Association between Kidney Stones and CKD: A Bidirectional Mendelian Randomization Study.

BACKGROUND: Kidney stones and CKD are common disorders with a substantial interaction. Although observational studies have suggested a potential for enhanced CKD risk after prior kidney stones, the exact relationship remains ambiguous. METHODS: Shared comorbidities between two diseases were identified using unbiased screening. Genome-wide association study summary statistics were obtained from the UK Biobank (UKBB), FinnGen, and CKDGen, followed by genetic association analyses across various traits. Bidirectional Mendelian randomization (MR) analyses were performed to define causal links, complemented by multivariable MR that included the shared comorbidities including hypertension, diabetes, and obesity. Observational analyses were undertaken using cohorts from the Mayo Clinic and a UKBB subset. RESULTS: Despite identifying a total of 123 conditions as shared comorbidities, there was no significant genetic correlation between kidney stones and CKD. Unadjusted MR analysis revealed no significant association between kidney stones and CKD risk (UKBB [exposure]/FinnGen [outcome]: OR=0.97, 95% CI: 0.88∼1.06; FinnGen/UKBB: OR=1.17, 95% CI:0.98∼1.39). Kidney stones did significantly associate with a higher urinary albumin-creatinine ratio (UACR) (ß=0.014, 95% CI: 0.002∼0.025), but this association disappeared in the multivariable MR model (ß=0.009, 95% CI: -0.003∼0.020). Furthermore, in a cross-sectional analysis limited to the UKBB cohort, a robust regression model did not detect an independent association between kidney stones and UACR (ß=0.16, 95% CI: -0.04∼0.35) or eGFR (ß=0.10, 95% CI: -0.07∼0.28). Conversely, CKD associated with a diminished risk of kidney stones in multivariable MR models (UKBB/FinnGen: OR=0.77, 95% CI: 0.69∼0.87; FinnGen/UKBB: OR=0.73, 95% CI: 0.66∼0.81). Furthermore, in the Mayo Clinic cohort with available urinary biochemistries, lower eGFR was associated with lower urinary calcium excretion and urinary calcium oxalate/phosphate supersaturation. CONCLUSIONS: In this study, kidney stones were not independently associated with CKD. Conversely, CKD was associated with a lower risk of calcium kidney stones likely via changes in key urinary traits, including lower calcium excretion.

Effectiveness of immune checkpoint inhibitor therapy on bone metastases in non-small-cell lung cancer.

Background: Bone metastases (BoMs) are prevalent in patients with metastatic non-small-cell lung cancer (NSCLC) however, there are limited data detailing how BoMs respond to immune checkpoint inhibitors (ICIs). The purpose of this study was to compare the imaging response to ICIs of BoMs against visceral metastases and to evaluate the effect of BoMs on survival. Materials and methods: A retrospective, multicentre cohort study was conducted in patients with NSCLC treated with nivolumab or pembrolizumab in Alberta, Canada from 2015 to 2020. The primary endpoint was the real-world organ specific progression free survival (osPFS) of bone versus visceral metastases. Visceral metastases were categorized as adrenal, brain, liver, lung, lymph node, or other intra-abdominal lesions. The secondary outcome was overall survival (OS) amongst patients with and without BoMs. Results: A total of 573 patients were included of which all patients had visceral metastases and 243 patients (42.4%) had BoMs. High PD-L1 expression was identified in 268 patients (46.8%). No significant difference in osPFS was observed between bone, liver, and intra-abdominal metastases (p=0.20 and p=0.76, respectively), with all showing shorter osPFS than other disease sites. There was no difference in the osPFS of extra-thoracic sites of disease in patients with high PD-L1 expression. There was significant discordance between visceral disease response and bone disease response to ICI (p=0.047). The presence of BoMs was an independent poor prognostic factor for OS (HR 1.26, 95%CI: 1.05-1.53, p=0.01). Conclusion: Metastatic bone, liver, and intra-abdominal lesions demonstrated inferior clinical responses to ICI relative to other sites of disease. Additionally, the presence of bone and liver metastases were independent poor prognostic factors for overall survival. This real-world data suggests that BoMs respond poorly to ICI and may require treatment adjuncts for disease control.

A Qualitative Study of Internal Medicine Subspecialty Fellowship Program Directors' Perspectives on Short-Term Hospitalist Employment Prior to Fellowship.

Background Some internal medicine (IM) residents pursuing subspecialty training choose short-term hospitalist employment prior to fellowship, or "pre-fellowship hospitalist years." Residency and fellowship program directors (PDs) advise residents on this decision, but PD experience with fellows pursuing pre-fellowship hospitalist years and the impact on fellowship applications is unknown. Objective We aimed to explore perceptions of fellowship PDs regarding experience with fellows who pursued pre-fellowship hospitalist years, including perceived effects on how such years affect fellowship application candidacy. Methods A purposive sample of 20 fellowship PDs in the most highly competitive and commonly selected IM fellowships (cardiology, pulmonology/critical care medicine, hematology/oncology, gastroenterology) from 5 academic institutions were approached for participation in fall 2021. Interviews included semi-structured questions about pre-fellowship hospitalist employment. Utilizing rapid qualitative analysis, interview transcripts were summarized and reviewed to identify themes and subthemes describing fellowship PDs' perspectives of pre-fellowship hospitalist years. Results Sixteen fellowship PDs (80%) participated. PDs identified 4 major themes as important for trainees considering pre-fellowship hospitalist years: (1) Explain the "Why"-why the year was pursued; (2) Characteristics of the Hospitalist Position-what type of employment; (3) The Challenges-potential concerns faced with pre-fellowship hospitalist years; and (4) Describe the "What"-the experience's contribution to resident professional development. Conclusions Fellowship PDs in 4 competitive IM subspecialities placed a strong emphasis on explaining a clear, logical reason for seeking short-term hospitalist employment prior to fellowship, describing how it fits into the overall career trajectory, and selecting activities that demonstrate continued commitment to the subspecialty.

Avian influenza viruses in wild birds in Canada following incursions of highly pathogenic H5N1 virus from Eurasia in 2021-2022.

Following the detection of novel highly pathogenic avian influenza virus (HPAIV) H5N1 clade 2.3.4.4b in Newfoundland, Canada, in late 2021, avian influenza virus (AIV) surveillance in wild birds was scaled up across Canada. Herein, we present the results of Canada's Interagency Surveillance Program for Avian Influenza in Wild Birds during the first year (November 2021-November 2022) following the incursions of HPAIV from Eurasia. The key objectives of the surveillance program were to (i) identify the presence, distribution, and spread of HPAIV and other AIVs; (ii) identify wild bird morbidity and mortality associated with HPAIV; (iii) identify the range of wild bird species infected by HPAIV; and (iv) genetically characterize detected AIV. A total of 6,246 sick and dead wild birds were tested, of which 27.4% were HPAIV positive across 12 taxonomic orders and 80 species. Geographically, HPAIV detections occurred in all Canadian provinces and territories, with the highest numbers in the Atlantic and Central Flyways. Temporally, peak detections differed across flyways, though the national peak occurred in April 2022. In an additional 11,295 asymptomatic harvested or live-captured wild birds, 5.2% were HPAIV positive across 3 taxonomic orders and 19 species. Whole-genome sequencing identified HPAIV of Eurasian origin as most prevalent in the Atlantic Flyway, along with multiple reassortants of mixed Eurasian and North American origins distributed across Canada, with moderate structuring at the flyway scale. Wild birds were victims and reservoirs of HPAIV H5N1 2.3.4.4b, underscoring the importance of surveillance encompassing samples from sick and dead, as well as live and harvested birds, to provide insights into the dynamics and potential impacts of the HPAIV H5N1 outbreak. This dramatic shift in the presence and distribution of HPAIV in wild birds in Canada highlights a need for sustained investment in wild bird surveillance and collaboration across interagency partners. IMPORTANCE: We present the results of Canada's Interagency Surveillance Program for Avian Influenza in Wild Birds in the year following the first detection of highly pathogenic avian influenza virus (HPAIV) H5N1 on the continent. The surveillance program tested over 17,000 wild birds, both sick and apparently healthy, which revealed spatiotemporal and taxonomic patterns in HPAIV prevalence and mortality across Canada. The significant shift in the presence and distribution of HPAIV in Canada's wild birds underscores the need for sustained investment in wild bird surveillance and collaboration across One Health partners.

Deciphering Distinct Genetic Risk Factors for FTLD-TDP Pathological Subtypes via Whole-Genome Sequencing.

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 cases and 3,153 controls, and meta-analysis with the Dementia-seq cohort, compiled from 26 institutions/brain banks in the United States, Europe and Australia. We confirm UNC13A as the strongest overall FTLD-TDP risk factor and identify TNIP1 as a novel FTLD-TDP risk factor. In subgroup analyses, we further identify for the first time genome-wide significant loci specific to each of the three main FTLD-TDP pathological subtypes (A, B and C), as well as enrichment of risk loci in distinct tissues, brain regions, and neuronal subtypes, suggesting distinct disease aetiologies in each of the subtypes. Rare variant analysis confirmed TBK1 and identified VIPR1 , RBPJL , and L3MBTL1 as novel subtype specific FTLD-TDP risk genes, further highlighting the role of innate and adaptive immunity and notch signalling pathway in FTLD-TDP, with potential diagnostic and novel therapeutic implications.

The Academic Catalyst Group: A Tactical Framework for Working Groups to Enhance Clinician-Educator Academic Career Development.

ABSTRACT: Working groups have tremendous potential to contribute to the academic career development of early-career clinician-educators. These individuals may find themselves engaged in many different working spaces, including working groups or committees such as those found within specialty societies or professional organizations. Such working groups may be underrecognized opportunities for academic skill building and professional growth because they are often characterized as primarily service-oriented, citizenship, or administrative work. Working groups can use their natural cross-institutional collaborations for mentorship and externalization-2 key building blocks for academic success that frequently represent challenges for early-career clinician-educators. In this article, the authors review common challenges that early-career clinician-educators may encounter during their academic development and propose a 3-step tactical framework, the academic catalyst group, that working group leaders can apply to groups to purposefully enhance professional development for clinician-educators. The framework urges working group leaders and members to conceptualize and develop academic catalyst groups as communities of practice by (1) assembling with intention, (2) mining the mission, and (3) finding an easy win. This framework can inspire working group leaders to align their work with academic career development and ultimately foster career growth for all group members.

COVID-19 Incidence, Risk Factors, Impact, and Related Stigma Among a Cohort of Persons With HIV in Washington, DC.

BACKGROUND: Studies on the incidence of COVID-19 among persons with HIV (PWHs) present varied results. Few studies have investigated the impact of COVID-19 infection on health and socioeconomic factors or COVID-19 stigma. We sought to measure the incidence and severity of COVID-19 infection among a cohort of PWHs, characterize associated risk factors and impact, and document perceptions of COVID-19-related stigma. METHODS: Data for this cross-sectional study come from the COVID-19 survey of participants in the DC Cohort longitudinal study from October 30, 2020, through December 31, 2022. Survey results were linked to electronic health records, including HIV laboratory test results and COVID test results. We conducted analyses comparing demographic, socioeconomic, HIV measures, and stigma among those with and without self-reported COVID-19. RESULTS: Of 1972 survey respondents, 17% self-reported COVID-19 infection, with the greatest incidence in the Omicron wave of the pandemic. We found statistically significant differences by age, employment status, essential worker status, education, and household income. Longer duration of HIV diagnosis was associated with greater incidence of COVID-19. PWHs who were overweight or obese had a greater incidence of COVID-19 compared with those who were not. Over 40% of PWHs with COVID-19 reported experiencing at least 1 form of COVID-19-related stigma. CONCLUSION: We observed a high incidence of COVID-19 infection among PWHs in DC. Furthermore, a substantial proportion of PWHs with COVID-19 reported experiencing COVID-19-related stigma. These findings add to the existing literature on COVID-19 coinfection among PWHs and highlight the need for awareness and support for those experiencing COVID-19 stigma.

Vertical pelvic movement asymmetry and lameness location in ipsilateral combined forelimb and hindlimb lameness cases.

BACKGROUND: Compensatory vertical head and pelvis movement asymmetry may occur in trotting horses with a primary cause of lameness in one end of the body due to the weight shifting between limbs, leading to apparent combined forelimb and hindlimb lameness (CFHL). Little is known about CFHL patterns observed with body-mounted inertial sensors (BMIS) and regardless of their underlying mechanisms, compensatory and secondary lameness may complicate the definitive identification of the primary causes of lameness. OBJECTIVE: Determine associations between vertical pelvic movement asymmetry and location of primary lameness in ipsilateral CFHL cases where hindlimb lameness is solely impact or push-off type. STUDY DESIGN: Retrospective cohort. METHODS: From a body-mounted inertial sensor (BMIS) evaluated equine lameness database, we identified cases with a consistent, low-variability ipsilateral impact (IpI) or ipsilateral pushoff (IpP) hindlimb lameness in a straight-line trot and that had definitive diagnoses. Cases were categorised by lameness location to the limb(s), diagnosis, and ratio of the amplitude of forelimb to hindlimb lameness (Forea/Hinda). Differences in the numbers of IpI and IpP cases in these categories were analysed with chi-square tests, effect sizes, and odds ratios. RESULTS: Among the 2375 total lameness cases screened, 49 IpI and 36 IpP cases met the criteria for consistency, low variability, and definitive diagnosis. IpI cases were more likely than IpP cases to have forelimb-only lameness causes when Forea/Hinda >1 (OR = 43, 95% CI = 2.3-798). IpP cases were more likely than IpI cases to have hindlimb-only causes at both Forea/Hinda >1.0 (OR = 20, 95% CI = 2.2-200) and <1.0 (OR = 14, 95% CI = 2.9-66.7). Compared with IpI, IpP cases were more frequently diagnosed with tendon, suspensory ligament, or high-motion joint disorders in hindlimbs (OR = 3.6, 95% CI = 1.1-12.3) and less with unknown causes (OR = 13.2, 95% CI = 3.2-75.2). In IpI cases, positive forelimb regional anaesthesia often reduced hindlimb lameness, whereas in IpP cases, positive hindlimb regional anaesthesia typically lessened forelimb lameness. MAIN LIMITATIONS: Most cases were Quarter Horses. The likelihood of location and cause of lameness may be different for other breeds. CONCLUSIONS: The type of pelvic movement asymmetry observed in IpI and IpP cases is linked to the location and underlying cause of the primary lameness.

Key Considerations for Studying the Effects of High-Fat Diet on the Nulligravid Mouse Endometrium.

The obesity epidemic continues to increase, with half of US women predicted to be obese by 2030. Women with obesity are at increased risk for not only cardiovascular and liver disease, but also reproductive disorders. Although mouse models are useful in studying the effects of obesity, there is inconsistency in obesity-induction methods, diet composition, and mouse strains, and studies using female mice are limited. In this study, we sought to compare the effects of a 45% high-fat diet (HFD) versus a 60% HFD on the uterine estrous cycle of nulligravid C57BL/6J mice. For 22 weeks, we placed a total of 20 mice on either a 60% HFD, 45% HFD, or each HFD-matched control diet (CD). Both HFDs produced significant weight gain, with 60% HFD and 45% HFD gaining significant weight after 2 weeks and 15 weeks, respectively. Additionally, both HFDs led to glucose intolerance, fatty liver, and adipocyte hypertrophy. Mice fed 60% HFD displayed hyperphagia in the first 12 weeks of HFD treatment. Moreover, 60% HFD-treated mice had a longer estrous cycle length and an increased percentage of estrus stage samplings compared to CD-treated mice. Estrous cycle stage-controlled 60% HFD-treated mice displayed an increased estrogen-to-progesterone ratio and decreased ovarian corpora lutea compared to CD-treated mice, which may underlie the observed estrous cycle differences. There was no significant difference between diets regarding endometrial morphology or the percent of endometrial CD45+ immune cells. Our results indicate that consideration is needed when selecting a HFD-induced obesity mouse model for research involving female reproductive health.

Upregulation of HOXA3 by isoform-specific Wilms tumour 1 drives chemotherapy resistance in acute myeloid leukaemia.

Upregulation of the Wilms' tumour 1 (WT1) gene is common in acute myeloid leukaemia (AML) and is associated with poor prognosis. WT1 generates 12 primary transcripts through different translation initiation sites and alternative splicing. The short WT1 transcripts express abundantly in primary leukaemia samples. We observed that overexpression of short WT1 transcripts lacking exon 5 with and without the KTS motif (sWT1+/- and sWT1-/-) led to reduced cell growth. However, only sWT1+/- overexpression resulted in decreased CD71 expression, G1 arrest, and cytarabine resistance. Primary AML patient cells with low CD71 expression exhibit resistance to cytarabine, suggesting that CD71 may serve as a potential biomarker for chemotherapy. RNAseq differential expressed gene analysis identified two transcription factors, HOXA3 and GATA2, that are specifically upregulated in sWT1+/- cells, whereas CDKN1A is upregulated in sWT1-/- cells. Overexpression of either HOXA3 or GATA2 reproduced the effects of sWT1+/-, including decreased cell growth, G1 arrest, reduced CD71 expression and cytarabine resistance. HOXA3 expression correlates with chemotherapy response and overall survival in NPM1 mutation-negative leukaemia specimens. Overexpression of HOXA3 leads to drug resistance against a broad spectrum of chemotherapeutic agents. Our results suggest that WT1 regulates cell proliferation and drug sensitivity in an isoform-specific manner.

Five-year analysis of neoadjuvant dabrafenib and trametinib for stage III melanoma.

BACKGROUND: Neoadjuvant dabrafenib plus trametinib has a high pathological response rate and impressive short-term survival in patients with resectable stage III melanoma. We report 5-year outcomes from the phase II NeoCombi trial. PATIENTS AND METHODS: NeoCombi (NCT01972347) was a single-arm, open-label, single-centre, phase II trial. Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, American Joint Committee on Cancer seventh edition clinical stage IIIB-C BRAF V600E/K-mutant melanoma and Eastern Cooperative Oncology Group performance status ≤1. Patients received 52 weeks of treatment with dabrafenib 150 mg (orally twice per day) plus trametinib 2 mg (orally once per day), with complete resection of the pre-therapy tumour bed at week 12. RESULTS: Between 20 August 2014 and 19 April 2017, 35 patients were enrolled. At data cut-off (17 August 2021), the median follow-up was 60 months [95% confidence interval (CI) 56-72 months]. Overall, 21 of 35 (60%) patients recurred, including 12 (57%) with first recurrence in locoregional sites (followed by later distant recurrence in 6) and 9 (43%) with first recurrence in distant sites, including 3 in the brain. Most recurrences occurred within 2 years, with no recurrences beyond 3 years. At 5 years, recurrence-free survival (RFS) was 40% (95% CI 27% to 60%), distant metastasis-free survival (DMFS) was 57% (95% CI 42% to 76%), and overall survival was 80% (95% CI 67% to 94%). Five-year survival outcomes were stratified by pathological response: RFS was 53% with pathological complete response (pCR) versus 28% with non-pCR (P = 0.087), DMFS was 59% versus 55% (P = 0.647), and overall survival was 88% versus 71% (P = 0.205), respectively. CONCLUSIONS: Neoadjuvant dabrafenib plus trametinib has high pathological response rates in clinical stage III melanoma, but low rates of RFS, similar to those achieved with adjuvant targeted therapy alone. Patients with a pCR to dabrafenib plus trametinib still had a high risk of recurrence, unlike that seen with immunotherapy where recurrences are rare.

Perceived Workplace Discrimination on the Basis of Parent Status in Australia: Who Is Vulnerable and How Does It Link to Mothers' and Fathers' Mental Health?

OBJECTIVE: This study focused on employees' perceived discrimination due to parenthood; and mental health, occupational stress and turnover intention. Methods: Survey (2016) of an Australian convenience sample of employed parents: women ( n = 2950) and men ( n = 1318). Results: Forty-two percent of all mothers reported missing out on promotion ( n = 1234/2950); one-third reported negative comments from managers ( n = 805/2950, 27%) or colleagues ( n = 832/2950, 28%). One in five fathers reported these forms of discrimination. In adjusted analyses, perceived discrimination was associated with poorer mental health (ß = 0.23, P < 0.001); higher occupational stress (ß = 0.30, P < 0.001); and increased odds of turnover intention (adjusted odds ratio = 1.5, P < 0.001) for mothers; and poorer mental health (ß = 0.34, P < 0.001); stress (ß = 0.35, P < 0.001); and increased odds of turnover intention (adjusted odds ratio = 1.7, P < 0.001) for fathers. Conclusions: Experiences of negativity and hostility at work are common and link to employee health and well-being.

Racializing Motherhood and Maternity Care in News Representations of Breastfeeding.

Racial inequalities in breastfeeding have been a U.S. national concern, prompting health science research and public discourse. Social science research reveals structural causes, including racism in labor conditions, maternity care practices, and lactation support. Yet research shows that popular and health science discourses disproportionately focus on individual and community factors, blaming Black women and communities for unequal breastfeeding rates. This study examines how scientific reports are communicated to the public through a critical analysis of 104 U.S. news articles reporting research on racial disparities in breastfeeding. Findings show that articles acknowledge unequal treatment within maternity care but justify it by presenting Black patients as overburdening the maternity care systems they use due to low socioeconomic status, welfare dependency, poor family support, and poor health. Through these representations, articles co-construct racialized motherhood and maternity care systems in ways that hide manifestations of obstetric racism and combat social support for systemic change.

Impact of aerobic granular sludge sizes and dissolved oxygen concentration on greenhouse gas N2O emission.

Aerobic granular sludge (AGS) at wastewater treatment plants (WWTPs) are known to produce nitrous oxide (N2O), a greenhouse gas which has a ∼300 times higher global warming potential than carbon dioxide. In this research, we studied N2O emissions from different sizes of AGS developed at a dissolved oxygen (DO) level of 2 mgO2/L while exposing them to disturbances at various DO concentrations ranging from 1 to 4 mgO2/L. Five different AGS size classes were studied: 212-600 µm, 600-1000 µm, 1000-1400 µm, 1400-2000 µm, and > 2000 µm. Metagenomic data showed N2O reductase genes (nosZ) were more abundant in the smaller AGS sizes which aligned with the observation of higher N2O reduction rates in small AGS under anaerobic conditions. However, when oxygen was present, the activity measurements of N2O emission showed an opposite trend compared to metagenomic data, smaller AGS (212 to 1000 µm) emitted significantly higher N2O (p < 0.05) than larger AGS (1000 µm to >2000 µm) at DO of 2, 3, and 4 mgO2/L. The N2O emission rate showed positive correlation with both oxygen levels and nitrification rate. This pattern indicates a connection between N2O emission and nitrification. In addition, the data suggested the penetration of oxygen into the anoxic zone of granules might have hindered nitrous oxide reduction, resulting in incomplete denitrification stopping at N2O and consequently contributing to an increase in N2O emissions. This work sets the stage to better understand the impacts of AGS size on N2O emissions in WWTPs under different disturbance of DO conditions, and thus ensure that wastewater treatment will comply with possible future regulations demanding lowering greenhouse gas emissions in an effort to combat climate change.

Genetic loci regulate Sarbecovirus pathogenesis: A comparison across mice and humans.

Coronavirus (CoV) cause considerable morbidity and mortality in humans and other mammals, as evidenced by the emergence of Severe Acute Respiratory CoV (SARS-CoV) in 2003, Middle East Respiratory CoV (MERS-CoV) in 2012, and SARS-CoV-2 in 2019. Although poorly characterized, natural genetic variation in human and other mammals modulate virus pathogenesis, as reflected by the spectrum of clinical outcomes ranging from asymptomatic infections to lethal disease. Using multiple human epidemic and zoonotic Sarbecoviruses, coupled with murine Collaborative Cross genetic reference populations, we identify several dozen quantitative trait loci that regulate SARS-like group-2B CoV pathogenesis and replication. Under a Chr4 QTL, we deleted a candidate interferon stimulated gene, Trim14 which resulted in enhanced SARS-CoV titers and clinical disease, suggesting an antiviral role during infection. Importantly, about 60 % of the murine QTL encode susceptibility genes identified as priority candidates from human genome-wide association studies (GWAS) studies after SARS-CoV-2 infection, suggesting that similar selective forces have targeted analogous genes and pathways to regulate Sarbecovirus disease across diverse mammalian hosts. These studies provide an experimental platform in rodents to investigate the molecular-genetic mechanisms by which potential cross mammalian susceptibility loci and genes regulate type-specific and cross-SARS-like group 2B CoV replication, immunity, and pathogenesis in rodent models. Our study also provides a paradigm for identifying susceptibility loci for other highly heterogeneous and virulent viruses that sporadically emerge from zoonotic reservoirs to plague human and animal populations.

Targeting CCL2/CCR2 Signaling Overcomes MEK Inhibitor Resistance in Acute Myeloid Leukemia.

PURPOSE: Emerging evidence underscores the critical role of extrinsic factors within the microenvironment in protecting leukemia cells from therapeutic interventions, driving disease progression, and promoting drug resistance in acute myeloid leukemia (AML). This finding emphasizes the need for the identification of targeted therapies that inhibit intrinsic and extrinsic signaling to overcome drug resistance in AML. EXPERIMENTAL DESIGN: We performed a comprehensive analysis utilizing a cohort of ∼300 AML patient samples. This analysis encompassed the evaluation of secreted cytokines/growth factors, gene expression, and ex vivo drug sensitivity to small molecules. Our investigation pinpointed a notable association between elevated levels of CCL2 and diminished sensitivity to the MEK inhibitors (MEKi). We validated this association through loss-of-function and pharmacologic inhibition studies. Further, we deployed global phosphoproteomics and CRISPR/Cas9 screening to identify the mechanism of CCR2-mediated MEKi resistance in AML. RESULTS: Our multifaceted analysis unveiled that CCL2 activates multiple prosurvival pathways, including MAPK and cell-cycle regulation in MEKi-resistant cells. Employing combination strategies to simultaneously target these pathways heightened growth inhibition in AML cells. Both genetic and pharmacologic inhibition of CCR2 sensitized AML cells to trametinib, suppressing proliferation while enhancing apoptosis. These findings underscore a new role for CCL2 in MEKi resistance, offering combination therapies as an avenue to circumvent this resistance. CONCLUSIONS: Our study demonstrates a compelling rationale for translating CCL2/CCR2 axis inhibitors in combination with MEK pathway-targeting therapies, as a potent strategy for combating drug resistance in AML. This approach has the potential to enhance the efficacy of treatments to improve AML patient outcomes.

"I didn't want to let go of the dream": Exploring women's personal stories of how their low milk supply was discovered.

PROBLEM: Low milk supply is the most common reason women give for stopping breastfeeding early and yet there is a lack of understanding about these women's experiences. BACKGROUND: Most women plan to breastfeed but many experience challenges such as low milk production, leading them to seek help and support. AIM: To explore women's personal stories of how their low supply was discovered. METHODS: Inductive template analysis was used to analyse free-text online survey responses of women from the United States of America, Australia and the United Kingdom. FINDINGS: 384 women responded to the open-ended survey item between October 2021 and January 2022. We identified three themes: (i) Events and observations: From 'risk factors' to 'failure of breast changes' to 'my baby was so unhappy', (ii) Seeking support and taking action: 'I tried everything' and (iii) A rollercoaster of emotion: 'I didn't want to let go of the dream'. DISCUSSION: Our findings emphasise women's need to feel heard and understood and their quest to find answers. The rollercoaster of emotions they experienced largely stemmed from a gap between the expectations and reality of breastfeeding. Some participants described accepting a different feeding journey. CONCLUSION: Findings underscore the need for quality and accessible psychosocial support for women experiencing low milk supply, in addition to the provision of evidence-based advice.