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Breast cancer screening recommendations for transgender and gender diverse (TGD) patients have only been recently developed and many primary care practitioners (PCPs) are unaware of these specific recommendations. The aim of this study is to assess the level of familiarity and knowledge PCPs have with breast cancer screening recommendations for TGD patients. An anonymous survey was distributed to primary care physicians, primary care advanced practice practitioners, and internal medicine and family medicine residents at three academic medical systems in the United States (Mayo Clinic, University of Michigan, University of Texas – Medical Branch). Survey questions assessed the familiarity and knowledge base of TGD breast cancer screening recommendations, training and experience with TGD patients, and basic demographics of the practitioners. Of the 95 survey respondents, only 35% of respondents were aware that breast cancer screening recommendations for TGD patients existed. PCPs who had increased transgender specific health care training and direct clinical exposure to TGD patients demonstrated significantly higher levels of screening recommendation awareness. Two-thirds of respondents received TGD specific medical education during training or medical career and those who had increased transgender specific medical education or direct clinical exposure to TGD patients demonstrated significantly higher levels of screening recommendation awareness. Awareness of breast cancer screening recommendations for TGD patients is low among PCPs and varied based on the practitioner’s prior TGD education and experience. Up-to-date breast cancer screening recommendations for TGD patients should be readily available across multiple platforms, target key audiences, and integrated into transgender health educational curriculums to maximize awareness of these important recommendations.

A physician in his 70s describes his path to a diagnosis of inflammatory arthritis, which included completely normal laboratory results.

Transgender and gender diverse (TGD) individuals may undergo a wide range of care during gender transition including mental health counseling, gender-affirming hormonal therapy, and various surgeries. Hormone therapy effectively converts the hormonal milieu into that of the affirmed gender and produces measurable alterations in serum markers for coronary artery disease and other hematologic conditions (eg, erythrocytosis, venous thrombosis). Although illegal in the United States, some transgender women may receive silicone injections for breast and soft tissue augmentation, which can lead to devastating local complications, as well as silicone migration, pulmonary embolism, systemic reactions, and death. Smoking rates are higher among transgender and sexual minority populations, placing them at elevated risk of smoking-related diseases, including lung cancer. Some opportunistic infections may be more common in the TGD populations, attributable to higher rates of coexisting infection with human immunodeficiency virus. Radiologists should be aware that these patients may develop cancer of their natal organs (eg, breast, prostate), especially as some of these tissues are not completely removed during gender-affirming surgery, which may manifest with thoracic involvement by secondary neoplasia. As more TGD patients seek medical care, thoracic radiologists can reasonably expect to interpret imaging performed in this population and should be aware of possible disease processes and potential complications of hormonal and surgical therapies.

Transgender and gender diverse (TGD) people experience health disparities, and many avoid necessary medical care because of fears of discrimination or mistreatment. Disparate care is further compounded by limited understanding of gender-affirming hormone therapy (GAHT) and gender-affirming surgery among the medical community. Specific to radiology, TGD patients report more negative imaging experiences than negative general health encounters, highlighting the need for guidance and best practices for inclusive imaging care. A patient's imaging journey provides numerous opportunities for improvement. Inclusive practice in a radiology department starts with ordering and scheduling the examination, facilitated by staff education on appropriate use of a patient's chosen name, gender identity, and pronouns. Contemporary electronic health record systems have the capacity for recording detailed sexual orientation and gender identity data, but staff must be trained to solicit and use this information. A welcoming environment can help TGD patients to feel safe during the imaging experience and may include institutional nondiscrimination policies, gender-neutral signage, and all-gender single-user dressing rooms and bathrooms. Image acquisition should be performed using trauma-informed and patient-centered care. Finally, radiologists should be aware of reporting considerations for TGD patients, such as avoiding the use of gender in reports when it is not medically relevant and using precise, respectful language for findings related to GAHT and gender-affirming surgical procedures. As a field, radiology has a range of opportunities for improving care delivery for TGD patients, and the authors summarize recommended best practices. See the invited commentary by Stowell in this issue.

Background The Nursing department within an acute general hospital wished to illuminate and build on positive local enhanced care practices. A collaborative research team was formed between academics in the linked higher education institution and nurses within the hospital to address this intent by building nurse-led research capacity, while addressing the practice derived research question. Methods A mixed methods approach was employed involving; site visits, audit of enhanced care staffing requirements, documentary and activity box analyses and use of appreciative inquiry (AI) methodology. AI is a collaborative and strengths-oriented approach supporting organisational development. It was implemented via three World Café events (www.theworldcafe.com 2021) bringing together hospital stakeholders (n = 17) with direct experience of delivering enhanced care, to consider pre-defined questions. Thematic analysis was used to analyse the resultant data. Ethical approval was obtained. Results Overall, the findings demonstrated a positive focus on implementing therapeutic enhanced care within the hospital in contrast to a more passive primarily observational orientation. The site visits facilitated shared learning. Thematic findings from the World Cafés identified positive care practices and enabled a multidisciplinary, inclusive approach, which facilitated pragmatic suggestions on how to plan for, and build on existing foundations of, enhanced care practice. Conclusion Both the study approach and outcome resulted in positive impacts. Working collaboratively supported research capacity building for hospital-based members of the research team. Using AI supported constructive and inclusive stakeholder participation in the World Cafés with a focus on good practices and ways in which they could be strengthened. One year post completion, study recommendations have led to

The inclusion and celebration of LGBTQIA+ staff in radiology and radiation oncology departments is crucial in developing a diverse and thriving workplace. Despite the substantial social change in Australia, LGBTQIA+ people still experience harassment and exclusion, negatively impacting their well-being and workplace productivity. We need to be proactive in creating policies that are properly implemented and translate to a safe and inclusive space for marginalised groups. In this work, we outline the role we all can play in creating inclusive environments, for both individuals and leaders working in radiology and radiation oncology. We can learn how to avoid normative assumptions about gender and sexuality, respect people's identities and speak out against witnessed discrimination or slights. Robust policies are needed to protect LGBTQIA+ members from discrimination and provide equal access across other pertinent parts of work life such as leave entitlements, representation in data collection and safe bathroom access. We all deserve to feel safe and respected at work and further effort is needed to ensure this extends to LGBTQIA+ staff in the radiology and radiation oncology workforces.

Multiple myeloma (MM), a cancer of plasma cells, occurs in ~34,000 new patients every year in the USA. Although therapeutic regimens, including anti-CD38 monospecific IgG antibodies such as daratumumab and isatuximab in combination with chemotherapies, demonstrate clinical efficacy, most patients eventually develop resistance. Several bispecific (CD38xCD3) or trispecific (CD38xCD3xCD28) T cell engager (TCE) antibody therapies are currently in development to improve upon the efficacy of CD38 targeted therapies by leveraging T cell dependent cellular cytotoxicity (TDCC) of MM cells. However, CD38 is also expressed on some normal hematopoietic cells which could potentially lead to undesired pharmacological activity such as depleting CD38+ immune cells, including activated cytotoxic T cells (i.e., fratricide). IGM-2644 is a novel, pentameric IgM antibody engineered to have ten CD38 binding sites, and an anti-CD3ε single chain Fv domain fused to a joining chain to engage CD3 on T cells, and retains the potential for complement-dependent cytotoxicity (CDC). Here we report the functional characterization of IGM-2644 using in vitro, ex vivo and in vivo anti-tumor efficacy studies with a safety evaluation of this novel IgM TCE. In vitro, IGM-2644 demonstrated significantly improved CDC activity in comparison with daratumumab and isatuximab, with >30-fold increased potency on CD38+ MM and lymphoma cell lines. IGM-2644 induced TDCC similar to a bispecific CD38xCD3 IgG on low CD38 expressing cell lines resistant to daratumumab, while demonstrating significantly lower levels of cytokine release than the bispecific IgG. In ex vivo colony forming unit (CFU) assays, IGM-2644 was able to reduce MM CFUs using primary MM patient bone marrow samples containing autologous T cells and myeloma cells, while no effect was observed on erythroid, granulocyte and macrophage CFUs in normal bone marrow samples.​ IGM-2644 dose dependently inhibited tumor growth in humanized xenograft models of CD38+ NCI-H929 (myeloma) and Raji (lymphoma). Importantly, IGM-2644 also demonstrated significantly reduced T cell fratricide compared to bispecific IgGs both ex vivo and in vivo. Significantly reduced activity of IGM-2644 on normal CD38+ innate immune cells was observed in ex vivo studies. CD38 expression has also been reported on human RBCs and platelets. However, minimal IGM-2644 binding was observed and at levels lower than daratumumab. In summary, IGM-2644 is a novel, potent, bispecific IgM TCE that has both CDC and TDCC mechanisms of cytotoxicity with the potential to be active in daratumumab resistant tumors. The balance of potent TDCC and CDC cytotoxic activity, along with an improved preclinical safety profile compared to other CD38xCD3 bispecific IgG TCEs, supports the clinical development of IGM-2644 in MM. Citation Format: Keyu Li, Rui Yun, Min Chai, Poonam Yakkundi, Rodnie Rosete, Gene Li, Liqin Liu, Mandy Li, Daniel Santos, Kevin C. Hart, Dean Ng, Paul R. Hinton, Umesh Muchhal, Thomas Manley, Maya F. Kotturi, Stephen F. Carroll, Angus M. Sinclair, Bruce A. Keyt. Novel CD38xCD3 bispecific IgM T cell engager, IGM-2644, potently kills multiple myeloma cells though complement and T cell dependent mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2959.

Imvotamab (IGM-2323) is an engineered high-affinity, high-avidity bispecific anti-CD20 IgM antibody T cell engager (TCE) that is currently being studied as monotherapy in a Phase 1/2 clinical trial for relapsed/refractory non-Hodgkin’s lymphoma (NHL) (NCT04082936). Imvotamab offers a novel treatment strategy in NHL by depleting CD20-expressing tumor cells through multiple mechanisms, including the recruitment of T cells to kill tumor cells through T cell dependent cellular cytotoxicity, complement-dependent cytotoxicity, and enhanced immune modulation via IFNγ-dominant cytokine stimulation. We evaluated the activity of a surrogate cynomolgus monkey cross-reactive CD20xCD3 IgM bispecific TCE, IGM-2324, in depleting CD20-expressing B cells in peripheral blood and lymphoid tissues of cynomolgus monkeys in vivo. We hypothesized that the high affinity and valency of IGM-2324 would enable potent B cell killing in blood and tissues even when B cells express low levels of CD20. Cynomolgus monkeys were administered vehicle or IGM-2324 at 5 mg/kg or 25 mg/kg through intravenous infusion twice weekly for a total of four doses on days 1, 4, 7, and 10. B cell depletion in peripheral blood was assessed by measuring the frequency of CD19+ B cells through flow cytometry. Administration of IGM-2324 at 5 and 25 mg/kg resulted in a nearly complete depletion in peripheral CD19+ B cells at 8 hours post the 1st dose through 24 hours post the last dose on day 11. Depletion of tissue-resident B cells was evaluated in the spleen, mesenteric lymph node (MLN) and bone marrow (BM) of monkeys at 24 hours post the last dose of vehicle or IGM-2324 on day 11. Immunohistochemistry studies were conducted on the formalin-fixed paraffin-embedded lymphoid tissues by staining for CD19 and CD20 expression. The number and intensity of CD19 or CD20 positive B cells were determined by quantitative imaging analysis. Compared to vehicle-treated animals, significant dose-dependent reductions in both CD19 and CD20-expressing B cells were observed in spleen, MLN and BM following treatment with 5 and 25 mg/kg of IGM-2324. Most importantly, IGM-2324 treatment led to the depletion of not only high and moderate tissue-resident CD20-expressing B cells, but also B cells that expressed low levels of CD20. Our preclinical data indicate that a CD20xCD3 IgM bispecific TCE can penetrate tissues and mediate direct killing of CD20-expressing target cells. B cell depletion in the periphery and tumors of relapsed/refractory NHL patients is currently being evaluated as biomarker of pharmacodynamic activity and/or efficacy for imvotamab in a Phase 1/2 clinical study. Citation Format: Miho Oyasu, Angus M. Sinclair, Haben Ghermazien, Genevive Hernandez, Thomas Manley, Maya K. Leabman, Stephen F. Carroll, Bruce A. Keyt, Maya F. Kotturi. Depletion of tissue-resident B cells by a CD20xCD3 IgM bispecific T cell engager in cynomolgus monkeys demonstrates effective tissue penetration and potent target cell killing. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4120.

Ongoing declines in insect populations have led to substantial concern and calls for conservation action. However, even for relatively well-studied groups, like butterflies, information relevant to species-specific status and risk is scattered across field guides, the scientific literature, and agency reports. Consequently, attention and resources have been spent on a miniscule fraction of insect diversity, including a few well-studied butterflies. Here we bring together heterogenous sources of information for 396 butterfly species to provide the first regional assessment of butterflies for the 11 western US states. For 184 species, we use monitoring data to characterize historical and projected trends in population abundance. For another 212 species (for which monitoring data are not available, but other types of information can be collected), we use exposure to climate change, development, geographic range, number of host plants, and other factors to rank species for conservation concern. A phylogenetic signal is apparent, with concentrations of declining and at-risk species in the families Lycaenidae and Hesperiidae. A geographic bias exists in that many species that lack monitoring data occur in more southern states where we expect that impacts of warming and drying trends will be most severe. Legal protection is rare among the taxa with the highest risk values: of the top 100 species, one is listed as threatened under the US Endangered Species Act and one is a candidate for listing. Among the many taxa not currently protected, we highlight a short list of species in decline, includingVanessa annabella,Thorybes mexicanus,Euchloe ausonides, andPholisora catullus. Notably, many of these species have broad geographic ranges, which perhaps highlights a new era of insect conservation in which small or fragmented ranges will not be the only red flags that attract conservation attention.

Objectives Acidic urine pH may be protective against recurrent urinary tract infections (RUTIs). After reviewing the literature, we primarily analyzed urine pH fluctuations and secondarily compared them with diet in older women with RUTIs. Methods After IRB approval, postmenopausal women with documented RUTIs were enrolled. Participants were given preformatted charts to record urinalysis reagent strips (Medimpex) findings 4 times per day and concomitant food/beverage intake (food diary). Urine cultures at baseline ensured no infection during measurement period. Nutrient content reported in food diaries was analyzed by an experienced registered dietitian and compared with parallel fluctuations in urine pH. Results Of 26 women with median age of 72 years (55-86 years), the first 3 days of diet and urine pH recordings found that 17 (65%) of 26 exhibited urine pH variation greater than 1 unit, with an overall median of 6 (5-9). Comparing dietary analysis and urine pH changes, beta-carotene (P = 0.017) and total dietary sugar intake (P = 0.036) were associated with a decrease in urine pH, whereas monounsaturated fatty acids (MFA, 22:1, P = 0.023) and protein (P = 0.028) were associated with an increase in urine pH. Conclusions In this real-life, observational study, 65% of older women with RUTIs exhibited notable changes in urine pH, with decreased urine pH associated with nutrients found in orange and yellow vegetables and several major food groups. A longitudinal study is needed to determine if changing an individual's diet and/or adding supplements could decrease the urine pH, thus affecting the rate of RUTIs.

Successful osteochondral defect repair requires regenerating the subchondral bone whilst simultaneously promoting the development of an overlying layer of articular cartilage that is resistant to vascularization and endochondral ossification. During skeletal development articular cartilage also functions as a surface growth plate, which postnatally is replaced by a more spatially complex bone-cartilage interface. Motivated by this developmental process, the hypothesis of this study is that bi-phasic, fibre-reinforced cartilaginous templates can regenerate both the articular cartilage and subchondral bone within osteochondral defects created in caprine joints. To engineer mechanically competent implants, we first compared a range of 3D printed fibre networks (PCL, PLA and PLGA) for their capacity to mechanically reinforce alginate hydrogels whilst simultaneously supporting mesenchymal stem cell (MSC) chondrogenesis in vitro. These mechanically reinforced, MSC-laden alginate hydrogels were then used to engineer the endochondral bone forming phase of bi-phasic osteochondral constructs, with the overlying chondral phase consisting of cartilage tissue engineered using a co-culture of infrapatellar fat pad derived stem/stromal cells (FPSCs) and chondrocytes. Following chondrogenic priming and subcutaneous implantation in nude mice, these bi-phasic cartilaginous constructs were found to support the development of vascularised endochondral bone overlaid by phenotypically stable cartilage. These fibre-reinforced, bi-phasic cartilaginous templates were then evaluated in clinically relevant, large animal (caprine) model of osteochondral defect repair. Although the quality of repair was variable from animal-to-animal, in general more hyaline-like cartilage repair was observed after 6 months in animals treated with bi-phasic constructs compared to animals treated with commercial control scaffolds. This variability in the quality of repair points to the need for further improvements in the design of 3D bioprinted implants for joint regeneration. STATEMENT OF SIGNIFICANCE: Successful osteochondral defect repair requires regenerating the subchondral bone whilst simultaneously promoting the development of an overlying layer of articular cartilage. In this study, we hypothesised that bi-phasic, fibre-reinforced cartilaginous templates could be leveraged to regenerate both the articular cartilage and subchondral bone within osteochondral defects. To this end we used 3D printed fibre networks to mechanically reinforce engineered transient cartilage, which also contained an overlying layer of phenotypically stable cartilage engineered using a co-culture of chondrocytes and stem cells. When chondrogenically primed and implanted into caprine osteochondral defects, these fibre-reinforced bi-phasic cartilaginous grafts were shown to spatially direct tissue development during joint repair. Such developmentally inspired tissue engineering strategies, enabled by advances in biofabrication and 3D printing, could form the basis of new classes of regenerative implants in orthopaedic medicine.

The COVID-19 pandemic is now approaching 2 years old, with more than 440 million people infected and nearly six million dead worldwide, making it the most significant pandemic since the 1918 influenza pandemic. The severity and significance of SARS-CoV-2 was recognized immediately upon discovery, leading to innumerable companies and institutes designing and generating vaccines and therapeutic antibodies literally as soon as recombinant SARS-CoV-2 spike protein sequence was available. Within months of the pandemic start, several antibodies had been generated, tested, and moved into clinical trials, including Eli Lilly's bamlanivimab and etesevimab, Regeneron's mixture of imdevimab and casirivimab, Vir's sotrovimab, Celltrion's regdanvimab, and Lilly's bebtelovimab. These antibodies all have now received at least Emergency Use Authorizations (EUAs) and some have received full approval in select countries. To date, more than three dozen antibodies or antibody combinations have been forwarded into clinical trials. These antibodies to SARS-CoV-2 all target the receptor-binding domain (RBD), with some blocking the ability of the RBD to bind human ACE2, while others bind core regions of the RBD to modulate spike stability or ability to fuse to host cell membranes. While these antibodies were being discovered and developed, new variants of SARS-CoV-2 have cropped up in real time, altering the antibody landscape on a moving basis. Over the past year, the search has widened to find antibodies capable of neutralizing the wide array of variants that have arisen, including Alpha, Beta, Gamma, Delta, and Omicron. The recent rise and dominance of the Omicron family of variants, including the rather disparate BA.1 and BA.2 variants, demonstrate the need to continue to find new approaches to neutralize the rapidly evolving SARS-CoV-2 virus. This review highlights both convalescent plasma- and polyclonal antibody-based approaches as well as the top approximately 50 antibodies to SARS-CoV-2, their epitopes, their ability to bind to SARS-CoV-2 variants, and how they are delivered. New approaches to antibody constructs, including single domain antibodies, bispecific antibodies, IgA- and IgM-based antibodies, and modified ACE2-Fc fusion proteins, are also described. Finally, antibodies being developed for palliative care of COVID-19 disease, including the ramifications of cytokine release syndrome (CRS) and acute respiratory distress syndrome (ARDS), are described.

The aim of this study was to evaluate the role of oral fosfomycin to prevent the use of intravenous (IV) antibiotic therapy in women with recurrent urinary tract infection (RUTI) complicated by antibiotic allergies and/or multidrug-resistant organisms.After institutional review board approval, a retrospective review of women prescribed fosfomycin for RUTI at our institution was performed. Excluded were patients who did not take fosfomycin. Data collected included demographics, baseline voiding function/urological anatomic abnormalities, need for IV antibiotic therapy for RUTI, RUTI-related surgery, antibiotic allergies, and urine culture results before and after taking fosfomycin. Success was defined as no subsequent IV antibiotic use for RUTI management after fosfomycin within the study follow-up. Secondary outcomes included time to next UTI after fosfomycin, time to next extended-spectrum beta-lactamase UTI, factors predicting failure, urine culture results after fosfomycin, and need for surgical intervention.Between 2013 and 2019, 105 women met study criteria. At a median follow-up (including phone interviews) of 1.7 years (interquartile range, 0.3-5.8) after fosfomycin, the success rate was 74%. Twenty-seven patients had documented sterile urine cultures immediately after fosfomycin. Prior history of hospitalization for UTI and infection with resistant organisms were predictive of failure. After fosfomycin, 25 women underwent bladder electrofulguration, and 3 required cystectomy.Fosfomycin reduced the rate of IV antibiotic therapy in the management of RUTI in women with multidrug-resistant organisms and/or antibiotic allergies. Fosfomycin was less effective in those with prior hospitalization for UTI or infection with resistant organisms.

Mesenchymal stem/stromal cells (MSCs) represent a promising cell type for treating damaged synovial joints. The therapeutic potential of MSCs will be facilitated by the engineering of biomaterial environments capable of directing their fate. Here the interplay between matrix elasticity and cell morphology in regulating the chondrogenic differentiation of MSCs when seeded onto or encapsulated within hydrogels made of interpenetrating networks (IPN) of alginate and collagen type I is explored. This IPN system enables the independent control of substrate stiffness (in 2D and in 3D) and cell morphology (3D only). The expression of chondrogenic markers SOX9, ACAN, and COL2 increases when MSCs are cultured onto the soft substrate, which correlates with increased SMAD2/3 nuclear localization, enhanced MSCs condensation, and the formation of larger cellular aggregates. The encapsulation of spread MSCs within a soft IPN increases the expression of cartilage-specific genes, which is linked to cellular condensation and nuclear SMAD2/3 localization. Surprisingly, cells forced to adopt a more rounded morphology within the same soft IPNs expressed higher levels of the osteogenic markers RUNX2 and COL1. The insight provided by this study suggests that a mechanobiology informed approach to biomaterial development will be integral to the development of successful cartilage tissue engineering strategies.

We investigate the topological classification of the subgap bands induced in a two-dimensional superconductor by a densely packed chain of magnetic moments with ferromagnetic or spiral alignments. The wave functions for these bands are composites of Yu-Shiba-Rusinov-type states and magnetic scattering states and have a significant spatial extension away from the magnetic moments. We show that this spatial structure prohibits a straightforward extraction of a Hamiltonian useful for the topological classification. To address the latter correctly we construct a family of spatially varying topological Hamiltonians for the subgap bands adapted for the broken translational symmetry caused by the chain. The spatial dependence in particular captures the transition to the topologically trivial bulk phase when moving away from the chain by showing how this, necessarily discontinuous, transition can be understood from an alignment of zeros with poles of Green's functions. Through the latter the topological Hamiltonians reflect a characteristic found otherwise primarily in strongly interacting systems., Comment: 15 pages, 8 figures. This is Part II of manuscript at arXiv:1709.06093 and covers topological classification

The Los Angeles (LA) classification is the most accurate means of assessing esophageal injury from caustic gastric acid with focused and greater concentrations in areas of erosive disease.1 However, data from animal models and patients have proposed that an initial diffuse inflammatory pathway contributes to injury in gastroesophageal reflux disease (GERD) mediated by interleukin (IL) 8, IL1β,2,3 and hypoxia-inducible factors.4,5 These observations demonstrate a lymphocyte predominant inflammatory process over course of 1-2 weeks associated with basal zone hyperplasia and dilation of intercellular spaces.6 In cultured human esophageal epithelial cells and patients, it is further suggested that acid causes this chronic inflammatory reaction.