Mapping the Neural Substrates of Behavior.

Assigning behavioral functions to neural structures has long been a central goal in neuroscience and is a necessary first step toward a circuit-level understanding of how the brain generates behavior. Here, we map the neural substrates of locomotion and social behaviors for Drosophila melanogaster using automated machine-vision and machine-learning techniques. From videos of 400,000 flies, we quantified the behavioral effects of activating 2,204 genetically targeted populations of neurons. We combined a novel quantification of anatomy with our behavioral analysis to create brain-behavior correlation maps, which are shared as browsable web pages and interactive software. Based on these maps, we generated hypotheses of regions of the brain causally related to sensory processing, locomotor control, courtship, aggression, and sleep. Our maps directly specify genetic tools to target these regions, which we used to identify a small population of neurons with a role in the control of walking.

Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma.

The discovery of new genetic determinants of inherited skin disorders has been instrumental to the understanding of epidermal function, differentiation, and renewal. Here, we show that mutations in KDSR (3-ketodihydrosphingosine reductase), encoding an enzyme in the ceramide synthesis pathway, lead to a previously undescribed recessive Mendelian disorder in the progressive symmetric erythrokeratoderma spectrum. This disorder is characterized by severe lesions of thick scaly skin on the face and genitals and thickened, red, and scaly skin on the hands and feet. Although exome sequencing revealed several of the KDSR mutations, we employed genome sequencing to discover a pathogenic 346 kb inversion in multiple probands, and cDNA sequencing and a splicing assay established that two mutations, including a recurrent silent third base change, cause exon skipping. Immunohistochemistry and yeast complementation studies demonstrated that the mutations cause defects in KDSR function. Systemic isotretinoin therapy has achieved nearly complete resolution in the two probands in whom it has been applied, consistent with the effects of retinoic acid on alternative pathways for ceramide generation.

Cosmic-ray antinuclei as messengers of new physics: status and outlook for the new decade.

The precise measurement of cosmic-ray antinuclei serves as an important means for identifying the nature of dark matter and other new astrophysical phenomena, and could be used with other cosmic-ray species to understand cosmic-ray production and propagation in the Galaxy. For instance, low-energy antideuterons would provide a "smoking gun" signature of dark matter annihilation or decay, essentially free of astrophysical background. Studies in recent years have emphasized that models for cosmic-ray antideuterons must be considered together with the abundant cosmic antiprotons and any potential observation of antihelium. Therefore, a second dedicated Antideuteron Workshop was organized at UCLA in March 2019, bringing together a community of theorists and experimentalists to review the status of current observations of cosmic-ray antinuclei, the theoretical work towards understanding these signatures, and the potential of upcoming measurements to illuminate ongoing controversies. This review aims to synthesize this recent work and present implications for the upcoming decade of antinuclei observations and searches. This includes discussion of a possible dark matter signature in the AMS-02 antiproton spectrum, the most recent limits from BESS Polar-II on the cosmic antideuteron flux, and reports of candidate antihelium events by AMS-02; recent collider and cosmic-ray measurements relevant for antinuclei production models; the state of cosmic-ray transport models in light of AMS-02 and Voyager data; and the prospects for upcoming experiments, such as GAPS. This provides a roadmap for progress on cosmic antinuclei signatures of dark matter in the coming years.

9/11-related PTSD among highly exposed populations: a systematic review 15 years after the attack.

BACKGROUND: The 11 September 2001 (9/11) attacks were unprecedented in magnitude and mental health impact. While a large body of research has emerged since the attacks, published reviews are few, and are limited by an emphasis on cross-sectional research, short time frame, and exclusion of treatment studies. Additionally, to date, there has been no systematic review of available longitudinal information as a unique data set. Consequently, knowledge regarding long-term trajectories of 9/11-related post-traumatic stress disorder (PTSD) among highly exposed populations, and whether available treatment approaches effectively address PTSD within the context of mass, man-made disaster, remains limited. METHODS: The present review aimed to address these gaps using a systematic review of peer-reviewed reports from October 2001 to May 2016. Eligible reports were of longitudinal studies of PTSD among highly exposed populations. We identified 20 reports of 9/11-related PTSD, including 13 longitudinal prevalence studies and seven treatment studies. RESULTS: Findings suggest a substantial burden of 9/11-related PTSD among those highly exposed to the attack, associated with a range of sociodemographic and back-ground factors, and characteristics of peri-event exposure. While most longitudinal studies show declining rates of prevalence of PTSD, studies of rescue/recovery workers have documented an increase over time. Treatment studies were few, and generally limited by methodological shortcomings, but support exposure-based therapies. CONCLUSION: Future directions for research, treatment, and healthcare policy are discussed.

Evaluation of antibody response to an adjuvanted hapten-protein vaccine as a potential inhibitor of sexual maturation for farmed Atlantic salmon.

An experimental contraceptive vaccine was evaluated in Atlantic salmon (Salmo salar). A peptide derived from the beta subunit of luteinizing hormone (LH) was conjugated to two different carrier proteins, bovine serum albumin (BSA) and keyhole limpet hemocyanin (KLH), and formulated with one of four immunostimulants in a water-in-oil emulsion. Specific antibody responses to the peptide and each carrier protein were evaluated. While the antibody response to KLH was stronger than the response to BSA, both carrier proteins stimulated comparable antibody responses to the LH peptide. The immunostimulant proved to be more important for enhancing the LH peptide antibody response than the carrier protein selection; vaccines containing a combination of Aeromonas salmonicida and Vibrio anguillarum stimulated significantly greater LH peptide antibody production than any of the other three immunostimulants evaluated at 12 weeks post-vaccination. This study provides proof-of-concept for specific antibody production against a hapten-carrier protein antigen in Atlantic salmon and reinforces the importance of vaccine immunostimulant selection.

Effects of the Immunocontraceptive Gonacon on Pregnancy in Brucella-Seropositive American bison (Bison bison).

The purpose of this study was to determine if the number of pregnancies in naturally infected Brucella abortus-positive bison (Bison bison) cows would be reduced over a period of 5 yr after one treatment with 3000 µg gonadotropin-releasing hormone immunocontraceptive (GonaCon) compared to a similar group of naturally infected B. abortus-positive bison cows not treated with GonaCon. In each of the 5 yr, GonaCon-treated cows produced fewer offspring in relation to number of cows than the nontreated cows. Fisher's Exact test comparing offspring produced during the first reproductive season showed a significant difference between the two groups (P=0.0028). Differences in number of calves produced in GonaCon-treated and control groups were also noted in remaining years, but statistics were not applied because of data constraints. These data indicate that one treatment with GonaCon in brucellosis-seropositive female bison reduced pregnancies over five reproductive years. Thus, immunocontraception could potentially be used to manage brucellosis in affected herds.

Twenty years of immunocontraceptive research: lessons learned.

The National Wildlife Research Center (NWRC) began immunocontraception vaccine research by testing porcine zona pellucida (PZP) on white-tailed deer (Odocoileus virginianus). Early PZP research demonstrated that PZP induced infertility; however, increased length of the rut was observed in PZP-treated deer. An alternative vaccine using a keyhole limpet hemocyanin-gonadotropin-releasing hormone (KLH-GnRH) conjugate formulated with modified Freund's adjuvant was developed at NWRC. Suppression of GnRH has reduced reproduction in both sexes but is most effective in females. This vaccine was effective in preventing contraception in female deer for several years after a prime and boost. Due to adverse side effects of Freund's adjuvant, NWRC developed a new adjuvant called AdjuVac, a mineral oil/surfactant adjuvant with the addition of Mycobacterium avium as an immunostimulant. The price of KLH prompted a search for a more economical hemocyanin carrier protein for the GnRH peptide. Blue protein, derived from the mollusk Concholepas concholepas, proved to be a successful option. Formulation improvements resulted in a vaccine that can be effective as a single injection for multiple years, now called GonaCon. GonaCon is registered with the Environmental Protection Agency (EPA) for use in white-tailed deer in urban/suburban areas and for wild horses (Equus caballus) and burros (Equus asinus). Future GonaCon applications may include reducing reproduction to manage populations of other wildlife species, such as prairie dogs (Cynomys ludovicianus) in urban areas and suppressing reproduction to reduce the spread of venereal diseases such as brucellosis. Research is being conducted to develop a GnRH vaccine used in combination with the rabies vaccine to control population growth in free-roaming dogs, with the secondary effect of managing the spread of rabies. The EPA would regulate all these uses. Research is also ongoing on a GnRH vaccine to delay the onset of adrenocortical disease in pet ferrets (Mustela putorius), a use regulated by the United States Department of Agriculture.

The use of contraception as a disease management tool in wildlife.

Contraception offers potential as a tool for managing certain diseases in wildlife, most notably venereally transmitted diseases or diseases transmitted at parturition. Brucellosis is an excellent example of an infectious disease present in wild populations that could potentially be managed through immunocontraception. Previous studies in bison (Bison bison) suggest that a single injection of GonaCon (National Wildlife Research Center, U.S. Department of Agriculture/Animal and Plant Health Inspection Service/Wildlife Services, Fort Collins, Colorado 80521, USA) results in 3 or more yr of infertility. Ongoing studies will determine if the use of GonaCon in bison decreases shedding of Brucella abortus from infected animals and will better define the duration of infertility following a single injection

Immunocontraception in Eastern gray squirrels (Sciurus carolinensis): morphologic changes in reproductive organs.

Eastern gray squirrels (EGS) (Sciurus carolinensis) damage trees through bark stripping or gnawing due to territorial marking or agonistic gnawing behavior in concert with higher densities. This study was conducted to determine the effects of a contraceptive vaccine on EGS and its reproductive organ histology. Free-ranging urban EGS were vaccinated with the immunocontraceptive GonaCon. All EGS were > or = 6 mo of age as determined by a combination of pelage characteristics and body weights. The vaccine was administered by injection at a dosage rate of 0.4 ml containing 400 microg of GnRH-mollusk protein conjugate i.m. in the thigh to 33 EGS (17 male [m], 16 female [f]) in trapping session 1 (TS1), 23 (14 m, 9 f) in trapping session 2 (TS2), and 11 (8 m, 3 f) in trapping session 3 (TS3). A sham injection containing 0.4 ml saline-AdjuVac was given as control to 22 EGS (16 m, 6 f) in TS1, 20 (12 m, 8 f) in TS2, and 8 (4 m, 4 f) in TS3. In the last trapping session (TS4), 35 EGS (16 treated, 19 control) were killed for necropsy to evaluate histologic changes in testes and ovaries. Treated EGS males had testicular, prostatic, and epididymal atrophy compared with control EGS males. The tubuli seminiferi and prostatic glandular lumen of treated EGS males were atrophic, and the epididymal lumen contained no sperm cells. No histologic changes were observed in treated EGS females; however, females likely were not collected when changes due to GonaCon would have been observed. There were no observable histologic differences in the pituitary gland of treated and control EGS. There were no statistically significant differences in either testosterone or progesterone concentrations between control and treated EGS. Although there were no serious side effects to the vaccine, six EGS developed injection site abscesses. GonaCon may be a potential tool for EGS population control.

The Essential Role of Dermatology Publications in Enhancing Professional Diversity, Equity, and Inclusion.

Dermatology publications have substantial untapped potential to improve patient care for all patients and communities. The leadership role of both editors and editorial boards of these journals, books, and digital media provides an important opportunity to support professional diversity, equity, and inclusion (DEI) plus democratization of knowledge.1 Multiple events in many countries in recent times have revealed the need to work harder at DEI to ensure a level playing field for all patients, clinicians, and researchers.

The safety of in-office laryngologic procedures during active antithrombotic therapy.

OBJECTIVES: To determine whether patients undergoing in-office laryngologic procedures on antithrombotic therapy are at increased risk for treatment-related complications. METHODS: Patients were those who underwent at least one in-office laryngologic procedure with any of three fellowship-trained laryngologists. Procedures were identified by current procedural terminology (CPT) code and included biopsies, excisions, laser ablations, and injections (therapeutic and augmentative). Patients were divided into two groups based on the use of antithrombotic therapy at the time of their procedure. Retrospective chart review was performed to identify any complications, with an average follow-up of 186 days. RESULTS: Five hundred-sixty-four unique individuals were identified with ages ranging from 18 to 93 years old and with a relatively even distribution between females (45%) and males (55%). They underwent 647 procedures in total, 310 of which were performed while on some form of antithrombotic therapy. Sixteen procedures were associated with complications either during or after the procedure. In comparing overall complication rates, there was no significant difference between non-antithrombotic (2.4%) and antithrombotic (3.3%) cohorts (OR 1.09, 95% CI [0.46-2.60], P = .8454). CONCLUSIONS: In spite of known risks in other settings, antithrombotic agents do not appear to confer increased risk of treatment-related complications during in-office laryngologic procedures, obviating the need for cessation of therapy prior to these interventions. LEVEL OF EVIDENCE: 4.

Attitudes of dermatologists in the southeastern United States regarding treatment of alopecia areata: a cross-sectional survey study.

BACKGROUND: Little evidence exists to guide treatment of alopecia areata (AA). The current practices in treatment of children compared to adults and of progressive stages of hair loss are unknown. The objective of this study was to examine the current practices of southeastern United States dermatologists for the treatment of AA. METHODS: Dermatologists were sent anonymous questionnaires regarding their treatment practices by mail. Respondents' frequencies of treatment in children compared to adults and in patchy hair loss compared to widespread hair loss were compared with Wilcoxon signed-ranks tests and Friedman tests. As a secondary source, the National Alopecia Areata Registry (NAAR) database was analyzed for patients' treatment histories. RESULTS: Survey results suggested that dermatologists recommend treatment less frequently for children than adults and for more advanced hair loss. NAAR data confirmed that offering no treatment for AA is relatively common. CONCLUSION: Dermatologists' treatment of AA is inconsistent. A stronger evidence base will provide more consistent treatment options.

Perceptions of pediatric clinical research among African American and Caucasian parents.

Difficulty in recruiting African American adults for clinical trials is well documented, but there is no consensus on African American children. Responses of a survey completed by 90 African American and Caucasian parents from December 2004 to April 2005 were analyzed to determine if racial disparities exist in research participation interest in an academic pediatric dermatology clinic. The majority of questions (32 of 38) were answered similarly by subjects of both races. However, when compared to African Americans, Caucasians were slightly more trusting (84% vs 65%) in regard to either total or moderate trust (p = .03). African Americans were 3 times as likely to feel that their child might be "treated like a guinea pig" if the child was a research subject (p = .03). Nearly a third more Caucasians than African Americans would be more inclined to enroll their healthy child in a research study if they had an established relationship with the health care provider informing them of the study (p = .0001). Caucasians had more exposure to research (p = .03). Nevertheless, there was no racial difference in the willingness to theoretically allow their child to participate in research studies. Accordingly, the possible lack of trust should not be used as the only reason racially representative recruitment goals are not accomplished.

The major lung cancer-derived mutants of ERBB2 are oncogenic and are associated with sensitivity to the irreversible EGFR/ERBB2 inhibitor HKI-272.

Mutations in the ERBB2 gene were recently found in approximately 2% of primary non-small cell lung cancer (NSCLC) specimens; however, little is known about the functional consequences and the relevance to responsiveness to targeted drugs for most of these mutations. Here, we show that the major lung cancer-derived ERBB2 mutants, including the most frequent mutation, A775insYVMA, lead to oncogenic transformation in a cellular assay. Murine cells transformed with these mutants were relatively resistant to the reversible epidermal growth factor receptor (EGFR) inhibitor erlotinib, resembling the resistant phenotype found in cells carrying the homologous mutations in exon 20 of EGFR. However, the same cells were highly sensitive to the irreversible dual-specificity EGFR/ERBB2 kinase inhibitor HKI-272, as were those overexpressing wild-type ERBB2. Finally, the NSCLC cell line, Calu-3, overexpressing wild-type ERBB2 owing to a high-level amplification of the ERBB2 gene were highly sensitive to HKI-272. These results provide a rationale for treatment of patients with ERBB2-mutant or ERBB2-amplified lung tumors with HKI-272.

A study of targeted enhanced patient care for pediatric atopic dermatitis (STEP PAD).

Atopic dermatitis is a common chronic skin condition in children. Treatment strategies often require stringent adherence to skin care regimens for symptom resolution. As many factors influence the course of the condition, we investigated the role of a designated "atopic dermatitis educator" in a pediatric dermatology clinic. We planned to determine whether the individual interaction with an atopic dermatitis educator affects the course of disease severity, resolution, and quality of life in atopic children. New and return pediatric atopic dermatitis patients from English-speaking families were recruited from a pediatric dermatology clinic with a single pediatric dermatologist. The 151 subjects were randomized to either the control or the intervention group. A total of 106 subjects completed the study. Those in the intervention group received the atopic dermatitis educator's individual counseling/education session. Subjects' severity was determined by the Scoring Atopic Dermatitis severity index and quality of life by either the Children's Dermatology Life Quality Index or the Infants' Dermatitis Quality of Life index depending on the patient's age. Analysis of covariance was measured. No significant difference was found in the percentage change of severity or quality of life between the groups.

Ebola Virus Persistence in Ocular Tissues and Fluids (EVICT) Study: Reverse Transcription-Polymerase Chain Reaction and Cataract Surgery Outcomes of Ebola Survivors in Sierra Leone.

BACKGROUND: Ebola virus disease (EVD) survivors are at risk for uveitis during convalescence. Vision loss has been observed following uveitis due to cataracts. Since Ebola virus (EBOV) may persist in the ocular fluid of EVD survivors for an unknown duration, there are questions about the safety and feasibility of vision restorative cataract surgery in EVD survivors. METHODS: We conducted a cross-sectional study of EVD survivors anticipating cataract surgery and patients with active uveitis to evaluate EBOV RNA persistence in ocular fluid, as well as vision outcomes post cataract surgery. Patients with aqueous humor that tested negative for EBOV RNA were eligible to proceed with manual small incision cataract surgery (MSICS). FINDINGS: We screened 137 EVD survivors from June 2016 - August 2017 for enrolment. We enrolled 50 EVD survivors; 46 with visually significant cataract, 1 with a subluxated lens, 2 with active uveitis and 1 with a blind painful eye due to uveitis. The median age was 24.0years (IQR 17-35) and 35 patients (70%) were female. The median logMAR visual acuity (VA) was 3.0 (Snellen VA Hand motions; Interquartile Range, IQR: 1.2-3.0, Snellen VA 20/320 - Hand motions). All patients tested negative for EBOV RNA by RT-PCR in aqueous humor/vitreous fluid and conjunctiva at a median of 19months (IQR 18-20) from EVD diagnosis in Phase 1 of ocular fluid sampling and 34months (IQR 32-36) from EVD diagnosis in Phase 2 of ocular fluid sampling. Thirty-four patients underwent MSICS, with a preoperative median VA improvement from hand motions to 20/30 at three-month postoperative follow-up (P<0.001). INTERPRETATION: EBOV persistence by RT-PCR was not identified in ocular fluid or conjunctivae of fifty EVD survivors with ocular disease. Cataract surgery can be performed safely with vision restorative outcomes in patients who test negative for EBOV RNA in ocular fluid specimens. These findings impact the thousands of West African EVD survivors at-risk for ocular complications who may also require eye surgery during EVD convalescence.

Genome sequence of the dissimilatory metal ion-reducing bacterium Shewanella oneidensis.

Shewanella oneidensis is an important model organism for bioremediation studies because of its diverse respiratory capabilities, conferred in part by multicomponent, branched electron transport systems. Here we report the sequencing of the S. oneidensis genome, which consists of a 4,969,803-base pair circular chromosome with 4,758 predicted protein-encoding open reading frames (CDS) and a 161,613-base pair plasmid with 173 CDSs. We identified the first Shewanella lambda-like phage, providing a potential tool for further genome engineering. Genome analysis revealed 39 c-type cytochromes, including 32 previously unidentified in S. oneidensis, and a novel periplasmic [Fe] hydrogenase, which are integral members of the electron transport system. This genome sequence represents a critical step in the elucidation of the pathways for reduction (and bioremediation) of pollutants such as uranium (U) and chromium (Cr), and offers a starting point for defining this organism's complex electron transport systems and metal ion-reducing capabilities.

Comparison of immune and adverse effects induced by AdjuVac and Freund's complete adjuvant in New Zealand white rabbits (Oryctolagus cuniculus).

Though Freund's complete adjuvant effectively increases immune response to vaccines in various species, its potentially severe inflammatory effects have led many animal researchers to seek alternative immunological adjuvants. In a study of New Zealand white rabbits, the authors compared the immune and adverse effects of Freund's complete adjuvant with the effects of two formulations of AdjuVac, an immunological adjuvant previously developed by their group. All three adjuvants improved humoral immune response but also caused inflammation. Inflammatory reactions caused by AdjuVac, however, tended to be less severe than those caused by Freund's complete adjuvant.

Epidemiological investigation, cleanup, and eradication of pullorum disease in adult chickens and ducks in two small-farm flocks.

Pullorum disease causing acute septicemia and mortality in adult brown chickens was diagnosed in a small-farm chicken flock in Iowa. Also, Salmonella Pullorum was isolated from the intestine of one of four rats trapped on this index farm. Tracing movements of spent hens from the index farm resulted in identification of a second infected flock on a contact farm. Poultry on the contact farm were tested with the stained-antigen, rapid whole-blood test, and two ducks and one chicken gave positive reactions. Reactors were necropsied and cultures of appropriate tissues resulted in isolation of Salmonella Pullorum from one duck and the chicken. Pulsed-field gel electrophoresis banding patterns of Salmonella Pullorum isolates from chickens on the index and contact farms, the duck, and the rat demonstrated that all isolates were genetically very similar. Both flocks were quarantined and depopulated and a detailed flock cleanup plan was created for both farms. After extensive cleaning and disinfection procedures were completed on the index farm, environmental monitoring and bioassays of trapped mice were conducted. Negative cultures of environmental swabs and trapped mice and negative blood tests of all birds conducted 4 mo after placement of a new flock on the index farm demonstrated that cleaning and disinfection methods used in this outbreak had successfully eliminated Salmonella Pullorum organisms from this farm.