Immune cell-antibody interactions in health and disease.

The human immune system safeguards against pathogens through a multitude of cellular and molecular signals, involving different components of the innate and adaptive response. Contrastingly, autoimmune diseases, allergic conditions, and cancer evoke different aspects of these otherwise protective processes. Understanding the immunological hallmarks for each pathological setting is essential for improving prevention, diagnosis, prognosis, and treatment. The activatory states of immune effector cells, especially in relation to their direct or indirect interactions with antibodies, are important determinants of an efficient, protective response that results in target clearance and improved clinical outcomes. Dysregulation of effector cells and their functions alongside alternatively activated humoral immune responses may contribute to several chronic diseases including allergic inflammation, autoimmune disorders and cancer. This Review Series brings to the forefront several key activation and regulatory features of immune effector cells in different diseases including cancer, infection allergy, and autoimmunity. Specific attention is drawn on how antibodies can impact effector cell states, and their pro-inflammatory and immune protective functions. Articles in this Series discuss different effector cells and antibody isotypes in infection, inflammation, tolerance and cancer immune surveillance, covering basic and translational mechanisms, clinical and epidemiological insights into these immune responses. Understanding the critical attributes of immune cells, especially those needed to effectively engage antibodies, will undoubtedly help better exploit their potential for disease management and therapy.

Macrophages in ovarian cancer and their interactions with monoclonal antibody therapies.

The unmet clinical need for effective treatments in ovarian cancer has yet to be addressed using monoclonal antibodies (mAbs), which have largely failed to overcome tumour-associated immunosuppression, restrict cancer growth, and significantly improve survival. In recent years, experimental mAb design has moved away from solely targeting ovarian tumours and instead sought to modulate the wider tumour microenvironment (TME). Tumour-associated macrophages (TAMs) may represent an attractive therapeutic target for mAbs in ovarian cancer due to their high abundance and close proximity to tumour cells and their active involvement in facilitating several pro-tumoural processes. Moreover, the expression of several antibody crystallisable fragment (Fc) receptors and broad phenotypic plasticity of TAMs provide opportunities to modulate TAM polarisation using mAbs to promote anti-tumoural phenotypes. In this review, we discuss the role of TAMs in ovarian cancer TME and the emerging strategies to target the contributions of these cells in tumour progression through the rationale design of mAbs.

A comprehensive transcriptional map of primate brain development.

The transcriptional underpinnings of brain development remain poorly understood, particularly in humans and closely related non-human primates. We describe a high-resolution transcriptional atlas of rhesus monkey (Macaca mulatta) brain development that combines dense temporal sampling of prenatal and postnatal periods with fine anatomical division of cortical and subcortical regions associated with human neuropsychiatric disease. Gene expression changes more rapidly before birth, both in progenitor cells and maturing neurons. Cortical layers and areas acquire adult-like molecular profiles surprisingly late in postnatal development. Disparate cell populations exhibit distinct developmental timing of gene expression, but also unexpected synchrony of processes underlying neural circuit construction including cell projection and adhesion. Candidate risk genes for neurodevelopmental disorders including primary microcephaly, autism spectrum disorder, intellectual disability, and schizophrenia show disease-specific spatiotemporal enrichment within developing neocortex. Human developmental expression trajectories are more similar to monkey than rodent, although approximately 9% of genes show human-specific regulation with evidence for prolonged maturation or neoteny compared to monkey.

Enuresis in Children: Common Questions and Answers.

Nocturnal enuresis is defined as nighttime urinary incontinence occurring at least twice weekly in children five years and older. Approximately 14% of children have spontaneous resolution each year without treatment. Subtypes of nocturnal enuresis include nonmonosymptomatic enuresis and primary and secondary monosymptomatic nocturnal enuresis. Monosymptomatic enuresis is characterized by nighttime bedwetting without daytime urinary incontinence. Pathophysiology of primary monosymptomatic nocturnal enuresis may be due to sleep arousal disorder, overproduction of urine, small bladder storage capacity, or detrusor overactivity. Children with nonmonosymptomatic enuresis have daytime and nighttime symptoms resulting from a variety of underlying etiologies. An in-depth history is an integral component of the initial evaluation. For all types of enuresis, a comprehensive physical examination and urinalysis should be performed to help identify the cause. It is important to reiterate to the family that bedwetting is not the child's fault. Treatment should begin with behavioral modification, which then progresses to enuresis alarm therapy and oral desmopressin. Enuresis alarm therapy is more likely to produce long-term success; desmopressin yields earlier symptom improvement. Treatment of secondary monosymptomatic nocturnal enuresis and nonmonosymptomatic enuresis should primarily focus on the underlying etiology. Pediatric urology referral should be made for refractory cases in which underlying genitourinary anomalies or neurologic disorders are more likely. .

Peripheral Nerve Entrapment and Injury in the Upper Extremity.

Peripheral nerves in the upper extremities are at risk of injury and entrapment because of their superficial nature and length. Injury can result from trauma, anatomic abnormalities, systemic disease, and entrapment. The extent of the injury can range from mild neurapraxia, in which the nerve experiences mild ischemia caused by compression, to severe neurotmesis, in which the nerve has full-thickness damage and full recovery may not occur. Most nerve injuries seen by family physicians will involve neurapraxia, resulting from entrapment along the anatomic course of the nerve. In the upper extremity, the brachial plexus branches into five peripheral nerves, three of which are commonly entrapped at the shoulder, elbow, and wrist. Patients with nerve injury typically present with pain, weakness, and paresthesia. A detailed history and physical examination alone are often enough to identify the injury or entrapment; advanced diagnostic testing with magnetic resonance imaging, ultrasonography, or electrodiagnostic studies can help confirm the clinical diagnosis and is indicated if conservative management is ineffective. Initial treatment is conservative, with surgical options available for refractory injuries or entrapment caused by anatomic abnormality.

Transcriptional landscape of the prenatal human brain.

The anatomical and functional architecture of the human brain is mainly determined by prenatal transcriptional processes. We describe an anatomically comprehensive atlas of the mid-gestational human brain, including de novo reference atlases, in situ hybridization, ultra-high-resolution magnetic resonance imaging (MRI) and microarray analysis on highly discrete laser-microdissected brain regions. In developing cerebral cortex, transcriptional differences are found between different proliferative and post-mitotic layers, wherein laminar signatures reflect cellular composition and developmental processes. Cytoarchitectural differences between human and mouse have molecular correlates, including species differences in gene expression in subplate, although surprisingly we find minimal differences between the inner and outer subventricular zones even though the outer zone is expanded in humans. Both germinal and post-mitotic cortical layers exhibit fronto-temporal gradients, with particular enrichment in the frontal lobe. Finally, many neurodevelopmental disorder and human-evolution-related genes show patterned expression, potentially underlying unique features of human cortical formation. These data provide a rich, freely-accessible resource for understanding human brain development.

Intrapartum Fetal Monitoring.

Continuous electronic fetal monitoring was developed to screen for signs of hypoxic-ischemic encephalopathy, cerebral palsy, and impending fetal death during labor. Because these events have a low prevalence, continuous electronic fetal monitoring has a false-positive rate of 99%. The widespread use of continuous electronic fetal monitoring has increased operative and cesarean delivery rates without improved neonatal outcomes, but its use is appropriate in high-risk labor. Structured intermittent auscultation is an underused form of fetal monitoring; when employed during low-risk labor, it can lower rates of operative and cesarean deliveries with neonatal outcomes similar to those of continuous electronic fetal monitoring. However, structured intermittent auscultation remains difficult to implement because of barriers in nurse staffing and physician oversight. The National Institute of Child Health and Human Development terminology is used when reviewing continuous electronic fetal monitoring and delineates fetal risk by three categories. Category I tracings reflect a lack of fetal acidosis and do not require intervention. Category II tracings are indeterminate, are present in the majority of laboring patients, and can encompass monitoring predictive of clinically normal to rapidly developing acidosis. Presence of moderate fetal heart rate variability and accelerations with absence of recurrent pathologic decelerations provides reassurance that acidosis is not present. Category II tracing abnormalities can be addressed by treating reversible causes and providing intrauterine resuscitation, which includes stopping uterine-stimulating agents, fetal scalp stimulation and/or maternal repositioning, intravenous fluids, or oxygen. Recurrent deep variable decelerations can be corrected with amnioinfusion. Category III tracings are highly concerning for fetal acidosis, and delivery should be expedited if immediate interventions do not improve the tracing.

Future technology on the flight deck: assessing the use of touchscreens in vibration environments.

Use of touchscreens in the flight deck has been steadily increasing, however, their usability may be severely impacted when turbulent conditions arise. Most previous research focusses on using touchscreens in static conditions; therefore, this study assessed touchscreen use whilst undergoing turbulent representative motion, generated using a 6-axis motion simulator. Touchscreens were tested in centre, side and overhead positions, to investigate how turbulence affected: (1) error rate, movement times and accuracy, (2) arm fatigue and discomfort. Two touchscreen technologies were compared: a 15" infra-red and a 17.3" projected capacitive touchscreen with force sensing capability. The potential of the force sensing capability to minimise unintentional interactions was also investigated. Twenty-six participants undertook multi-direction tapping (ISO 9241; ISO 2010 ) and gesture tasks, under four vibration conditions (control, light chop, light turbulence and moderate turbulence). Error rate, movement time and workload increased and usability decreased significantly, with screen position and increasing turbulence level. Practitioner Summary: This study evaluated the use of infra-red and projected capacitive touchscreen technologies using multi-directional tapping and gesture tasks, whilst being subjected to different levels of turbulence representative motion. Performance degraded significantly with increasing turbulence level and touchscreen location. This has implications for future flight deck design.

Equivalent comfort contours for fore-and-aft, lateral, and vertical whole-body vibration in the frequency range 1.0 to 10 Hz.

Standards assume vibration discomfort depends on the frequency and direction of whole-body vibration, with the same weightings for frequency and direction at all magnitudes. This study determined equivalent comfort contours from 1.0 to 10 Hz in each of three directions (fore-and-aft, lateral, vertical) at magnitudes in the range 0.1 to 3.5 ms-2 r.m.s. Twenty-four subjects sat on a rigid flat seat with and without a beanbag, altering the pressure distribution on the seat but not the transmission of vibration. The rate of growth of vibration discomfort with increasing magnitude of vibration differed between the directions of vibration and varied with the frequency of vibration. The frequency-dependence and direction-dependence of discomfort, therefore, depended on the magnitude of vibration. The beanbag did not affect the frequency-dependence or direction-dependence of vibration discomfort. It is concluded that different weightings for the frequency and direction of vibration are required for low and high magnitude vibration. Practitioner summary: When evaluating whole-body vibration to predict vibration discomfort, the weightings appropriate to different frequencies and different directions of vibration should depend on the magnitude of vibration. This is overlooked in all current methods of evaluating the severity of whole-body vibration.

Exercise Stress Testing: Indications and Common Questions.

Exercise stress testing is a validated diagnostic test for coronary artery disease in symptomatic patients, and is used in the evaluation of patients with known cardiac disease. Testing of asymptomatic patients is generally not indicated. It may be performed in select deconditioned adults before starting a vigorous exercise program, but no studies have compared outcomes from preexercise testing vs. encouraging light exercise with gradual increases in exertion. Preoperative exercise stress testing is helpful for risk stratification in patients undergoing vascular surgery or who have active cardiac symptoms before undergoing nonemergent noncardiac surgery. Exercise stress testing without imaging is the preferred initial choice for risk stratification in most women. Sensitivity and specificity increase with the use of adjunctive imaging such as echocardiography or myocardial perfusion imaging with single-photon emission computed tomography. Exercise stress testing is rarely an appropriate option to evaluate persons with known coronary artery disease who have no new symptoms less than two years after percutaneous intervention or less than five years after coronary artery bypass grafting. The Duke treadmill score has excellent prognostic value for exercise stress testing. Imaging is not necessary if patients are able to achieve more than 10 metabolic equivalents on exercise stress testing. Exercise stress testing is not indicated before noncardiac surgeries in patients who can achieve 4 metabolic equivalents without symptoms.

Air, hand wipe, and surface wipe sampling for Bisphenol A (BPA) among workers in industries that manufacture and use BPA in the United States.

For decades, bisphenol A (BPA) has been used in making polycarbonate, epoxy, and phenolic resins and certain investment casting waxes, yet published exposure data are lacking for U.S. manufacturing workers. In 2013-2014, BPA air and hand exposures were quantified for 78 workers at six U.S. companies making BPA or BPA-based products. Exposure measures included an inhalable-fraction personal air sample on each of two consecutive work days (n = 146), pre- and end-shift hand wipe samples on the second day (n = 74 each), and surface wipe samples (n = 88). Potential determinants of BPA air and end-shift hand exposures (after natural log transformation) were assessed in univariate and multiple regression mixed models. The geometric mean (GM) BPA air concentration was 4.0 µg/m3 (maximum 920 µg/m3). The end-shift GM BPA hand level (26 µg/sample) was 10-times higher than the pre-shift level (2.6 µg/sample). BPA air and hand exposures differed significantly by industry and job. BPA air concentrations and end-shift hand levels were highest in the BPA-filled wax manufacturing/reclaim industry (GMAir = 48 µg/m3, GMHand-End = 130 µg/sample) and in the job of working with molten BPA-filled wax (GMAir = 43 µg/m3, GMHand-End = 180 µg/sample), and lowest in the phenolic resins industry (GMAir = 0.85 µg/m3, GMHand-End = 0.43 µg/sample) and in the job of flaking phenolic resins (GMAIR = 0.62 µg/m3, GMHand-End = 0.38 µg/sample). Determinants of increased BPA air concentration were industry, handling BPA containers, spilling BPA, and spending ≥50% of the shift in production areas; increasing age was associated with lower air concentrations. BPA hand exposure determinants were influenced by high values for two workers; for all other workers, tasks involving contact with BPA-containing materials and spending ≥50% of the shift in production areas were associated with increased BPA hand levels. Surface wipe BPA levels were significantly lower in eating/office areas (GM = 9.3 µg/100 cm2) than in production areas (GM = 140 µg/100 cm2). In conclusion, worker BPA exposure was associated with tasks and conditions affecting both inhalation and dermal exposure. The potential for BPA-related health effects among these workers is unknown.

Integrative Pathway Analysis of Metabolic Signature in Bladder Cancer: A Linkage to The Cancer Genome Atlas Project and Prediction of Survival.

PURPOSE: We used targeted mass spectrometry to study the metabolic fingerprint of urothelial cancer and determine whether the biochemical pathway analysis gene signature would have a predictive value in independent cohorts of patients with bladder cancer. MATERIALS AND METHODS: Pathologically evaluated, bladder derived tissues, including benign adjacent tissue from 14 patients and bladder cancer from 46, were analyzed by liquid chromatography based targeted mass spectrometry. Differential metabolites associated with tumor samples in comparison to benign tissue were identified by adjusting the p values for multiple testing at a false discovery rate threshold of 15%. Enrichment of pathways and processes associated with the metabolic signature were determined using the GO (Gene Ontology) Database and MSigDB (Molecular Signature Database). Integration of metabolite alterations with transcriptome data from TCGA (The Cancer Genome Atlas) was done to identify the molecular signature of 30 metabolic genes. Available outcome data from TCGA portal were used to determine the association with survival. RESULTS: We identified 145 metabolites, of which analysis revealed 31 differential metabolites when comparing benign and tumor tissue samples. Using the KEGG (Kyoto Encyclopedia of Genes and Genomes) Database we identified a total of 174 genes that correlated with the altered metabolic pathways involved. By integrating these genes with the transcriptomic data from the corresponding TCGA data set we identified a metabolic signature consisting of 30 genes. The signature was significant in its prediction of survival in 95 patients with a low signature score vs 282 with a high signature score (p = 0.0458). CONCLUSIONS: Targeted mass spectrometry of bladder cancer is highly sensitive for detecting metabolic alterations. Applying transcriptome data allows for integration into larger data sets and identification of relevant metabolic pathways in bladder cancer progression.

Common Questions About Recurrent Urinary Tract Infections in Women.

Recurrent urinary tract infections (UTIs) are common in women, including healthy women with normal genitourinary anatomy. Recurrent UTI is typically defined as three or more UTIs within 12 months, or two or more occurrences within six months. The same species that caused previous infections is typically responsible for recurrences. In premenopausal women, sexual intercourse three or more times per week, spermicide use, new or multiple sex partners, and having a UTI before 15 years of age are established risk factors. In postmenopausal women, risk is primarily increased by sequelae of lower estrogen levels. Episodes of recurrent UTI are typically characterized by dysuria and urinary frequency or hesitancy. Findings from the history or physical examination that suggest complicated infection or another disease process warrant additional evaluation. At least one symptomatic episode should be verified by urine culture to confirm the diagnosis and guide treatment. Imaging is rarely warranted. Short courses of antibiotics are as effective as longer courses. Patient-initiated treatment lowers the cost of diagnosis, number of physician visits, and number of symptomatic days compared with physician-initiated treatment. It also reduces antibiotic exposure compared with antibiotic prophylaxis. Antibiotic prophylaxis effectively limits UTI recurrence but increases the risk of antibiotic resistance and adverse effects. Cranberry products may reduce recurrent UTIs in premenopausal women, but are less effective than antibiotic prophylaxis, and data are conflicting. Optimal dosing is unknown. Postmenopausal women with atrophic vaginitis may benefit from topical estrogen therapy.

Provision of Contraception: Key Recommendations from the CDC.

The Centers for Disease Control and Prevention has released comprehensive recommendations for provision of family planning services. Contraceptive services may be addressed in five steps, and counseling may be provided in a tiered approach, whereby the most effective options are presented before less effective options. Clinicians should discuss all contraceptive methods that can be used safely by the patient, regardless of whether a method is available on site and even if the patient is an adolescent or a nulliparous woman. Physical assessment is usually limited to blood pressure evaluation before starting hormonal contraceptives or pelvic examination before placing an intrauterine device. Monitoring the patient's weight also may be helpful. If it is reasonably certain that the patient is not pregnant, any contraceptive may be started immediately. When hormonal contraceptives are selected, one year's supply should be prescribed to reduce barriers to use. Condoms should be made readily available. Documentation of visits for contraception should include patient understanding of use, benefits, and risks, plus an individualized follow-up plan. Bleeding irregularities generally are not harmful and may resolve with continued use of the contraceptive method. All patients-including adolescents; those who identify as lesbian, gay, bisexual, or transgender; and patients with disabilities or limited English proficiency-should receive high-quality care in an accommodating, nonjudgmental environment. The Centers for Disease Control and Prevention supports advance provision of emergency contraceptives. Because no test reliably verifies cessation of fertility, it is prudent to consider contraceptive use until menopause, or at least until 50 to 55 years of age.

PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma.

High-grade serous ovarian carcinoma (HGSC) remains a disease of poor prognosis that is unresponsive to current immune checkpoint inhibitors. Although PI3K pathway alterations, such as PTEN loss, are common in HGSC, attempts to target this pathway have been unsuccessful. We hypothesized that aberrant PI3K pathway activation may alter the HGSC immune microenvironment and present a targeting opportunity. Single-cell RNA sequencing identified populations of resident macrophages specific to Pten-null omental tumors in murine models, which were confirmed by flow cytometry. These macrophages derived from peritoneal fluid macrophages and had a unique gene expression program, marked by high expression of the enzyme heme oxygenase-1 (HMOX1). Targeting resident peritoneal macrophages prevented the appearance of HMOX1hi macrophages and reduced tumor growth. Furthermore, direct inhibition of HMOX1 extended survival in vivo. RNA sequencing identified IL33 in Pten-null tumor cells as a likely candidate driver leading to the appearance of HMOX1hi macrophages. Human HGSC tumors also contained HMOX1hi macrophages with a corresponding gene expression program. Moreover, the presence of these macrophages correlated with activated tumoral PI3K/mTOR signaling and poor overall survival in HGSC patients. In contrast, tumors with low numbers of HMOX1hi macrophages were marked by increased adaptive immune response gene expression. These data suggest targeting HMOX1hi macrophages as a potential therapeutic strategy for treating poor prognosis HGSC.

Foreign body impaction of the vertebral canal.

Foreign body impactions in the aerodigestive tract are common, but have the potential for serious complications. A foreign body may disrupt the mucosal lining and migrate regionally thereby risking impingement or injury to critical neurovascular structures in the cervical region. It is important to recognize potential complications that may arise from luminal compromise. In such cases, expeditious surgical treatment is warranted.