Summary
Fcγ receptors (FcγRs) are key immune receptors responsible for the effective control of both humoral and innate immunity and are central to maintaining the balance between generating ...appropriate responses to infection and preventing autoimmunity. When this balance is lost, pathology results in increased susceptibility to cancer, autoimmunity, and infection. In contrast, optimal FcγR engagement facilitates effective disease resolution and response to monoclonal antibody immunotherapy. The underlying genetics of the FcγR gene family are a central component of this careful balance. Complex in humans and generated through ancestral duplication events, here we review the evolution of the gene family in mammals, the potential importance of copy number, and functionally relevant single nucleotide polymorphisms, as well as discussing current approaches and limitations when exploring genetic variation in this region.
The SNO+ Collaboration reports the first evidence of reactor antineutrinos in a Cherenkov detector. The nearest nuclear reactors are located 240 km away in Ontario, Canada. This analysis uses events ...with energies lower than in any previous analysis with a large water Cherenkov detector. Two analytical methods are used to distinguish reactor antineutrinos from background events in 190 days of data and yield consistent evidence for antineutrinos with a combined significance of 3.5σ.
The Mid-Brunhes Event (MBE) is a climatic transition occurring between MIS 13 and 11 that separates two climatic modes: (1) early Middle Pleistocene interglacials (780–450
ka) that are characterised ...by only moderate warmth and (2) Middle and Late Pleistocene interglacials (occurring after 450
ka) that are characterised by greater warmth consistent with, or warmer than, the Holocene. This event is observable within a variety of long climate records, such as SPECMAP and EPICA, but its effect on terrestrial systems is poorly understood. The impact of this event is examined in the British terrestrial sequence by comparing the occurrence of a range of thermophilous plant and animal species, and climate reconstructions derived from assemblages containing them, from interglacials of the early Middle Pleistocene with those from the late Middle and Late Pleistocene. This comparison reveals that interglacial climates during the early Middle Pleistocene in Britain were as warm as, and in some cases warmer than, those that occurred during the late Middle and Late Pleistocene. This interpretation is supported by sea surface temperature records in the North Atlantic, which show that temperatures during early Middle Pleistocene interglacials were at least as warm as those experienced during the Holocene. There is, therefore, no evidence in climate records of Britain and the North Atlantic for a Mid-Brunhes Event. This suggests that the MBE is not a global climatic transition but is restricted to specific regions, in particular the higher latitudes of the southern Hemisphere. Further work is needed to understand the regional variability and cause of the MBE.
Cancer immunotherapy has been revolutionised by the use monoclonal antibodies (mAb) that function through their interaction with Fc gamma receptors (FcγRs). The low-affinity FcγR genes are highly ...homologous, map to a complex locus at 1p23 and harbour single nucleotide polymorphisms (SNPs) and copy number variation (CNV) that can impact on receptor function and response to therapeutic mAbs. This complexity can hinder accurate characterisation of the locus. We therefore evaluated and optimised a suite of assays for the genomic analysis of the FcγR locus amenable to peripheral blood mononuclear cells and formalin-fixed paraffin-embedded (FFPE) material that can be employed in a high-throughput manner. Assessment of TaqMan genotyping for FCGR2A-131H/R, FCGR3A-158F/V and FCGR2B-232I/T SNPs demonstrated the need for additional methods to discriminate genotypes for the FCGR3A-158F/V and FCGR2B-232I/T SNPs due to sequence homology and CNV in the region. A multiplex ligation-dependent probe amplification assay provided high quality SNP and CNV data in PBMC cases, but there was greater data variability in FFPE material in a manner that was predicted by the BIOMED-2 multiplex PCR protocol. In conclusion, we have evaluated a suite of assays for the genomic analysis of the FcγR locus that are scalable for application in large clinical trials of mAb therapy. These assays will ultimately help establish the importance of FcγR genetics in predicting response to antibody therapeutics.
Clear guidelines exist to guide the dosing of direct-acting oral anticoagulants (DOACs). It is not known how consistently these guidelines are followed in practice.
We studied patients from the ...Veterans Health Administration (VA) with non-valvular atrial fibrillation who received DOACs (dabigatran, rivaroxaban, apixaban) between 2010 and 2016. We used patient characteristics (age, creatinine, body mass) to identify which patients met guideline recommendations for low-dose therapy and which for full-dose therapy. We examined how often patient dosing was concordant with these recommendations. We examined variation in guideline-concordant dosing by site of care and over time. We examined patient-level predictors of guideline-concordant dosing using multivariable logistic models.
A total of 73,672 patients who were prescribed DOACS were included. Of 5837 patients who were recommended to receive low-dose therapy, 1331 (23%) received full-dose therapy instead. Of 67,935 patients recommended to receive full-dose therapy, 4079 (6%) received low-dose therapy instead. Sites varied widely on guideline discordant dosing; on inappropriate low-dose therapy, sites varied from 0 to 15%, while on inappropriate high-dose therapy, from 0 to 41%. Guideline discordant therapy decreased by about 20% in a relative sense over time, but its absolute numbers grew as DOAC therapy became more common. The most important patient-level predictors of receiving guideline-discordant therapy were older age and creatinine function being near the cutoff value.
A substantial portion of DOAC prescriptions in the VA system are dosed contrary to clinical guidelines. This phenomenon varies widely across sites of care and has persisted over time.
During their violent merger, two neutron stars can shed a few percent of their mass. As this ejecta expands, it collides with the surrounding interstellar gas, producing a slowly fading radio flare ...that lasts for years. Radio flares uniquely probe the neutron star merger populations as many events from past decades could still be detectable. Nonetheless, no radio flare observation has been reported to date. Here we show that the radio transient FIRST J1419+3940, first observed in 1993 and still detectable, could have originated from a neutron star merger. We carry out numerical simulations of neutron star merger ejecta to demonstrate that the observed radio light curve is well reproduced by a merger model with astrophysically expected parameters. We examine the observed radio data, as well as the host galaxy, to find clues that could differentiate the transient's neutron star merger origin from the alternative explanation-the afterglow of an off-axis long gamma-ray burst. Near-future observations could find further evidence for the FIRST J1419+3940 radio transient's origin. We show that existing radio surveys likely already recorded multiple radio flares, informing us of the origin and properties of neutron star mergers and their role in the nucleosynthesis of the heaviest elements in the universe.
We conducted a factorial shipboard continuous culture experiment to examine the interactive effects of altered iron, irradiance and CO2 on the summer phytoplankton community of the Ross Sea, ...Antarctica. After 18 days of continuous incubation, iron enrichment increased phytoplankton biomass, nutrient drawdown, diatom and Phaeocystis abundance, and some photosynthetic parameters. High irradiance significantly increased the number of Phaeocystis antarctica colonies, as well as P. antarctica abundance relative to diatoms. Iron and light had significant interactive effects on diatom and P. antarctica pigment concentrations, P. antarctica colony abundance, and Si:N, Si:C, and N:P ratios. The major influence of high CO2 was on diatom community structure, by favoring the large centric diatom Chaetoceros lineola over the small pennate species Cylindrotheca closterium. The ratio of centric to pennate diatoms was significantly responsive to changes in all three variables individually, and to all of their possible two- and three-way combinations. These results suggest that shifts in light, iron, and CO2 and their mutual interactions all play a role in controlling present day Ross Sea plankton community structure, and need to be considered when predicting the possible future responses of biology and biogeochemistry in this region.
To estimate the modified societal costs of cervical cancer treatment in Kenya; and to compare the modified societal costs of treatment for pre-cancerous cervical lesions integrated into same-day HIV ...care compared to "non-integrated" treatment when the services are not coordinated on the same day.
A micro-costing study was conducted at Coptic Hope Center for Infectious Diseases and Kenyatta National Hospital from July 1-October 31, 2014. Interviews were conducted with 54 patients and 23 staff. Direct medical, non-medical (e.g., overhead), and indirect (e.g., time) costs were calculated for colposcopy, cryotherapy, Loop Electrosurgical Excision Procedure (LEEP), and treatment of cancer. All costs are reported in 2017 US dollars.
Patients had a mean age of 41 and daily earnings of $6; travel time to the facility averaged 2.8 hours. From the modified societal perspective, per-procedure costs of colposcopy were $41 (integrated) vs. $91 (non-integrated). Per-procedure costs of cryotherapy were $22 (integrated) vs. $46 (non-integrated), whereas costs of LEEP were $50 (integrated) and $99 (non-integrated). This represents cost savings of $25 for cryotherapy and $50 for colposcopy and LEEP when provided on the same day as an HIV-care visit. Treatment for cervical cancer cost $1,345-$6,514, depending on stage. Facility-based palliative care cost $59/day.
Integrating treatment of pre-cancerous lesions into HIV care is estimated to be cost-saving from a modified societal perspective. These costs can be applied to financial and economic evaluations in Kenya and similar urban settings in other low-income countries.
Introduction
For some immune-mediated disorders, despite the range of therapies available there is limited evidence on which treatment sequences are best for patients and healthcare systems. We ...investigated how their selection can impact outcomes in an Italian setting.
Methods
A 3-year state-transition treatment-sequencing model calculated potential effectiveness improvements and budget reallocation considerations associated with implementing optimal sequences in ankylosing spondylitis (AS), Crohn’s disease (CD), non-radiographic axial spondyloarthritis (NR-AxSpA), plaque psoriasis (PsO), psoriatic arthritis (PsA), rheumatoid arthritis (RA), and ulcerative colitis (UC). Sequences included three biological or disease-modifying treatments, followed by best supportive care. Disease-specific response measures were selected on the basis of clinical relevance, data availability, and data quality. Efficacy was differentiated between biologic-naïve and experienced populations, where possible, using published network meta-analyses and real-world data. All possible treatment sequences, based on reimbursement as of December 2022 in Italy (analyses’ base country), were simulated.
Results
Sequences with the best outcomes consistently employed the most efficacious therapies earlier in the treatment pathway. Improvements to prescribing practice are possible in all diseases; however, most notable was UC, where the per-patient 3-year average treatment failure was 37.3% higher than optimal. The results focused on the three most crowded and prevalent immunological sub-condition diseases in dermatology, rheumatology, and gastroenterology: PsO, RA, and UC, respectively. By prescribing from within the top 20% of the most efficacious sequences, the model found a 15.1% reduction in treatment failures, with a 1.59% increase in drug costs.
Conclusions
Prescribing more efficacious treatments earlier provides a greater opportunity to improve patient outcomes and minimizes treatment failures.
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