A practical evidence-based approach to management of type 2 diabetes in children and young people (CYP): UK consensus.

BACKGROUND: Type 2 diabetes in young people is an aggressive disease with a greater risk of complications leading to increased morbidity and mortality during the most productive years of life. Prevalence in the UK and globally is rising yet experience in managing this condition is limited. There are no consensus guidelines in the UK for the assessment and management of paediatric type 2 diabetes. METHODS: Multidisciplinary professionals from The Association of Children's Diabetes Clinicians (ACDC) and the National Type 2 Diabetes Working Group reviewed the evidence base and made recommendations using the Grading Of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. RESULTS AND DISCUSSION: Young people with type 2 diabetes should be managed within a paediatric diabetes team with close working with adult diabetes specialists, primary care and other paediatric specialties. Diagnosis of diabetes type can be challenging with many overlapping features. Diabetes antibodies may be needed to aid diagnosis. Co-morbidities and complications are frequently present at diagnosis and should be managed holistically. Lifestyle change and metformin are the mainstay of early treatment, with some needing additional basal insulin. GLP1 agonists should be used as second-line agents once early ketosis and symptoms are controlled. Glycaemic control improves microvascular but not cardiovascular risk. Reduction in excess adiposity, smoking prevention, increased physical activity and reduction of hypertension and dyslipidaemia are essential to reduce major adverse cardiovascular events. CONCLUSIONS: This evidence-based guideline aims to provide a practical approach in managing this condition in the UK.

In situ polymer gelation in confined flow controls intermittent dynamics.

Polymer flows through pores, nozzles and other small channels govern engineered and naturally occurring dynamics in many processes, from 3D printing to oil recovery in the earth's subsurface to a wide variety of biological flows. The crosslinking of polymers can change their material properties dramatically, and it is advantageous to know a priori whether or not crosslinking polymers will lead to clogged channels or cessation of flow. In this study, we investigate the flow of a common biopolymer, alginate, while it undergoes crosslinking by the addition of a crosslinker, calcium, driven through a microfluidic channel at constant flow rate. We map the boundaries defining complete clogging and flow as a function of flow rate, polymer concentration, and crosslinker concentration. Interestingly, the boundaries of the dynamic behavior qualitatively match the thermodynamic jamming phase diagram of attractive colloidal particles. That is, polymer clogging occurs in a region analogous to colloids in a jammed state, while the polymer flows in regions corresponding to colloids in a liquid phase. However, between the dynamic regimes of complete clogging and unrestricted flow, we observe a remarkable phenomenon in which the crosslinked polymer intermittently clogs the channel. This pattern of deposition and removal of a crosslinked gel is simultaneously highly reproducible, long-lasting, and controllable by system parameters. Higher concentrations of polymer and cross-linker result in more frequent ablation, while gels formed at lower component concentrations ablate less frequently. Upon ablation, the eluted gel maintains its shape, resulting in micro-rods several hundred microns long. Our results suggest both rich dynamics of intermittent flows in crosslinking polymers and the ability to control them.

Measurement of the Positive Muon Anomalous Magnetic Moment to 0.20 ppm.

We present a new measurement of the positive muon magnetic anomaly, a_{µ}≡(g_{µ}-2)/2, from the Fermilab Muon g-2 Experiment using data collected in 2019 and 2020. We have analyzed more than 4 times the number of positrons from muon decay than in our previous result from 2018 data. The systematic error is reduced by more than a factor of 2 due to better running conditions, a more stable beam, and improved knowledge of the magnetic field weighted by the muon distribution, ω[over ˜]_{p}^{'}, and of the anomalous precession frequency corrected for beam dynamics effects, ω_{a}. From the ratio ω_{a}/ω[over ˜]_{p}^{'}, together with precisely determined external parameters, we determine a_{µ}=116 592 057(25)×10^{-11} (0.21 ppm). Combining this result with our previous result from the 2018 data, we obtain a_{µ}(FNAL)=116 592 055(24)×10^{-11} (0.20 ppm). The new experimental world average is a_{µ}(exp)=116 592 059(22)×10^{-11} (0.19 ppm), which represents a factor of 2 improvement in precision.

Pediatric Trauma and Posttraumatic Symptom Screening at Well-child Visits.

Adverse childhood experiences (ACEs), including abuse or neglect, parental substance abuse, mental illness, or separation, are public health crises that require identification and response. We aimed to increase annual rates of trauma screening during well-child visits from 0% to 70%, post-traumatic stress disorder (PTSD) symptom screening for children with identified trauma from 0% to 30%, and connection to behavioral health for children with symptoms from 0% to 60%. Methods: Our interdisciplinary behavioral and medical health team implemented 3 plan-do-study-act cycles to improve screening and response to pediatric traumatic experiences. Automated reports and chart reviews measured progress toward goals as we changed screening methods and provider training. Results: During plan-do-study-act cycle 1, a chart review of patients with positive trauma screenings identified various trauma types. During cycle 2, a comparison of screening methods demonstrated that written screening identified trauma among more children than verbal screening (8.3% versus 1.7%). During cycle 3, practices completed trauma screenings at 25,287 (89.8%) well-child visits. Among screenings, 2,441 (9.7%) identified trauma. The abbreviated Post Traumatic Stress Disorder Reaction Index was conducted at 907 (37.2%) encounters and identified 520 children (57.3%) with PTSD symptoms. Among a sample of 250, 26.4% were referred to behavioral health, 43.2% were already connected, and 30.4% had no connection. Conclusions: It is feasible to screen and respond to trauma during well-child visits. Screening method and training implementation changes can improve screening and response to pediatric trauma and PTSD. Further work is needed to increase rates of PTSD symptomology screening and connection to behavioral health.

Probing the Degree of Coherence through the Full 1D to 3D Crossover.

We experimentally study a gas of quantum degenerate ^{87}Rb atoms throughout the full dimensional crossover, from a one-dimensional (1D) system exhibiting phase fluctuations consistent with 1D theory to a three-dimensional (3D) phase-coherent system, thereby smoothly interpolating between these distinct, well-understood regimes. Using a hybrid trapping architecture combining an atom chip with a printed circuit board, we continuously adjust the system's dimensionality over a wide range while measuring the phase fluctuations through the power spectrum of density ripples in time-of-flight expansion. Our measurements confirm that the chemical potential µ controls the departure of the system from 3D and that the fluctuations are dependent on both µ and the temperature T. Through a rigorous study we quantitatively observe how inside the crossover the dependence on T gradually disappears as the system becomes 3D. Throughout the entire crossover the fluctuations are shown to be determined by the relative occupation of 1D axial collective excitations.

Development and Preclinical Evaluation of New Inhaled Lipoglycopeptides for the Treatment of Persistent Pulmonary Methicillin-Resistant Staphylococcus aureus Infections.

Chronic pulmonary methicillin-resistant Staphylococcus aureus (MRSA) disease in cystic fibrosis (CF) has a high probability of recurrence following treatment with standard-of-care antibiotics and represents an area of unmet need associated with reduced life expectancy. We developed a lipoglycopeptide therapy customized for pulmonary delivery that not only demonstrates potent activity against planktonic MRSA, but also against protected colonies of MRSA in biofilms and within cells, the latter of which have been linked to clinical antibiotic failure. A library of next-generation potent lipoglycopeptides was synthesized with an emphasis on attaining superior pharmacokinetics (PK) and pharmacodynamics to similar compounds of their class. Our strategy focused on hydrophobic modification of vancomycin, where ester and amide functionality were included with carbonyl configuration and alkyl length as key variables. Candidates representative of each carbonyl attachment chemistry demonstrated potent activity in vitro, with several compounds being 30 to 60 times more potent than vancomycin. Selected compounds were advanced into in vivo nose-only inhalation PK evaluations in rats, where RV94, a potent lipoglycopeptide that utilizes an inverted amide linker to attach a 10-carbon chain to vancomycin, demonstrated the most favorable lung residence time after inhalation. Further in vitro evaluation of RV94 showed superior activity to vancomycin against an expanded panel of Gram-positive organisms, cellular accumulation and efficacy against intracellular MRSA, and MRSA biofilm killing. Moreover, in vivo efficacy of inhaled nebulized RV94 in a 48 h acute model of pulmonary MRSA (USA300) infection in neutropenic rats demonstrated statistically significant antibacterial activity that was superior to inhaled vancomycin.

Measurement of the Positive Muon Anomalous Magnetic Moment to 0.46 ppm.

We present the first results of the Fermilab National Accelerator Laboratory (FNAL) Muon g-2 Experiment for the positive muon magnetic anomaly a_{µ}≡(g_{µ}-2)/2. The anomaly is determined from the precision measurements of two angular frequencies. Intensity variation of high-energy positrons from muon decays directly encodes the difference frequency ω_{a} between the spin-precession and cyclotron frequencies for polarized muons in a magnetic storage ring. The storage ring magnetic field is measured using nuclear magnetic resonance probes calibrated in terms of the equivalent proton spin precession frequency ω[over ˜]_{p}^{'} in a spherical water sample at 34.7 °C. The ratio ω_{a}/ω[over ˜]_{p}^{'}, together with known fundamental constants, determines a_{µ}(FNAL)=116 592 040(54)×10^{-11} (0.46 ppm). The result is 3.3 standard deviations greater than the standard model prediction and is in excellent agreement with the previous Brookhaven National Laboratory (BNL) E821 measurement. After combination with previous measurements of both µ^{+} and µ^{-}, the new experimental average of a_{µ}(Exp)=116 592 061(41)×10^{-11} (0.35 ppm) increases the tension between experiment and theory to 4.2 standard deviations.

Teleneurology-Enabled Determination of Death by Neurologic Criteria After Cardiac Arrest or Severe Neurologic Injury.

OBJECTIVE: To determine whether providing teleneurology (TN) consultations aiding in determination of death by neurologic criteria (DNC) to a bedside intensivist is feasible and whether timely access and expert input increase the quality of the DNC examination and identification of potential organ donors, we reviewed retrospective data related to outcomes of such consultations. METHODS: Between November 2017 and March 2019, TN consults were requested for sequential comatose patients in the intensive care unit (ICU). We recorded patients' demographic information, causes leading to coma or suspected DNC, and the results of TN consultations. We obtained data on the number of referrals to the organ bank and number of organ donors. RESULTS: Ninety-nine consults were performed with a median time from request to start of the consult of 20.2 minutes (interquartile range 5.4-65.3 minutes). Eighty consults were requested for determination of prognosis, whereas 19 consults were requested for supervision of the DNC examination. In 1 of 80 (1.2%) prognostication consults, the patient was determined by the neurologist to require assessment of DNC and was found to meet DNC criteria; determination of DNC occurred in 11 of the 19 (57.9%) consultations for a supervised DNC examination. In a comparison of the pre-TN (94 months) and post-TN (17 months) periods, there was 2.56-fold increase in the proportion of patients meeting DNC criteria who were medically suitable for donation (pre-TN 8.9% vs post-TN 21.1%, p = 0.02) and a 2.12-fold increase in the proportion of donors (pre-TN 6.14% vs post-TN 13.1%, p = 0.14). CONCLUSIONS: It is feasible to perform TN consultations for patients with severe neurologic damage and to allow expert supervision for DNC examination. Having a teleneurologist as part of the ICU assessment team helped differentiate severe neurologic deficits from DNC and was associated with increase in organ donation.

Acute kidney injury: prevention, detection, and management. Summary of updated NICE guidance for adults receiving iodine-based contrast media.

The National Institute for Health and Care Excellence (NICE) has recently updated the guideline for Acute kidney injury: prevention, detection and management (NG148), providing new recommendations on preventing acute kidney injury (AKI) in adults receiving intravenous iodine-based contrast media. The association between intravenous iodinated contrast media and AKI is controversial, particularly with widespread use of iso-osmolar agents. Associations between contrast media administration and AKI are largely based on observational studies, with inherent heterogeneity in patient populations, definitions applied, and timing of laboratory investigations. In an attempt to mitigate risk, kidney protection has typically been employed using intravenous volume expansion and/or oral acetylcysteine. Such interventions are in widespread use, despite lacking high-quality evidence of benefit. In the non-emergency setting, glomerular filtration rate (GFR) measurements should be obtained within the preceding 3 months before offering intravenous iodine-based contrast media. In the acute setting, adults should also have their risk of AKI assessed before offering intravenous iodine-based contrast media; however, this should not delay emergency imaging. Based on the evidence available from randomised controlled trials, the NICE committee recommends that oral hydration should be encouraged in adults at increased risk of AKI and that volume expansion with intravenous V fluids should only be considered for inpatients at particularly high risk.

A subset of broadly responsive Type III taste cells contribute to the detection of bitter, sweet and umami stimuli.

Taste receptor cells use multiple signaling pathways to detect chemicals in potential food items. These cells are functionally grouped into different types: Type I cells act as support cells and have glial-like properties; Type II cells detect bitter, sweet, and umami taste stimuli; and Type III cells detect sour and salty stimuli. We have identified a new population of taste cells that are broadly tuned to multiple taste stimuli including bitter, sweet, sour, and umami. The goal of this study was to characterize these broadly responsive (BR) taste cells. We used an IP3R3-KO mouse (does not release calcium (Ca2+) from internal stores in Type II cells when stimulated with bitter, sweet, or umami stimuli) to characterize the BR cells without any potentially confounding input from Type II cells. Using live cell Ca2+ imaging in isolated taste cells from the IP3R3-KO mouse, we found that BR cells are a subset of Type III cells that respond to sour stimuli but also use a PLCß signaling pathway to respond to bitter, sweet, and umami stimuli. Unlike Type II cells, individual BR cells are broadly tuned and respond to multiple stimuli across different taste modalities. Live cell imaging in a PLCß3-KO mouse confirmed that BR cells use this signaling pathway to respond to bitter, sweet, and umami stimuli. Short term behavioral assays revealed that BR cells make significant contributions to taste driven behaviors and found that loss of either PLCß3 in BR cells or IP3R3 in Type II cells caused similar behavioral deficits to bitter, sweet, and umami stimuli. Analysis of c-Fos activity in the nucleus of the solitary tract (NTS) also demonstrated that functional Type II and BR cells are required for normal stimulus induced expression.

Quality Comparison of 3 Tesla multiparametric MRI of the prostate using a flexible surface receiver coil versus conventional surface coil plus endorectal coil setup.

PURPOSE: To subjectively and quantitatively compare the quality of 3 Tesla magnetic resonance imaging of the prostate acquired with a novel flexible surface coil (FSC) and with a conventional endorectal coil (ERC). METHODS: Six radiologists independently reviewed 200 pairs of axial, high-resolution T2-weighted and diffusion-weighted image data sets, each containing one examination acquired with the FSC and one with the ERC, respectively. Readers selected their preferred examination from each pair and assessed every single examination using six quality criteria on 4-point scales. Signal-to-noise ratios were measured and compared. RESULTS: Two readers preferred FSC acquisition (36.5-45%) over ERC acquisition (13.5-15%) for both sequences combined, and four readers preferred ERC acquisition (41-46%). Analysis of pooled responses for both sequences from all readers shows no significant preference for FSC or ERC. Analysis of the individual sequences revealed a pooled preference for the FSC in T2WI (38.7% vs 17.8%) and for the ERC in DWI (50.9% vs 19.6%). Patients' weight was the only weak predictor of a preference for the ERC acquisition (p = 0.04). SNR and CNR were significantly higher in the ERC acquisitions (p<0.001) except CNR differentiating tumor lesions from benign prostate (p=0.1). CONCLUSION: Although readers have strong individual preferences, comparable subjective image quality can be obtained for prostate MRI with an ERC and the novel FSC. ERC imaging might be particularly valuable for sequences with inherently lower SNR as DWI and larger patients whereas the FSC is generally preferred in T2WI. FSC imaging generates a lower SNR than with an ERC.

Folliculitis decalvans and lichen planopilaris phenotypic spectrum: a case series of biphasic clinical presentation and theories on pathogenesis.

We present a series of 13 patients with clinical and histological features of both folliculitis decalvans (FD) and lichen planopilaris (LPP), either concomitantly, or sequentially as the clinical phenotype changed over time. This biphasic presentation of FD-LPP is not as uncommon as would be expected from the lack of description in the literature. We discuss current theories about the pathogenesis of both LPP and FD, and speculate how abnormal immune responses may either predispose to secondary bacterial infection or be influenced by dysbiosis of the skin/hair follicle microbiome, resulting in inflammation and permanent hair follicle damage.

Similarities and differences between Likert and PIRADS v2.1 scores of prostate multiparametric MRI: a pictorial review of histology-validated cases.

The UK National Institute for Health and Care Excellence (NICE) 2019 "Prostate cancer: diagnosis and management" guidelines have recommended that all patients suspected of prostate cancer undergo multiparametric magnetic resonance imaging (mpMRI) prior to biopsy. The Likert scoring system is advocated for mpMRI reporting based on multicentre studies that have demonstrated its effectiveness within the National Health Service (NHS). In recent years, there has been considerable drive towards standardised prostate reporting, which led to the development of "Prostate Imaging-Reporting And Data System" (PI-RADS). The PI-RADS system has been adopted by the majority of European countries and within the US. This paper reviews these systems indicating the similarities and specific differences that exist between PI-RADS and Likert assessment through a series of histologically proven clinical cases.

Three-year experience of a dedicated prostate mpMRI pre-biopsy programme and effect on timed cancer diagnostic pathways.

AIM: To evaluate the effect of pre-biopsy magnetic resonance imaging (MRI) on cancer diagnostic times, and to report MRI-directed pathology outcomes. MATERIALS AND METHODS: In total, 1483 patients were referred with prostate cancer suspicion during a 30-month period. Upfront MRI was performed in 745 patients: 332 MRIs in the 15 months prior to dedicated scanning slots (group 1), and 413 in the 15 months post-introduction (group 2). A further 88 patients had initial MRI following clinical assessment. Biopsy via the transrectal (TR) or transperineal (TP) approach was performed, with MRI/ultrasound fusion for MRI targets. Clinically significant cancer (csPCa) was defined as Gleason ≥3+4. Negative MRIs were defined as Likert 1-2. Per-case clinical decisions were taken to biopsy or not. RESULTS: 44.4% of patients avoided biopsy. 484/833 (58.1%) MRIs were negative; 37.4% of these patients had biopsy with a negative predictive value (NPV) of 92.8% for Gleason ≥3+4 and 98.3% for ≥4+3. Overall prostate cancer prevalence was 34.3% (24.6% csPCa). In 323 MRI-positive cases, any cancer was present in 78.9% (csPCa 60.4%). Of the 1483 patients, 1232 (83.1%) completed all diagnostic tests within 28 days. Upfront MRI patients met this standard in 621/833 (74.5%), improving from 66.9% to 81.1% with reserved slots (group 2) with a reduced diagnostic time from median 25.5 to 20.9 days. Biopsy scheduling delayed the pathway in 69.7%, with MRI responsible in 22.3%, reducing to 10.3% in group 2. TP biopsies met the 28-day standard in significantly less cases (29.7%), compared to TR (67.4%, p<0.0001). CONCLUSION: Reserved MRI slots reduces time-to-diagnosis, and upfront MRI safely avoids biopsy in a significant proportion of men, whilst maintaining expected csPCa detection rates.

A multicentre assessment of prostate MRI quality and compliance with UK and international standards.

AIM: To assess prostate magnetic resonance imaging (MRI) image quality and compliance with technical standards between centres in the South West region of the UK. MATERIALS AND METHODS: Fifteen imaging sites in the region submitted seven consecutive anonymised MRI studies. These were assessed by two experienced radiologists in consensus. Overall, subjective image quality for T2-weighted imaging (T2W), diffusion weighted imaging (DWI), and dynamic contrast enhancement (DCE) was scored on a five-point Likert scale. Five additional quality parameters were also assessed visually, including image noise, motion, artefact, and distortion. The degree of compliance by each site with 21 published technical standards was also assessed. RESULTS: Ninety-four MRI examinations were reviewed from across all sites (mean 6.3 scans per site, range 5-7). Mean compliance with technical standards was 63% (range 38-86%). Forty-seven percent of sites did not perform DCE. One site used a 3 T scanner. The percentage of patients with overall quality scores of ≥3 (diagnostically acceptable) were 68% for T2W, 81% for DWI, and 60% for both T2W and DWI. Ninety-three percent of the 45 patients who underwent DCE had diagnostically acceptable studies. By scanner age, the percentage of patients with diagnostically acceptable T2W scores was 53% for scanners ≥7 years and 80% when <7 years (p=0.006). Comparing individual sites, the mean overall quality scores were 2.9 (range 2.2-4.2) for T2W, 3.2 (1.8-4.7) for DWI, and 3.4 (2.5-4.7) for DCE. CONCLUSION: There is wide variation in compliance with recognised technical standards and image quality across sites. If MRI is to replace biopsy in selected low-risk patients, improvements in image quality may be required.

PI-RADS version 2.1: one small step for prostate MRI.

Multiparametric (mp) prostate magnetic resonance imaging (MRI) is playing an increasingly prominent role in the diagnostic work-up of patients with suspected prostate cancer. Performing mpMRI before biopsy offers several advantages including biopsy avoidance under certain clinical circumstances and targeting biopsy of suspicious lesions to enable the correct diagnosis. The success of the technique is heavily dependent on high-quality image acquisition, interpretation, and report communication, all areas addressed by previous versions of the Prostate Imaging-Reporting and Data System (PI-RADS) recommendations. Numerous studies have validated the approach, but the widespread adoption of PI-RADS version 2 has also highlighted inconsistencies and limitations, particularly relating to interobserver variability for evaluation of the transition zone. These limitations are addressed in the recently released version 2.1. In this article, we highlight the key changes proposed in PI-RADS v2.1 and explore the background reasoning and evidence for the recommendations.

Added value of diffusion-weighted MRI for nodal radiotherapy planning in pelvic malignancies.

PURPOSE: To evaluate the added value of diffusion-weighted imaging (DWI) to T2-weighted imaging (T2WI) for improved identification of pelvic lymph nodes (LN) by radiation oncologists. METHODS/PATIENTS: This retrospective study included 20 patients with histopathologically proven node-negative prostate cancer. All patients underwent 3T-MRI of the prostate; matched axial T2WI and DWI sequences were assessed by an experienced uro-radiologist as the reference standard. Consultant and specialist registrar radiation oncologists were asked to identify all LN first on T2WI alone (read 1) and then on T2WI and DWI combined (read 2); LN were measured in size and divided into true positives (TP), false positives (FP) and false negatives (FN). Sensitivity, positive predictive value (PPV) and false negative rate (FNR) were then calculated and compared using Pearson's Chi square test. RESULTS: A total of 177 LN comprised the reference standard. 16 TP, 16 FP and 161 FN LN (sensitivity 9.0%, PPV 50.0%, FNR 91.0%) and 124, 15 and 53 LN (70.1%, 89.2%, 30%) were identified by reader 1 on reads 1 and 2, respectively; χ2 (2, N = 385) = 137.8, p < 0.0001. 27, 21 and 150 LN (15.3%, 56.3%, 84.8%) and 120, 13 and 57 LN (67.8%, 90.2%, 32.2%) were identified by reader 2 on the two reads; χ2 (2, N = 388) = 102.4, p < 0.0001. CONCLUSIONS: Adding DWI to T2WI significantly improved identification of pelvic LN by radiation oncologists and can therefore be regarded as a useful LN contouring technique for RT planning in pelvic malignancies.