A Phase 1 dose escalation and expansion trial of the next-generation oral SERD camizestrant in women with ER-positive, HER2-negative advanced breast cancer: SERENA-1 monotherapy results.

BACKGROUND: SERENA-1 (NCT03616587) is a Phase 1, multi-part, open-label study of camizestrant in pre- and post-menopausal women with ER+, HER2- advanced breast cancer. Parts A and B aim to determine the safety and tolerability of camizestrant monotherapy and define doses for clinical evaluation. Patients and Methods Women aged 18 years or older with metastatic or recurrent ER+, HER2- breast cancer, refractory (or intolerant) to therapy were assigned 25 mg up to 450 mg once daily (QD; escalation) or 75, 150, or 300 mg QD (expansion). Safety and tolerability, anti-tumor efficacy, pharmacokinetics, and impact on ESR1m circulating tumor (ct)DNA levels were assessed. RESULTS: By 9 March 2021, 108 patients received camizestrant monotherapy at 25-450 mg doses. Of these, 93 (86.1%) experienced treatment-related adverse events (TRAEs), 82.4% of which were grade 1 or 2. The most common TRAEs were visual effects (56%), (sinus) bradycardia (44%), fatigue (26%), and nausea (15%). There were no TRAEs grade 3 or higher, or treatment-related serious adverse events (TRSAEs) at doses ≤150 mg. Median tmax was achieved ∼2-4 hours post-dose at all doses investigated, with an estimated half-life of 20-23 hours. Efficacy was observed at all doses investigated, including in patients with prior CDK4/6 inhibitor and/or fulvestrant treatment, with and without baseline ESR1 mutations, and with visceral disease, including liver metastases. CONCLUSIONS: Camizestrant is a next-generation oral SERD and pure ER antagonist with a tolerable safety profile. The pharmacokinetics profile supports once-daily dosing, with evidence of pharmacodynamic and clinical efficacy in heavily pre-treated patients, regardless of ESR1m. This study established 75, 150 and 300 mg QD doses for Phase 2 testing (SERENA-2, NCT04214288 and SERENA-3, NCT04588298).

Limb presentations of invasive Group A Streptococci infection in children.

Infections with invasive Group A streptococcus can have a wide range of presentations and be life threatening if not diagnosed and managed rapidly. Limb presentations in children can be especially challenging and we present our experience to help manage such cases. There can be multiple foci of infection with seeding to avascular structures. Therefore, we advocate maintaining a high degree of clinical suspicion when assessing this group of patients, who are often critically unwell, and have varying presentation. Early and aggressive surgical intervention may be key for disease control.

Rapid preparation of binary mixtures of sodium carboxylates as anodes in sodium-ion batteries.

Sodium-ion batteries are emerging as a sustainable solution to tackle the growing global energy demands. In this context, organic electrode materials complement such technologies as they are composed of earth-abundant elements. As organic anodes, sodium carboxylates exhibit promising applicability in a wide range of molecules. To harness the advantages of individual systems and to minimise their limitations, in this work, an approach to form binary mixtures of sodium carboxylates using one-pot, microwave-assisted synthesis is presented. The target mixtures were synthesised in 30 min with disodium naphthalene-2,6-dicarboxylate (Na-NDC) as a common constituent in all. Both components in all mixtures were shown to participate in the charge storage and had a considerable effect on the performance characteristics, such as specific capacity and working voltage, in half and full cell formats. This approach opens a new avenue for enabling organic materials to be considered as more competitive candidates in sodium-ion batteries and promote their use in other material classes to overcome their limitations.

The impact of the COVID-19 pandemic on TB diagnosis in the Brazilian prison population, 2020-2021.

BACKGROUND: TB is an infectious disease with a worldwide impact. TB is closely associated with social and housing conditions, exerting a significant impact on the prison population, which is particularly susceptible to the disease. Evidence suggests that the COVID-19 pandemic has exacerbated social vulnerability. This study therefore aimed to analyse the impact of the pandemic on the diagnosis of new cases of TB in the Brazilian prison population in the years 2020 and 2021.METHODS: This is an ecological study involving cases of TB recorded in the prison population of Brazil from 2015 to 2021. Data were collected from the Brazil's Information System for Notifiable Diseases.RESULTS: The incidence of TB in the prison population in Brazil fell from 1,005.9/100,000 population between 2015 and 2019 to 852.3/100,000 population between 2020 and 2021. In 2021, there was a deficit of 539 cases (-7.6%) compared to what was expected for the year. In 2020, there was a 10% reduction in TB diagnoses in January and February, reaching 3.8% in March. A negative percentage was observed in most of the subsequent months. In 2021, the year began with a 21.6% decline in January, returning to positive values only in August and September.CONCLUSION: The first years of the COVID-19 pandemic resulted in underdiagnosis of TB in the Brazilian prison population.

Randomized Phase 3 trial demonstrating high efficacy, favourable safety and convenience of a novel calcipotriol and betamethasone dipropionate cream for the treatment of psoriasis.

BACKGROUND: The fixed dose combination of calcipotriene (CAL) and betamethasone dipropionate (BDP) is a well-established topical treatment option for psoriasis based on strong scientific rationale for the single agents having complementary efficacy and safety. CAL/BDP PAD-cream is an easily spreadable cream based on PAD Technology™, an innovative formulation and drug delivery system. OBJECTIVES AND METHODS: A Phase 3, multicentre, randomized, investigator-blind, active and vehicle-controlled trial enrolling 490 patients with mild to moderate psoriasis according to the Physician Global Assessment (PGA) scale was conducted in three European countries. Products were applied once daily for 8 weeks. The aim of the trial was to evaluate the efficacy and safety of CAL/BDP PAD-cream as well as treatment acceptability compared to CAL/BDP gel and PAD-cream vehicle. Primary endpoint was percentage change in modified Psoriasis Area and Severity Index (mPASI) from baseline to Week 8. RESULTS: The percentage mean change from baseline to Week 8 in mPASI for CAL/BDP PAD-cream (67.5%) was superior compared to PAD-cream vehicle (11.7%; p < 0.0001) and non-inferior to CAL/BDP gel (63.5%). The proportion of patients achieving PGA treatment success (at least two-step improvement to clear or almost clear) after 8 weeks was superior for CAL/BDP PAD-cream (50.7%) compared to PAD-cream vehicle (6.1%, p < 0.0001) and statistically significantly greater than CAL/BDP gel (42.7%, p = 0.0442). Patient-reported psoriasis treatment convenience score (PTCS) for CAL/BDP PAD-cream was rated superior to CAL/BDP gel at Week 8 (p < 0.0001) and the mean change in DLQI from baseline to Week 8 improved statistically significantly more in the CAL/BDP PAD-cream group compared to both PAD-cream vehicle (p < 0.0001) and CAL/BDP gel (p = 0.0110). Safety assessments during the trial demonstrated that CAL/BDP PAD-cream was well-tolerated. CONCLUSION: CAL/BDP PAD-cream is a novel topical treatment of psoriasis that has a high efficacy and a favourable safety profile combined with a superior patient-reported treatment convenience.

Fragmentomic analysis of circulating tumor DNA-targeted cancer panels.

BACKGROUND: The isolation of cell-free DNA (cfDNA) from the bloodstream can be used to detect and analyze somatic alterations in circulating tumor DNA (ctDNA), and multiple cfDNA-targeted sequencing panels are now commercially available for Food and Drug Administration (FDA)-approved biomarker indications to guide treatment. More recently, cfDNA fragmentation patterns have emerged as a tool to infer epigenomic and transcriptomic information. However, most of these analyses used whole-genome sequencing, which is insufficient to identify FDA-approved biomarker indications in a cost-effective manner. PATIENTS AND METHODS: We used machine learning models of fragmentation patterns at the first coding exon in standard targeted cancer gene cfDNA sequencing panels to distinguish between cancer and non-cancer patients, as well as the specific tumor type and subtype. We assessed this approach in two independent cohorts: a published cohort from GRAIL (breast, lung, and prostate cancers, non-cancer, n = 198) and an institutional cohort from the University of Wisconsin (UW; breast, lung, prostate, bladder cancers, n = 320). Each cohort was split 70%/30% into training and validation sets. RESULTS: In the UW cohort, training cross-validated accuracy was 82.1%, and accuracy in the independent validation cohort was 86.6% despite a median ctDNA fraction of only 0.06. In the GRAIL cohort, to assess how this approach performs in very low ctDNA fractions, training and independent validation were split based on ctDNA fraction. Training cross-validated accuracy was 80.6%, and accuracy in the independent validation cohort was 76.3%. In the validation cohort where the ctDNA fractions were all <0.05 and as low as 0.0003, the cancer versus non-cancer area under the curve was 0.99. CONCLUSIONS: To our knowledge, this is the first study to demonstrate that sequencing from targeted cfDNA panels can be utilized to analyze fragmentation patterns to classify cancer types, dramatically expanding the potential capabilities of existing clinically used panels at minimal additional cost.

K2Fe(C2O4)2: An Oxalate Cathode for Li/Na-Ion Batteries Exhibiting a Combination of Multielectron Cation and Anion Redox.

The development of multielectron redox-active cathode materials is a top priority for achieving high energy density with long cycle life in the next-generation secondary battery applications. Triggering anion redox activity is regarded as a promising strategy to enhance the energy density of polyanionic cathodes for Li/Na-ion batteries. Herein, K2Fe(C2O4)2 is shown to be a promising new cathode material that combines metal redox activity with oxalate anion (C2O4 2-) redox. This compound reveals specific discharge capacities of 116 and 60 mAh g-1 for sodium-ion batterie (NIB) and lithium-ion batterie (LIB) cathode applications, respectively, at a rate of 10 mA g-1, with excellent cycling stability. The experimental results are complemented by density functional theory (DFT) calculations of the average atomic charges.

Surface-Functionalized Metal-Organic Frameworks for Binding Coronavirus Proteins.

Since the outbreak of SARS-CoV-2, a multitude of strategies have been explored for the means of protection and shielding against virus particles: filtration equipment (PPE) has been widely used in daily life. In this work, we explore another approach in the form of deactivating coronavirus particles through selective binding onto the surface of metal-organic frameworks (MOFs) to further the fight against the transmission of respiratory viruses. MOFs are attractive materials in this regard, as their rich pore and surface chemistry can easily be modified on demand. The surfaces of three MOFs, UiO-66(Zr), UiO-66-NH2(Zr), and UiO-66-NO2(Zr), have been functionalized with repurposed antiviral agents, namely, folic acid, nystatin, and tenofovir, to enable specific interactions with the external spike protein of the SARS virus. Protein binding studies revealed that this surface modification significantly improved the binding affinity toward glycosylated and non-glycosylated proteins for all three MOFs. Additionally, the pores for the surface-functionalized MOFs can adsorb water, making them suitable for locally dehydrating microbial aerosols. Our findings highlight the immense potential of MOFs in deactivating respiratory coronaviruses to be better equipped to fight future pandemics.

Azo-functionalised metal-organic framework for charge storage in sodium-ion batteries.

Sodium-ion batteries (NIBs) are emerging as promising devices for energy storage applications. Porous solids, such as metal-organic frameworks (MOFs), are well suited as electrode materials for technologies involving bulkier charge carriers. However, only limited progress has been made using pristine MOFs, primarily due to lack of redox-active organic groups in the materials. In this work a azo-functional MOF, namely UiO-abdc, is presented as an electrode compound for sodium-ion insertion. The MOF delivers a stable capacity (∼100 mA h g-1) over 150 cycles, and post-cycling characterisation validates the stability of the MOF and participation of the azo-group in charge storage. This study can accelerate the realisation of pristine solids, such as MOFs and other porous organic compounds, as battery materials.

Effects of acute femoral head ischemia on the growth plate and metaphysis in a piglet model of Legg-Calvé-Perthes disease.

OBJECTIVE: To determine the effects of acute (≤7 days) femoral head ischemia on the proximal femoral growth plate and metaphysis in a piglet model of Legg-Calvé-Perthes disease (LCPD). We hypothesized that qualitative and quantitative histological assessment would identify effects of ischemia on endochondral ossification. DESIGN: Unilateral femoral head ischemia was surgically induced in piglets, and femurs were collected for histological assessment at 2 (n = 7) or 7 (n = 5) days post-ischemia. Samples were assessed qualitatively, and histomorphometry of the growth plate zones and primary spongiosa was performed. In a subset of samples at 7 days, hypertrophic chondrocytes were quantitatively assessed and immunohistochemistry for TGFß1 and Indian hedgehog was performed. RESULTS: By 2 days post-ischemia, there was significant thinning of the proliferative and hypertrophic zones, by 63 µm (95% CI -103, -22) and -19 µm (95% CI -33, -5), respectively. This thinning persisted at 7 days post-ischemia. Likewise, at 7 days post-ischemia, the primary spongiosa was thinned to absent by an average of 311 µm (95% CI -542, -82) in all ischemic samples. TGFß1 expression was increased in the hypertrophic zone at 7 days post-ischemia. CONCLUSIONS: Alterations to the growth plate zones and metaphysis occurred by 2 days post-ischemia and persisted at 7 days post-ischemia. Our findings suggest that endochondral ossification may be disrupted at an earlier time point than previously reported and that growth disruption may occur in the piglet model as occurs in some children with LCPD.

Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer.

BACKGROUND: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. PATIENTS AND METHODS: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. RESULTS: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. CONCLUSION: With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals.

Definitions of remission in psoriasis: a systematic literature review from the National Psoriasis Foundation.

Psoriasis studies increasingly employ outcomes that indicate complete disease resolution, yet remission and cure are poorly defined for psoriasis. We conducted a systematic literature review to identify definitions of psoriasis remission and cure reported in the literature. Medline, EMBASE, and The Cochrane Central Register of Controlled Trials databases were searched on July 22, 2020, for full-text studies providing definitions for psoriasis remission/cure. Definitions were analysed descriptively for endpoint, time-frame, on/off treatment, patient-reported outcomes, and disease domains. We identified 106 studies that provided 41 unique remission definitions. Most definitions included endpoints based on Psoriasis Area and Severity Index (PASI), such as PASI75 (n = 16 studies), PASI90 (n = 10), PASI100 (n = 10), and PASI of 0 (n = 3), and descriptive endpoints related to 'skin clearance' (n = 18). Few definitions specified time-frame, on/off treatment or other psoriasis-related disease domains. One small consensus-initiative defined drug-free remission for plaque psoriasis by BSA of 0 without any therapy for at least 12 months. While there is no cure for psoriasis, seven studies defined psoriasis cure using similar endpoints to those used to define remission. We identified a variety of definitions of psoriasis remission. These results will inform the development of consensus-based definitions for psoriasis remission to support efforts to improve research and clinical outcomes.

Exploiting anion and cation redox chemistry in lithium-rich perovskite oxalate: a novel next-generation Li/Na-ion battery electrode.

The fundamental understanding of electrochemical reaction kinetics for lithium/sodium-ion batteries (LIBs & NIBs) is a significant criterion for advancing new-generation electrode materials. Herein, we demonstrate a novel lithium-rich perovskite oxalate KLi3Fe(C2O4)3 (KLFC) cathode with the combination of cation and anion redox delivering discharge capacities of 86 and 99 mA h g-1 after 100 cycles for a LIB and NIB, respectively, with good cyclability. Experimental Raman spectroscopy analysis combined with DFT calculations of charged/discharged samples illustrate the oxalate anion redox activity. Further, first-principles calculations of the partial density of states and Bader charges analysis have also characterised the redox behaviour and charge transfer during the potassium extraction processes.

To mask or not to mask mosaicism? The impact of reporting embryo mosaicism on reproductive potential.

PURPOSE: To evaluate euploidy rates and probability of having at least one euploid embryo for transfer per cycle when mosaicism is reported compared to when it is masked. METHODS: Women age 18-46 years who underwent PGT-A with next generation sequencing of blastocyst biopsies were analyzed. When reported, mosaic embryos were classified as low-level, 20-40% mosaic, or high-level, 41-80% mosaic. When masked, low-level mosaics were categorized as euploid and high-level mosaics were considered aneuploid. Comparative analyses were performed with χ2 tests and t-tests. RESULTS: A total of 22,504 PGT-A biopsy cycles from 18,401 patients were included. These cycles were from 293 different clinics with a mean of 1.22 cycles per patient. The majority of cycles (94.8%) reported mosaicism, and only 5.2% cycles were masked. The euploidy rate was significantly lower when mosaicism was reported versus masked (38.7% v 47.4%, p < 0.0001), which remained significant for age 40 years old and younger. The mosaic reporting cohort was less likely to have at least one euploid embryo for transfer (68.8%) compared to the masked cohort (75.7%) (p < 0.0001); however, this was no longer significant after stratification by age. CONCLUSION: Mosaicism reporting shows an overall expected reduction in euploidy rate. In turn, the probability of having a euploid embryo to transfer depends on clinic transfer practices and patient preference. If mosaic embryos are not transferred, we observe a reduction in probability of having an embryo for transfer. Although the magnitude of these differences is small, our data show that mosaic reporting may contribute to embryo attrition rate.

Quantitative T2 and T1ρ mapping are sensitive to ischemic injury to the epiphyseal cartilage in an in vivo piglet model of Legg-Calvé-Perthes disease.

OBJECTIVE: To determine if the quantitative MRI techniques T2 and T1ρ mapping are sensitive to ischemic injury to epiphyseal cartilage in vivo in a piglet model of Legg-Calvé-Perthes disease using a clinical 3T MRI scanner. We hypothesized that T2 and T1ρ relaxation times would be increased in the epiphyseal cartilage of operated vs contralateral-control femoral heads 1 week following onset of ischemia. DESIGN: Unilateral femoral head ischemia was surgically induced in eight piglets. Piglets were imaged 1 week post-operatively in vivo at 3T MRI using a magnetization-prepared 3D fast spin echo sequence for T2 and T1ρ mapping and a 3D gradient echo sequence for cartilage segmentation. Ischemia was confirmed in all piglets using gadolinium contrast-enhanced MRI. Median T2 and T1ρ relaxation times were measured in the epiphyseal cartilage of the ischemic and control femoral heads and compared using paired t-tests. Histological assessment was performed on a subset of five piglets. RESULTS: T2 and T1ρ relaxation times were significantly increased in the epiphyseal cartilage of the operated vs control femoral heads (ΔT2 = 11.9 ± 3.7 ms, 95% CI = [8.8, 15.0] ms, P < 0.0001; ΔT1ρ = 12.8 ± 4.1 ms, 95% CI = [9.4, 16.2] ms, P < 0.0001). Histological assessment identified chondronecrosis in the hypertrophic and deep proliferative zones within ischemic epiphyseal cartilage. CONCLUSIONS: T2 and T1ρ mapping are sensitive to ischemic injury to the epiphyseal cartilage in vivo at clinical 3T MRI. These techniques may be clinically useful to assess injury and repair to the epiphyseal cartilage to better stage the extent of ischemic damage in Legg-Calvé-Perthes disease.