Quantum Interference between Quasi-2D Fermi Surface Sheets in UTe_{2}.

UTe_{2} is a spin-triplet superconductor candidate for which high quality samples with long mean free paths have recently become available, enabling quantum oscillation measurements to probe its Fermi surface and effective carrier masses. It has recently been reported that UTe_{2} possesses a 3D Fermi surface component [Phys. Rev. Lett. 131, 036501 (2023)PRLTAO0031-900710.1103/PhysRevLett.131.036501]. The distinction between 2D and 3D Fermi surface sections in triplet superconductors can have important implications regarding the topological properties of the superconductivity. Here we report the observation of oscillatory components in the magnetoconductance of UTe_{2} at high magnetic fields. We find that these oscillations are well described by quantum interference between quasiparticles traversing semiclassical trajectories spanning magnetic breakdown networks. Our observations are consistent with a quasi-2D model of this material's Fermi surface based on prior dHvA-effect measurements. Our results strongly indicate that UTe_{2}-which exhibits a multitude of complex physical phenomena-possesses a remarkably simple Fermi surface consisting exclusively of two quasi-2D cylindrical sections.

Quasi-2D Fermi surface in the anomalous superconductor UTe2.

The heavy fermion paramagnet UTe2 exhibits numerous characteristics of spin-triplet superconductivity. Efforts to understand the microscopic details of this exotic superconductivity have been impeded by uncertainty regarding the underlying electronic structure. Here we directly probe the Fermi surface of UTe2 by measuring magnetic quantum oscillations in pristine quality crystals. We find an angular profile of quantum oscillatory frequency and amplitude that is characteristic of a quasi-2D Fermi surface, which we find is well described by two cylindrical Fermi sheets of electron- and hole-type respectively. Additionally, we find that both cylindrical Fermi sheets possess considerable undulation but negligible small-scale corrugation, which may allow for their near-nesting and therefore promote magnetic fluctuations that enhance the triplet pairing mechanism. Importantly, we find no evidence for the presence of any 3D Fermi surface sections. Our results place strong constraints on the possible symmetry of the superconducting order parameter in UTe2.

The evolutionary conserved TLDc domain defines a new class of (H+)V-ATPase interacting proteins.

We recently found that nuclear receptor coactivator 7 (Ncoa7) and Oxr1 interact with the proton-pumping V-ATPase. Ncoa7 and Oxr1 belong to a group of proteins playing a role in the oxidative stress response, that contain the conserved "TLDc" domain. Here we asked if the three other proteins in this family, i.e., Tbc1d24, Tldc1 and Tldc2 also interact with the V-ATPase and if the TLDc domains are involved in all these interactions. By co-immunoprecipitation, endogenous kidney Tbc1d24 (and Ncoa7 and Oxr1) and overexpressed Tldc1 and Tldc2, all interacted with the V-ATPase. In addition, purified TLDc domains of Ncoa7, Oxr1 and Tldc2 (but not Tbc1d24 or Tldc1) interacted with V-ATPase in GST pull-downs. At the amino acid level, point mutations G815A, G845A and G896A in conserved regions of the Ncoa7 TLDc domain abolished interaction with the V-ATPase, and S817A, L926A and E938A mutations resulted in decreased interaction. Furthermore, poly-E motifs upstream of the TLDc domain in Ncoa7 and Tldc2 show a (nonsignificant) trend towards enhancing the interaction with V-ATPase. Our principal finding is that all five members of the TLDc family of proteins interact with the V-ATPase. We conclude that the TLDc motif defines a new class of V-ATPase interacting regulatory proteins.

Vitamin D3 reduces risk of cardiovascular and liver diseases by lowering homocysteine levels: double-blinded, randomised, placebo-controlled trial.

The objective of this study was to evaluate the effect of vitamin D3 on total homocysteine (tHcy) and C-reactive protein (CRP) levels and liver and kidney function tests in overweight women with vitamin D deficiency. Therefore, a randomised, double-blind placebo, controlled clinical trial was conducted on 100 eligible women. Subjects were randomly divided into two groups: the placebo (n 50) and the vitamin D (n 50) which received 1250 µg vitamin D3 per week for 2 months. The participants' 25-hydroxyvitamin D (25(OH)D), tHcy, CRP, alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, creatinine and estimated glomerular filtration rate (eGFR) were measured and compared before and after treatment. Results showed that the tHcy, CRP, AST, ALT and eGFR levels after the 2nd month of vitamin D3 intervention were significantly (P < 0·001) decreased and the 25(OH)D, urea and creatinine levels were significantly (P < 0·001) increased in the treatment group. In the placebo group, no significant changes were identified throughout the follow-up period. In conclusion, vitamin D3 intervention with a treatment dose of 1250 µg/week for at least 2 months may help in lowering Hcy and CRP levels and may improve liver function tests, which in turn might help in minimising the risk of CVD and liver diseases among overweight women but negatively affect kidney function.

Single versus repeated exposure to human polarized intestinal epithelial monolayers for in vitro protein hazard characterization.

Recent studies suggest human-derived intestinal epithelial cell (IEC) lines cultured as polarized monolayers on permeable Transwell® filters are effective at differentiating between hazardous and non-hazardous proteins following a single exposure. In this study, IEC polarized monolayers were subjected to hazardous or non-hazardous proteins in nine exposures over 30 days and compared to a single exposure of the same protein. The objective was to evaluate whether repeated exposures to a protein differently alter barrier integrity or compromise cell viability compared to single exposures. Proteins tested included Clostridium difficile toxin A, Streptolysin O, Wheat Germ Agglutinin, Phaseolus vulgaris Hemagglutinin-E, bovine serum albumin, porcine serum albumin, and fibronectin. Evidence of diminished barrier integrity and/or cell viability following exposure to hazardous proteins was more pronounced in magnitude when IECs were subjected to multiple rather than single exposures. In some cases, an effect on IEC monolayers was observed only with repeated exposures. In general, IEC responses to non-hazardous proteins following either single or repeated exposures were minimal. Results from these studies support the utility of using cultured human IEC polarized monolayers to differentiate between hazardous and non-hazardous proteins and suggest that repeated exposures may reveal a greater magnitude of response when compared to single exposures.

Extended exposure duration of cultured intestinal epithelial cell monolayers in characterizing hazardous and non-hazardous proteins.

Recent studies suggest that human derived intestinal epithelial cells (IECs) cultured as polarized monolayers on Transwell® filters may respond differently when exposed to hazardous and non-hazardous proteins. This experimental platform was based on apical exposure of IEC monolayers to test proteins for 24 h followed by assessment of barrier integrity and cell viability. In this study, Caco-2 and T84 IEC polarized monolayers were evaluated for barrier integrity and cytotoxicity following exposure to hazardous and non-hazardous proteins for 24, 48 and 72 h. Hazardous proteins included Clostridium difficile toxin A (ToxA), Streptolysin O (SLO), Wheat Germ Agglutinin (WGA), and Phaseolus vulgaris haemagglutinin-E (PHA-E). Non-hazardous proteins included bovine serum albumin (BSA), porcine serum albumin (PSA), and fibronectin (Fbn). In general, evidence of diminished barrier integrity or cell viability observed following exposure to hazardous proteins for 24 h was more pronounced after 48 and 72 h for both IEC monolayers. Non-hazardous proteins exhibiting no impact following 24 h of exposure elicited minimal effects over longer exposure durations. These results support the utility of using cultured human IEC polarized monolayers to differentiate between hazardous and non-hazardous proteins and suggest that longer durations of exposure may further improve the ability to distinguish between them.

Post-licensure safety surveillance study of routine use of quadrivalent meningococcal diphtheria toxoid conjugate vaccine (MenACWY-D) in infants and children.

BACKGROUND: Menactra® vaccine (MenACWY-D) was licensed in the United States in 2005 for persons 11-55 years of age, in 2007 for children 2-10 years of age, and in 2011 for infants/toddlers 9-23 months of age. We conducted two studies at Kaiser Permanente Northern California (KPNC), an integrated health care organization, to assess the safety of MenACWY-D in 2-10-year-olds and 9-23-month-olds receiving the vaccine during routine clinical care. METHODS: We conducted observational, retrospective studies of MenACWY-D in 2-10-year-olds (October 2007-October 2010) and in 9-23-month-olds (June 2011-June 2014). We monitored all subjects for non-elective hospitalizations, emergency department visits, and selected outpatient outcomes (specified neurological conditions, hypersensitivity reactions and new-onset autoimmune diseases) up to 6 months after vaccination, depending on the study. Using a self-control risk-interval design, we calculated incidence rate ratios (IRRs) comparing outcomes during the post-vaccination risk interval (0-30 days) with those during more remote post-vaccination comparison intervals (31-60 and 31-180 days [children] or 31-75 days [infants/toddlers]). RESULTS: There were 1421 children aged 2-10 years and 116 infants/toddlers aged 9-23 months who received MenACWY-D. Approximately 30% of the 2-10-year-olds and 67% of the 9-23-month-olds were considered at increased risk of meningococcal disease. Among 2-10-year-olds, there was 1 hospitalization on post-vaccination day 5 for fever, which was considered possibly related to vaccination. The only significantly elevated outcome among 2-10-year-olds was cellulitis/abscess (2 cases occurred during the risk interval versus 0 during comparison interval; IRR not evaluable [NE], 95% CI: 1.42, NE). After medical record review, the 2 cases were considered unrelated to vaccination. Among 9-23-month-olds, no outcomes were significantly elevated after vaccination and there were no hospitalizations. There were no deaths observed during the three-year accrual and subsequent six-month surveillance period for either study. CONCLUSIONS: Immunization of infants and young children with MenACWY-D vaccine was not associated with any new safety concerns; however, these small studies had limited power to detect rare or uncommon safety events. ClinicalTrials.gov Identifiers are NCT00728260 and NCT01689155.

Primary human polarized small intestinal epithelial barriers respond differently to a hazardous and an innocuous protein.

An experimental platform employing human derived intestinal epithelial cell (IEC) line monolayers grown on permeable Transwell® filters was previously investigated to differentiate between hazardous and innocuous proteins. This approach was effective at distinguishing these types of proteins and perturbation of monolayer integrity, particularly transepithelial electrical resistance (TEER), was the most sensitive indicator. In the current report, in vitro indicators of monolayer integrity, cytotoxicity, and inflammation were evaluated using primary (non-transformed) human polarized small intestinal epithelial barriers cultured on Transwell® filters to compare effects of a hazardous protein (Clostridium difficile Toxin A [ToxA]) and an innocuous protein (bovine serum albumin [BSA]). ToxA exerted a reproducible decrease on barrier integrity at doses comparable to those producing effects observed from cell line-derived IEC monolayers, with TEER being the most sensitive indicator. In contrast, BSA, tested at concentrations substantially higher than ToxA, did not cause changes in any of the tested variables. These results demonstrate a similarity in response to certain proteins between cell line-derived polarized IEC models and a primary human polarized small intestinal epithelial barrier model, thereby reinforcing the potential usefulness of cell line-derived polarized IECs as a valid experimental platform to differentiate between hazardous and non-hazardous proteins.

Programmed death ligand 1 is expressed in canine B cell lymphoma and downregulated by MEK inhibitors.

Programmed death ligand 1 (PD-L1) expression in antigen-presenting cells and tumors can inhibit T cell-mediated immunity. In this study, PD-L1 mRNA and protein expression was evaluated in canine B cell lymphoma (CLL17-71), large T-cell leukemia (CLGL-90), B cell leukemia (GL-1) and primitive leukocyte round cell neoplasia (CLL-1390). Variable PD-L1 mRNA and protein were observed in these cells with high endogenous expression present in CLL17-71 cells. PD-L1 protein was also observed in canine patient B cell lymphoma tissues using immunostaining. PD-L1 and signal transducer and activator of transcription 1 ( STAT1 ) mRNA expression were reduced in the presence of mitogen-activated protein kinase kinase 1.2 (MEK1/2) inhibitors RDEA119 and AZD6244 in CLL 17-71 cells. RDEA119 had similar effect on PD-L1 and STAT-1 in IFN-γ activated CLL-1390 cells. Overall, these results indicate that PD-L1 is expressed in canine B cell lymphoma. Its inhibition by MEK1/2 inhibitors suggests a possible treatment strategy using targeted drugs which likely could enhance antitumor immune response.

A novel eye drop application monitor to assess patient compliance with a prescribed regimen: a pilot study.

PURPOSE: To assess the ability of a novel imaging device to allow physicians to personalize therapeutic regimens based on objective patient drop administration data. METHODS: A novel imaging system was used to record video of the drop technique of subjects in clinic (n=25) or at home (n=17) for 1 week. Video assessment by a reading center was compared with patient reporting and their prescribed regimen with respect to how many drops were applied and how many landed in the eye. RESULTS: Reading center assessment of both drops dispensed and drops landing in the eye was significantly different from the prescribed regimen in the clinic (Pd=0.005, Pi<0.001, respectively) and at-home arms (Pd=0.003, Pi<0.001, respectively). CONCLUSIONS: This imaging system is a powerful tool to help physicians tailor patient therapy more accurately, to help researchers evaluate new drop therapies with objective rather than subjective data, and to potentially facilitate better patient training for improved drug delivery.

Nipple-sparing mastectomy in patients with BRCA1/2 mutations and variants of uncertain significance.

BACKGROUND: Nipple-sparing mastectomy (NSM) is associated with improved cosmesis and is being performed increasingly. Its role in BRCA mutation carriers has not been well described. This was a study of the indications for, and outcomes of, NSM in BRCA mutation carriers. METHODS: BRCA mutation carriers who underwent NSM were identified. Details of patient demographics, surgical procedures, complications, and relevant disease stage and follow-up were recorded. RESULTS: A total of 177 NSMs were performed in 89 BRCA mutation carriers between September 2005 and December 2013. Twenty-six patients of median age 41 years had NSM for early-stage breast cancer and a contralateral prophylactic mastectomy. Mean tumour size was 1·4 (range 0·1-3·5) cm. Sixty-three patients of median age 39 years had prophylactic NSM, eight of whom had an incidental diagnosis of ductal carcinoma in situ. There were no local or regional recurrences in the 26 patients with breast cancer at a median follow-up of 28 (i.q.r. 15-43) months. There were no newly diagnosed breast cancers in the 63 patients undergoing prophylactic NSM at a median follow-up of 26 (11-42) months. All patients had immediate breast reconstruction. Five patients (6 per cent) required subsequent excision of the nipple-areola complex for oncological or other reasons. Skin desquamation occurred in 68 (38·4 per cent) of the 177 breasts, and most resolved without intervention. Debridement was required in 13 (7·3 per cent) of the 177 breasts, and tissue-expander or implant removal was necessary in six instances (3·4 per cent). CONCLUSION: NSM is an acceptable choice for patients with BRCA mutations, with no evidence of compromise to oncological safety at short-term follow-up. Complication rates were acceptable, and subsequent excision of the nipple-areola complex was rarely required.

Concurrent sexual partnerships among individuals in HIV sero-discordant heterosexual couples.

The objective of the study was to assess the level at which individuals in HIV discordant couples engage in concurrent sexual partnerships and factors associated with this risk of transmitting HIV. By using data from a group of HIV discordant heterosexual couples (n = 145), we examined the frequency of concurrent sexual partners and factors associated with such partnerships. The prevalence of concurrent partnerships with heterosexual partners was 16%. Fewer than half of individuals with concurrent partnerships reported that their main study partner knew about these relationships. Of individuals involved in concurrent partnerships, 30% reported inconsistent condom use in these relationships. Unmarried individuals in new HIV sero-discordant relationships were particularly at risk for concurrent partnerships. In conclusion, more frequent HIV testing may complement increased attention to communication, disclosure and condom use in this population that is especially vulnerable to acquiring and transmitting HIV infection.

Clinical experience with a glucose oxidase-containing dressing on recalcitrant wounds.

This large open study investigated the clinical benefits of a new hydrogel dressing when used on chronic wounds of different aetiologies in real-life clinical settings. Nearly three-quarters of the patients assessed either healed or improved.

The provision of transurethral prostatectomy on a day-case basis using bipolar plasma kinetic technology.

OBJECTIVE: To evaluate, in a prospective study, the potential for providing elective transurethral prostatectomy on a day-case basis, using new bipolar electrosurgical technology. PATIENTS AND METHODS: Forty men with confirmed bladder outlet obstruction caused by benign prostatic enlargement underwent plasma kinetic vaporization of the prostate (PKVP) in the Day Surgery Unit; they were scheduled to be discharged on the day of surgery with an indwelling catheter, returning for a trial removal of the catheter at 48 h, and followed up at 2 and 4 months after surgery. RESULTS: Thirty-four (85%) of the 40 patients were able to return home on the day of surgery. All patients, including the six who failed to return home as a day-case, successfully voided at 48 h; 78% felt the procedure was acceptable on a day-case basis. At 4 months the mean improvement in the International Prostate Symptom Score and Quality of Life score were 64% and 84%, respectively. The mean improvement in flow rate was 200-250%. CONCLUSION: PKVP effectively relieves prostatic obstruction, at least in the short-term (a longer term follow-up is required). The procedure can be delivered safely on a day-case basis and was very acceptable to the patients.

Comparison of quality and cost-effectiveness in the evaluation of symptomatic cholelithiasis with different approaches to ultrasound availability in the ED.

Ultrasound is the imaging study of choice for the detection of gallstones, but ultrasound through medical imaging departments (MI Sono) is not readily available on an immediate basis in many emergency departments (EDs). Several studies have shown that emergency physicians can perform ultrasound themselves (ED Sono) to rule out gallstones with acceptable accuracy after relatively brief training periods, but there have been no studies to date specifically addressing the effect of ED Sono of the gallbladder on quality and cost-effectiveness in the ED. In this study, we investigated measures of quality and cost-effectiveness in evaluating patients with suspected symptomatic cholelithiasis during three different years with distinctly different approaches to ultrasound availability. The study retrospectively identified a total of 418 patients who were admitted for cholecystectomy or for a complication of cholelithiasis within 6 months of an ED visit for possible biliary colic. The percentage of patients who had gallstones documented at the first ED visit improved from 28% in 1993, when there was limited availability of ultrasound through the Medical Imaging Department (MI Sono), to 56% in 1995, when MI Sono was readily available, to 70% in 1997, when both MI Sono and ED Sono were readily available (P <.001). There were also significant differences over the 3 years in the mean number of days from the first ED visit to documentation of gallstones (19.7 in 1993, 10.7 in 1995, 7.4 in 1997, P <.001); the mean number of return visits for possible biliary colic before documentation of gallstones (1.67 in 1993, 1.24 in 1995, and 1.25 in 1997, P <.001); and the incidence of complications of cholelithiasis in the interval between the first ED visit for possible biliary colic and the date of documentation of cholelithiasis (6.8% in 1993, 5.9% in 1995, 1.5% in 1997, P =.049). The number of MI Sonos ordered by emergency physicians per case of symptomatic cholelithiasis identified increased from 1.7 in 1993 to 2.5 in 1995 and dropped back to 1.7 in 1997, when 4.2 ED Sonos per study case were also done. The cost of ED Sonos was more than offset by savings in avoiding calling in ultrasound technicians after regular Medical Imaging Department hours. The indeterminate rate for ED Sonos was 18%. Excluding indeterminates, the sensitivity of ED Sono for detection of gallstones was 88.6% (95% CI 83.1-92.8%), the specificity 98.2% (95% CI 96.0-99.3%), and the accuracy 94.8% (95% CI 92.5-96.5%). We conclude that greater availability of MI Sono in the ED was associated with improved quality in the evaluation of patients with suspected symptomatic cholelithiasis but also with increased ultrasound costs. The availability of ED Sono in addition to readily available MI Sono was associated with further improved quality and decreased costs. The indeterminate rate for ED Sono was relatively high, but excluding indeterminates, the accuracy of ED Sono was comparable with published reports of MI Sono.

Polymorphisms in the DNA repair gene XRCC1 and breast cancer.

X-ray repair cross complementing group 1 (XRCC1) encodes a protein involved in base excision repair. We examined the association of polymorphisms in XRCC1 (codon 194 Arg-->Trp and codon 399 Arg-->Gln) and breast cancer in the Carolina Breast Cancer Study, a population-based case-control study in North Carolina. No association was observed between XRCC1 codon 194 genotype and breast cancer, and odds ratios (ORs) were not modified by smoking or radiation exposure. A positive association for XRCC1 codon 399 Arg/Gln or Gln/Gln genotypes compared with Arg/Arg was found among African Americans (253 cases, 266 controls; OR = 1.7, 95% confidence interval, 1.1-2.4) but not whites (386 cases, 381 controls; OR =1.0, 95% confidence interval, 0.8-1.4). Among African-American women, ORs for the duration of smoking were elevated among women with XRCC1 codon 399 Arg/Arg genotype (trend test; P < 0.001) but not Arg/Gln or Gln/Gln (P = 0.23). There was no difference in OR for smoking according to XRCC1 codon 399 genotype in white women. ORs for occupational exposure to ionizing radiation were stronger for African-American and white women with codon 399 Arg/Arg genotype. High-dose radiation to the chest was more strongly associated with breast cancer among white women with XRCC1 codon 399 Arg/Arg genotype. Our results suggest that XRRC1 codon 399 genotype may influence breast cancer risk, perhaps by modifying the effects of environmental exposures. However, interpretation of our results is limited by incomplete knowledge regarding the biological function of XRCC1 alleles.

An assessment of the quality of referral letters sent to a specialist periodontist during a nine month period.

There have been concerns about the quality of referral letters received by specialist periodontists. This retrospective study aimed to assess the quality of all referral letters received over a nine month period, by a specialist periodontist working in a publicly financed community clinic, and to compare the results with those obtained from a study which assessed referral letters received by the periodontal department of a London teaching hospital during the same period. After the assessors had trained for intra- and inter-examiner reproducibility, the letters were assessed using the Categorisation System for Periodontal Referral Quality (CSPRQ) (Snoad et al., 1999). The year and country of qualification (UK or non-UK), and possession or otherwise of postgraduate qualifications for each of the referring dentists was ascertained from the UK Dentists Register. The results from this study and those from the hospital study were statistically tested using the Chi-squared test. Before the studies commenced the assessors achieved 100% inter-examiner reproducibility when applying the CSPRQ. A total of 114 letters was received, six of which were excluded. Of the remaining 108, 38 were categorised as of an acceptable standard. There were differences in the performance of dentists from different age groups in that 56% of letters from those qualified from 10-20 years, 29% of those from dentists qualified < 10 years and 27% of those qualified > 20 years were of an acceptable standard. The results were broadly similar to those of the hospital study except that there was a statistically significant difference (P< 0.05) between the quality of referrals from dentists qualified between 10 and 20 years and those with non-UK primary qualifications. It was concluded that the overall quality of referral letters assessed in this study was poor and that the CSPRQ provided a highly reproducible technique for assessing the quality of periodontal referral letters.