Cost-effectiveness analysis of endometrial cancer prevention strategies for obese women

OBJECTIVE: It is unknown whether obese women would benefit from oral contraceptives or screening as endometrial cancer prevention strategies. We estimated the net health benefits and cost-effectiveness of these strategies in a hypothetical cohort of obese women. METHODS: A Markov decision-analytic model evaluated 4 strategies: 1) no prevention (reference strategy); 2) oral contraceptive pills (OCPs) for 5 years; 3) annual screening with endometrial biopsy from age 30; 4) biennial screening from age 30. Net health benefit was life expectancy and primary outcome was the incremental cost-effectiveness ratio. Baseline and transition probabilities were obtained from published literature and the Surveillance Epidemiology and End Results database, and costs were from the U.S. Department of Health and Human Services and Agency for Healthcare Research and Quality. Sensitivity analyses were performed for uncertainty around various measures. RESULTS: Average life expectancy for all strategies ranged from 74.52 to 74.60 years. None of the strategies had an incremental cost-effectiveness ratio less than $50,000 per year of life saved relative to the next best strategy. Endometrial cancer risk in obese women had to be 13 times greater than the general population risk before OCPs were a cost-effective intervention. CONCLUSION: Oral contraceptives and current screening methods are not cost-effective endometrial cancer prevention strategies for obese women. Risk factors such as morbid obesity and longstanding anovulation may define a subgroup at highest risk of endometrial cancer for whom OCPs may be a cost-effective strategy. Interventions that reduce endometrial cancer risk further or those with additional health benefits are needed in this population. LEVEL OF EVIDENCE: III.     

When is a pathology review indicated in endometrial cancer?

OBJECTIVE: Discrepancies may exist between an original pathology report and formal pathology review, with subsequent implications for treatment. We conducted a study of pathology review in endometrial cancer from a population-based study to identify areas of discrepancy and effect on treatment. METHODS: This was a retrospective cohort study in Ontario, Canada from 1996 to 2000. We identified hysterectomy cases from patients with endometrial cancer that were subject to formal pathology review by a gynecologic pathologist at one of six tertiary care centers. Sarcomas and other rare histologic subtypes with fewer than five cases were excluded. We evaluated discrepancy between original pathology and review by demographics, stage, grade, and risk group. Four risk groups were defined: 1) low (stage I), 2) intermediate (stage I and II), 3) high-risk (stage I and II), and 4) advanced stage (all stage III and IV). Reclassification from one risk group to another upon pathology review represented a potential change in treatment. Factors associated with significant discrepancy were identified by a multivariable logistic regression model. RESULTS: Formal pathology review was available on 450 cases. There were no differences by age, year, or hospital type. The overall discrepancy rate was 42.7% (95% confidence interval 38.2-47.3%). The intermediate-risk group had the highest rate of reclassification into another group (33.1%). The most significant rates of discrepancy were associated with endometrioid grades 2 and 3 tumors and stage IIA disease (39.8%, 50.9%, and 79.6%, respectively). CONCLUSION: There was significant discrepancy between original pathology and formal review in endometrial cancer, with implications for guidelines on pathology review at a population level. LEVEL OF EVIDENCE: III     

Effects of Interleukin-17A on the Early Stages of Arterial Thrombosis in Mice

PurposeInterleukin (IL)-17A has been suggested to play a role in the growth and organization of thrombi. We examined whether IL-17A plays a role in the early stages of thrombosis and whether there are sex differences in the effects of IL-17A.Materials and MethodsWe performed a blinded, randomized, placebo-controlled study to compare time to thrombotic occlusion and sex differences therein between mice treated with IL-17A and those treated with saline using a ferric chloride-induced model. We also assessed thrombus histology, blood coagulation, and plasma levels of coagulation factors.ResultsTime to occlusion values did not differ between the IL-17A group and the control group (94.6±86.9 sec vs. 121.0±84.4 sec, p=0.238). However, it was significantly shorter in the IL-17A group of female mice (74.6±57.2 sec vs. 130.0±76.2 sec, p=0.032). In rotational thromboelastometry, the IL-17A group exhibited increased maximum clot firmness (71.3±4.5 mm vs. 66.7±4.7 mm, p=0.038) and greater amplitude at 30 min (69.7±5.2 mm vs. 64.5±5.3 mm, p=0.040) than the control group. In Western blotting, the IL-17A group showed higher levels of coagulation factor XIII (2.2±1.5 vs. 1.0±0.9, p=0.008), monocyte chemoattractant protein-1 (1.6±0.6 vs. 1.0±0.4, p=0.023), and tissue factor (1.5±0.6 vs. 1.0±0.5, p=0.003).ConclusionIL-17A plays a role in the initial st ages of arterial thrombosis in mice. Coagulation factors and monocyte chemoattractant protein-1 may be associated with IL-17A-mediated thrombosis.     

Dromedary camel nanobodies broadly neutralize SARS-CoV-2 variants

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike is a trimer of S1/S2 heterodimers with three receptor-binding domains (RBDs) at the S1 subunit for human angiotensin-converting enzyme 2 (hACE2). Due to their small size, nanobodies can recognize protein cavities that are not accessible to conventional antibodies. To isolate high-affinity nanobodies, large libraries with great diversity are highly desirable. Dromedary camels (Camelus dromedarius) are natural reservoirs of coronaviruses like Middle East respiratory syndrome CoV (MERS-CoV) that are transmitted to humans. Here, we built large dromedary camel V_HH phage libraries to isolate nanobodies that broadly neutralize SARS-CoV-2 variants. We isolated two V_HH nanobodies, NCI-CoV-7A3 (7A3) and NCI-CoV-8A2 (8A2), which have a high affinity for the RBD via targeting nonoverlapping epitopes and show broad neutralization activity against SARS-CoV-2 and its emerging variants of concern. Cryoelectron microscopy (cryo-EM) complex structures revealed that 8A2 binds the RBD in its up mode with a long CDR3 loop directly involved in the ACE2 binding residues and that 7A3 targets a deeply buried region that uniquely extends from the S1 subunit to the apex of the S2 subunit regardless of the conformational state of the RBD. At a dose of ≥5 mg/kg, 7A3 efficiently protected transgenic mice expressing hACE2 from the lethal challenge of variants B.1.351 or B.1.617.2, suggesting its therapeutic use against COVID-19 variants. The dromedary camel V_HH phage libraries could be helpful as a unique platform ready for quickly isolating potent nanobodies against future emerging viruses.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of COVID-19 (1, 2) that enters human cells by binding its envelope anchored type I fusion protein (spike) to angiotensin-converting enzyme 2 (ACE2) (3, 4). The SARS-CoV-2 spike is a trimer of S1/S2 heterodimers with three ACE2 receptor-binding domains (RBDs) attached to the distal end of the spike via a hinge region that allows conformational flexibility (4). In the all-down conformation, the RBDs are packed with their long axes contained in a plane perpendicular to the axis of symmetry of the trimer. Transition to the roughly perpendicular up conformation exposes the receptor-binding motif (RBM), located at the distal end of the RBD, which is sterically occluded in the down state. Numerous neutralizing antibodies targeting the spike, particularly its RBD, have been developed to treat COVID-19 using common strategies such as single B cell cloning, animal immunization, and phage display (5–9). Most vaccines, including those that are messenger RNA based, are designed to induce immunity against the spike or RBD (10–12). However, emerging SARS-CoV-2 variants such as D614G, B.1.1.7 (Alpha, United Kingdom), B.1.351 (Beta, South Africa), and P.1 (Gamma, Brazil) have exhibited increased resistance to neutralization by monoclonal antibodies or postvaccination sera elicited by the COVID-19 vaccines (13, 14). Monoclonal antibodies with Emergency Use Authorization for COVID-19 treatment partially (Casirivimab) or completely (Bamlanivimab) failed to inhibit the B.1.351 and P.1 variants. Similarly, these variants were less effectively inhibited by convalescent plasma and sera from individuals vaccinated with a COVID-19 vaccine (BNT162b2) (13). The B.1.617.2 (Delta, India) variant became the prevailing strain in many countries (15). Highly effective and broadly neutralizing antibody therapy is urgently demanded for COVID-19 patients.Due to their small size and unique conformations, camelid V_HH single-domain antibodies (also known as nanobodies) can recognize protein cavities that are not accessible to conventional antibodies (16). To isolate high-affinity nanobodies without a need for further affinity maturation, it is highly desirable to construct large nanobody libraries with great diversity. Dromedary camels have been found as potential natural reservoirs of Middle East respiratory syndrome CoV (MERS-CoV) (17). We speculated that dromedary camels would be an ideal source of neutralizing nanobodies against coronaviruses. In the present study, we built large camel V_HH single-domain antibody phage libraries with a diversity of over 10¹¹ from six dromedary camels (Camelus dromedarius), three males and three females, with ages ranging from 3 mo to 20 y. We used both the SARS-CoV-2 RBD and the stabilized spike ectodomain trimer protein as baits to conduct phage panning for nanobody screening. Among all the binders, we found NCI-CoV-7A3 (7A3), NCI-CoV-1B5 (1B5), NCI-CoV-8A2 (8A2), and NCI-CoV-2F7 (2F7) to be potent ACE2 blockers. In addition, these dromedary camel nanobodies displayed potent neutralization activity against the B.1.351 and B.1.1.7 variants and the original strain (Wuhan-Hu-1). The cryoelectron microscopy (cryo-EM) structure of the spike trimer protein complex with these V_HH nanobodies revealed two distinct nonoverlapping epitopes for neutralizing SARS-CoV-2. In particular, 7A3 recognizes a unique and deeply buried region that extends to the apex of the S2 subunit of the spike. Combined treatment with 7A3 and 8A2 shows more potent protection against various variants in culture and mice infected with the B.1.351 variant. Interestingly, 7A3 alone retains its neutralization activity against the lethal challenge of the B.1.617.2 variant in mice.     

Antimicrobial second skin using copper nanomesh

The functional support and advancement of our body while preserving inherent naturalness is one of the ultimate goals of bioengineering. Skin protection against infectious pathogens is an application that requires common and long-term wear without discomfort or distortion of the skin functions. However, no antimicrobial method has been introduced to prevent cross-infection while preserving intrinsic skin conditions. Here, we propose an antimicrobial skin protection platform copper nanomesh, which prevents cross-infectionmorphology, temperature change rate, and skin humidity. Copper nanomesh exhibited an inactivation rate of 99.99% for Escherichia coli bacteria and influenza virus A within 1 and 10 min, respectively. The thin and porous nanomesh allows for conformal coating on the fingertips, without significant interference with the rate of skin temperature change and humidity. Efficient cross-infection prevention and thermal transfer of copper nanomesh were demonstrated using direct on-hand experiments.

The functional support and advancement of our body while preserving the inherent naturalness is one of the ultimate goals of bioengineering (1–4). A functional layer is placed on the skin to complement the intrinsic biological and interactive functions (5, 6) and to add functions that do not yet exist (7–9). During use, the second skin layer should completely exploit its function and underlay skin functions without deforming the skin or interfering with the skin’s external interaction. Materials and structures need to be conformal and mechanically similar to the skin to minimize the distortion of natural sensations and movements. In addition, the air and heat transfer on the skin must be unimpeded to obtain a natural and comfortable wear fit (10).Body protection that requires common and long-term wear is an application in which both functionality and naturalness are important. As the outermost layer connecting our body to the environment, the skin is exposed to physical damage, hazardous chemicals, and infectious pathogens (11, 12). Therefore, we add a protective layer on the skin that blocks or filters out external contaminants. This entails the isolation and accumulation of biochemical compounds, which can lead to self-contamination and the subsequent cross-contamination/infection by interacting with other objects. In contrast to chemical contamination, which is not self-reproductive, the biological contamination of infectious microbes, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a considerable issue to be addressed.By containing an antimicrobial material on the surface of the skin protective layer, cross-infection can be prevented in the long term. Unlike temporary rinsing or disinfection, the use of antibacterial or antiviral substances such as chemical or natural disinfectants and metal nanomaterials inhibits the growth of microorganisms on the surface (13–17). These materials are embedded in a complete covering polymer layer, such as gloves (18, 19), to isolate and protect both the inner and outer surfaces from the infection. To add breathability to the textile especially for the mask (13, 20, 21), many antibacterial fibers have been developed based on these materials. Moreover, various skin-attachable platforms with antimicrobial properties have been developed for convenient usage in daily lives. Antimicrobial nanofibers with conformal attachment to the skin have been developed for drug delivery, wound healing (22, 23), and electrophysiology (24, 25). In addition, stretchable and antibacterial hydrogels have been developed to allow more natural skin movement in wound-healing applications (26–28).However, there has been no practical skin protective solution to prevent cross-infection while preserving intrinsic skin conditions such as surface morphology, thermal transfer, and skin humidity. The thickening of the additional skin layer frequently results in a significant modification of the surface morphology, heat transfer, and the corresponding sensation. Thin layers have limited performance in terms of antimicrobial duration and speed. The skin coverage of polymer or hydrogel film blocks the transfer of air, moisture, and heat. In addition, the antimicrobial performance is focused on the skin side rather than the external side that affects cross-infection. Voids owing to the stiffness of the film or fiber and morphological differences compared to the skin further limit conformality, heat transfer, and water/air permeability (29).Here, we propose an antimicrobial skin protection platform copper nanomesh, which prevents cross-infection while minimizing modification of intrinsic skin properties such as interfacial morphology, temperature change rate, and skin humidity. The thin thickness and porous structure of the nanomesh allow conformal attachment to the fingertips, regardless of the mechanical and structural variations of the fingerprints, nails, and interfaces. To impart antimicrobial properties, copper, one of the most well-known antimicrobial (nano)materials (30–33), was coated with maintaining the nanomesh structure (copper nanomesh, from here onward). The measured inactivation rates of copper nanomesh against Escherichia coli bacteria and influenza virus A (H1N1) were 99.99% within 1 min and 10 min, respectively. It was found that the nanomesh structure contributed to the acceleration of bacterial inactivation compared to the copper film. Furthermore, it exhibited high biocompatibility with the skin cells and stable antibacterial performance even after long-term use (more than 6 h), including water immersion (more than 1 h).In addition, we investigated the naturalness of the copper nanomesh compared to that of the copper film and conventional gloves. As confirmed using the artificial skin and fingerprint recognition, the proposed copper nanomesh exhibited a higher conformability compared to that of the copper film. The copper nanomesh showed a high hydrophobicity to block external contaminants in solution while having high gas permeability and maintaining the skin humidity in a safe range. Additionally, the insertion of copper nanomesh did not affect the temperature change rate, which is important to maintain the sensation and comfort fit of the skin. Finally, the copper nanomesh was compared to the glove by wearing on our hands and interacting with various real-life objects. Using the proposed copper nanomesh, we successfully achieved an effective prevention of cross-infection and less-hindered thermal recognition of objects.     

Newly Developed Central Diabetes Insipidus Following Kidney Transplantation: A Case Report

Polyuria after kidney transplantation is a common, usually self-limiting disorder. However, persistent polyuria can cause not only patient discomfort, including polyuria and polydipsia, but also volume depletion that can produce allograft dysfunction. Herein, we have report a case of central diabetes insipidus newly diagnosed after kidney transplantation. A 45-year-old woman with end-stage kidney disease underwent deceased donor kidney transplantation. Two months after the transplantation, she was admitted for persistent polyuria, polydipsia, and nocturia with urine output of more than 4 L/d. Urine osmolarity was 100 mOsm/kg, which implied that the polyuria was due to water rather than solute diuresis. A water deprivation test was compatible with central diabetes insipidus; desmopressin treatment resulted in immediate symptomatic relief. Brain magnetic resonance imaging (MRI) demonstrated diffuse thickening of the pituitary stalk, which was considered to be nonspecific finding. MRI 12 months later showed no change in the pituitary stalk, although the patient has been in good health without polyuria or polydipsia on desmopressin treatment. The possibility of central diabetes insipidus should be considered in patients presenting with persistent polyuria after kidney transplantation.     

Comparative Genomics of Korean Infectious Bronchitis Viruses (IBVs) and an Animal Model to Evaluate Pathogenicity of IBVs to the Reproductive Organs

The K-I and nephropathogenic K-II genotypes of infectious bronchitis virus (IBV) have been isolated since 1995 and 1990, respectively, in Korea and commercial inactivated oil-emulsion vaccines containing KM91 (K-II type) and Massachusetts 41 strains have been used in the field. To date, genomic analyses of Korean IBV strains and animal models to test the pathogenicity of Korean IBVs to the reproductive organs have been rare. In the present study, comparative genomics of SNU8067 (K-I type) and KM91 IBVs was performed, and an animal model to test the pathogenicity of SNU8067 was established and applied to vaccine efficacy test. The genome sizes of SNU8067 (27,708 nt) and KM91 (27,626 nt) were slightly different and the nucleotide and amino acid identities of the S1 (79%, 77%), 3a (65%, 52%), and 3b (81%, 72%) genes were lower than those of other genes (94%–97%, 92%–98%). A recombination analysis revealed that SNU8067 was a recombinant virus with a KM91-like backbone except S1, 3a, and 3b genes which might be from an unknown virus. An SNU8067 infection inhibited formation of hierarchal ovarian follicles (80%) and oviduct maturation (50%) in the control group, whereas 70% of vaccinated chickens were protected from lesions.