Disordered clock protein interactions and charge blocks turn an hourglass into a persistent circadian oscillator.

Organismal physiology is widely regulated by the molecular circadian clock, a feedback loop composed of protein complexes whose members are enriched in intrinsically disordered regions. These regions can mediate protein-protein interactions via SLiMs, but the contribution of these disordered regions to clock protein interactions had not been elucidated. To determine the functionality of these disordered regions, we applied a synthetic peptide microarray approach to the disordered clock protein FRQ in Neurospora crassa. We identified residues required for FRQ's interaction with its partner protein FRH, the mutation of which demonstrated FRH is necessary for persistent clock oscillations but not repression of transcriptional activity. Additionally, the microarray demonstrated an enrichment of FRH binding to FRQ peptides with a net positive charge. We found that positively charged residues occurred in significant "blocks" within the amino acid sequence of FRQ and that ablation of one of these blocks affected both core clock timing and physiological clock output. Finally, we found positive charge clusters were a commonly shared molecular feature in repressive circadian clock proteins. Overall, our study suggests a mechanistic purpose for positive charge blocks and yielded insights into repressive arm protein roles in clock function.

Hospitalisation rates for youth living with perinatally acquired HIV in England.

INTRODUCTION: Complex challenges amongst ageing cohorts of adolescents and adults living with perinatally acquired HIV (PaHIV) may impact on hospitalisation. We report hospitalisation rates and explored predictive factors for hospitalisation in adolescents and adults (10-35 years) living with PaHIV in England. METHOD: Retrospective observational cohort study over a three-year period 2016-2019. Data collected included cause and duration of hospitalisation, HIV viral load and CD4 lymphocyte count. The primary outcome was overnight hospitalisation. Patients exited at study end/ transfer of care (TOC)/ loss to follow up (LTFU) or death. Maternity/hospital admissions at other centres were excluded. Admission rates per 100 person-years (95% CI) were calculated by age group. Negative binomial regression with generalized estimating equations was performed. RESULTS: 255 patients contributed 689 person-years of follow up. 56% were female and 83% were of a Black, Black British, Caribbean or African ethnicity. At baseline, the median age was 19 years (IQR 16-22). 36 individuals experienced a total of 62 admissions which resulted in 558 overnight stays (median stay was 5 nights). One person died (lymphoma), six had TOC and one was LTFU by the end of the three-year study period. Crude incidence of admission for the whole cohort was 9.0 per 100 PY (6.9-11.6). The respective crude incidence rates were 1.5 PY (0.0-8.2) in those aged 10-14 years and 3.5 PY (1.5-7.0) in the 15-19-year-olds. In those aged 20-24 years it was 14.5 PY (10.1-20.2) and in those >25 years the crude incidence rate was 11.7 PY (6.9-18.5). Factors significantly associated with admission were a CD4 lymphocyte count <200 cells/uL, adjusted IRR 4.0 (1.8-8.8) and a history of a CDC-C diagnosis, adjusted IRR 2.9 (1.6-5.3). 89% admissions were HIV-related: 45% new/current CDC-C diagnoses, 76% due to infection. CONCLUSIONS: Hospitalisation rates were four-fold higher in adults (>20 years of age) compared to adolescents (10-19-year-olds). The continuing challenges experienced by PaHIV youth require enhanced multidisciplinary support throughout adulthood.

Functional screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed Repair.

Homology Directed Repair (HDR) enables precise genome editing, but the implementation of HDR-based therapies is hindered by limited efficiency in comparison to methods that exploit alternative DNA repair routes, such as Non-Homologous End Joining (NHEJ). In this study, we develop a functional, pooled screening platform to identify protein-based reagents that improve HDR in human hematopoietic stem and progenitor cells (HSPCs). We leverage this screening platform to explore sequence diversity at the binding interface of the NHEJ inhibitor i53 and its target, 53BP1, identifying optimized variants that enable new intermolecular bonds and robustly increase HDR. We show that these variants specifically reduce insertion-deletion outcomes without increasing off-target editing, synergize with a DNAPK inhibitor molecule, and can be applied at manufacturing scale to increase the fraction of cells bearing repaired alleles. This screening platform can enable the discovery of future gene editing reagents that improve HDR outcomes.

Development of a Novel DNA Mono-alkylator Platform for Antibody-Drug Conjugates.

Although microtubule inhibitors (MTI) remain a therapeutically valuable payload option for antibody-drug conjugates (ADC), some cancers do not respond to MTI-based ADCs. Efforts to fill this therapeutic gap have led to a recent expansion of the ADC payload "toolbox" to include payloads with novel mechanisms of action such as topoisomerase inhibition and DNA cross-linking. We present here the development of a novel DNA mono-alkylator ADC platform that exhibits sustained tumor growth suppression at single doses in MTI-resistant tumors and is well tolerated in the rat upon repeat dosing. A phosphoramidate prodrug of the payload enables low ADC aggregation even at drug-to-antibody ratios of 5:1 while still delivering a bystander-capable payload that is effective in multidrug resistant (MDR)-overexpressing cell lines. The platform was comparable in xenograft studies to the clinical benchmark DNA mono-alkylator ADC platform DGN459 but with a significantly better tolerability profile in rats. Thus, the activity and tolerability profile of this new platform make it a viable option for the development of ADCs.

Artificial selection of microbial communities: what have we learnt and how can we improve?

Microbial communities are capable of performing diverse functions with important bioindustrial and medical applications. One approach to improving community function is to breed new communities by artificially selecting for those displaying high community function ('community selection'). Importantly, community selection can improve the function of interest without needing to understand how the function arises, just like in classical artificial selection of individuals. However, experimental studies of community selection have had varied and largely limited success. Here, we review a conceptual framework to help foster an understanding of community selection and its associated challenges, and provide broad insights for designing effective selection strategies.

Mechanism of co-operation of mutant IL-7Rα and mutant NRAS in acute lymphoblastic leukemia: role of MYC.

Acute lymphoblastic leukemia (ALL) is an aggressive leukemia which can be derived from either T-cell or B-cell precursors. With current treatments, the survival rate is high, but the treatments are highly toxic with severe side effects. Individual mutations in IL7Rssand RAS pathways have been previously shown to be prevalent in ALL and especially in relapsed patients. The relationship of IL-7R77and RAS was investigated by transducing immature mouse thymocytes with the combination of these mutants. The resultant ALL cells were analyzed to identify the regulators and the oncoproteins that are upregulated or downregulated by the combination of IL7Rα with NRAS. Leukemia cells showed a significant increase in IL7Rw-mediated BCL2 expression, and an increase in MYC protein levels, was mainly induced by NRAS signaling. MYC was both necessary and sufficient to replace mutant NRAS and drugs targeting the MYC pathway showed a therapeutic benefit in IL-7R7/NRAS T-ALL. We suggest that MYC protein stability can be regulated by PLK-1 kinase, which was increased mainly by the NRAS signal. These studies identify novel pathways of oncogenesis and new targets for intervention that could lead to better therapeutic development.

Virtual student-led neuroscience conferencing: a UK multicentre prospective study investigating delegate outcomes and delivery mode.

BACKGROUND: Clinical neuroscience training programmes are becoming increasingly competitive to enter. UK university neuroscience societies act as a local environment for students to develop their career interests and provide portfolio building opportunities through hosting events such as annual conferences. Recently there has been a transition to more of these events being held online yet the impact of this, if any, remains unclear. This prospective study aimed to identify the impact of student-led neuroscience conferences on delegates and examine attitudes towards an online delivery approach. METHODS: Multi-centre prospective survey study using pre-conference, post-conference, and 6-month post-conference online questionnaires distributed at 6 virtual student-led neuroscience conferences in 2021. The questionnaires had five-domains: demographics, career aspirations, academic skillsets, an educational manipulation check (EMC) and mode of delivery preference. RESULTS: Nine hundred twenty-four surveys were completed across 559 conference attendances. 79.9% of delegates were medical students. Interest in a neuroscience career (p < 0.001), preparedness to undertake research (p < 0.001) and presentation (p < 0.001), as well as EMC scores (p < 0.001) increased immediately post conference. Most participants at 6 months post-attendance had completed an academic project (71.9%) or presentation (50.9%), although 88.8% were lost to follow up. Online format was preferred (65%) with reasons including elimination of travel and access to home facilities whilst lack of face-to-face interaction and engagement were recognised limitations. CONCLUSION: UK student-led online neuroscience conferences play a role in developing knowledge and may facilitate career interest, academic skillset and longer term portfolio building. A hybrid virtual and in-person experience would offer an ideal solution to future conferencing, providing options promoting engagement and interactivity whilst advocating sustainability, accessibility and widening participation.

Discovery and Optimization of a STING Agonist Platform for Application in Antibody Drug Conjugates.

While STING agonists have proven to be effective preclinically as anti-tumor agents, these promising results have yet to be translated in the clinic. A STING agonist antibody-drug conjugate (ADC) could overcome current limitations by improving tumor accessibility, allowing for systemic administration as well as tumor-localized activation of STING for greater anti-tumor activity and better tolerability. In line with this effort, a STING agonist ADC platform was identified through systematic optimization of the payload, linker, and scaffold based on multiple factors including potency and specificity in both in vitro and in vivo evaluations. The platform employs a potent non-cyclic dinucleotide STING agonist, a cleavable ester-based linker, and a hydrophilic PEG8-bisglucamine scaffold. A tumor-targeted ADC built with the resulting STING agonist platform induced robust and durable anti-tumor activity and demonstrated high stability and favorable pharmacokinetics in nonclinical species.

An approach for in-situ detection of gold colloid aggregates amyloid formations within the hippocampus of the Cohen's Alzheimer's disease rat model by surface enhanced raman scattering methods.

BACKGROUND: Amyloid beta (Aß) peptides, such as Aß1-40 or Aß1-42 are regarded as hallmark neuropathological biomarkers associated with Alzheimer's disease (AD). The formation of an aggregates by Aß1-40 or Aß1-42-coated gold nano-particles are hypothesized to contain conformation of Aß oligomers, which could exist only at an initial stage of fibrillogenesis. NEW METHOD: The attempt of in-situ detection of externally initiated gold colloid (ca. 80 nm diameter) aggregates in the middle section of the hippocampus of the Long Evans Cohen's Alzheimer's disease rat model was conducted through the Surface Enhanced Raman Scattering (SERS) method. RESULTS: The SERS spectral features contained modes associated with ß-sheet interactions and a significant number of modes that were previously reported in SERS shifts for Alzheimer diseased rodent and human brain tissues; thereby, strongly implying a containment of amyloid fibrils. The spectral patterns were further examined and compared with those collected from in-vitro gold colloid aggregates which were formed from Aß1-40 - or Aß1-42 -coated 80 nm gold colloid under pH ∼4, pH ∼7, and pH ∼10, and the best matched datasets were found with that of the aggregates of Aß1-42 -coated 80 nm gold colloid at ∼pH 4.0. The morphology and physical size of this specific gold colloid aggregate was clearly different from those found in-vitro. COMPARISON WITH EXISTING METHOD(S): The amyloid fibril with a ß-sheet conformation identified in previously reported in AD mouse/human brain tissues was involved in a formation of the gold colloid aggregates. However, to our surprise, best explanation for the observed SERS spectral features was possible with those in vitro Aß1-42 -coated 80 nm gold colloid under pH ∼4. CONCLUSIONS: A formation of gold colloid aggregates was confirmed in the AD rat hippocampal brain section with unique physical morphology compared to those observed in in-vitro Aß1-42 or Aß1-40 mediated gold colloid aggregates. It was concluded that a ß-sheet conformation identified in previously reported in AD mouse/human brain tissues was in volved in a formation of the gold colloid aggregates.

The cost effectiveness of tranexamic acid for preventing periprosthetic joint infection following total shoulder arthroplasty: a break-even analysis.

BACKGROUND: The use of tranexamic acid (TXA) has become widespread in orthopedics to promote hemostasis and has been successfully used to reduce blood loss and infection risk in joint arthroplasty. However, the cost effectiveness of routine TXA use for the prevention of periprosthetic infections in total shoulder arthroplasty remains unknown. METHODS: The acquisition cost of TXA ($5.22) for our institution, along with values from the literature for the average cost of infection-related care ($55,243) and the baseline infection rates for patients without TXA use (0.70%),were used to perform a break-even analysis. The absolute risk reduction (ARR) of infection necessary to justify the prophylactic use of TXA in shoulder arthroplasty was calculated from the nontreated and break-even infection rates. RESULTS: TXA is considered cost-effective if it prevents one infection out of 10,583 total shoulder arthroplasty's (ARR = 0.009%). It is economically justifiable with an ARR range of 0.001% at a cost of $0.50/g to 0.181% at $100/g. At varying costs of infection-related care ($10,000-$100,000) and varying baseline infection rates (0.50%-8.00%) and routine use of TXA remained cost-effective. CONCLUSION: The use of TXA is an economically viable practice for infection prevention following shoulder arthroplasty if it reduces the infection rate by 0.009%. Future, prospective studies should be conducted to observe whether TXA reduces the infection rate by more than 0.009%, showing cost effectiveness.

Exploring a global interpretation mechanism for deep learning networks when predicting sepsis.

The purpose of this study is to identify additional clinical features for sepsis detection through the use of a novel mechanism for interpreting black-box machine learning models trained and to provide a suitable evaluation for the mechanism. We use the publicly available dataset from the 2019 PhysioNet Challenge. It has around 40,000 Intensive Care Unit (ICU) patients with 40 physiological variables. Using Long Short-Term Memory (LSTM) as the representative black-box machine learning model, we adapted the Multi-set Classifier to globally interpret the black-box model for concepts it learned about sepsis. To identify relevant features, the result is compared against: (i) features used by a computational sepsis expert, (ii) clinical features from clinical collaborators, (iii) academic features from literature, and (iv) significant features from statistical hypothesis testing. Random Forest was found to be the computational sepsis expert because it had high accuracies for solving both the detection and early detection, and a high degree of overlap with clinical and literature features. Using the proposed interpretation mechanism and the dataset, we identified 17 features that the LSTM used for sepsis classification, 11 of which overlaps with the top 20 features from the Random Forest model, 10 with academic features and 5 with clinical features. Clinical opinion suggests, 3 LSTM features have strong correlation with some clinical features that were not identified by the mechanism. We also found that age, chloride ion concentration, pH and oxygen saturation should be investigated further for connection with developing sepsis. Interpretation mechanisms can bolster the incorporation of state-of-the-art machine learning models into clinical decision support systems, and might help clinicians to address the issue of early sepsis detection. The promising results from this study warrants further investigation into creation of new and improvement of existing interpretation mechanisms for black-box models, and into clinical features that are currently not used in clinical assessment of sepsis.

Mechanistic and therapeutic role of Drp1 in the pathogenesis of stroke.

Stroke had emerged as one of the leading causes of death and long-term disability across the globe. Emerging evidence suggests a significant increase in the incidence of stroke with age, which is further expected to increase dramatically owing to an ever-expanding elderly population. The current situation imposes a significant burden on the healthcare system and requires a deeper understanding of the underlying mechanisms and development of novel interventions. It is well established that mitochondrial dysfunction plays a pivotal role in the onset of stroke. Dynamin-related protein 1 (Drp1), is a key regulator of mitochondria fission, and plays a crucial role during the pathogenesis of stroke. Drp1 protein levels significantly increase after stroke potentially in a p38 mitogen-activated protein kinases (MAPK) dependent manner. Protein phosphatase 2A (PP2A) facilitate mitochondrial fission and cell death by dephosphorylating the mitochondrial fission enzyme Drp1 at the inhibitory phosphorylation site serine 637. Outer mitochondrial membrane A-Kinase Anchoring Proteins 1 (AKAP 1) and protein kinase A complex (PKA) complex inhibits Drp1-dependent mitochondrial fission by phosphorylating serine 637. Drp1 activation promotes the release of cytochrome C from mitochondria and therefore leads to apoptosis. In addition, Drp1 activation inhibits mitochondrial glutathione dependent free radical scavenging, which further enhances the ROS level and exacerbate mitochondrial dysfunction. Drp1 translocate p53 to mitochondrial membrane and leads to mitochondria-related necrosis. The current review article discusses the possible mechanistic pathways by which Drp1 can influence the pathogenesis of stroke. Besides, it will describe various inhibitors for Drp1 and their potential role as therapeutics for stroke in the future.

Detection of 10 cases of ceftriaxone-resistant Neisseria gonorrhoeae in the United Kingdom, December 2021 to June 2022.

Between December 2021 and June 2022, 10 cases of ceftriaxone-resistant Neisseria gonorrhoeae (ST8123; n = 8) were detected in the United Kingdom, compared with nine cases during the previous 6 years. Most of these cases were associated with travel from the Asia-Pacific region; all were heterosexual people, with most in their 20s. Although all cases were successfully treated, not all partners of cases could be traced, and there is a risk of further transmission of ceftriaxone-resistant gonococcal infection within the UK.

Evaluating the baseline auscultation abilities of second-year chiropractic students using simulated patients and high-fidelity manikin simulators: A pilot study.

OBJECTIVE: To assess the ability of 2nd-year students to identify normal and abnormal findings during cardiac and lung auscultation using high-fidelity manikin simulators and standardized patients. A secondary objective was to assess students' perceived competence and confidence in their abilities. METHODS: This was a descriptive pilot study of randomly selected 2nd-year students at 1 chiropractic training program. Participants were asked to perform cardiac and lung auscultation on high-fidelity manikins (2 stations) and standardized human patients (2 stations) with normal and abnormal auscultation sounds. Participants described the auscultated sound as "abnormal" or "normal" and were also asked to score their confidence in describing the sound and competence in performing auscultation on a 100-mm visual analog scale. Descriptive statistics were calculated for all study variables. RESULTS: Thirty-two students (23 women and 9 men) were included. For lung auscultation, 15.6% were incorrect on the human subject and 6.2% were incorrect on the manikin. For cardiac auscultation, 62.5% were incorrect on the human subject and 40.6% were incorrect on the manikin. Confidence mean scores ranged from 34.8 to 60. Competence mean scores ranged from 34.8 to 50. CONCLUSION: Results identified that 2nd-year students from 1 institution were correct in identifying an abnormal sound during lung auscultation but reported low levels of perceived competence or confidence in their responses. They performed poorly on cardiac auscultation and reported low perceived confidence and competence in their abilities to perform cardiac auscultation and identify sounds.

Discovery of novel polyamide-pyrrolobenzodiazepine hybrids for antibody-drug conjugates.

Pyrrolobenzodiazepine (PBD) dimers are well-known highly potent antibody drug conjugate (ADC) payloads. The corresponding PBD monomers, in contrast, have received much less attention from the ADC community. We prepared several novel polyamide-linked PBD monomers and evaluated their utility as ADC payloads. The unconjugated polyamide-PBD hybrids exhibited potent antiproliferative activity (IC50 range: 10-11-10-8 M) against a variety of HER2-expressing cancer cell lines. Several peptide-linked variants of the lead compound were prepared and conjugated to trastuzumab to afford ADCs with drug-to-antibody (DAR) ratios ranging from 3 to 5. The ADCs exhibited antigen-dependent cytotoxicity in vitro and potently suppressed tumor xenograft growth in vivo in a target-dependent manner. Moreover, the ADCs were well-tolerated in both mouse and rat. This work demonstrates for the first time that PBD polyamide hybrids can serve as effective ADC payloads.

Characteristics of Forces at the Clinician-Patient and Patient-Table Interfaces During Thoracic Spinal Manipulation in Asymptomatic Adults Are Consistent With Deformable Body Models.

Investigating all forces exerted on the patient's body during high-velocity, low-amplitude spinal manipulative therapy (SMT) remains fundamental to elucidate how these may contribute to SMT's effects. Previous conflicting findings preclude our understanding of the relationship between SMT forces acting at the clinician-patient and patient-table interfaces. This study aimed to quantify forces at the clinician-participant and participant-table interfaces during thoracic SMT in asymptnomatic adults. An experienced clinician provided a posterior to anterior SMT centered to T7 transverse processes using predetermined force-time characteristics to 40 asymptomatic volunteers (20 females; average age = 27.2 [4.9] y). Forces at the clinician-participant interface were recorded by triaxial load cells; whereas, forces at the participant-table interface were recorded by the force-sensing table technology. Preload force, total peak force, time to peak, and loading rate at each interface were analyzed descriptively. Total peak vertical forces at the clinician-participant interface averaged 532 (71) N while total peak forces at the participant-table interface averaged 658 (33) N. Forces at the participant-table interface were, on average, 1.27 (0.25) times larger than the ones at the clinician-participant interface. Larger forces at the participant-table interface compared with the ones at the clinician-participant interface during thoracic SMT are consistent with mathematical models developed to investigate thoracic impact simulating a dynamic force-deflection response.

Mechanistic and therapeutic implications of EphA-4 receptor tyrosine kinase in the pathogenesis of Alzheimer's disease.

Erythropoietin-producing hepatoma (Eph) receptors belong to a family of tyrosine kinase receptors that plays a pivotal role in the development of the brain. Eph can be divided broadly into two groups, namely, EphA and EphB, comprising nine and five members, respectively. In recent years, the role of EphA-4 has become increasingly apparent in the onset of Alzheimer's disease (AD). Emerging evidence suggests that EphA-4 results in synaptic dysfunction, which in turn promotes the progression of AD. Moreover, pharmacological or genetic ablation of EphA-4 in the murine model of AD can alleviate the symptoms. The current review summarizes different pathways by which EphA-4 can influence pathogenesis. Since, majority of the studies had reported the protective effect of EphA-4 inhibition during AD, designing therapeutics based on decreasing its enzymatic activity might be necessary for introducing the novel interventions. Therefore, the review described peptide and nanobodies inhibitors of EphA-4 that exhibit the potential to modulate EphA-4 and could be used as lead molecules for the targeted therapy of AD.

Use of contraceptives and risk of inflammatory bowel disease: a nested case-control study.

BACKGROUND: How contraceptive formulation, dose, duration of therapy and mode of delivery affects the risk of inflammatory bowel disease (IBD) is poorly described. AIM: To examine associations between types of hormonal contraception and development of IBD. METHODS: This was a nested case-control study using IQVIA Medical Research Data. Women aged 15-49 years with a new diagnosis of IBD were matched with up to six controls by age, practice and year. Odds ratios (OR) and 95% confidence intervals (95% CI) for incident IBD and use of contraception were calculated. RESULTS: 4932 incident cases of IBD were matched to 29 340 controls. Use of combined oral contraceptive pills (COCPs) was associated with the development of Crohn's disease and ulcerative colitis (OR 1.60 [1.41-1.82] and 1.30 [1.15-1.45], respectively). Each additional month of COCP exposure per year of follow-up increased risk of Crohn's disease by 6.4% (5.1%-7.7%) and ulcerative colitis by 3.3% (2.1%-4.4%). Progestogen-only pills had no effect on Crohn's disease risk (OR 1.09 [0.84-1.40]) but there was a modest association with ulcerative colitis (OR 1.35 [1.12-1.64]). Parenteral contraception was not associated with the development of Crohn's disease or ulcerative colitis (OR 1.15 [0.99-1.47] and 1.17 [0.98-1.39], respectively). CONCLUSIONS: We observed an increase in the risk of IBD with increasing duration of exposure to COCPs. Progestogen-only pills were not associated with Crohn's disease but there was a modest association with ulcerative colitis. There was no association between parenteral progestogen-only contraception and IBD. These findings are broadly consistent with a hypothesis that the oestrogen component of contraception may drive IBD pathogenesis.

Time trends in contraceptive prescribing in UK primary care 2000-2018: a repeated cross-sectional study.

BACKGROUND: Over the last 20 years, new contraceptive methods became available and incentives to increase contraceptive uptake were introduced. We aimed to describe temporal trends in non-barrier contraceptive prescribing in UK primary care for the period 2000-2018. METHODS: A repeated cross-sectional study using patient data from the IQVIA Medical Research Data (IMRD) database. The proportion (95% CI) of women prescribed non-barrier contraception per year was captured. RESULTS: A total of 2 705 638 women aged 15-49 years were included. Between 2000 and 2018, the proportion of women prescribed combined hormonal contraception (CHC) fell from 26.2% (26.0%-26.3%) to 14.3% (14.2%-14.3%). Prescriptions for progestogen-only pills (POPs) and long-acting reversible contraception (LARC) rose from 4.3% (4.3%-4.4%) to 10.8% (10.7%-10.9%) and 4.2% (4.1%-4.2%) to 6.5% (6.5%-6.6%), respectively. Comparing 2018 data for most deprived versus least deprived areas, women from the most deprived areas were more likely to be prescribed LARC (7.7% (7.5%-7.9%) vs 5.6% (5.4%-5.8%)) while women from the least deprived areas were more likely to be prescribed contraceptive pills (20.8% (21.1%-21.5%) vs 26.2% (26.5%-26.9%)). In 2009, LARC prescriptions increased irrespective of age and social deprivation in line with a pay-for-performance incentive. However, following the incentive's withdrawal in 2014, LARC prescriptions for adolescents aged 15-19 years fell from 6.8% (6.6%-7.0%) in 2013 to 5.6% (5.4%-5.8%) in 2018. CONCLUSIONS: CHC prescribing fell by 46% while POP prescribing more than doubled. The type of contraception prescribed was influenced by social deprivation. Withdrawal of a pay-for-performance incentive may have adversely affected adolescent LARC uptake, highlighting the need for further intervention to target this at-risk group.

Can Donor-Derived Cell-Free DNA Detect Graft-Versus-Host Disease in Solid Organ Transplantation: A Case Report.

Graft-versus-host disease (GVHD) is a rare complication after solid organ transplant. We present a case of GVHD after simultaneous pancreas kidney transplant. The patient was diagnosed with a cutaneous biopsy after developing the classic symptoms of maculopapular rash, diarrhea, and pancytopenia. However, this patient had unexplained elevations in donor-derived cell-free DNA (dd-cfDNA) for months before the onset of GVHD symptoms. We hypothesize that GVHD may be associated with elevated dd-cfDNA as a result of massive donor lymphocyte proliferation and turnover. Further investigation is warranted because earlier diagnosis and treatment could improve outcomes in an otherwise lethal disease.