUSIONS: Early tocilizumab administration was associated with decreased mortality in critically ill severe acute respiratory syndrome coronavirus-2 patients, but a potential detriment was suggested by dosing later in a patient's course.

Tocilizumab as a Therapeutic Agent for Critically Ill Patients Infected with SARS-CoV-2.

Tocilizumab is an IL-6 receptor antagonist with the ability to suppress the cytokine storm in critically ill patients infected with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). We evaluated patients treated with tocilizumab for a SARS-CoV-2 infection who were admitted between March 13, 2020, and April 16, 2020. This was a multicenter study with data collected by chart review both retrospectively and concurrently. Parameters evaluated included age, sex, race, use of mechanical ventilation (MV), usage of steroids and vasopressors, inflammatory markers, and comorbidities. Early dosing was defined as a tocilizumab dose administered prior to or within 1 day of intubation. Late dosing was defined as a dose administered > 1 day after intubation. In the absence of MV, the timing of the dose was related to the patient's date of admission only. We evaluated 145 patients. The average age was 58.1 years, 64% were men, 68.3% had comorbidities, and 60% received steroid therapy. Disposition of patients was 48.3% discharged and 29.3% died, of which 43.9% were African American. MV was required in 55.9%, of which 34.5% died. Avoidance of MV (P = 0.002) and increased survival (P < 0.001) was statistically associated with early dosing. Tocilizumab therapy was effective at decreasing mortality and should be instituted early in the management of critically ill patients with coronavirus disease 2019) COVID-19).

Sexual assault as a risk factor for gynaecological morbidity: An exploratory systematic review and meta-analysis.

Among Australian females, sexual assault affects 1 in 5 Australian women [1], and 1 in 10 girls [2]. While it is well known that females who experience sexual assault have an increased risk of future pelvic pain, there is limited knowledge regarding the occurrence of other gynaecological morbidity. We performed systematic review and meta-analysis for the relationship between sexual assault and gynaecological morbidity. We searched online electronic databases for observational studies on the subject published between 1993 and 2018. Search terms included variants of 'sexual abuse', 'sexual assault' and a range of gynaecological morbidity. Two independent reviewers completed study selection, quality assessment and data extraction. For each gynaecological symptom we calculated common odds ratios and 95 % confidence intervals in relation to sexual abuse history. Our search identified 1846 studies, of which 38 studies were included. A history of sexual assault was significantly associated with overall gynaecological morbidity (RR 1.42; 95%CI, 1.27-1.59), pelvic pain (RR 1.60; 95%CI, 1.36-1.89), 'dyspareunia' (pooled RR 1.74, 95%CI, 1.50-2.02); 'dysmenorrhea' (pooled RR 1.20; 95%CI, 1.11-1.29); 'abnormal menstrual bleeding' (pooled RR 1.29; 95%CI, 1.12-1.49)) and 'urinary incontinence' (pooled RR 1.31; 95%CI, 1.12-1.53)), while association was not statistically significant for 'vaginismus'(pooled RR 1.71; 95%CI, 0.87-3.36) and 'vulvodynia' (pooled RR 1.49; 95%CI, 0.76-2.91). There was no relation with 'prolapse' (pooled RR 1.10; 95%CI, 0.53-2.30). Females with a history of sexual assault have a significantly increased risk of different gynaecological disorders later in life.

A Real-World Assessment of Clinical Outcomes and Safety of Eravacycline: A Novel Fluorocycline.

BACKGROUND: Eravacycline is a novel fluorocycline approved for treatment of intraabdominal infections, with a broad spectrum of activity against a range of pathogens including multidrug-resistant species, including ESBL- or KPC-producing isolates. It is approved for twice-daily dosing with no need for adjustment in renal dysfunction. In the concomitant administration with CYP 3A4-inducing drugs, eravacycline dosing should be modified. OBJECTIVE: To evaluate the efficacy and safety of eravacycline in a range of infections such as intraabdominal infections, pneumonia and diabetic foot infections in seriously ill patients. METHODS: A retrospective observational cohort study using electronic patient records of 50 consecutive patients administered eravacycline during inpatient acute care admission or as part of outpatient antibiotic therapy (OPAT). RESULTS: Therapy of 1.5 mg/kg q24h was initiated in the hospital in most patients, although some of the less sick were managed in the office or OPAT setting. All patients concluded their management outside of the hospital. Of the 50 patients, 47 (94%) achieved clinical resolution of their infection and 3 (6%) clinical failures occurred. Only three (6%) patients did not have comorbidities, three had a single comorbidity (6%), and the majority (88%) of patients had two or more comorbidities. Most common infections were intraabdominal (36%), pneumonia (18%), diabetic foot (12%), spontaneous bacterial peritonitis (8%) and empyema (8%). Almost half of infections had more than one pathogen isolated, and resistant isolates were frequent. The drug was well tolerated with only two reports of nausea, which did not result in treatment discontinuation, and in 30 days of post-eravacycline therapy only one case of Clostridiodes difficile. CONCLUSIONS: In this real-world setting, eravacycline demonstrated a similar high level of clinical efficacy as seen in clinical trials, 94%, in a variety of infections, including against multidrug-resistant bacteria, and was well tolerated.

Bioenergetic Analyses of In Vitro and In Vivo Samples to Guide Toxicological Endpoints.

Toxicology is a broad field that requires the translation of biochemical responses to xenobiotic exposures into useable information to ensure the safety of the public. Modern techniques are improving rapidly, both quantitatively and qualitatively, to provide the tools necessary to expand available toxicological datasets and refine our ability to translate that data into relevant information via bioinformatics. These new techniques can, and do, impact many of the current critical roles in toxicology, including the environmental, forensic, preclinical/clinical, and regulatory realms. One area of rapid expansion is our understanding of bioenergetics, or the study of the transformation of energy in living organisms, and new mathematical approaches are needed to interpret these large datasets. As bioenergetics are intimately involved in the regulation of how and when a cell responds to xenobiotics, monitoring these changes (i.e., metabolic fluctuations) in cells/tissues post-exposure provides an approach to define the temporal scale of pharmacodynamic responses, which can be used to guide additional toxicological techniques (e.g., "omics"). This chapter will summarize important in vitro assays and in vivo imaging techniques to take real-time measurements. Using this information, our laboratory has utilized bioenergetics to identify significant time points of pharmacodynamic relevance as well as forecast the cell's eventual fate.

Salivary cytokines as a biomarker of social stress in a mock rescue mission.

Using salivary inflammatory markers as a noninvasive biomonitoring technique within natural social contexts has become increasingly important to link social and biological responses. Many studies have associated circulating cytokines to distinct aspects of physical activity and social/emotional behavior; however, they have not been linked to success and failure in a naturalistic setting for military personnel performing tasks. In this study, salivary cytokines were studied in a group of fifteen Air Force Reserve Officers' Training Corps (ROTC; 14 males, 1 female) subjects performing three mock hostage rescue missions, designed to prompt responses associated with baseline, success, and failure. Each subject completed the tasks of the mission individually and again in randomly assigned teams. Participants were outfitted via direct skin contact with comfortable external Zephyr™ sensors to monitor heart rate, breathing rate, and activity while completing each task. Saliva samples were collected before and after the completion of each mission, and cytokine levels were quantified using enzyme-labelled immunoassay (ELISA) beads. These biomarkers were used to describe the body's immune response to success and failure when performing a mock rescue mission individually and in a team. All measured cytokine levels increased following failed missions performed individually, compared to cytokine levels associated with successful missions. When completing the tasks as a team, there were no significant differences in cytokine response between success and failure; however, being in a team stimulated an increased pre-mission cytokine response, suggesting the concept of teamwork and performing with peers for the first time had a more significant impact than the notion of failing. Additionally, none of the cytokines tested for individual missions correlated to physical activity markers (heart rate, breathing rate, activity) measured during performance. These results indicate a potentially new noninvasive method of determining social stress levels under taxing conditions.

Physiologically Based Pharmacokinetic Modeling of Salivary Concentrations for Noninvasive Biomonitoring of 2,4-Dichlorophenoxyacetic Acid (2,4-D).

Saliva has become a favorable sample matrix for biomonitoring due to its noninvasive attributes and overall flexibility in collection. To ensure measured salivary concentrations reflect the exposure, a solid understanding of the salivary transport mechanism and relationships between salivary concentrations and other monitored matrices (ie, blood, urine) is needed. Salivary transport of a commonly applied herbicide, 2,4-dichlorophenoxyacetic acid (2,4-D), was observed in vitro and in vivo and a physiologically based pharmacokinetic (PBPK) model was developed to translate observations from the cell culture model to those in animal models and further evaluate 2,4-D kinetics in humans. Although apparent differences in experimental in vitro and in vivo saliva:plasma ratios (0.034 and 0.0079) were observed, simulations with the PBPK model demonstrated dynamic time and dose-dependent saliva:plasma ratios, elucidating key mechanisms affecting salivary transport. The model suggested that 2,4-D exhibited diffusion-limited transport to saliva and was additionally impacted by protein binding saturation and permeability across the salivary gland. Consideration of sampling times post-exposure and potential saturation of transport mechanisms are then critical aspects for interpreting salivary 2,4-D biomonitoring observations. This work utilized PBPK modeling in in vitro to in vivo translation to explore benefits and limitations of salivary analysis for occupational biomonitoring.

Evaluation of non-invasive biomonitoring of 2,4-Dichlorophenoxyacetic acid (2,4-D) in saliva.

The objective of this study was to evaluate the potential for non-invasive biomonitoring of 2,4-Dichlorophenoxyacetic acid (2,4-D) in saliva. Using an in vitro rat salivary gland epithelial cell (SGEC) system, a collection of experiments investigating chemical protein binding, temporal and directional transport, as well as competitive transport with para-aminohippuric acid (PAH), a substrate for renal organic anion transporters, was conducted to identify cellular transport parameters required to computationally model salivary transport of 2,4-D. Additionally, a physiological protein gradient was implemented to mimic physiologically relevant concentrations of protein in rat plasma and saliva, and under these conditions the transfer of 2,4-D was markedly slower, driven by increased protein binding (i.e. reduced free 2,4-D species available to cross salivary barrier). The rate of transfer was directly proportional to the amount of unbound 2,4-D and demonstrated no indication of active transport. An in vivo assessment of 2,4-D exposure in rats revealed non-linear protein binding in plasma, indicating saturated protein binding and increased levels of unbound 2,4-D species at higher doses. A strong correlation between 2,4-D concentrations in saliva and unbound 2,4-D in plasma was observed (Pearson correlation coefficient = 0.95). Saliva:plasma 2,4-D ratios measured in vivo (0.0079) were consistent within the linear protein binding range and expected 2,4-D levels from occupational exposures but were significantly different than ratios measured in vitro (physiological conditions) (0.034), possibly due to 2,4-D concentrations in saliva not being at equilibrium with 2,4-D concentrations in blood, as well as physiological features absent in in vitro settings (e.g. blood flow). We demonstrated that 2,4-D is consistently transported into saliva using both in vitro and in vivo models, making 2,4-D a potential candidate for human non-invasive salivary biomonitoring. Further work is needed to understand whether current sensor limits of detection are sufficient to measure occupationally relevant exposures.

The Effects of Platelet-Activating Factor on Uterine Contractility, Perfusion, Hypoxia, and Pain in Mice.

It is widely hypothesized that menstrual pain is triggered by prostaglandin synthesis that evokes high-pressure uterine contractions and ischemia. However, the effects of molecules implicated in menstrual pain on uterine contractility, perfusion, and oxygenation in vivo have been rarely demonstrated. Studies in women that do not respond to nonsteroidal anti-inflammatory drugs (NSAIDs) have reported elevated levels of platelet-activating factor (PAF). To establish in vivo evidence of PAF's capability to impair uterine homeostasis and to elicit visceral pain, we examined the effects of the PAF receptor agonist (carbamyl PAF [CPAF]) in comparison to other molecules hypothesized to play a role in uterine pain in mice. Uterine pressure was increased by oxytocin, prostaglandin F2α (PGF2α), and CPAF. Even in the absence of inflammatory molecules, uterine contractions reduced uterine oxygenation by 38%. CPAF reduced uterine perfusion by 40% ± 8% and elicited further oxygen desaturation approaching hypoxia (9.4 ± 3.4 mm Hg Pao2). Intraperitoneal injections of CPAF and PGF2α evoked visceral pain and pelvic hyperalgesia in awake wild-type mice. However, pain was not observed in identically injected PAF-receptor knockout mice. Thus, our model provides a demonstration that a molecule implicated in NSAID-resistant dysmenorrhea has a detrimental effect on uterine homeostasis and is capable of causing visceral pain. Our results support the general hypothesis that menstrual cramps are caused by uterine contractions, impaired perfusion, and reduced oxygenation. Since this study was limited to mice, confirmation of these results in humans would be valuable for development of novel therapeutics targeted at inflammatory precursors, contractility, perfusion, and tissue oxygenation.

Bone mineral density in children with acute lymphoblastic leukemia.

BACKGROUND: Children with acute lymphoblastic leukemia (ALL) can develop reduced bone mineral density (BMD). However, data from patients who received treatment on a frontline regimen without cranial irradiation are limited, and no genome-wide analysis has been reported. METHODS: Lumbar BMD was evaluated by quantitative computed tomography at diagnosis, after 120 weeks of continuation therapy, and after 2 years off therapy in pediatric patients with ALL (ages 2-18 years at diagnosis) who were treated on the St. Jude Total XV Protocol. Clinical, pharmacokinetic, and genetic risk factors associated with decreased BMD Z-scores were evaluated. RESULTS: The median BMD Z-score in 363 patients was 0.06 at diagnosis, declined to -1.08 at week 120, but partly recovered to -0.72 after 2 years off therapy; BMD in patients with low BMD Z-scores at diagnosis remained low after therapy. Older age (≥10 years vs 2-9.9 years at diagnosis; P < .001), a higher BMD Z-score at diagnosis (P = .001), and a greater area under the plasma drug concentration-time curve for dexamethasone in weeks 7 and 8 of continuation therapy (P = .001) were associated with a greater decrease in BMD Z-score from diagnosis to week 120. Single-nucleotide polymorphisms in 2 genes important in osteogenesis and bone mineralization (COL11A1 [reference single-nucleotide polymorphism rs2622849]; P = 2.39 × 10-7 ] and NELL1 [rs11025915]; P = 4.07 × 10-6 ]) were associated with a decreased BMD Z-score. NELL1 (P = .003) also was associated with a greater dexamethasone area under the plasma drug concentration-time curve. CONCLUSIONS: BMD Z-scores decreased during therapy, especially in patients who had clinical, pharmacokinetic, and genetic risk factors. Early recognition of BMD changes and strategies to optimize bone health are essential. Cancer 2018;124:1025-35. © 2017 American Cancer Society.

The impact of cytokine responses in the intra- and extracellular signaling network of a traumatic injury.

Investigations of cellular responses involved in injury and repair processes have generated valuable information contributing to the advancement of wound healing and treatments. Intra- and extracellular regulators of healing mechanisms, such as cytokines, signaling proteins, and growth factors, have been described to possess significant roles in facilitating optimal recovery. This study explored a collection of 30 spatiotemporal responses comprised of cytokines (IL-1α, IL-1ß, IL-2, IL-6, TNF-α, MIP-1α), intracellular proteins (Akt, c-Jun, CREB, ERK1/2, JNK, MEK1, p38, p53, p90RSK), phosphorylated proteins (p-Akt, p-c-Jun, p-CREB, p-ERK1/2, p-GSK-3α/ß, p-HSP27, p-IκBα, p-JNK, p-MEK1, p-p38, p-p70S6K, p-p90RSK, p-STAT2, p-STAT3), and a protease (Caspase-3), measured in skeletal muscle tissue following a traumatic injury (rodent Gustilo IIIB fracture). To optimize the analysis of context-specific data sets, a network centrality parameter approach was used to assess the impact of each response in relation to all other measured responses. This approach identified proteins that were substantially amplified and potentially central in the wound healing network by evaluation of their corresponding centrality parameter, radiality. Network analysis allowed us to distinguish the progression of healing that occurred at certain time points and regions of injury. Notably, new tissue formation was proposed to occur by 168 h post-injury in severely injured tissue, while tissue 1-cm away from the site of injury that experienced relatively minor injury appeared to exhibit signs of new tissue formation as early as 24 h post-injury. In particular, hallmarks of inflammation, cytokines IL-1ß, IL-6, and IL-2, appear to have a pronounced impact at earlier time points (0-24 h post-injury), while intracellular proteins involved in cell proliferation, differentiation, or proteolysis (c-Jun, CREB, JNK, p38, p-c-Jun; p-MEK1, p-p38, p-STAT3) are more significant at later times (24-168 h). Overall, this study demonstrates the feasibility of a network analysis approach to extract significant information and also offers a spatiotemporal visualization of the intra- and extracellular signaling responses that regulate healing mechanisms.

Current Reports on Perinatal Intimate Partner Violence.

PURPOSE OF REVIEW: The purpose of this study was to review the literature on perinatal intimate partner violence, focusing on recent knowledge to guide mental health professionals on the best approaches to identify and treat women exposed to perinatal intimate partner violence. RECENT FINDINGS: Risk factors have been broadened from individual victim and perpetrator factors to include relationship, community, and societal factors which interact together. Better information is now available on how to identify, document, and treat women exposed to violence around the time of conception, pregnancy, and the postpartum period. Recent information helps psychiatrists and other mental health professionals assist women exposed to violence related to the perinatal period; however, further research is needed to provide improved evidence for optimal interventions for better patient outcomes.