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.

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.

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.

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.

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.

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.

Video microscopy, video cameras, and image enhancement.

Video microscopy is the application of video technology to microscopy, resulting in two fields of microscopy called video-enhanced contrast microscopy (VEC) and video-intensified microscopy (VIM). VEC involves the production of an image from a specimen that is invisible to the eye, either because of a lack of contrast or because of its spectral characteristics (UV or infrared). VIM involves imaging a specimen when the light levels are too low for standard cameras or, in some cases, even for the eye. Images are produced by VIM using image analysis computers.

Nonsurgical fertility control for managing free-roaming dog populations: a review of products and criteria for field applications.

About 75% of dogs worldwide are free to roam and reproduce, thus creating locally overabundant populations. Problems caused by roaming dogs include diseases transmitted to livestock and humans, predation on livestock, attacks on humans, road traffic accidents, and nuisance behavior. Nonsurgical fertility control is increasingly advocated as more cost-effective than surgical sterilization to manage dog populations and their impact. The aims of this review were to 1) analyze trends in numbers of scientific publications on nonsurgical fertility control for dogs; 2) illustrate the spectrum of fertility inhibitors available for dogs; 3) examine how differences between confined and free-roaming dogs might affect the choice of fertility inhibitors to be used in dog population management; and 4) provide a framework of criteria to guide decisions regarding the use of nonsurgical fertility control for dog population management. The results showed that the 117 articles published between 1982 and 2011 focussed on long-term hormonal contraceptives, such as gonadotropin-releasing hormone agonists, immunocontraceptives, and male chemical sterilants. The number of articles published biennially increased from one to five papers produced in the early 1980s to 10 to 20 in the past decade. Differences between confined dogs and free-roaming dogs include reproduction and survival as well as social expectations regarding the duration of infertility, the costs of sterilization, and the responsibilities for meeting these costs. These differences are likely to dictate which fertility inhibitors will be used for confined or free-roaming dogs. The criteria regarding the use of fertility control for dog population management, presented as a decision tree, covered social acceptance, animal welfare, effectiveness, legal compliance, feasibility, and sustainability. The review concluded that the main challenges for the future are evaluating the feasibility, effectiveness, sustainability, and effects of mass nonsurgical sterilization campaigns on dog population size and impact as well as integrating nonsurgical fertility control with disease vaccination and public education programs.

Use of a GnRH vaccine, GonaCon, for prevention and treatment of adrenocortical disease (ACD) in domestic ferrets.

Adrenocortical disease (ACD) is a common problem in surgically sterilized, middle-aged to old ferrets (Mustela putorius furo). The adrenal tissues of these ferrets develop hyperplasia, adenomas, or adenocarcinomas, which produce steroid hormones including estradiol, 17-hydroxyprogesterone, and androstenedione. Major clinical signs attributable to overproduction of these hormones are alopecia (hair loss) in both sexes and a swollen vulva in females. Pruritus, muscle atrophy, hind limb weakness, and sexual activity or aggression are also observed in both sexes. Males can develop prostatic cysts, prostatitis, and urethral obstruction. ACD is thought to be linked to continuous and increased LH secretion, due to lack of gonadal hormone feedback in neutered ferrets. This continuous elevated LH acts on adrenal cortex LH receptors, resulting in adrenal hyperplasia or adrenal tumor. This study investigated whether the immunocontraceptive vaccine GonaCon, a GnRH vaccine developed to reduce the fertility of wildlife species and the spread of disease, could prevent or delay onset of ACD and treat alopecia in ferrets with existing ACD. Results showed that GonaCon provided relief from ACD by causing production of antibodies to GnRH, probably suppressing production and/or release of LH. Treatment caused many ACD symptoms to disappear, allowing the ferrets to return to a normal life. The study also found that the probability of developing ACD was significantly reduced in ferrets treated with GonaCon when young (1-3 years old) compared to untreated control animals. GonaCon caused injection site reaction in some animals when administered as an intramuscular injection but caused few side effects when administered subcutaneously. Both intramuscular and subcutaneous vaccination resulted in similar levels of GnRH antibody titers. Subcutaneous vaccination with GonaCon is thus recommended to prevent the onset of ACD and as a possible treatment for ACD-signs in domestic ferrets.

Concomitant administration of GonaCon™ and rabies vaccine in female dogs (Canis familiaris) in Mexico.

Mexico serves as a global model for advances in rabies prevention and control in dogs. The Mexican Ministry of Health (MMH) annual application of approximately 16 million doses of parenteral rabies vaccine has resulted in significant reductions in canine rabies during the past 20 years. One collateral parameter of rabies programs is dog population management. Enhanced public awareness is critical to reinforce responsible pet ownership. Surgical spaying and neutering remain important to prevent reproduction, but are impractical for achieving dog population management goals. GonaCon™, an anti-gonadotropin releasing hormone (GnRH) vaccine, was initially tested in captive female dogs on the Navajo Nation, 2008. The MMH led this international collaborative study on an improved formulation of GonaCon™ in captive dogs with local representatives in Hidalgo, Mexico in 2011. This study contained 20 bitches assigned to Group A (6 control), Group B (7 GonaCon™), and Group C (7 GonaCon™ and rabies vaccine). Vaccines were delivered IM. Animals were placed under observation and evaluated during the 61-day trial. Clinically, all dogs behaved normally. No limping or prostration was observed, in spite of minor muscle atrophy post-mortem in the left hind leg of dogs that received GonaCon™. Two dogs that began the study pregnant give birth to healthy pups. Dogs that received a GonaCon™ injection had macro and microscopic lesions consistent with prior findings, but the adverse injection effects were less frequent and lower in intensity. Both vaccines were immunogenic based on significant increases in rabies virus neutralizing antibodies and anti-GnRH antibodies in treatment Groups B and C. Simultaneous administration of GonaCon™ and rabies vaccine in Group C did not affect immunogenicity. Progesterone was suppressed significantly in comparison to controls. Future studies that monitor fertility through multiple breeding cycles represent a research need to determine the value of integrating this vaccine into dog rabies management.

Immunization with a synthetic peptide vaccine fails to protect mule deer (Odocoileus hemionus) from chronic wasting disease.

Chronic wasting disease (CWD) adversely affects both wild and captive cervid populations. A vaccine to prevent CWD would be a highly desirable tool to aid in disease management. To this end, we tested in mule deer a combination of CWD vaccines consisting of cervid prion peptide sequences 168-VDQYNNQNTFVHDC-182 and 145-NDYEDRYYRENMYRYPNQ-164 that had previously been shown to delay onset of clinical disease and increase survival in a mouse-adapted scrapie model. Thirteen captive mule deer (Odocoileus hemionus) were divided into vaccine (n=7) and control groups (n=6), and given prime and boost vaccinations intramuscularly 5 wk apart. Eight weeks postprime (3 wk postboost), all animals were challenged via natural exposure to an environment contaminated with infective CWD prions. Deer were monitored intermittently for prion infection by rectal and tonsil biopsies beginning 275 days postchallenge. All vaccinates responded to both peptide conjugates present in the combination vaccine as measured by enzyme-linked immunosorbent assay. However, all deer eventually became infected regardless of vaccine status.

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

Relationship of resistant hypertension and treatment outcomes with total arterial compliance in a predominantly African American hypertensive cohort.

Resistant hypertension (RH) affects 8% to 30% of hypertensive patients. Blood pressure (BP) reflects the interaction between vascular compliance, resistance to flow, intravascular volume, and cardiac contractility. The relationship of RH with total arterial compliance index (TACI) has not been adequately explored. The RH period prevalence (RH at baseline or follow-up) was determined in a hypertensive cohort (N=156) and compared across quartiles of TACI. Age- and sex-adjusted systolic BP, diastolic BP, and antihypertensive therapeutic intensity score (TIS) were also determined at the time of first BP control. The cohort was 85.3% African American and 67.3% female. Median follow-up was 7 months. The prevalence of RH at baseline was 14.7% while the period prevalence was 43.6%. The period prevalence of RH by ascending quartile for TACI was 66%, 36.8%, 40%, and 30.8% (P=.008). The average BP and antihypertensive TIS at first BP control across TACI quartiles was 122.3/73.4 mm Hg (2.26), 120.7/72.5 mm Hg (1.88), 122.4/75.3 mm Hg (1.71), and 120.0/79.4 mm Hg (1.64) (P=.62, P=.03, P=.13). Low TACI was linked to higher RH prevalence and antihypertensive TIS at first attainment of goal BP according to the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. TACI provides prognostic information that is clinically and perhaps pathophysiologically relevant in RH.