Increased CXCL10 (IP-10) is associated with advanced myeloproliferative neoplasms and its loss dampens erythrocytosis in mouse models.

Key studies in pre-leukemic disorders have linked increases in pro-inflammatory cytokines with accelerated phases of the disease, but the precise role of the cellular microenvironment in disease initiation and evolution remains poorly understood. In myeloproliferative neoplasms (MPNs), higher levels of specific cytokines have been previously correlated with increased disease severity (tumor necrosis factor-alpha [TNF-α], interferon gamma-induced protein-10 [IP-10 or CXCL10]) and decreased survival (interleukin 8 [IL-8]). Whereas TNF-α and IL-8 have been studied by numerous groups, there is a relative paucity of studies on IP-10 (CXCL10). Here we explore the relationship of IP-10 levels with detailed genomic and clinical data and undertake a complementary cytokine screen alongside functional assays in a wide range of MPN mouse models. Similar to patients, levels of IP-10 were increased in mice with more severe disease phenotypes (e.g., JAK2V617F/V617F TET2-/- double-mutant mice) compared with those with less severe phenotypes (e.g., CALRdel52 or JAK2+/V617F mice) and wild-type (WT) littermate controls. Although exposure to IP-10 did not directly alter proliferation or survival in single hematopoietic stem cells (HSCs) in vitro, IP-10-/- mice transplanted with disease-initiating HSCs developed an MPN phenotype more slowly, suggesting that the effect of IP-10 loss was noncell-autonomous. To explore the broader effects of IP-10 loss, we crossed IP-10-/- mice into a series of MPN mouse models and showed that its loss reduces the erythrocytosis observed in mice with the most severe phenotype. Together, these data point to a potential role for blocking IP-10 activity in the management of MPNs.

Inherited polygenic effects on common hematological traits influence clonal selection on JAK2V617F and the development of myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPNs) are chronic cancers characterized by overproduction of mature blood cells. Their causative somatic mutations, for example, JAK2V617F, are common in the population, yet only a minority of carriers develop MPN. Here we show that the inherited polygenic loci that underlie common hematological traits influence JAK2V617F clonal expansion. We identify polygenic risk scores (PGSs) for monocyte count and plateletcrit as new risk factors for JAK2V617F positivity. PGSs for several hematological traits influenced the risk of different MPN subtypes, with low PGSs for two platelet traits also showing protective effects in JAK2V617F carriers, making them two to three times less likely to have essential thrombocythemia than carriers with high PGSs. We observed that extreme hematological PGSs may contribute to an MPN diagnosis in the absence of somatic driver mutations. Our study showcases how polygenic backgrounds underlying common hematological traits influence both clonal selection on somatic mutations and the subsequent phenotype of cancer.

Tamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis.

Current therapies for myeloproliferative neoplasms (MPNs) improve symptoms but have limited effect on tumor size. In preclinical studies, tamoxifen restored normal apoptosis in mutated hematopoietic stem/progenitor cells (HSPCs). TAMARIN Phase-II, multicenter, single-arm clinical trial assessed tamoxifen's safety and activity in patients with stable MPNs, no prior thrombotic events and mutated JAK2V617F, CALRins5 or CALRdel52 peripheral blood allele burden ≥20% (EudraCT 2015-005497-38). 38 patients were recruited over 112w and 32 completed 24w-treatment. The study's A'herns success criteria were met as the primary outcome ( ≥ 50% reduction in mutant allele burden at 24w) was observed in 3/38 patients. Secondary outcomes included ≥25% reduction at 24w (5/38), ≥50% reduction at 12w (0/38), thrombotic events (2/38), toxicities, hematological response, proportion of patients in each IWG-MRT response category and ELN response criteria. As exploratory outcomes, baseline analysis of HSPC transcriptome segregates responders and non-responders, suggesting a predictive signature. In responder HSPCs, longitudinal analysis shows high baseline expression of JAK-STAT signaling and oxidative phosphorylation genes, which are downregulated by tamoxifen. We further demonstrate in preclinical studies that in JAK2V617F+ cells, 4-hydroxytamoxifen inhibits mitochondrial complex-I, activates integrated stress response and decreases pathogenic JAK2-signaling. These results warrant further investigation of tamoxifen in MPN, with careful consideration of thrombotic risk.

Different niches for stem cells carrying the same oncogenic driver affect pathogenesis and therapy response in myeloproliferative neoplasms.

Aging facilitates the expansion of hematopoietic stem cells (HSCs) carrying clonal hematopoiesis-related somatic mutations and the development of myeloid malignancies, such as myeloproliferative neoplasms (MPNs). While cooperating mutations can cause transformation, it is unclear whether distinct bone marrow (BM) HSC-niches can influence the growth and therapy response of HSCs carrying the same oncogenic driver. Here we found different BM niches for HSCs in MPN subtypes. JAK-STAT signaling differentially regulates CDC42-dependent HSC polarity, niche interaction and mutant cell expansion. Asymmetric HSC distribution causes differential BM niche remodeling: sinusoidal dilation in polycythemia vera and endosteal niche expansion in essential thrombocythemia. MPN development accelerates in a prematurely aged BM microenvironment, suggesting that the specialized niche can modulate mutant cell expansion. Finally, dissimilar HSC-niche interactions underpin variable clinical response to JAK inhibitor. Therefore, HSC-niche interactions influence the expansion rate and therapy response of cells carrying the same clonal hematopoiesis oncogenic driver.

Convergent somatic evolution commences in utero in a germline ribosomopathy.

Clonal tracking of cells using somatic mutations permits exploration of clonal dynamics in human disease. Here, we perform whole genome sequencing of 323 haematopoietic colonies from 10 individuals with the inherited ribosomopathy Shwachman-Diamond syndrome to reconstruct haematopoietic phylogenies. In ~30% of colonies, we identify mutually exclusive mutations in TP53, EIF6, RPL5, RPL22, PRPF8, plus chromosome 7 and 15 aberrations that increase SBDS and EFL1 gene dosage, respectively. Target gene mutations commence in utero, resulting in a profusion of clonal expansions, with only a few haematopoietic stem cell lineages (mean 8, range 1-24) contributing ~50% of haematopoietic colonies across 8 individuals (range 4-100% clonality) by young adulthood. Rapid clonal expansion during disease transformation is associated with biallelic TP53 mutations and increased mutation burden. Our study highlights how convergent somatic mutation of the p53-dependent nucleolar surveillance pathway offsets the deleterious effects of germline ribosomopathy but increases opportunity for TP53-mutated cancer evolution.

Iron homeostasis governs erythroid phenotype in polycythemia vera.

Polycythemia vera (PV) is a myeloproliferative neoplasm driven by activating mutations in JAK2 that result in unrestrained erythrocyte production, increasing patients' hematocrit and hemoglobin concentrations, placing them at risk of life-threatening thrombotic events. Our genome-wide association study of 440 PV cases and 403 351 controls using UK Biobank data showed that single nucleotide polymorphisms in HFE known to cause hemochromatosis are highly associated with PV diagnosis, linking iron regulation to PV. Analysis of the FinnGen dataset independently confirmed overrepresentation of homozygous HFE variants in patients with PV. HFE influences the expression of hepcidin, the master regulator of systemic iron homeostasis. Through genetic dissection of mouse models of PV, we show that the PV erythroid phenotype is directly linked to hepcidin expression: endogenous hepcidin upregulation alleviates erythroid disease whereas hepcidin ablation worsens it. Furthermore, we demonstrate that in PV, hepcidin is not regulated by expanded erythropoiesis but is likely governed by inflammatory cytokines signaling via GP130-coupled receptors. These findings have important implications for understanding the pathophysiology of PV and offer new therapeutic strategies for this disease.

Maternity services' responses to the COVID-19 pandemic: how Public Health England guidance was implemented in practice.

INTRODUCTION: The rapidly evolving COVID-19 pandemic required systemic change in how healthcare was delivered to minimize virus transmission whilst maintaining safe service delivery. Deemed at 'moderate-high risk', maternity patients are an important patient group that require consideration. Public Health England (PHE) issued national guidance on how to adjust these services. AIM: To explore how maternity units in England implemented PHE guidance. METHODS: An online survey of 22 items was distributed to individuals that had worked on an England-based maternity unit during the COVID-19 pandemic. The questionnaire was designed and tested by the multidisciplinary research team. Data was collected from November 2020 to July 2021. FINDINGS: Forty-four participants across 33 maternity units responded. Ninety-three percent were able to test all women requiring an overnight stay for COVID-19. Only 27% reported birth partners were tested for COVID-19. Only 73% reported they were able to isolate all COVID-19-positive patients in single rooms. Eighty-four percent stated they were aware of current PHE guidance on personal protective equipment (PPE) and 82% felt 'confident' in donning/doffing of PPE. Priorities for the future include rapid testing and a focus on community service provision. CONCLUSIONS: PHE COVID-19 guidance was implemented differently in maternity units across England due to the varying resources available at each trust leading to variable ability to test and isolate patients as recommended. More specific, tailored guidance for infection control measures against COVID-19 is needed for maternity settings due to their unique position.

Implementation of Public Health England infection prevention and control guidance in maternity units in response to the COVID-19 pandemic.

BACKGROUND: This study aimed to explore the successes and barriers to the implementation of Public Health England (PHE) infection prevention and control guidance in English maternity units during the COVID-19 pandemic. METHODS: Qualitative semi-structured interviews with obstetricians, midwives and neonatologists who worked in a maternity unit in England, UK, between March 2020 and July 2021. A thematic analysis was performed. RESULTS: Successes to the implementation of PHE guidance were related to existing infrastructure, training satisfaction, and organisational culture where subthemes considered the importance of a multidisciplinary approach, COVID-19 dedicated roles and hospital-wide communication. Barriers to implementation related to the applicability of the guidance with subthemes highlighting contradictions between updates, specialties and hospitals, undesirable timings and frequency of guidance updates, reductions in staff compliance and delayed implementation. Finally, the layout of some units made it difficult to implement various aspects of the guidance (e.g., social distancing), and many detailed issues related to information technology compatibility, a lack of availability and accessibility to appropriate personal protective equipment (PPE), and variations in testing arrangements between units. CONCLUSIONS: This research provides information on the experiences of healthcare professionals working on maternity units during the COVID-19 pandemic. Findings illustrate the importance of effective hospital-wide communication and the need for consistent, easily understood guidance. These results will be used to inform the content of an expert panel consensus meeting.

Life histories of myeloproliferative neoplasms inferred from phylogenies.

Mutations in cancer-associated genes drive tumour outgrowth, but our knowledge of the timing of driver mutations and subsequent clonal dynamics is limited1-3. Here, using whole-genome sequencing of 1,013 clonal haematopoietic colonies from 12 patients with myeloproliferative neoplasms, we identified 580,133 somatic mutations to reconstruct haematopoietic phylogenies and determine clonal histories. Driver mutations were estimated to occur early in life, including the in utero period. JAK2V617F was estimated to have been acquired by 33 weeks of gestation to 10.8 years of age in 5 patients in whom JAK2V617F was the first event. DNMT3A mutations were acquired by 8 weeks of gestation to 7.6 years of age in 4 patients, and a PPM1D mutation was acquired by 5.8 years of age. Additional genomic events occurred before or following JAK2V617F acquisition and as independent clonal expansions. Sequential driver mutation acquisition was separated by decades across life, often outcompeting ancestral clones. The mean latency between JAK2V617F acquisition and diagnosis was 30 years (range 11-54 years). Estimated historical rates of clonal expansion varied substantially (3% to 190% per year), increased with additional driver mutations, and predicted latency to diagnosis. Our study suggests that early driver mutation acquisition and life-long growth and evolution underlie adult myeloproliferative neoplasms, raising opportunities for earlier intervention and a new model for cancer development.

Early detection of T-cell lymphoma with T follicular helper phenotype by RHOA mutation analysis.

Angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma with T follicular helper phenotype (PTCL-TFH) are a group of complex clinicopathological entities that originate from T follicular helper cells and share a similar mutation profile. Their diagnosis is often a challenge, particularly at an early stage, because of a lack of specific histological and immunophenotypic features, paucity of neoplastic T cells and prominent polymorphous infiltrate. We investigated whether the lymphoma-associated RHOA Gly17Val (c.50G>T) mutation, occurring in 60% of cases, is present in the early "reactive" lesions, and whether mutation analysis could help to advance the early diagnosis of lymphoma. The RHOA mutation was detected by quantitative polymerase chain reaction with a locked nucleic acid probe specific to the mutation, and a further peptide nucleic acid clamp oligonucleotide to suppress the amplification of the wild-type allele. The quantitative polymerase chain reaction assay was highly sensitive and specific, detecting RHOA Gly17Val at an allele frequency of 0.03%, but not other changes in Gly17, nor in 61 controls. Among the 37 cases of AITL and PTCL-TFH investigated, RHOA Gly17Val was detected in 62.2% (23/37) of which 19 had multiple biopsies including preceding biopsies in ten and follow-up biopsies in 11 cases. RHOA Gly17Val was present in each of these preceding or follow-up biopsies including 18 specimens that showed no evidence of lymphoma by combined histological, immunophenotypic and clonality analyses. The mutation was seen in biopsies 0-26.5 months (mean 7.87 months) prior to the lymphoma diagnosis. Our results show that RHOA Gly17Val mutation analysis is valuable in the early detection of AITL and PTCL-TFH.

Surgical management of advanced pleomorphic dermal sarcoma of the occipital scalp.

Pleomorphic dermal sarcoma is a rare neoplasm of mesenchymal origin that most commonly affects the head. We describe the presentation of a 61-year-old man with a 10-week history of an exophytic lesion affecting the occipital scalp, demonstrating rapid growth. The final histopathology revealed a completely excised 9cm pleomorphic dermal sarcoma (pT2aN0M0, Stage 3), one of the largest such lesions reported in the literature to date. This patient's management involved a wide local subperiosteal excision onto the cranium, with a reconstruction with an Integra dermal regeneration template (Integra LifeSciences, Princeton, NJ, USA) and healing with secondary intention. This was mainly due to poorly defined clinical margins on primary excision, the potential for further excision of involved margins (later confirmed as not needed) and the patient's comorbidities, making a return to theatre for definitive reconstruction undesirable.

Minimally invasive biomarkers to detect maternal physiological status in sow saliva and milk.

In this study, we aimed to validate existing plasma assays to measure biomarkers for maternal signalling in milk and saliva of lactating sows. These biological samples are minimally invasive to the animal and could give a physiological profile of maternal qualities available to their piglets. Sows were farrowed in a zero-confinement system, and their colostrum and milk samples were manually collected during naturally occurring let-downs (i.e. not induced) over the lactation period. Saliva sampling involved sows voluntarily accepting cotton buds to chew without restraint. Commercial kits designed for blood plasma were tested, and any modifications and results are given. We successfully measured total protein, cortisol, tumour necrosis factor-α (TNF-α) and oxytocin in pig milk and saliva and immunoglobulin G (IgG) in pig milk samples. We were unsuccessful at measuring relaxin and serotonin in these biological samples. We observed higher levels of biomarkers in milk than in saliva. The measurement of TNF-α in pig milk for the first time revealed increased levels with larger litters. This development will allow more detailed understanding of biomarkers in milk. There was also evidence that the minimally invasive technique of using saliva sampling did not interrupt natural oxytocin production around parturition.

Zinc-dependent multimerization of mutant calreticulin is required for MPL binding and MPN pathogenesis.

Calreticulin (CALR) is mutated in the majority of JAK2/MPL-unmutated myeloproliferative neoplasms (MPNs). Mutant CALR (CALRdel52) exerts its effect by binding to the thrombopoietin receptor MPL to cause constitutive activation of JAK-STAT signaling. In this study, we performed an extensive mutagenesis screen of the CALR globular N-domain and revealed 2 motifs critical for CALRdel52 oncogenic activity: (1) the glycan-binding lectin motif and (2) the zinc-binding domain. Further analysis demonstrated that the zinc-binding domain was essential for formation of CALRdel52 multimers, which was a co-requisite for MPL binding. CALRdel52 variants incapable of binding zinc were unable to homomultimerize, form CALRdel52-MPL heteromeric complexes, or stimulate JAK-STAT signaling. Finally, treatment with zinc chelation disrupted CALRdel52-MPL complexes in hematopoietic cells in conjunction with preferential eradication of cells expressing CALRdel52 relative to cells expressing other MPN oncogenes. In addition, zinc chelators exhibited a therapeutic effect in preferentially impairing growth of CALRdel52-mutant erythroblasts relative to unmutated erythroblasts in primary cultures of MPN patients. Together, our data implicate zinc as an essential cofactor for CALRdel52 oncogenic activity by enabling CALRdel52 multimerization and interaction with MPL, and suggests that perturbation of intracellular zinc levels may represent a new approach to abrogate the oncogenic activity of CALRdel52 in the treatment of MPNs.

A midwifery-led prevalence programme for caesarean section surgical site infections.

Caesarean section (CS) is a common procedure accounting for 29% of all deliveries. Surgical site infections (SSI) are a risk with any surgical procedure. A CS SSI prevalence programme led by a midwife, who is also an infection prevention and control matron, was implemented to determine the rate of CS SSI within the trust. The initial CS SSI rate was 26% over a 3-month period (June-August 2012). Targeted interventions were put in place to reduce the CS SSI rate, and by 2019, it had decreased to 8%. Hospitals should consider implementing CS SSI surveillance and prevention programmes. Real benefits can be realized with minimal resources.

Longitudinal Cytokine Profiling Identifies GRO-α and EGF as Potential Biomarkers of Disease Progression in Essential Thrombocythemia.

Myeloproliferative neoplasms (MPNs) are characterized by deregulation of mature blood cell production and increased risk of myelofibrosis (MF) and leukemic transformation. Numerous driver mutations have been identified but substantial disease heterogeneity remains unexplained, implying the involvement of additional as yet unidentified factors. The inflammatory microenvironment has recently attracted attention as a crucial factor in MPN biology, in particular whether inflammatory cytokines and chemokines contribute to disease establishment or progression. Here we present a large-scale study of serum cytokine profiles in more than 400 MPN patients and identify an essential thrombocythemia (ET)-specific inflammatory cytokine signature consisting of Eotaxin, GRO-α, and EGF. Levels of 2 of these markers (GRO-α and EGF) in ET patients were associated with disease transformation in initial sample collection (GRO-α) or longitudinal sampling (EGF). In ET patients with extensive genomic profiling data (n = 183) cytokine levels added significant prognostic value for predicting transformation from ET to MF. Furthermore, CD56+CD14+ pro-inflammatory monocytes were identified as a novel source of increased GRO-α levels. These data implicate the immune cell microenvironment as a significant player in ET disease evolution and illustrate the utility of cytokines as potential biomarkers for reaching beyond genomic classification for disease stratification and monitoring.

COVID-19: how prepared are front-line healthcare workers in England?

National efforts are underway to prepare the UK National Health Service (NHS) for the COVID-19 pandemic; however, the efficacy of these interventions is unknown. In view of this, a cross-sectional survey of front-line healthcare workers (HCWs) at two large acute NHS hospital trusts in England was undertaken to assess their confidence and perceived level of preparedness for the virus. The survey found that there has been moderate success in readying HCWs to manage COVID-19, but that more still needs to be done, particularly in relation to educating HCWs about laboratory diagnostics.

Sow behaviour and piglet weight gain after late cross-fostering in farrowing crates and pens.

Determining best practices for managing free farrowing systems is crucial for uptake. Cross-fostering, the exchange of piglets between litters, is routinely performed amongst crate-housed sows. However, cross-fostering can increase fighting amongst the litter and may be more challenging within free farrowing systems as sows have more freedom to respond to cross-fostered piglets. This study compared the effect of either cross-fostering (FOS), or a control of sham-fostering (CON), of four focal piglets per litter on Day 6 postpartum in crates (CRATE) and free farrowing pens (PEN). The post-treatment behavioural responses of sows were recorded (Day 6 = 60 min; Day 7 = 300 min; n = 48), as were the average daily gain (ADG; g/day), total weight gain (TWG; kg) and body lesion scores of focal piglets and their littermates throughout lactation (Day 6, Day 8, Day 11 and Day 26; n = 539) and the post-weaning period (Day 29, Day 32 and Day 60; n = 108). On Day 6, though post-reunion latency to nursing did not differ, latency to successful nursing was longer amongst FOS than CON litters (P < 0.001), more so amongst CRATE FOS than PEN FOS (P < 0.01). On Day 7, PEN FOS sows had fewer successful nursing bouts (P < 0.05) and exhibited decreased lateral (P < 0.01) and increased ventral lying frequencies (P < 0.01) compared to all other housing and treatment combinations. Focal piglet ADG was lower for FOS than CON in the CRATE during Day 6 to Day 8 (P < 0.01) and lower in the PEN during Day 6 to Day 8 (P < 0.001), Day 8 to Day 11 (P < 0.01) and Day 11 to Day 26 (P < 0.05). The TWG of pre-weaned focal piglets (Day 6 to Day 26) was higher amongst CON than FOS litters (P = 0.01). Post-weaning, piglet ADG was higher for PEN than CRATE during Day 26 to Day 29 (P < 0.01) and higher for FOS than CON during Day 26 to Day 29 (P < 0.05), Day 29 to Day 32 (P < 0.001) and Day 32 to Day 60 (P < 0.01); thus, TWG was higher for FOS than CON during the weaner (P = 0.001) and the combined lactation and weaner periods (P = 0.09). In conclusion, sow behaviour was disrupted by cross-fostering in the crates and pens and continued to be disturbed on the following day amongst penned sows. FOS piglets exhibited reduced ADG after cross-fostering, which extended throughout lactation in the pens. However, the increased post-weaning weight gain of FOS piglets meant that their TWG was higher than CON piglets, irrespective of the farrowing system used.

Standardized protocols for differentiation of THP-1 cells to macrophages with distinct M(IFNγ+LPS), M(IL-4) and M(IL-10) phenotypes.

In vitro models of differing macrophage functions are useful since human monocyte-derived macrophages are short-lived, finite and vary from donor to donor. Published protocols using the promonocytic cell line THP-1 have tended to result in cells that closely resemble classically-activated macrophages, differentiated in IFNγ and LPS. However, no protocol, to date, has fully recapitulated polarization of THP-1 to the M(IL-4) or M(IL-10) macrophage phenotypes seen when human monocyte-derived macrophages are exposed to each cytokine. Here we present protocols that can be used to prepare M(IL-4) polarized THP-1 that transcribe CCL17, CCL26, CD200R and MRC1 and M(IL-10) cells which transcribe CD163, C1QA and SEPP1. We show that the inhibitory Fcγ Receptor IIb is preferentially expressed on the surface of M(IL-4) cells, altering the balance of activating to inhibitory Fcγ Receptors. Adoption of standardized experimental conditions for macrophage polarization will make it easier to compare downstream effector functions of different macrophage polarization states, where the impact of PMA exposure is minimized and rest periods and cytokine exposure have been optimized.

Detection of CMB-Cluster Lensing using Polarization Data from SPTpol.

We report the first detection of gravitational lensing due to galaxy clusters using only the polarization of the cosmic microwave background (CMB). The lensing signal is obtained using a new estimator that extracts the lensing dipole signature from stacked images formed by rotating the cluster-centered Stokes QU map cutouts along the direction of the locally measured background CMB polarization gradient. Using data from the SPTpol 500 deg^{2} survey at the locations of roughly 18 000 clusters with richness λ≥10 from the Dark Energy Survey (DES) Year-3 full galaxy cluster catalog, we detect lensing at 4.8σ. The mean stacked mass of the selected sample is found to be (1.43±0.40)×10^{14}M_{⊙} which is in good agreement with optical weak lensing based estimates using DES data and CMB-lensing based estimates using SPTpol temperature data. This measurement is a key first step for cluster cosmology with future low-noise CMB surveys, like CMB-S4, for which CMB polarization will be the primary channel for cluster lensing measurements.

Cosmological Constraints from Multiple Probes in the Dark Energy Survey.

The combination of multiple observational probes has long been advocated as a powerful technique to constrain cosmological parameters, in particular dark energy. The Dark Energy Survey has measured 207 spectroscopically confirmed type Ia supernova light curves, the baryon acoustic oscillation feature, weak gravitational lensing, and galaxy clustering. Here we present combined results from these probes, deriving constraints on the equation of state, w, of dark energy and its energy density in the Universe. Independently of other experiments, such as those that measure the cosmic microwave background, the probes from this single photometric survey rule out a Universe with no dark energy, finding w=-0.80_{-0.11}^{+0.09}. The geometry is shown to be consistent with a spatially flat Universe, and we obtain a constraint on the baryon density of Ω_{b}=0.069_{-0.012}^{+0.009} that is independent of early Universe measurements. These results demonstrate the potential power of large multiprobe photometric surveys and pave the way for order of magnitude advances in our constraints on properties of dark energy and cosmology over the next decade.