The clinical spectrum of HbSC sickle cell disease-not a benign condition.

Sickle cell disease (SCD) includes a group of heterogenous disorders that result in significant morbidities. HbSS is the most common type of SCD and HbSC is the second most common type of SCD. The prevalence of HbSC disease in the United States and United Kingdom is ~1 in 7174 births and 1 in 6174 births respectively. Despite its frequency, however, HbSC disease has been insufficiently studied and was historically categorized as a more 'mild' form of SCD. We conducted this study of HbSC disease as part of the NHLBI funded Sickle Cell Disease Implementation Consortium (SCDIC). The SCDIC registry included 2282 individuals with SCD, ages 15-45 years of whom 502 (22%) had HbSC disease. Compared with people with sickle cell anaemia (SCA), the study found that people with HbSC disease had a higher frequency of splenomegaly (n (%) = 169 (33.7) vs. 392 (22.1)) and retinopathy (n (%) = 116 (23.1) vs. 189 (10.6)). A Many people with HbSC also had avascular necrosis (n (%) = 112 (22.3)), pulmonary embolism (n (%) = 43 (8.6)) and acute chest syndrome (n (%) = 228 (45.4)) demonstrating significant disease severity. HbSC disease is more clinically severe than was previously recognized and deserves additional evaluation and targeted treatments.

Genome-wide association studies and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer.

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC. PATIENTS AND METHODS: We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR. RESULTS: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) ß, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors-such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin-higher alcohol drinking, and lower education attainment with increased EOCRC risk. CONCLUSIONS: Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions.

First Measurement of the Nuclear-Recoil Ionization Yield in Silicon at 100 eV.

We measured the nuclear-recoil ionization yield in silicon with a cryogenic phonon-sensitive gram-scale detector. Neutrons from a monoenergetic beam scatter off of the silicon nuclei at angles corresponding to energy depositions from 4 keV down to 100 eV, the lowest energy probed so far. The results show no sign of an ionization production threshold above 100 eV. These results call for further investigation of the ionization yield theory and a comprehensive determination of the detector response function at energies below the keV scale.

The safety of tranexamic acid administration in total knee arthroplasty: a population-based study from Taiwan.

Tranexamic acid is an effective treatment to reduce blood loss. We performed a retrospective observational study to evaluate safety in unilateral total knee arthroplasty. We utilised Taiwan's national health insurance database to identify relevant patients and to retrieve information on peri-operative blood transfusions and tranexamic acid administration within 60 days of follow-up. We examined changes in the rate of transfusions and adverse events with respect to tranexamic acid administration using logistic regression. We observed a total of 226,719 knee arthroplasty cases during 2010-2019. Transfusion and tranexamic acid administration rates were 38.9% (88,258) and 42.9% (97,237), respectively. Tranexamic acid was associated with a 50% decrease in blood transfusions (RR: 0.50, 95%CI: 0.48-0.51). After propensity-score matching, tranexamic acid was not associated with pulmonary embolism; deep vein thromboembolism; artery vein thromboembolism; acute myocardial infarction; ischaemic stroke; or in-hospital mortality, but was significantly associated with acute kidney injury. Patients with existing chronic kidney disease suffered a high absolute risk of kidney injury irrespective of tranexamic acid administration (832 per 10,000, 95%CI 797-869). Tranexamic acid was also associated with surgical site infection. There was strong interaction between blood transfusion; tranexamic aid administration; and development of surgical site infection. In conclusion, tranexamic acid use was associated with decreased blood transfusion and was not associated with thromboembolic events. However, careful consideration is required before use in patients with pre-existing renal disease. Further, our observed interaction between patients given tranexamic acid who subsequently require transfusion requires careful consideration with respect to enhanced prophylaxis against surgical site infection.

Breakthrough infections with the SARS-CoV-2 Delta variant: vaccinations halved transmission risk.

OBJECTIVES: The SARS-CoV-2 Delta variant (B.1.617.2) is associated with increased infectivity. Data on breakthrough SARS-CoV-2 Delta variant infections in vaccinated individuals and transmission risk are limited. The aim of this study was to provide estimates of transmission risk in Delta variant breakthrough infections. STUDY DESIGN: A matched case-control study was performed.. METHODS: To analyse onward transmission of fully vaccinated individuals infected with B.1.617.2, we compared 85 patients (vaccination group [VG]) with an age- and sex-matched unvaccinated control group (CG; n = 85). RESULTS: Transmission of B.1.617.2 was significantly reduced (halved) in the VG. The number of infected contacts to total number of contacts per infected person was 0.26 ± 0.40 in the VG vs 0.56 ± 0.45 in the CG (P = .001). Similarly, fully vaccinated contacts were less likely to be infected by fully vaccinated infected persons (IPs) than by unvaccinated IPs (20.0% vs 37.5%), although this association was not significant. CONCLUSIONS: Fully vaccinated contacts had 50% less transmissions than unvaccinated individuals. These findings must be verified in larger sample populations, and it is especially important to investigate the role of vaccination status of close contacts.

Constraints on Lightly Ionizing Particles from CDMSlite.

The Cryogenic Dark Matter Search low ionization threshold experiment (CDMSlite) achieved efficient detection of very small recoil energies in its germanium target, resulting in sensitivity to lightly ionizing particles (LIPs) in a previously unexplored region of charge, mass, and velocity parameter space. We report first direct-detection limits calculated using the optimum interval method on the vertical intensity of cosmogenically produced LIPs with an electric charge smaller than e/(3×10^{5}), as well as the strongest limits for charge ≤e/160, with a minimum vertical intensity of 1.36×10^{-7} cm^{-2} s^{-1} sr^{-1} at charge e/160. These results apply over a wide range of LIP masses (5 MeV/c^{2} to 100 TeV/c^{2}) and cover a wide range of ßγ values (0.1-10^{6}), thus excluding nonrelativistic LIPs with ßγ as small as 0.1 for the first time.

Light Dark Matter Search with a High-Resolution Athermal Phonon Detector Operated above Ground.

We present limits on spin-independent dark matter-nucleon interactions using a 10.6 g Si athermal phonon detector with a baseline energy resolution of σ_{E}=3.86±0.04(stat)_{-0.00}^{+0.19}(syst) eV. This exclusion analysis sets the most stringent dark matter-nucleon scattering cross-section limits achieved by a cryogenic detector for dark matter particle masses from 93 to 140 MeV/c^{2}, with a raw exposure of 9.9 g d acquired at an above-ground facility. This work illustrates the scientific potential of detectors with athermal phonon sensors with eV-scale energy resolution for future dark matter searches.

The Sickle Cell Pro-Inflammatory Response to Interval Testing Study (SPRINTS) in children and young adults with sickle cell anemia - Study design and methodological strategies.

The impact of sickle cell anemia (SCA) and its complications on physical functioning and cardiopulmonary/aerobic fitness in affected individuals is significant. Although limited data support the safety of maximal cardiopulmonary exercise testing (CPET) for children and adults with SCA, the safety of submaximal moderate and high intensity, and longer duration, exercise in this population is not clear. The Sickle Cell Pro-Inflammatory Response to Interval Testing Study (SPRINTS) is a multicenter, randomized, prospective trial. SPRINTS leverages unique collaborations between investigators in pediatric hematology and exercise science to evaluate the impact of exercise intensity on the acute phase inflammatory response to exercise and changes in airway dynamics in children and young adults with SCA. Here we describe the study design and methodological strategies employed in SPRINTS, including an exercise challenge that mimics real-life patterns of childhood physical activity, characterized by multiple moderate and high intensity brief bouts of exercise interspersed with rest periods. Primary outcomes comprise pre- and post-exercise biomarkers of inflammation and endothelial dysfunction and spirometry. Secondary outcomes include assessment of physical activity and functioning, genomic studies and near-infrared spectroscopy measurements to assess tissue oxygenation status during exercise. SPRINTS aims to enroll 70 subjects with SCA and 70 matched, healthy controls. We anticipate that data from SPRINTS will address gaps in our understanding of exercise responses and safety in SCA and support the future development of evidence-based, exercise prescription guidelines in this population.

Incorrect diagnoses in patients with neutralizing anti-interferon-gamma-autoantibodies.

OBJECTIVES: Early diagnosis of adult-onset immunodeficiency associated with neutralizing anti-interferon-gamma autoantibodies (anti-IFNγ Abs) remains difficult given the lack of a distinctive phenotype and a routine test. This study aimed to investigate the determinants of incorrect tentative diagnoses and useful clues for early disease recognition. METHODS: This study enrolled adult patients who had unexplained opportunistic infections diagnosed at six hospitals and identified those having neutralizing anti-IFNγ Abs (cases). Demographics, medical history, initial presentations and laboratory data, causative pathogens, tentative diagnoses, and treatment were analysed and compared among individuals having neutralizing anti-IFNγ Abs (cases) and those without (controls). RESULTS: Among the 154 patients enrolled, neutralizing anti-IFN-γ Abs were detected in 50 (71%) of 70 patients with disseminated non-tuberculous mycobacterial infection (dNTM) but not in 84 patients without dNTM. The median time from disease onset to the recognition of dNTM associated with neutralizing anti-IFNγ Abs was 1.6 years (range, 0.25-19 years). Incorrect tentative diagnoses resulted in the administration of anti-tuberculosis regimens (60%, 30/50), immunosuppressants (48%, 24/50), and systemic chemotherapy (2%, 10/50) to the 50 cases. Multivariate analysis revealed that case patients were more likely than controls to present with multiple bone lesions (adjusted odds ratio (OR), 27.16; 95% confidence interval (CI), 1.21-609.59) and leukocytosis (adjusted OR, 1.48; 95% CI, 1.12-1.95); however, the controls had a higher rate of mycobacterial bloodstream infection (adjusted OR, 0.05; 95% CI 0.00-0.66). CONCLUSIONS: The high rate of incorrect tentative diagnoses led to frequent inappropriate management in patients with neutralizing anti-IFNγ Abs, and highlighted the need for increased awareness among clinicians.

Endodontic considerations of survival rate for autotransplanted third molars: a nationwide population-based study.

AIM: To investigate whether the timing of root canal treatment (primary aim) or other endodontic parameters (secondary aim) is associated with the survival probability of autotransplanted third molars, using a nationwide population-based database. METHODOLOGY: A total of 1811 third molars autotransplanted between 2000 and 2013 met the inclusion criteria and were followed until the end of 2016. The teeth were classified into three groups on the basis of timing between root canal treatment and the autotransplantation: preoperative, extraoral and postoperative treatment groups. Univariate and multivariate Cox proportional hazards models were used to estimate the association between the timing of root canal treatment and the risk of tooth extraction after autotransplantation. RESULTS: Of the 1811 autotransplanted third molars, 462 were extracted, yielding a 17-year survival probability of 0.578. The survival probability of autotransplanted teeth that received postoperative root fillings after 17 years was 0.583, which was significantly higher than the 0.434 and 0.566 for teeth that received preoperative and extraoral root fillings, respectively (P = 0.0013). After adjustment for potential confounding factors, teeth that received postoperative root fillings were associated with a significantly lower tooth extraction hazard ratio (HR) compared with those that received extraoral root fillings (adjusted HR, 1.43; 95% confidence interval [CI], 1.14-1.78) and those that received preoperative root fillings (adjusted HR, 2.13; 95% CI, 1.19-3.82). Furthermore, the use of a rubber dam during postoperative root filling was associated with a significantly lower extraction rate after autotransplantation (adjusted HR, 0.54; 95% CI, 0.43-0.69). CONCLUSIONS: Postoperative root canal treatment resulted in a significantly lower extraction rate than did preoperative or extraoral root canal treatment amongst autotransplanted third molars during a mean follow-up period of 8.33 years. Rubber dam use is recommended during postoperative root canal treatment to improve the outcomes of autotransplantation.

Association of depression and diabetes complications and mortality: a population-based cohort study.

AIMS: Several studies suggested that depression might worsen the clinical outcome of diabetes mellitus; however, such association was confounded by duration of illness and baseline complications. This study aimed to assess whether depression increases the risk of diabetes complications and mortality among incident patients with diabetes. METHODS: This was a population-based matched cohort study using Taiwan's National Health Insurance Research Database. A total of 38 537 incident patients with diabetes who had depressive disorders and 154 148 incident diabetes patients without depression who were matched by age, sex and cohort entry year were randomly selected. The study endpoint was the development of macrovascular and microvascular complications, all-cause mortality and cause-specific mortality. RESULTS: Among participants, the mean (±SD) age was 52.61 (±12.45) years, and 39.63% were male. The average duration of follow-up for mortality was 5.5 years, ranging from 0 to 14 years. The adjusted hazard ratios were 1.35 (95% confidence interval [CI], 1.32-1.37) for macrovascular complications and 1.08 (95% CI, 1.04-1.12) for all-cause mortality. However, there was no association of depression with microvascular complications, mortality due to cardiovascular diseases or mortality due to diabetes mellitus. The effect of depression on diabetes complications and mortality was more prominent among young adults than among middle-aged and older adults. CONCLUSIONS: Depression was associated with macrovascular complications and all-cause mortality in our patient cohort. However, the magnitude of association was less than that in previous studies. Further research should focus on the benefits and risks of treatment for depression on diabetes outcome.

Standardization of Temporal Bone CT Planes across a Multisite Academic Institution.

BACKGROUND AND PURPOSE: Variable head positioning in the CT gantry results in variable and inconsistent temporal bone imaging planes. Our aim was to evaluate whether an automated postprocessing algorithm or an educational intervention with postprocessing by a technologist could result in consistent temporal bone image reformations into planes referenced to the lateral semicircular canal. MATERIALS AND METHODS: Instructions to reformat small-FOV images in planes referenced to the lateral semicircular canal were posted at 12 CT scanner consoles and e-mailed to 65 CT technologists at a single multisite institution. Automated reformatted images were also produced. The angles between the technologist- and automated-reformatted axial image planes and lateral semicircular canal planes were measured. Group differences were calculated with Mann-Whitney-Wilcoxon tests. Differences in homogeneity of variances were calculated with Fligner-Killeen tests. RESULTS: Two hundred ten temporal bones were imaged in 4 months following the intervention. Reformats by technologists were accurate in 87% of the axial and 81% of the coronal planes, with a trend toward improvement with time. Eighty percent of incorrectly reformatted images occurred at off-site, inpatient, and emergency department scanners. The error angle was significantly lower for technologist-reformatted images (median, 4.9°) than for acquisition plane images (median, 14.6°; P = 3 × 10-14) or automated-reformatted images (median, 13.8°; P = 9 × 10-13). The angle error variance was significantly more homogeneous for technologist-reformatted images (P = 3 × 10-8) and automated-reformatted images (P = 1 × 10-5) than for acquisition plane images. CONCLUSIONS: Both technologist and automated reformatting of temporal bone images resulted in significantly less imaging plane variance compared with images reformatted in the acquisition plane, but reformatting by technologists remains necessary at our institution given our preference for standardized planes referencing the lateral semicircular canals.

Erratum: First Dark Matter Constraints from a SuperCDMS Single-Charge Sensitive Detector [Phys. Rev. Lett. 121, 051301 (2018)].

This corrects the article DOI: 10.1103/PhysRevLett.121.051301.

First Dark Matter Constraints from a SuperCDMS Single-Charge Sensitive Detector.

We present the first limits on inelastic electron-scattering dark matter and dark photon absorption using a prototype SuperCDMS detector having a charge resolution of 0.1 electron-hole pairs (CDMS HVeV, a 0.93 g CDMS high-voltage device). These electron-recoil limits significantly improve experimental constraints on dark matter particles with masses as low as 1 MeV/c^{2}. We demonstrate a sensitivity to dark photons competitive with other leading approaches but using substantially less exposure (0.49 g d). These results demonstrate the scientific potential of phonon-mediated semiconductor detectors that are sensitive to single electronic excitations.

Results from the Super Cryogenic Dark Matter Search Experiment at Soudan.

We report the result of a blinded search for weakly interacting massive particles (WIMPs) using the majority of the SuperCDMS Soudan data set. With an exposure of 1690 kg d, a single candidate event is observed, consistent with expected backgrounds. This analysis (combined with previous Ge results) sets an upper limit on the spin-independent WIMP-nucleon cross section of 1.4×10^{-44} (1.0×10^{-44}) cm^{2} at 46 GeV/c^{2}. These results set the strongest limits for WIMP-germanium-nucleus interactions for masses >12 GeV/c^{2}.

Effect of aerobic exercise on cancer-associated cognitive impairment: A proof-of-concept RCT.

BACKGROUND: Change in cognitive ability is a commonly reported adverse effect by breast cancer survivors. The underlying etiology of cognitive complaints is unclear and to date, there is limited evidence for effective intervention strategies. Exercise has been shown to improve cognitive function in older adults and animal models treated with chemotherapy. This proof-of-concept randomized controlled trial tested the effect of aerobic exercise versus usual lifestyle on cognitive function in postmenopausal breast cancer survivors. METHODS: Women, aged 40 to 65 years, postmenopausal, stages I to IIIA breast cancer, and who self-reported cognitive dysfunction following chemotherapy treatment, were recruited and randomized to a 24-week aerobic exercise intervention (EX; n = 10) or usual lifestyle control (CON; n = 9). Participants completed self-report measures of the impact of cognitive issues on quality of life (Functional Assessment of Cancer Therapy-Cognitive version 3), objective neuropsychological testing, and functional magnetic resonance imaging at baseline and 24 weeks. RESULTS: Compared to CON, EX had a reduced time to complete a processing speed test (trail making test-A) (-14.2 seconds, P < .01; effect size 0.35). Compared to CON, there was no improvement in self-reported cognitive function and effect sizes were small. Interestingly, lack of between-group differences in Stroop behavioral performance was accompanied by functional changes in several brain regions of interest in EX compared to CON at 24 weeks. CONCLUSION: These findings provide preliminary proof-of-concept results for the potential of aerobic exercise to improve cancer-related cognitive impairment and will serve to inform the development of future trials.

Long-term survival outcomes of triple-receptor negative breast cancer survivors who are disease free at 5 years and relationship with low hormone receptor positivity.

BACKGROUND: We counsel our triple-negative breast cancer (TNBC) patients that the risk of recurrence is highest in the first 5 years after diagnosis. However, there are limited data with extended follow-up on the frequency, characteristics, and predictors of late events. METHODS: We queried the MD Anderson Breast Cancer Management System database to identify patients with stage I-III TNBC who were disease free at 5 years from diagnosis. The Kaplan-Meier method was used to estimate yearly recurrence-free interval (RFI), recurrence-free survival (RFS), and distant relapse-free survival (DRFS), as defined by the STEEP criteria. Cox proportional hazards model was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We identified 873 patients who were disease free at least 5 years from diagnosis with median follow-up of 8.3 years. The 10-year RFI was 97%, RFS 91%, and DRFS 92%; the 15-year RFI was 95%, RFS 83%, and DRFS 84%. On a subset of patients with oestrogen receptor and progesterone receptor percentage recorded, low hormone receptor positivity conferred higher risk of late events on multivariable analysis for RFS only (RFI: HR=1.98, 95% CI=0.70-5.62, P-value=0.200; RFS: HR=1.94, 95% CI=1.05-3.56, P-value=0.034; DRFS: HR=1.72, 95% CI=0.92-3.24, P-value=0.091). CONCLUSIONS: The TNBC survivors who have been disease free for 5 years have a low probability of experiencing recurrence over the subsequent 10 years. Patients with low hormone receptor-positive cancers may have a higher risk of late events as measured by RFS but not by RFI or DRFS.

Neural mechanisms of single corrective steps evoked in the standing rabbit.

Single steps in different directions are often used for postural corrections. However, our knowledge about the neural mechanisms underlying their generation is scarce. This study was aimed to characterize the corrective steps generated in response to disturbances of the basic body configuration caused by forward, backward or outward displacement of the hindlimb, as well as to reveal location in the CNS of the corrective step generating mechanisms. Video recording of the motor response to translation of the supporting surface under the hindlimb along with contact forces and activity of back and limb muscles was performed in freely standing intact and in fixed postmammillary rabbits. In intact rabbits, displacement of the hindlimb in any direction caused a lateral trunk movement toward the contralateral hindlimb, and then a corrective step in the direction opposite to the initial displacement. The time difference between onsets of these two events varied considerably. The EMG pattern in the supporting hindlimb was similar for all directions of corrective steps. It caused the increase in the limb stiffness. EMG pattern in the stepping limb differed in steps with different directions. In postmammillary rabbits the corrective stepping movements, as well as EMG patterns in both stepping and standing hindlimbs were similar to those observed in intact rabbits. This study demonstrates that the corrective trunk and limb movements are generated by separate mechanisms activated by sensory signals from the deviated limb. The neuronal networks generating postural corrective steps reside in the brainstem, cerebellum, and spinal cord.