Evidence for the presence of Borrelia burgdorferi in invasive breast cancer tissues.

Borrelia burgdorferi, the causative agent of Lyme disease, has recently been demonstrated to infect and enhance the invasive properties of breast cancer cells, while also influencing the expression of inflammatory chemokines (CXCL8 and CXCL10). This study investigates the presence of B. burgdorferi in invasive breast cancer tissues using commercially available, FDA-approved breast cancer tissue microarrays consisting of 350 ductal, 32 lobular, and 22 intraductal invasive breast carcinomas, alongside 29 normal breast tissues. Employing fluorescent immunohistochemical staining and high-resolution imaging, the findings revealed that approximately 20% of invasive lobular and ductal carcinomas, followed by 14% of intraductal carcinomas, tested positive for B. burgdorferi, while all normal breast tissues tested negative. PCR analysis further confirmed the presence of B. burgdorferi DNA in breast cancer tissues. Moreover, 25% of B. burgdorferi-positive tissues exhibited expression of both chemokines, CXCL8 and CXCL10, which was not observed in B. burgdorferi-negative tissues. Analysis of available patient data, including age, indicated a correlation between older patients and B. burgdorferi-positive tissues. This study validates the presence of B. burgdorferi in invasive breast cancer tissues and highlights the involvement of key CXCL family members associated with inflammatory processes.

A robust and reliable methodology to perform GECI-based multi-time point neuronal calcium imaging within mixed cultures of human iPSC-derived cortical neurons.

Introduction: Human induced pluripotent stem cells (iPSCs), with their ability to generate human neural cells (astrocytes and neurons) from patients, hold great promise for understanding the pathophysiology of major neuropsychiatric diseases such as schizophrenia and bipolar disorders, which includes alterations in cerebral development. Indeed, the in vitro neurodifferentiation of iPSCs, while recapitulating certain major stages of neurodevelopment in vivo, makes it possible to obtain networks of living human neurons. The culture model presented is particularly attractive within this framework since it involves iPSC-derived neural cells, which more specifically differentiate into cortical neurons of diverse types (in particular glutamatergic and GABAergic) and astrocytes. However, these in vitro neuronal networks, which may be heterogeneous in their degree of differentiation, remain challenging to bring to an appropriate level of maturation. It is therefore necessary to develop tools capable of analyzing a large number of cells to assess this maturation process. Calcium (Ca2+) imaging, which has been extensively developed, undoubtedly offers an incredibly good approach, particularly in its versions using genetically encoded calcium indicators. However, in the context of these iPSC-derived neural cell cultures, there is a lack of studies that propose Ca2+ imaging methods that can finely characterize the evolution of neuronal maturation during the neurodifferentiation process. Methods: In this study, we propose a robust and reliable method for specifically measuring neuronal activity at two different time points of the neurodifferentiation process in such human neural cultures. To this end, we have developed a specific Ca2+ signal analysis procedure and tested a series of different AAV serotypes to obtain expression levels of GCaMP6f under the control of the neuron-specific human synapsin1 (hSyn) promoter. Results: The retro serotype has been found to be the most efficient in driving the expression of the GCaMP6f and is compatible with multi-time point neuronal Ca2+ imaging in our human iPSC-derived neural cultures. An AAV2/retro carrying GCaMP6f under the hSyn promoter (AAV2/retro-hSyn-GCaMP6f) is an efficient vector that we have identified. To establish the method, calcium measurements were carried out at two time points in the neurodifferentiation process with both hSyn and CAG promoters, the latter being known to provide high transient gene expression across various cell types. Discussion: Our results stress that this methodology involving AAV2/retro-hSyn-GCaMP6f is suitable for specifically measuring neuronal calcium activities over multiple time points and is compatible with the neurodifferentiation process in our mixed human neural cultures.

Global transcriptomic analysis of breast cancer and normal mammary epithelial cells infected with Borrelia burgdorferi.

The bacterial spirochete Borrelia burgdorferi, the causative agent of Lyme Disease, can disseminate and colonize various tissues and organs, orchestrating severe clinical symptoms including arthritis, carditis, and neuroborreliosis. Previous research has demonstrated that breast cancer tissues could provide an ideal habitat for diverse populations of bacteria, including B. burgdorferi, which is associated with a poor prognosis. Recently, we demonstrated that infection with B. burgdorferi enhances the invasion and migration of triple-negative MDA-MB-231 cells which represent a type of breast tumor with more aggressive cancer traits. In this study, we hypothesized that infection by B. burgdorferi affects the expression of cancer-associated genes to effectuate breast cancer phenotypes. We applied the high-throughput technique of RNA-sequencing on B. burgdorferi-infected MDA-MB-231 breast cancer and normal-like MCF10A cells to determine the most differentially expressed genes (DEG) upon infection. Overall, 142 DEGs were identified between uninfected and infected samples in MDA-MB-231 while 95 DEGs were found in MCF10A cells. A major trend of the upregulation of C-X-C and C-C motif chemokine family members as well as genes and pathways was associated with infection, inflammation, and cancer. These genes could serve as potential biomarkers for pathogen-related tumorigenesis and cancer progression which could lead to new therapeutic opportunities.

Investigating the Influence of Aromatic Counterions on the Micellar Structure and Aggregation Behavior of Morpholinium-Based Surface-Active Ionic Liquids in an Aqueous Solution.

Two morpholinium-based surface-active ionic liquids (SAILs) with aromatic counterions were synthesized, namely, n-dodecyl-n-methylmorpholinium salicylate [C12mmor][Sal] and n-dodecyl-n-methylmorpholinium 3-hydroxy-2-naphthoate [C12mmor][3-h-2-n], and explored their aggregation behavior in aqueous solutions systematically. Electrical conductivity, small-angle neutron scattering (SANS), surface tension (ST), and UV-vis spectroscopy measurements were employed to determine various thermodynamic, micellar, and interfacial parameters, like the degree of counterion binding (ß), critical micelle concentration (CMC), minimum area per molecule (Amin), surface excess concentration (Γmax), standard Gibbs free energy of adsorption (ΔGad0), aggregation number (Nagg), standard Gibbs free energy of micellization (ΔGm0), standard enthalpy of micelle formation (ΔHm0), and the standard entropy of micellization (ΔSm0) in an aqueous solution. Incorporating the aromatic counterions favors significantly excellent micellization properties over conventional halogenated SAILs such as [C12mmor][Br]. SANS analysis revealed that upon changing the counterion from salicylate to 3-hydroxy-2-naphthoate, the structure changed from prolate ellipsoidal micelles to large unilamellar vesicles. Also, increasing the concentration in the case of [C12mmor][Sal] resulted in a lower aggregation number.

Safety and Efficacy of Hizentra® Following Pediatric Hematopoietic Cell Transplant for Treatment of Primary Immunodeficiencies.

Primary immunodeficiency disease (PIDD) comprises a group of disorders of immune function. Some of the most severe PIDD can be treated with hematopoietic cell transplant (HCT). Hizentra® is a 20% liquid IgG product approved for subcutaneous administration in adults and children greater than 2 years of age with PIDD-associated antibody deficiency. Limited information is available on the use of Hizentra® in children following HCT for PIDD. A multicenter retrospective chart review demonstrated 37 infants and children (median age 70.1 [range 12.0 to 176.4] months) with PIDD treated by HCT who received Hizentra® infusions over a median duration of 31 (range 4-96) months post-transplant. The most common indication for HCT was IL2RG SCID (n = 16). Thirty-two patients switched from IVIG to SCIG administration, due to one or more of the following reasons: patient/caregiver (n = 17) or physician (n = 12) preference, discontinuation of central venous catheter (n = 16), desire for home infusion (n = 12), improved IgG serum levels following lower levels on IVIG (n = 10), and loss of venous access (n = 8). Serious bacterial infections occurred at a rate of 0.041 per patient-year while on therapy. Weight percentile increased by a mean of 16% during the observation period, with females demonstrating the largest gains. Mild local reactions were observed in 24%; 76% had no local reactions. One serious adverse event (death from sepsis) was reported. Hizentra® was discontinued in 15 (41%) patients, most commonly due to recovery of B cell function (n = 11). These data demonstrate that Hizentra® is a safe and effective option in children who have received HCT for PIDD.

Symptomatic Gastric Sarcoidosis in a Patient with Pulmonary and Neurosarcoidosis: A Case Report.

BACKGROUND Sarcoidosis is an inflammatory condition with multisystem involvement of unknown etiology that is characterized by noncaseating granulomas. Gastrointestinal (GI) involvement of sarcoidosis is not commonly seen in patients with extrapulmonary disease but can result in luminal narrowing, ulceration, and, less commonly, bleeding and obstruction. Patients that present with symptomatic gastric sarcoidosis are extremely rare. Definitive diagnosis can be challenging due to the need for endoscopic biopsy, which may not be performed if the diagnosis is not considered. Biopsy may be falsely negative due to the patchy mucosal involvement of this disease. CASE REPORT This case describes a 38-year-old mixed-race man who presented to the Emergency Department with GI symptoms including nausea, vomiting, and abdominal pain, which persisted after being recently discharged from an outside hospital. The patient had a known history of multisystem sarcoid including pulmonary and neurosarcoidosis, and was maintained on immunosuppressive therapy. The patient underwent upper endoscopy with biopsy confirming a new diagnosis of gastric sarcoidosis. CONCLUSIONS There is an important role for early endoscopy in the diagnosis of patients with symptomatic gastric sarcoidosis to facilitate early treatment initiation and escalation or titration of immunosuppressive therapy, especially in patients with a known history of sarcoidosis with extrapulmonary involvement. The described endoscopic appearance of gastric sarcoidosis is variable in the published literature; endoscopic biopsy is therefore essential to diagnosing this disease. This type of disease progression should be considered in all sarcoid patients with persistent GI symptoms that do not resolve with conservative management, including those who are already on established immunosuppressive therapy.

Systemic IgG exposure and safety in patients with primary immunodeficiency: a randomized crossover study comparing a novel investigational wearable infusor versus the Crono pump.

Aim: A novel, Investigational Wearable Infusor (IWI) was evaluated in a randomized, controlled, crossover, open-label study to determine if its delivery of subcutaneous immunoglobulin (IgPro20) achieved a comparable area under the concentration-time curve (AUC) for immunoglobulin G (IgG) versus the Crono S-PID-50 infusion pump (CP). EudraCT: 2016-003798-16. Materials & methods: Patients with primary immunodeficiency (PID) were randomized to receive IgPro20 in Sequence 1 (CP/IWI) or 2 (IWI/CP). The primary end point was AUC for IgG during the final week of each 4-week period. Results: 23 patients were enrolled. Evaluation of area under the concentration-time curve from time 0 (pre-infusion) to 7 days after infusion (AUC0-7 days) (IWI: 1806 h*g/l; CP: 1829 h*g/l) and geometric mean ratio indicated comparable AUCs for IgG for both devices. Conclusion: Similar IgG exposure, indicated by AUC values, can be achieved with IgPro20 using the IWI or CP in PID.

Patients with primary immunodeficiency (PID) are at a higher risk of developing serious infections than healthy individuals. Immunoglobulin G (IgG) replacement therapy reduces this risk, as it raises a patient's antibody levels to help fight off infections. IgG replacement therapy can be performed as an intravenous or subcutaneous (under the skin) infusion. The subcutaneous route is associated with improved quality of life for patients, as therapy can be carried out at home by the patient, allowing for more flexibility, convenience and autonomy. Wearable drug-delivery systems are devices that stick to the body and automatically deliver doses of a drug to the patient. In this study, we investigated whether a novel Investigational Wearable Infusor device could deliver the subcutaneous IgG replacement therapy, IgPro20, in patients with PID. We show that the new infusion device can deliver IgG replacement therapy and allows for similar levels of IgG to be achieved in patients as a comparator device. This wearable drug delivery device simplifies drug administration and could help address some of the challenges associated with self-injection such as complicated infusion preparation, needle phobia and concerns about pain. Trial Registration Number: 2016-003798-16 (EudraCT).

Synthesis, Self-Aggregation, Surface Characteristics, Electrochemical Property, Micelle Size, and Antimicrobial Activity of a Halogen-Free Picoline-Based Surface-Active Ionic Liquid.

We present a new approach toward the design of a halogen-free picoline-based surface-active ionic liquid (SAIL) (1-octyl-4-methyl pyridinium dodecyl sulfate) [C8γPic]DS consisting of long dodecyl sulfate (DS) as an anion. The surface properties, micellization behavior, and antimicrobial activity in an aqueous solution were investigated using tensiometry, conductometry, and ultraviolet (UV) spectroscopy. Incorporating the DS group in SAIL leads to lower critical micellar concentration (CMC) and enhanced adsorption at the air/water interface of the functionalized ionic liquid compared to the C8-alkyl chain-substituted pyridine ionic liquids. The antimicrobial activity was evaluated against a representative Gram-negative and Gram-positive bacteria panel. Antibacterial activities increased with the alkyl chain length, C8 being the homologous most effective antimicrobial agent. The micelle size of [C8γPic]DS was determined by the dynamic light-scattering (DLS) study. Cyclic voltammetry (CV) measurements have been employed to evaluate the interaction between the SAIL micelle and working electrode, diffusion coefficient, and micelle size of the SAIL solution. The diffusion coefficient explored the correlation of surface properties and the antimicrobial activity of [C8γPic]DS. This halogen-free SAIL is the future of wetting agents and emulsion studies in agriculture due to its small micelle size and surface characteristics.

RAVIR: A Dataset and Methodology for the Semantic Segmentation and Quantitative Analysis of Retinal Arteries and Veins in Infrared Reflectance Imaging.

The retinal vasculature provides important clues in the diagnosis and monitoring of systemic diseases including hypertension and diabetes. The microvascular system is of primary involvement in such conditions, and the retina is the only anatomical site where the microvasculature can be directly observed. The objective assessment of retinal vessels has long been considered a surrogate biomarker for systemic vascular diseases, and with recent advancements in retinal imaging and computer vision technologies, this topic has become the subject of renewed attention. In this paper, we present a novel dataset, dubbed RAVIR, for the semantic segmentation of Retinal Arteries and Veins in Infrared Reflectance (IR) imaging. It enables the creation of deep learning-based models that distinguish extracted vessel type without extensive post-processing. We propose a novel deep learning-based methodology, denoted as SegRAVIR, for the semantic segmentation of retinal arteries and veins and the quantitative measurement of the widths of segmented vessels. Our extensive experiments validate the effectiveness of SegRAVIR and demonstrate its superior performance in comparison to state-of-the-art models. Additionally, we propose a knowledge distillation framework for the domain adaptation of RAVIR pretrained networks on color images. We demonstrate that our pretraining procedure yields new state-of-the-art benchmarks on the DRIVE, STARE, and CHASE_DB1 datasets. Dataset link: https://ravirdataset.github.io/data.

Incidence of Sudden Cardiac Arrest and Death in Young Athletes and Military Members: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate the quality of the evidence on the incidence of sudden cardiac arrest (SCA) and sudden cardiac death (SCD) in athletes and military members and estimate the annual incidence of SCA and SCD. DATA SOURCES: We searched MEDLINE, Embase, Cochrane CENTRAL, Web of Science, BIOSIS, Scopus, SPORTDiscus, PEDro, and ClinicalTrials.gov from inception to dates between February 21 and July 29, 2019. STUDY SELECTION: Studies in which the incidence of SCA, SCD, or both in athletes or military members aged <40 years was reported were eligible for inclusion. We identified 40 studies for inclusion. DATA EXTRACTION: Risk of bias (ROB) was assessed using a validated, customized tool for prevalence studies. Twelve had a low ROB, while the remaining 28 had a moderate or high ROB. Data were extracted for narrative review and meta-analysis. DATA SYNTHESIS: Random-effects meta-analysis was performed in studies judged to have a low ROB in 2 categories: (1) 5 studies of regional- or national-level data, including athletes at all levels and both sexes, demonstrated 130 SCD events with a total of 11 272 560 athlete-years, showing a cumulative incidence rate of 0.98 (95% CI = 0.62, 1.53) per 100 000 athlete-years and high heterogeneity (I2 = 78%) and (2) 3 studies of competitive athletes aged 14 to 25 years were combined for a total of 183 events and 17 798 758 athlete-years, showing an incidence rate of 1.91 (95% CI = 0.71, 5.14) per 100 000 athlete-years and high heterogeneity (I2 = 97%). The remaining low-ROB studies involved military members and were not synthesized. CONCLUSIONS: The worldwide incidence of SCD is rare. Low-ROB studies indicated the incidence was <2 per 100 000 athlete-years. Overall, the quality of the available evidence was low, but high-quality individual studies inform the question of incidence levels. PROSPERO REGISTRATION: CRD42019125560.

Screening Electrocardiogram in Young Athletes and Military Members: A Systematic Review and Meta-Analysis.

OBJECTIVE: To determine the effect of electrocardiogram (ECG) screening on the prevention of sudden cardiac arrest and death in young athletes and military members. DATA SOURCES: MEDLINE, Embase, CENTRAL, Web of Science, BIOSIS, Scopus, SPORTDiscus, PEDro, and ClinicalTrials.gov were searched from inception to dates between February 21 and July 29, 2019. STUDY SELECTION: Randomized and nonrandomized controlled trials in which preparticipation examination including ECG was the primary intervention used to screen athletes or military members aged ≤40 years. Acceptable control groups were those receiving no screening, usual care, or preparticipation examination without ECG. Three published studies and 1 conference abstract were identified for inclusion. DATA EXTRACTION: In all 4 studies, risk of bias was assessed using the Cochrane risk-of-bias tool and was found to be generally high. Two studies had data extracted for random effects meta-analysis, and the remaining study and conference abstract were included in the narrative review. The overall quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation approach. DATA SYNTHESIS: We included 4 nonrandomized studies (11 689 172 participants), of which all had a high risk of bias. Pooled data from 2 studies (n = 3 869 274; very low-quality evidence) showed an inconclusive 42% relative decrease in risk of sudden cardiac death (relative risk = 0.58; 95% CI = 0.23, 1.45), equating to an absolute risk reduction of 0.0016%. The findings were consistent with a potential 77% relative decreased risk to a 45% relative increased risk in participants screened using ECG. Heterogeneity was found to be high, as measured using I2 statistic (71%). Data from the remaining study and abstract were similarly inconclusive. CONCLUSIONS: Existing evidence for the effect of ECG screening is inconclusive and of very low quality. In our meta-analysis, we observed that screening ECG may result in a considerable benefit or harm to participants. Higher-quality studies are needed to reduce this uncertainty.

High risk of relapsed disease in patients with NK/T-cell chronic active Epstein-Barr virus disease outside of Asia.

Chronic active Epstein-Barr virus (EBV) disease (CAEBV) is characterized by high levels of EBV predominantly in T and/or natural killer cells with lymphoproliferation, organ failure due to infiltration of tissues with virus-infected cells, hemophagocytic lymphohistiocytosis, and/or lymphoma. The disease is more common in Asia than in the United States and Europe. Although allogeneic hematopoietic stem cell transplantation (HSCT) is considered the only curative therapy for CAEBV, its efficacy and the best treatment modality to reduce disease severity prior to HSCT is unknown. Here, we retrospectively assessed an international cohort of 57 patients outside of Asia. Treatment of the disease varied widely, although most patients ultimately proceeded to HSCT. Though patients undergoing HSCT had better survival than those who did not (55% vs 25%, P < .01), there was still a high rate of death in both groups. Mortality was largely not affected by age, ethnicity, cell-type involvement, or disease complications, but development of lymphoma showed a trend with increased mortality (56% vs 35%, P = .1). The overwhelming majority (75%) of patients who died after HSCT succumbed to relapsed disease. CAEBV remains challenging to treat when advanced disease is present. Outcomes would likely improve with better disease control strategies, earlier referral for HSCT, and close follow-up after HSCT including aggressive management of rising EBV DNA levels in the blood.

Cost Effectiveness of Cognitive Behavioral Therapy for the Treatment of Subjective Tinnitus in Australia.

OBJECTIVES: The aim of this study was to conduct an economic evaluation for the treatment of subjective tinnitus using different modalities of cognitive behavioral therapy (CBT) in Australia. DESIGN: A decision tree model was used to conduct a cost-utility analysis for CBT to determine the cost effectiveness for tinnitus treatments, in terms of cost per responder and cost per quality-adjusted life-year (QALY), from a health system perspective using a 2-year time horizon. Meta-analysis was used to differentiate the levels of effectiveness between three delivery methods for CBT: individual face-to-face care (fCBT), group sessions (gCBT), and a supported internet program (iCBT). One-way sensitivity analysis and probabilistic sensitivity analysis (PSA) explored the uncertainty surrounding model inputs and outcomes. Results were presented as incremental cost-effectiveness ratios compared with no treatment, and as net monetary benefit at a $50,000 willingness-to-pay threshold. RESULTS: Compared with no treatment, the incremental cost per responder was $700 for gCBT, $871 for iCBT, and $1380 for fCBT. The base case incremental cost-effectiveness ratio was $35,363 per QALY for fCBT, $17,935 per QALY for gCBT, and $22,321 per QALY for iCBT compared with no treatment, although there was substantial uncertainty around the QALY gain for responders. Net monetary benefit was $356 (fCBT), $555 (gCBT), and $487 (iCBT), indicating the treatments were cost effective compared with no treatment. One-way sensitivity analysis revealed the results were most sensitive to the probability of a positive response to treatment and treatment length. The PSA found the probability of being cost effective compared with no treatment for gCBT was 99.8%, iCBT 98.4%, and fCBT 71.5% at a willingness-to-pay of $50,000 per QALY, although QALY gain remained at a fixed value in the PSA. CONCLUSIONS: CBT for tinnitus was likely to be cost effective compared with no treatment regardless of treatment modality, assuming they are not mutually exclusive. Of the interventions, gCBT was the lowest cost per responder and lowest cost per QALY. Internet CBT obtained comparable economic outcomes due to similar treatment effectiveness and cost. Group CBT and iCBT warrant greater adoption in clinical practice for the treatment of subjective tinnitus. Further research on preference-based utility measures for varying levels of tinnitus severity and the durability of treatment effect is required to enhance the quality of economic evaluation in this field.

Hepatotoxicity Secondary to Levofloxacin Use.

Levofloxacin is a broad-spectrum antibiotic that is used in the treatment of many infections. A rare adverse drug reaction following the use of levofloxacin is drug-induced liver injury. The exact mechanism behind fluoroquinolone-induced liver injury is unknown, but many severe, sometimes fatal hepatotoxicity cases are reported. Current recommendations advise clinicians to discontinue levofloxacin immediately if the patient develops signs and symptoms of hepatitis. This case report presents a 79-year-old male who was prescribed levofloxacin 500 mg by mouth daily for seven days. The patient had a past medical history of dementia, seizures, cerebral vascular accident, pulmonary fibrosis, and chronic kidney disease. Upon admission, the patient began to show signs and symptoms of liver injury. We hereby present a case report and a review of significant literature on levofloxacin-induced liver injury.

Subcutaneous Immunoglobulin Therapy with IgPro20 in Patients with Stiff Person Syndrome and Primary Immunodeficiency Disease.

Stiff Person Syndrome (SPS), a rare autoimmune neurologic disorder characterized by fluctuating muscle spasms and rigidity, is mediated by autoantibodies to glutamic acid decarboxylase (GAD) antibodies. Symptoms of SPS have been shown to improve after administration of intravenous immunoglobulin (IVIG) however, there is a paucity of information regarding use of SCIg in SPS. Four patients with Stiff Person Syndrome were treated with SCIgPro20 for a period between 31 to 101 months. Most reactions were local and mild. All patients reported improvement in spasticity, and 2 patients reported improvement in seizure frequency. SCIgPro20 was well tolerated in patients with SPS and was associated with improvement in symptoms.

Prescribing in Type 2 Diabetes Patients With and Without Cardiovascular Disease History: A Descriptive Analysis in the UK CPRD.

PURPOSE: Some classes of glucose-lowering medications, including sodium-glucose co-transporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1-receptor agonists (GLP1-RAs) have cardio-protective benefit, but it is unclear whether this influences prescribing in the United Kingdom (UK). This study aims to describe class-level prescribing in adults with type 2 diabetes mellitus (T2DM) by cardiovascular disease (CVD) history using the Clinical Practice Research Datalink (CPRD). METHODS: Four cross-sections of people with T2DM aged 18-90 and registered with their general practice for >1 year on 1st January 2017 (n = 166,012), 1st January 2018 (n = 155,290), 1st January 2019 (n = 152,602) and 31st December 2019 (n = 143,373) were identified. Age-standardised proportions for class use through time were calculated separately in those with and without CVD history and by total number of medications prescribed (one, two, three, four+). An analysis by UK country was also performed. FINDINGS: Around 31% of patients had CVD history at each cross-section. Metformin was the most common treatment (>70% of those with and without CVD had prescriptions across all treatment lines). Overall use of SGLT2is and GLP1-RAs was low, with slightly less use in patients with CVD (SGLT2i: 9.8% and 13.8% in those with and without CVD respectively; GLP1-RA: 4.3% and 4.9%, December 2019). Use of SGLT2is as part of dual therapy was low but rose throughout the study. In January 2017, estimated use was 8.0% (95% CI 6.9-9.1%) and 8.9% (8.6-9.3%) in those with and without CVD. By December 2019 this reached 18.3% (17.0-19.5%) and 21.2% (20.6-21.7%) for those with and without CVD respectively. SGLT2i use as triple therapy increased: 22.7% (21.0-24.4%) and 25.9% (25.2-26.6%) in January 2017 to 41.3% (39.5-43.0%) and 45.5% (44.7-46.3%) in December 2019. GLP1-RA use also increased, but observed usage remained lower than SGLT2 inhibitors. Insulin use remained stable throughout, with higher use observed in those with CVD (16% vs 9.7% Dec 2019). Time trends in England, Wales, Scotland and Northern Ireland were similar, although class prevalence varied. IMPLICATIONS: Although use of SGLT2is and GLP1-RAs has increased, overall usage remains low with slightly lower use in those with CVD history, suggesting there is opportunity to optimise use of these medicines in T2DM patients to manage CVD risk. Insulin use was substantially more prevalent in those with CVD despite no evidence of CVD benefit. Further investigation of factors influencing this finding may highlight strategies to improve patient access to the most appropriate treatments, including those with evidence of cardiovascular benefit.

Safety and Tolerability of Subcutaneous IgPro20 at High Infusion Parameters in Patients with Primary Immunodeficiency: Findings from the Pump-Assisted Administration Cohorts of the HILO Study.

PURPOSE: To evaluate the safety and tolerability of subcutaneous IgPro20 (Hizentra®, CSL Behring, King of Prussia, PA, USA) administered at high infusion parameters (> 25 mL and > 25 mL/h per injection site) in patients with primary immunodeficiency. METHODS: The Hizentra® Label Optimization (HILO) study was an open-label, parallel-arm, non-randomized study (NCT03033745) of IgPro20 using a forced upward titration design for infusion parameters. Patients experienced with pump-assisted IgPro20 infusions received weekly IgPro20 infusions at a stable dose in the Pump-Assisted Volume Cohort (N = 15; 25-50 mL per injection site) and in the Pump-Assisted Flow Rate Cohort (N = 18; 25-100 mL/h per injection site). Responder rates (percentage of patients who successfully completed ≥ 75% of planned infusions), safety outcomes, and serum immunoglobulin G (IgG) trough levels were evaluated. RESULTS: Responder rates were 86.7% (13/15, 25 mL) and 73.3% (11/15, 40 and 50 mL) in the Volume Cohort, and 77.8% (14/18, 25 and 50 mL/h), 66.7% (12/18, 75 mL/h), and 61.1% (11/18, 100 mL/h) in the Flow Rate Cohort. Infusion compliance was ≥ 90% in all patients in the Volume Cohort and in 83.3% of patients in the Flow Rate Cohort. The number of injection sites (Volume Cohort) and the infusion duration (Flow Rate Cohort) decreased with increasing infusion parameters. The rate of treatment-emergent adverse events per infusion was low (0.138 [Volume Cohort] and 0.216 [Flow Rate Cohort]). Serum IgG levels remained stable during the study. CONCLUSION: Pump-assisted IgPro20 infusions are feasible at 50 mL and 100 mL/h per injection site in treatment-experienced patients, which may result in fewer injection sites and shorter infusion times. TRIAL REGISTRATION: NCT03033745 ; registered January 27, 2017.

Hemophagocytic Lymphohistiocytosis in Langerhans Cell Histiocytosis: A Case Report and Review of the Literature.

A toddler undergoing treatment for refractory Langerhans cell histiocytosis (LCH) developed concurrent hemophagocytic lymphohistiocytosis (HLH). These are thought to be distinct histiocytic disorders, with different pathophysiologies, diagnostic criteria, and treatments. HLH in a patient with LCH is thought to be quite rare. In this report, we review the presentation of our patient, as well as review the existing literature of other pediatric patients who have been diagnosed with both LCH and HLH.