Salvage of Nipple-Areolar Complex Ischemia With Dimethyl Sulfoxide: A Case Series.

BACKGROUND: Nipple-areolar complex (NAC) necrosis is a known risk of breast surgery, particularly mastectomy. Disruption of the underlying blood supply to the NAC can lead to ischemia and subsequent necrosis. Nitroglycerin paste is currently used to combat NAC ischemia but has limited efficacy and an unfavorable side effect profile. Topical dimethyl sulfoxide (DMSO) has been shown to increase tissue perfusion in microsurgery and various skin flaps, but its role in the treatment and prevention of NAC ischemia has not been reported. Through a prospective case series, this study aims to introduce DMSO as a safe treatment for NAC ischemia after breast surgery. METHODS: Patients treated by 2 breast surgeons and a single plastic surgeon who underwent nipple-sparing mastectomy or breast reduction and developed NAC ischemia were identified via a prospectively maintained database. Ischemic changes were diagnosed, and treatment to the affected NAC with DMSO was initiated at the conclusion of the procedure, or postoperative day 1 in most cases, and continued 4 times daily until ischemic changes had resolved clinically. Collected demographic, surgical, and outcome variables were analyzed using descriptive statistics. RESULTS: Eleven patients with a mean age of 47.8 ± 9.5 years (range, 35-61 years) and mean body mass index of 26.0 ± 4.4 kg/m2 (range, 20.7-33.4 kg/m2) were identified. The mean duration of time between surgery and the clinical diagnosis of NAC ischemia was 1.3 ± 2.8 days (range, 0-7 days). The average length of time from DMSO initiation to clinical improvement or resolution of NAC ischemia was 7.5 ± 2.5 days (range, 5-12 days). All patients demonstrated significant improvement or complete resolution of NAC ischemia following serial topical DMSO application. CONCLUSIONS: This study demonstrates DMSO is a safe treatment for threatened NACs. All patients in this series showed either dramatic improvement or resolution of NAC ischemia after DMSO application, and threatened NACs of all 11 patients were successfully salvaged. These promising results set the basis for ongoing randomized controlled studies to determine the efficacy of DMSO treatment for NAC ischemia.

Healing Exposed Calvarial Hardware Using Negative-Pressure Wound Therapy and Vashe Wound Solution: Case Report.

OBJECTIVE: The management of cranioplasty infections has historically been explantation followed by delayed reimplantation/reconstruction. This treatment algorithm necessitates surgery, tissue expansion, and prolonged disfigurement. In this report, the authors describe a treatment approach consisting of serial vacuum-assisted closure (VAC) with hypochlorous acid (HOCl) solution (Vashe Wound Solution; URGO Medical) as a salvage strategy. METHODS: A 35-year-old man who sustained head trauma, neurosurgical complications, and severe syndrome of the trephined (SOT; devastating neurologic decline treated by cranioplasty) underwent titanium cranioplasty with free flap. Three weeks postoperation, he presented with pressure-related wound dehiscence/partial flap necrosis, exposed hardware, and bacterial infection. Given the severity of his precranioplasty SOT, hardware salvage was critical. He was treated with serial VAC with HOCl solution for 11 days followed by VAC for 18 days and definitive split-thickness skin graft placement over resulting granulation tissue. Authors also conducted a literature review of cranial reconstruction infection management. RESULTS: The patient remained healed 7 months postoperatively without recurrent infection. Importantly, his original hardware was retained, and his SOT remained resolved. Findings from the literature review support the use of conservative modalities to salvage cranial reconstructions without hardware removal. CONCLUSIONS: This study investigates a new strategy for managing cranioplasty infections. The VAC with HOCl solution regimen was effective in treating the infection and salvaging the cranioplasty, thus obviating the complications associated with explantation, new cranioplasty, and recurrence of SOT. There is limited literature on the management of cranioplasty infections using conservative treatments. A larger study to better determine the efficacy of VAC with HOCl solution is underway.

Characteristics and Treatment of Patients Diagnosed With Paradoxical Adipose Hyperplasia After Cryolipolysis: A Case Series and Scoping Review.

BACKGROUND: Paradoxical adipose hyperplasia (PAH), a rare side effect of CoolSculpting (cryolipolysis), is characterized by fatty enlargement of the treatment area occurring months after the procedure. OBJECTIVES: The purpose of this study was to report a retrospective case series of patients diagnosed with PAH at the authors' institution, increase the collective understanding of this complication and subsequent management, and raise the question of who should ethically perform cryolipolysis. METHODS: All participants diagnosed with PAH by a plastic surgeon at a large academic medical center were identified. Demographic information, medical history, procedure details, time to PAH diagnosis, and corrective surgical intervention details were collected. Mean duration of time from cryolipolysis treatment to diagnosis of PAH was calculated, along with other descriptive statistics. A scoping review of all PAH literature published in PubMed, Embase, and Web of Science was also conducted. RESULTS: Four patients diagnosed with PAH after cryolipolysis were identified for inclusion in this study. The calculated incidence of PAH at our center was 0.67%. All patients requested therapy for PAH and subsequently underwent either liposuction, abdominoplasty, or both. The mean duration of in-person follow-up time after final surgical treatment of PAH was 13.8 + 19.8 months (range, 2.8-43.5). Fortunately, no patients showed signs of PAH recurrence, and 3 out of 4 patients did not show signs of residual deformity. CONCLUSIONS: Findings from this patient cohort and scoping review provide evidence that although revisions may be required, conventional body contouring methods, not in the armamentarium of non-plastic surgeon practitioners, effectively alleviated PAH.

HPV/p16-positive oropharyngeal cancer treated with transoral robotic surgery: The roles of margins, extra-nodal extension and adjuvant treatment.

PURPOSE: Human papilloma virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) treatment outcomes are re-defining management. Traditional margins, the role of extranodal extension (ENE) and adjuvant treatment intensity continue to be debated. This study aimed to determine the impact of margins, ENE and adjuvant therapy on survival following transoral robotic surgery (TORS). METHODS: Patients treated with TORS at an academic center were retrospectively identified (2013-2019). Survival outcomes were evaluated using Kaplan-Meier curves. RESULTS: 48 patients were included. 40 (83%) were male. Mean age was 61.2 years. 43 (90%) were stage I. 22 (45.8%) had ENE. 31 (65%) had margins >1 mm. 38 (79%) had indications for radiation therapy; 9 (24%) refused. Chemotherapy was recommended in 36 (75%) patients; 24 (67%) refused. Locoregional control was 98%, metastasis-free survival was 96%, and disease-specific survival was 100% at 5-years. Overall survival was 95%. CONCLUSIONS: Given the high survival rate seen after TORS, it is likely that margins, ENE and adjuvant treatment may not significantly contribute to outcomes.

Active monitoring versus direct active monitoring for Ebola virus disease in the United States: experiences and perceptions of former persons under monitoring in the District of Columbia and Indiana.

OBJECTIVES: During the 2014-2016 West Africa Ebola outbreak, the Centers for Disease Control and Prevention recommended daily monitoring and surveillance of persons arriving in the United States (US) from impacted areas through either active monitoring (phone calls, online platforms, and so on) or direct active monitoring (in-person or electronic visualization). Intensiveness of policies implemented by state/local jurisdictions varied markedly. To study the experiences and perceptions of active monitoring versus direct active monitoring on former persons under monitoring (FPUMs) in the US, we compared two jurisdictions that utilized distinct polices: the District of Columbia (DC) and Indiana (IN). STUDY DESIGN: Retrospective assessment survey of FPUMs. METHODS: FPUMs from both jurisdictions (DC 826 and IN 246) monitored from October 2014 to September 2015 were surveyed regarding their overall perception of monitoring, communications with jurisdictional staff, negative consequences experienced, and risk for and concern about Ebola virus disease. A total of 294 DC FPUMs and 52 IN FPUMs responded. RESULTS: Directly actively monitored FPUMs in IN were more likely to report monitoring was difficult (P < 0.01), not being allowed to return to work (P = 0.01), and faster response times when reaching out to their assigned health department (P < 0.01). Overall all FPUMs, regardless of the monitoring method they underwent, perceived little risk and reported they felt monitoring protected public health. CONCLUSIONS: Our results display that while FPUMs preferred active monitoring, both polices equally reduced their concern, suggesting that less intensive polices achieve the same level of perceived effectiveness by those monitored while also reducing the amount of negative consequences they may face.

Factors influencing the quality of Myrmecia pilosula (Jack Jumper) ant venom for use in in vitro and in vivo diagnoses of allergen sensitization and in allergen immunotherapy.

BACKGROUND: Allergen immunotherapy uses pharmaceutical preparations derived from naturally occurring source materials, which contain water-soluble allergenic components responsible for allergic reactions. The success of in vivo and in vitro diagnoses in allergen sensitization and allergen immunotherapy largely depends on the quality, composition and uniformity of allergenic materials used to produce the active ingredients, and the formulation employed to prepare finished products. OBJECTIVES: We aimed to examine the factors influencing batch-to-batch consistency of Jack Jumper (Myrmecia pilosula) ant venom (JJAV) in the form of active pharmaceutical ingredient (AI) and informed whether factors such as temperature, artificial light and container materials influence the quality of JJAV AIs. We also aimed to establish handling and storage requirements of JJAV AIs to ensure preservation of allergenic activities during usage in the diagnosis of allergen sensitization and in allergen immunotherapy. METHODS: The quality and consistency of JJAV AIs were analysed using a combination of bicinchoninic acid assay for total protein quantification, HPLC-UV for JJAV allergen peptides quantification, ELISA inhibition for total allergenic potency, SDS-PAGE, AU-PAGE and immunoblot for qualitative assessment of JJAV components, and Limulus Amebocyte Lysate assay for the quantification of endotoxin concentration. API-ZYM and Zymogram assays were used to probe the presence of enzymatic activities in JJAV. RESULTS: Pharmaceutical-grade JJAV for allergen immunotherapy has good batch-to-batch consistency. Temporary storage at 4°C and light exposure do not affect the quality of JJAV. Exposure to temperature above 40°C degrades high MW allergens in JJAV. Vials containing JJAV must be stored frozen and in upright position during long-term storage. CONCLUSIONS AND CLINICAL RELEVANCE: We have identified factors, which can influence the quality and consistency of JJAV AIs, and provided a framework for appropriate handling, transporting and storage of JJAV to be used for the diagnosis of allergen sensitization and in AIT.

CRISPR-Cas9-mediated gene knockout in primary human airway epithelial cells reveals a proinflammatory role for MUC18.

Targeted knockout of genes in primary human cells using CRISPR-Cas9-mediated genome-editing represents a powerful approach to study gene function and to discern molecular mechanisms underlying complex human diseases. We used lentiviral delivery of CRISPR-Cas9 machinery and conditional reprogramming culture methods to knockout the MUC18 gene in human primary nasal airway epithelial cells (AECs). Massively parallel sequencing technology was used to confirm that the genome of essentially all cells in the edited AEC populations contained coding region insertions and deletions (indels). Correspondingly, we found mRNA expression of MUC18 was greatly reduced and protein expression was absent. Characterization of MUC18 knockout cell populations stimulated with TLR2, 3 and 4 agonists revealed that IL-8 (a proinflammatory chemokine) responses of AECs were greatly reduced in the absence of functional MUC18 protein. Our results show the feasibility of CRISPR-Cas9-mediated gene knockouts in AEC culture (both submerged and polarized), and suggest a proinflammatory role for MUC18 in airway epithelial response to bacterial and viral stimuli.

A case-control study examining inconsistencies in pain management following fractured neck of femur: an inferior analgesia for the cognitively impaired.

Previous research suggests individuals who suffer from cognitive impairment are less able to vocalise pain than the rest of the cognitively-intact population. This feature of cognitive impairment may be leading to a chronic underdetection of pain as current assessment tools strongly rely on the participation of the patient. To explore inconsistencies in pain management within the acute setting, we conducted a retrospective assessment of 224 patients presenting with fractured neck of femur at a large teaching hospital's accident and emergency (A&E) department between 2 June 2011 and 2 June 2012. These patients were split into either a cognitively-impaired or cognitively-intact cohort based on their Abbreviated Mental Test Scores. Patients with cognitive impairment, on average, received a weaker level of analgesia than individuals without impairment both in the ambulance and in A&E. In the ambulance, 45% of cognitively-impaired patients were prescribed no pain relief compared with just 8% of those individuals who remain cognitively intact. After arrival at A&E, these inconsistencies continued with 69% of the cognitively-intact cohort receiving the strongest opioid analgesia compared with just 37% of the cognitively-impaired cohort. The cognitively-impaired cohort would also wait on average an hour longer before receiving this initial pain relief. We believe that these differences stem from cognitively-impaired patients being unable to vocalise their pain through traditional assessment methods. This work discusses the potential development or adoption of a tool which can be applied in the acute setting and relies less on vocalisation but more on the objective features of pain, so making it applicable to cognitively-impaired individuals.

Safety of Outpatient Plastic Surgery: A Comparative Analysis Using the TOPS Registry with 286,826 Procedures.

BACKGROUND: Outpatient plastic surgery at office-based surgery facilities (OBSFs) and ambulatory surgery centers (ASCs) has become increasingly prevalent over the past 30 years. Importantly, historical data are inconsistent regarding the safety outcomes of these venues, with advocates for both citing supporting studies. This investigation's purpose is to provide a more definitive comparative evaluation of outcomes and safety for outpatient surgery performed in these facilities. METHODS: The most common outpatient procedures were identified using the Tracking Operations and Outcomes for Plastic Surgeons database between 2008 and 2016. Outcomes were analyzed for OBSFs and ASCs. Patient and perioperative information was also analyzed using regression analysis to identify risk factors for complications. RESULTS: A total of 286,826 procedures were evaluated, of which 43.8% were performed at ASCs and 56.2% at OBSFs. Most patients were healthy, middle-aged women categorized as American Society of Anesthesiologists class I. The incidence of adverse events was 5.7%, and most commonly included antibiotic requirement (1.4%), dehiscence (1.3%), or seroma requiring drainage (1.1%). Overall, there was no significant difference in adverse events between ASCs and OBSFs. Age, American Society of Anesthesiologists class, body mass index, diabetes, smoking history, general anesthesia, certified registered nurse anesthetist involvement, operative duration, noncosmetic indications, and body region were associated with adverse events. CONCLUSIONS: This study provides an extensive analysis of common plastic surgery procedures performed in an outpatient setting in a representative population. With appropriate patient selection, procedures are safely performed by board-certified plastic surgeons in ambulatory surgery centers and office-based settings, as evidenced by the low incidence of complications in both environments. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Blood mRNA biomarkers for detection of treatment response in acute pulmonary exacerbations of cystic fibrosis.

BACKGROUND: Acute pulmonary exacerbations accelerate pulmonary decline in cystic fibrosis (CF). There is a critical need for better predictors of treatment response. OBJECTIVE: To test whether expression of a panel of leucocyte genes directly measured from whole blood predicts reductions in sputum bacterial density. METHODS: A previously validated 10-gene peripheral blood mononuclear cell (PBMC) signature was prospectively tested in PBMC and whole blood leucocyte RNA isolated from adult subjects with CF at the beginning and end of treatment for an acute pulmonary exacerbation. Gene expression was simultaneously quantified from PBMCs and whole blood RNA using real-time PCR amplification. Test characteristics including sensitivity, specificity, positive and negative predictive values were calculated and receiver operating characteristic curves determined the best cut-off to diagnose a microbiological response. The findings were then validated in a smaller independent sample. RESULTS: Whole blood transcript measurements are more accurate than forced expiratory volume in 1 s (FEV(1)) or C reactive protein (CRP) alone in identifying reduction of airway infection. When added to FEV(1), the whole blood gene panel improved diagnostic accuracy from 64% to 82%. The specificity of the test to detect reduced infection was 88% and the positive predictive value for the presence of persistent infection was 86%. The area under the curve for detecting treatment response was 0.81. Six genes were the most significant predictors for identifying reduction in airway bacterial load beyond FEV(1) or CRP alone. The high specificity of the test was replicated in the validation cohort. CONCLUSIONS: The addition of blood leucocyte gene expression to FEV(1) and CRP enhances specificity in predicting reduced pulmonary infection and may bolster the assessment of CF treatment outcomes.

Relationship of thoracic kyphosis and lumbar lordosis to bone mineral density in women.

UNLABELLED: The relationship between spinal curvature and bone mineral density (BMD) in women was examined. Significant relationships were observed between spinal curvature and BMD in both pre- and postmenopausal women. Excessive spinal curvature may be associated with low bone mass in premenopausal women. INTRODUCTION: The purpose of this study was to examine the associations between spinal measurements of thoracic and lumbar curvatures and bone mineral density in pre- and postmenopausal women. METHODS: The data for this study were obtained from the Texas Woman's University Pioneer Project. Female participants (n = 242; premenopausal n = 104, postmenopausal n = 138) between the ages of 18 and 60 years were evaluated on multiple health measures. Thoracic and lumbar curvatures were measured with a 24-in. (60 cm) flexicurve. Bone mineral density was assessed via dual-energy X-ray absorptiometry (Lunar DPX IQ, version 4.6e). Pearson correlations and logistic regression analysis were used to examine the associations between the obtained spinal curvature measurements and bone mineral density. Significance was set at p < .05. RESULTS: Significant correlations were observed for the femoral neck and lumbar spine bone mineral density with thoracic and lumbar curve in premenopausal women (r = -.344 to - .525; p < .001). Slightly weaker, but significant, correlations were observed for femoral neck and lumbar spine in relation to thoracic and lumbar curve in postmenopausal women (r = -.288 to -.397; p < .01). Premenopausal women with thoracic curvature greater than 4 cm had a greater risk of having low bone mass compared to premenopausal women with less than 4 cm of curvature (odds ratio = 3.982, 95 % CI = 1.206, 13.144). CONCLUSIONS: The observed negative relationship suggests that as either thoracic or lumbar curvature increases, the regional bone mineral density decreases in both pre- and postmenopausal women.

Navigating the Ethical Landmines of ChatGPT: Implications of Intelligent Chatbots in Plastic Surgery Clinical Practice.

ChatGPT is a cutting-edge language model developed by OpenAI with the potential to impact all facets of plastic surgery from research to clinical practice. New applications for ChatGPT are emerging at a rapid pace in both the scientific literature and popular media. It is important for clinicians to understand the capabilities and limitations of these tools before patient-facing implementation. In this article, the authors explore some of the technical details behind ChatGPT: what it is, and what it is not. As with any emerging technology, attention should be given to the ethical and health equity implications of this technology on our plastic surgery patients. The authors explore these concerns within the framework of the foundational principles of biomedical ethics: patient autonomy, nonmaleficence, beneficence, and justice. ChatGPT and similar intelligent conversation agents have incredible promise in the field of plastic surgery but should be used cautiously and sparingly in their current form. To protect patients, it is imperative that societal guidelines for the safe use of this rapidly developing technology are developed.

Anatomy and Biomechanics of the Thumb Carpometacarpal Joint.

This review discusses the anatomy and biomechanics of the thumb carpometacarpal (CMC) joint. This articulation between the trapezium and first metacarpal is integral for opposition and other complex movements necessary for pinch and grasp maneuvers. Fortunately, this joint is well equipped to handle the extreme forces imposed by these movements, as it is stabilized by an elaborate arrangement of ligaments and muscles. Without this stability, thumb subluxation would occur with loading during pinch and grasp, and human prehension would be impossible. Understanding the interactions occurring within this joint is essential for adequately treating pathology arising in this crucial joint.

Contralateral Obturator to Femoral Nerve Branch Transfer for Multilevel Lumbosacral Plexus Avulsion Injury.

We report successful restoration of quadriceps function following contralateral obturator to lateral branch of the femoral nerve transfer (with intervening autograft) in two patients with multilevel lumbosacral root avulsions, resulting in severe unilateral motor and sensory deficits. Three years postoperatively, patient 1 had regained Medical Research Council grade 3 knee extension with the ability to extend against 10 pounds of resistance. At 28 months postoperatively, patient 2 had regained Medical Research Council grade 2 knee extension. Treatment options for severe lumbosacral plexus injuries with multiple root avulsions are limited. This approach offers a new option for these devastating injuries.

Pediatric upper extremity firearm injuries: an analysis of demographic factors and recurring mechanisms of injury.

BACKGROUND: Little is known regarding risk factors specific to pediatric upper extremity firearm injuries. The purpose of this study is to evaluate pediatric patients treated for these injuries to identify at-risk populations and recurring mechanisms of injury. METHODS: A 20-year retrospective review was conducted. Patients 17 years of age and younger, with upper extremity injuries related to a firearm, were included. Analysis involved Fisher's exact and Chi-square tests. RESULTS: One hundred and eighty patients were included. The mean age was 12.04 ± 4.3 years. Most included patients were male (85%). Interestingly, females were more frequently victims of assault (P = 0.03), and males were more frequently injured due to accidental discharge (P < 0.001). The most affected race/ethnicity was White-not Hispanic or Latino (48%). The hand was the most frequent location injured (31%) and was more likely to be accidental than proximal injuries (P = 0.003). Air rifles were the most common firearm type used (56%). Pistols were implicated in 47 (26%) cases, rifles in 17 (9%), and shotguns in 10 (6%). Ninety-nine (55%) patients had procedures in the operating room. The most frequent procedure was foreign body removal (55%). CONCLUSIONS: Risk factors such as male sex, White-not Hispanic or Latino race/ethnicity, and adolescent age were attributed to increased risk for injury. Male sex was associated with increased risk of injury by accidental discharge and female sex with intentional assault. Air rifles were the most common firearm type overall, although female sex was associated with increased risk for injury by powder weapon.

Relationship of depth of invasion to survival outcomes and patterns of recurrence for T3 oral tongue squamous cell carcinoma.

INTRODUCTION: Current research is elucidating how the addition of depth of invasion (DOI) to the 8th edition of the American Joint Committee on Cancer (AJCC) TNM staging for oral cavity squamous cell carcinoma influences its prognostic accuracy. However, there is limited research on survival in pT3N0M0 oral tongue SCC (OTSCC) patients when stratifying by DOI. OBJECTIVES: Determine 5-year overall survival (OS), and cancer-specific survival (CSS) for patients with pT3N0M0 oral OTSCC based on shallow DOI (<10 mm) and deep DOI (10-20 mm). METHODS: Retrospective review involving three tertiary care cancer centers in North America. cT3N0M0 OTSCC patients receiving primary surgical treatment from 2004 to 2018 were identified. Inclusion: age > 18 years old and confirmation of pT3N0M0 OTSCC on surgical pathology. Exclusion: patients undergoing palliative treatment or previous head and neck surgery/radiotherapy. Analysis comprised two groups: shallow pT3 (tumor diameter > 4 cm, DOI < 10 mm) and deep pT3 (DOI 10 mm-20 mm). RESULTS: One hundred and four patients with pT3N0M0 OTSCC were included. Mean age was 59.1 years (range: 18-80.74). Age, gender, and Charlson Comorbidity Index were similar between the two groups (p > 0.05). Recurrence, LVI, PNI, and positive margins were more common in deep T3 tumors (P < 0.05). 5-year OS (50% vs 26%, p = 0.006) and CSS (72% vs 24%, p = 0.005) were worse in deep pT3 tumors. Deep pT3 disease was an independent predictor of OS (p = 0.004) and CSS (p = 0.01) on Cox-Regression analysis. CONCLUSION: DOI is an independent predictor of poor survival in pT3N0M0 OTSCC patients. Consideration should be given to escalating adjuvant therapy for deep pT3N0M0 OTSCC patients.

Use of ichip for high-throughput in situ cultivation of "uncultivable" microbial species.

One of the oldest unresolved microbiological phenomena is why only a small fraction of the diverse microbiological population grows on artificial media. The "uncultivable" microbial majority arguably represents our planet's largest unexplored pool of biological and chemical novelty. Previously we showed that species from this pool could be grown inside diffusion chambers incubated in situ, likely because diffusion provides microorganisms with their naturally occurring growth factors. Here we utilize this approach and develop a novel high-throughput platform for parallel cultivation and isolation of previously uncultivated microbial species from a variety of environments. We have designed and tested an isolation chip (ichip) composed of several hundred miniature diffusion chambers, each inoculated with a single environmental cell. We show that microbial recovery in the ichip exceeds manyfold that afforded by standard cultivation, and the grown species are of significant phylogenetic novelty. The new method allows access to a large and diverse array of previously inaccessible microorganisms and is well suited for both fundamental and applied research.

Animal models of orthopoxvirus infection.

Smallpox was one of the most devastating diseases known to humanity. Although smallpox was eradicated through a historically successful vaccination campaign, there is concern in the global community that either Variola virus (VARV), the causative agent of smallpox, or another species of Orthopoxvirus could be used as agents of bioterrorism. Therefore, development of countermeasures to Orthopoxvirus infection is a crucial focus in biodefense research, and these efforts rely on the use of various animal models. Smallpox typically presented as a generalized pustular rash with 30 to 40% mortality, and although smallpox-like syndromes can be induced in cynomolgus macaques with VARV, research with this virus is highly restricted; therefore, animal models with other orthopoxviruses have been investigated. Monkeypox virus causes a generalized vesiculopustular rash in rhesus and cynomolgus macaques and induces fatal systemic disease in several rodent species. Ectromelia virus has been extensively studied in mice as a model of orthopoxviral infection in its natural host. Intranasal inoculation of mice with some strains of vaccinia virus produces fatal bronchopneumonia, as does aerosol or intranasal inoculation of mice with cowpox virus. Rabbitpox virus causes pneumonia and fatal systemic infections in rabbits and can be naturally transmitted between rabbits by an aerosol route similar to that of VARV in humans. No single animal model recapitulates all known aspects of human Orthopoxvirus infections, and each model has its advantages and disadvantages. This article provides a brief review of the Orthopoxvirus diseases of humans and the key pathologic features of animal models of Orthopoxvirus infections.

Building global development strategies for cf therapeutics during a transitional cftr modulator era.

As CFTR modulator therapy transforms the landscape of cystic fibrosis (CF) care, its lack of uniform access across the globe combined with the shift towards a new standard of care creates unique challenges for the development of future CF therapies. The advancement of a full and promising CF therapeutics pipeline remains a necessary priority to ensure maximal clinical benefits for all people with CF. It is through collaboration across the global CF community that we can optimize the evaluation and approval process of new therapies. To this end, we must identify areas for which harmonization is lacking and for which efficiencies can be gained to promote ethical, feasible, and credible study designs amidst the changing CF care landscape. This article summarizes the counsel from core advisors across multiple international regions and clinical trial networks, developed during a one-day workshop in October 2019. The goal of the workshop was to identify, in consideration of the highly transitional era of CFTR modulator availability, the drug development areas for which global alignment is currently uncertain, and paths forward that will enable advancement of CF therapeutic development.

Palynological and iridium anomalies at cretaceous-tertiary boundary, South-central Saskatchewan.

The Cretaceous-Tertiary boundary in south-central Saskatchewan is marked by coincident anomalies in abundance of iridium and fern spores at the extinction level of a suite of Cretaceous pollen taxa. Evidence of disruption of the terrestrial flora includes the fern-spore abundance anomaly and local extinction of as much as 30 percent of angiosperm species. The reorganized earliest Tertiary flora is made up largely of surviving species that assumed new roles of dominance. Persistence of climatically sensitive taxa across the boundary indicates that if paleoclimate was altered by the terminal Cretaceous event, it returned quickly to the pre-event condition.