Properties of Cosmic Deuterons Measured by the Alpha Magnetic Spectrometer.

Precision measurements by the Alpha Magnetic Spectrometer (AMS) on the International Space Station of the deuteron (D) flux are presented. The measurements are based on 21×10^{6} D nuclei in the rigidity range from 1.9 to 21 GV collected from May 2011 to April 2021. We observe that over the entire rigidity range the D flux exhibits nearly identical time variations with the p, ^{3}He, and ^{4}He fluxes. Above 4.5 GV, the D/^{4}He flux ratio is time independent and its rigidity dependence is well described by a single power law ∝R^{Δ} with Δ_{D/^{4}He}=-0.108±0.005. This is in contrast with the ^{3}He/^{4}He flux ratio for which we find Δ_{^{3}He/^{4}He}=-0.289±0.003. Above ∼13 GV we find a nearly identical rigidity dependence of the D and p fluxes with a D/p flux ratio of 0.027±0.001. These unexpected observations indicate that cosmic deuterons have a sizable primarylike component. With a method independent of cosmic ray propagation, we obtain the primary component of the D flux equal to 9.4±0.5% of the ^{4}He flux and the secondary component of the D flux equal to 58±5% of the ^{3}He flux.

Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer patients with brain metastases from the randomized DESTINY-Breast03 trial.

BACKGROUND: DESTINY-Breast03 is a randomized, multicenter, open-label, phase III study of trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab and a taxane. A statistically significant improvement in progression-free survival (PFS) versus T-DM1 was reported in the primary analysis. Here, we report exploratory efficacy data in patients with and without brain metastases (BMs) at baseline. PATIENTS AND METHODS: Patients were randomly assigned 1 : 1 to receive T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg. Patients with clinically inactive/asymptomatic BMs were eligible. Lesions were measured as per modified RECIST, version 1.1. Outcomes included PFS by blinded independent central review (BICR), objective response rate (ORR), and intracranial ORR as per BICR. RESULTS: As of 21 May 2021, 43/261 patients randomized to T-DXd and 39/263 patients randomized to T-DM1 had BMs at baseline, as per investigator assessment. Among patients with baseline BMs, 20/43 in the T-DXd arm and 19/39 in the T-DM1 arm had not received prior local BM treatment. For patients with BMs, median PFS was 15.0 months [95% confidence interval (CI) 12.5-22.2 months] for T-DXd versus 3.0 months (95% CI 2.8-5.8 months) for T-DM1; hazard ratio (HR) 0.25 (95% CI 0.13-0.45). For patients without BMs, median PFS was not reached (95% CI 22.4 months-not estimable) for T-DXd versus 7.1 months (95% CI 5.6-9.7 months) for T-DM1; HR 0.30 (95% CI 0.22-0.40). Confirmed systemic ORR was 67.4% for T-DXd versus 20.5% for T-DM1 and 82.1% for T-DXd versus 36.6% for T-DM1 for patients with and without BMs, respectively. Intracranial ORR was 65.7% with T-DXd versus 34.3% with T-DM1. CONCLUSIONS: Patients with HER2-positive mBC whose disease progressed after trastuzumab and a taxane achieved a substantial benefit from treatment with T-DXd compared with T-DM1, including those with baseline BMs.

Influence of Obstructive Sleep Apnea on the Risk of Dental Caries: Insights from a 13-Year Population-Based Retrospective Study.

KNOWLEDGE TRANSFER STATEMENT: Obstructive sleep apnea has been proven to have a great negative impact on patients, and the relationship between sleep apnea and dental caries is still inconclusive. Our study shows that patients with sleep apnea and those older than 45 y have a significant risk of dental caries.

Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

Low household income increases the risk of tuberculosis recurrence: a retrospective nationwide cohort study in South Korea.

OBJECTIVES: We assessed the impact of household income on tuberculosis (TB) recurrence and the long-term impact of TB on household income. STUDY DESIGN: This was a retrospective nationwide cohort study of patients with drug-susceptible TB (DS-TB) and TB recurrence. METHODS: Using the South Korean national TB cohort database, we identified a sub-set cohort of patients with newly diagnosed drug-susceptible TB between 2013 and 2016 and tracked their TB recurrence and longitudinal income data from 2007 to 2018. Income levels were evaluated as 'Medical aid' and quintile categories. To assess risk factors associated with TB recurrence, we used a sub-distribution hazard model, adjusting for the competing risks of death. RESULTS: Of 66,690 patients successfully treated with DS-TB, 2095 (3.1 %) experienced recurrence during a median follow-up of 39 months. The incidence of TB recurrence was 982.1/100,000 person-years, with 50.3 % of the recurrences occurring within 1 year of treatment completion. The risk of TB recurrence increased with decreasing income levels, with the highest risk observed in the lowest income group. The effect of income on TB recurrence was prominent in males but not in females. Overall, patients with TB recurrence experienced a linear decline in income levels, compared with those without recurrence. CONCLUSIONS: Household income during the initial TB episode was an important risk factor for TB recurrence, particularly in males.

Treatment outcome, recurrence and safety of multidrug-resistant TB treated with low-dose linezolid.

BACKGROUND: Linezolid (LZD) is a key treatment option for patients with multidrug-resistant/rifampicin-resistant TB (MDR/RR-TB). We investigated the long-term treatment outcomes and safety of MDR/RR-TB treatment using low-dose LZD.METHODS: Medical records of patients with MDR/RR-TB treated with LZD ≥4 weeks between 2004 and 2018 at the Asan Medical Center, Seoul, Republic of Korea, were reviewed. Standard-dose and low-dose LZD groups were defined as patients initially administered LZD ≥600 mg/day or 300 mg/day, respectively.RESULTS: Among 94 patients, 65 were included in the low-dose LZD group; mean age was 43.1 ± 15.6 years, 53 (56.4%) were men and 77 (83.7%) were resistant to fluoroquinolone. The low-dose LZD group showed features of less severe disease, such as limited MDR-TB history and less severe radiological findings. There was no difference in treatment outcomes, relapse and safety between groups. In the low-dose LZD group, 54 (83.1%) succeeded treatment, of whom 48 (88.9%) were followed-up for a median of 38 months; there was no recurrence. Adverse drug reactions were reported in 41 (63.1%); peripheral neuropathy was most frequently reported (n = 31, 47.7%), while myelosuppression was reported in 12 (18.5%).CONCLUSION: Low-dose LZD in selected patients with less severe disease is both effective in the long-term and safe for the treatment of MDR/RR-TB.

Temporal Structures in Positron Spectra and Charge-Sign Effects in Galactic Cosmic Rays.

We present the precision measurements of 11 years of daily cosmic positron fluxes in the rigidity range from 1.00 to 41.9 GV based on 3.4×10^{6} positrons collected with the Alpha Magnetic Spectrometer (AMS) aboard the International Space Station. The positron fluxes show distinctly different time variations from the electron fluxes at short and long timescales. A hysteresis between the electron fluxes and the positron fluxes is observed with a significance greater than 5σ at rigidities below 8.5 GV. On the contrary, the positron fluxes and the proton fluxes show similar time variation. Remarkably, we found that positron fluxes are modulated more than proton fluxes with a significance greater than 5σ for rigidities below 7 GV. These continuous daily positron fluxes, together with AMS daily electron, proton, and helium fluxes over an 11-year solar cycle, provide unique input to the understanding of both the charge-sign and mass dependencies of cosmic rays in the heliosphere.

Damage control surgery: old concepts and new indications.

PURPOSE OF REVIEW: While the principles of damage control surgery - rapid hemorrhage and contamination control with correction of physiologic derangements followed by delayed definitive reconstruction - have remained consistent, forms of damage control intervention have evolved and proliferated dramatically. This review aims to provide a historic perspective of the early trends of damage control surgery as well as an updated understanding of its current state and future trends. RECENT FINDINGS: Physiologically depleted patients in shock due to both traumatic and nontraumatic causes are often treated with damage control laparotomy and surgical principles. Damage control surgery has also been shown to be safe and effective in thoracic and orthopedic injuries. Damage control resuscitation is used in conjunction with surgical source control to restore patient physiology and prevent further collapse. The overuse of damage control laparotomy, however, is associated with increased morbidity and complications. With advancing technology, catheter- and stent-based endovascular modalities are playing a larger role in the resuscitation and definitive care of patients. SUMMARY: Optimal outcome in the care of the most severely injured patients requires judicious use of damage control surgery supplemented by advancements in resuscitation and surgical adjuncts.

Properties of Cosmic-Ray Sulfur and Determination of the Composition of Primary Cosmic-Ray Carbon, Neon, Magnesium, and Sulfur: Ten-Year Results from the Alpha Magnetic Spectrometer.

We report the properties of primary cosmic-ray sulfur (S) in the rigidity range 2.15 GV to 3.0 TV based on 0.38×10^{6} sulfur nuclei collected by the Alpha Magnetic Spectrometer experiment (AMS). We observed that above 90 GV the rigidity dependence of the S flux is identical to the rigidity dependence of Ne-Mg-Si fluxes, which is different from the rigidity dependence of the He-C-O-Fe fluxes. We found that, similar to N, Na, and Al cosmic rays, over the entire rigidity range, the traditional primary cosmic rays S, Ne, Mg, and C all have sizeable secondary components, and the S, Ne, and Mg fluxes are well described by the weighted sum of the primary silicon flux and the secondary fluorine flux, and the C flux is well described by the weighted sum of the primary oxygen flux and the secondary boron flux. The primary and secondary contributions of the traditional primary cosmic-ray fluxes of C, Ne, Mg, and S (even Z elements) are distinctly different from the primary and secondary contributions of the N, Na, and Al (odd Z elements) fluxes. The abundance ratio at the source for S/Si is 0.167±0.006, for Ne/Si is 0.833±0.025, for Mg/Si is 0.994±0.029, and for C/O is 0.836±0.025. These values are determined independent of cosmic-ray propagation.

Genome-wide mapping of gene-microbe interactions in the murine lung microbiota based on quantitative microbial profiling.

BACKGROUND: Mammalian lungs comprise a complex microbial ecosystem that interacts with host physiology. Previous research demonstrates that the environment significantly contributes to bacterial community structure in the upper and lower respiratory tract. However, the influence of host genetics on the makeup of lung microbiota remains ambiguous, largely due to technical difficulties related to sampling, as well as challenges inherent to investigating low biomass communities. Thus, innovative approaches are warranted to clarify host-microbe interactions in the mammalian lung. RESULTS: Here, we aimed to characterize host genomic regions associated with lung bacterial traits in an advanced intercross mouse line (AIL). By performing quantitative microbial profiling (QMP) using the highly precise method of droplet digital PCR (ddPCR), we refined 16S rRNA gene amplicon-based traits to identify and map candidate lung-resident taxa using a QTL mapping approach. In addition, the two abundant core taxa Lactobacillus and Pelomonas were chosen for independent microbial phenotyping using genus-specific primers. In total, this revealed seven significant loci involving eight bacterial traits. The narrow confidence intervals afforded by the AIL population allowed us to identify several promising candidate genes related to immune and inflammatory responses, cell apoptosis, DNA repair, and lung functioning and disease susceptibility. Interestingly, one genomic region associated with Lactobacillus abundance contains the well-known anti-inflammatory cytokine Il10, which we confirmed through the analysis of Il10 knockout mice. CONCLUSIONS: Our study provides the first evidence for a role of host genetic variation contributing to variation in the lung microbiota. This was in large part made possible through the careful curation of 16S rRNA gene amplicon data and the incorporation of a QMP-based methods. This approach to evaluating the low biomass lung environment opens new avenues for advancing lung microbiome research using animal models.

Behaviors of AlGaN Strain Relaxation on a GaN Porous Structure Studied with d-Spacing Crystal Lattice Analysis.

The high porosity of a GaN porous structure (PS) makes it mechanically semi-flexible and can shield against the stress from the thick growth template on an overgrown layer to control the lattice structure or composition within the overgrown layer. To understand this stress shield effect, we investigated the lattice constant variations among different growth layers in various samples of overgrown Al0.3Ga0.7N on GaN templates under different strain-relaxation conditions based on d-spacing crystal lattice analysis. The fabrication of a strain-damping PS in a GaN template shields against the stress from the thick GaN template on the GaN interlayer, which lies between the PS and the overgrown AlGaN layer, such that the stress counteraction of the AlGaN layer against the GaN interlayer can reduce the tensile strain in AlGaN and increase its critical thickness. If the GaN interlayer is thin, such that a strong AlGaN counteraction occurs, the increased critical thickness can become larger than the overgrown AlGaN thickness. In this situation, crack-free, thick AlGaN overgrowth is feasible.

Temporal Structures in Electron Spectra and Charge Sign Effects in Galactic Cosmic Rays.

We present the precision measurements of 11 years of daily cosmic electron fluxes in the rigidity interval from 1.00 to 41.9 GV based on 2.0×10^{8} electrons collected with the Alpha Magnetic Spectrometer (AMS) aboard the International Space Station. The electron fluxes exhibit variations on multiple timescales. Recurrent electron flux variations with periods of 27 days, 13.5 days, and 9 days are observed. We find that the electron fluxes show distinctly different time variations from the proton fluxes. Remarkably, a hysteresis between the electron flux and the proton flux is observed with a significance of greater than 6σ at rigidities below 8.5 GV. Furthermore, significant structures in the electron-proton hysteresis are observed corresponding to sharp structures in both fluxes. This continuous daily electron data provide unique input to the understanding of the charge sign dependence of cosmic rays over an 11-year solar cycle.

Rule of four: an anatomic and value-based approach to stent-graft inventory for blunt thoracic aortic injury.

PURPOSE: As blunt thoracic aortic injury (BTAI) treatment has shifted from open to thoracic endovascular aortic repair (TEVAR), logistical challenges exist in creating and maintaining inventories of appropriately sized stent-grafts, including storage demands, shelf-life management and cost. We hypothesized that most injured aortas can be successfully repaired with a narrow range of stent-graft sizes and present a value-based anatomic approach to optimizing inventory. METHODS: CT-scans of all patients with BTAI admitted to our Level I trauma center from Apr 2010-Dec 2018 were reviewed. Patients with anatomy incompatible with TEVAR were excluded. For each patient, after aortic sizing a set of two stent-grafts most likely to be utilized was selected from a list of twenty commercially available GORE conformable TAG endografts based on manufacturer instructions. Stent-graft sizes were then ranked based on the number of cases they would be suitable for. MATLAB was utilized to determine the combinations of stent-grafts which would cover the most patients. RESULTS: Twenty-eight patients with BTAI were identified and three were excluded based on iliac diameter. Most patients were male (68%), mean age 42.3 ± 20.2 years, mean ISS 37.0 ± 9.8. Overall mortality was 25%. Of the 20 available stent-graft options, a combination of four stent-grafts would successfully treat 100% of the patients in this series. CONCLUSIONS: Based on actual CT-scan aortic measurements, we demonstrated that an inventory of four sent-graft sizes was sufficient to treat 100% of patients with BTAI. These data can be utilized as a value-based anatomic approach to aortic stent-graft institutional inventory creation and maintenance.

Effects of Surface Plasmon Coupling on the Color Conversion of an InGaN/GaN Quantum-Well Structure into Colloidal Quantum Dots Inserted into a Nearby Porous Structure.

To further enhance the color conversion from a quantum-well (QW) structure into a color-converting colloidal quantum dot (QD) through Förster resonance energy transfer (FRET), we designed and implemented a device structure with QDs inserted into a GaN nano-porous structure near the QWs to gain the advantageous nanoscale-cavity effect. Additionally, surface Ag nanoparticles were deposited for inducing surface plasmon (SP) coupling with the QW structure. Based on the measurements of time-resolved and continuous-wave photoluminescence spectroscopies, the FRET efficiency from QW into QD is enhanced through the SP coupling. In particular, performance in the polarization perpendicular to the essentially extended direction of the fabricated pores in the nano-porous structure is more strongly enhanced when compared with the other linear polarization. A numerical simulation study was undertaken, and showed consistent results with the experimental observations.

Age- and Sex-Different Associations between Cognitive Performance and Inflammatory Biomarkers in Community Dwelling Older Adults: towards Precision Preventive Strategies.

BACKGROUND: Studies have demonstrated associations between inflammatory biomarkers and cognitive function in people with dementia or stroke, but little is known regarding these associations in healthy middle-aged and older populations. OBJECTIVES: This study aims to examine associations between inflammatory biomarkers (both vascular and systemic) and cognitive performance in stroke- and dementia-free middle-aged and older adults without apolipoprotein E4 (ApoE ε4) allele carriers. DESIGN: A cross-sectional study. SETTING: Social Environment and Biomarkers of Aging Study (SEBAS) 2006. PARTICIPANTS: A total of 983 participants aged 53 years and older. MEASUREMENTS: Composite cognitive function assessment, including the Short Portable Mental Status Questionnaire, the Rey Auditory Verbal Learning Test, and the Wechsler Adult Intelligence Scale. Overnight venous blood sampling for 6 inflammatory biomarkers (C-reactive protein, interleukin-6, fibrinogen, homocysteine, intercellular adhesion molecule-1 and E-selectin) and ApoE genotyping. RESULTS: Among 983 participants (mean age: 65.8±9.5 years), 808 were non-ApoE e4 allele carriers and were stroke- and dementia-free. Higher log fibrinogen was associated with poorer cognitive function after adjustment for potential confounding factors in non-ApoE e4 allele carriers and stroke- and dementia-free populations (unstandardized coefficients ß= -1.553, P value= 0.003). In participants aged 65 years or older, both of elevated fibrinogen and homocysteine were associated with poorer cognitive function (ß= -2.288, P value= 0.015; ß= -1.331, P value= 0.012, respectively). Elevated log CRP was significantly associated with lower cognitive function only in women (ß= -0.514, P value= 0.024). CONCLUSION: Higher serum levels of fibrinogen were negatively associated with cognitive function, which was independent of ApoE genotyping and prior cerebrovascular events in dementia-free community-dwelling older adults. Further studies are needed to validate the roles of fibrinogen in the pathophysiology of dementia and elucidate the underlying mechanisms.

Concordance of diagnostic modalities in atypical skin and soft tissue infections in hospitalized patients.

Skin and soft tissue infections (SSTIs) have high rates of morbidity and mortality worldwide but lack reliable standards for diagnostic workup. As a result, atypical infections, more prevalent among immunocompromised patients, can be missed due to deviance from classic features only to be revealed later through inconsistently performed ancillary studies. Our objectives included to evaluate the sensitivities of clinical impression, histopathology, tissue culture, and molecular and non-molecular ancillary tests in diagnosing inpatient SSTIs, as well as to qualitatively discuss the unusual features making a subset of infections "atypical." To do so, we retrospectively reviewed the histopathologic reports and charts of inpatient dermatologic consults at a single tertiary care institution over a 3-year period. We identified a total of 111 cases of SSTIs evaluated by the inpatient dermatology consultation service with concurrent skin or soft tissue biopsy, with 32.4% representing atypical infections. Among these, clinical impression suggested infection in 9(25.0%), routine histopathology in 21(58.3%), specialized stains for microorganisms in 22(68.8%), and tissue culture in 15(68.2%). Due to incomplete picture that each modality by itself creates, we conclude that clinicians and pathologists should carry a low threshold for including SSTIs in their differential diagnoses and should evaluate with skin biopsy, special stains for microorganisms, and ancillary studies, particularly in critically ill individuals who necessitate timely diagnoses.

The promising role of risk scoring system for Cushing syndrome: Time to reconsider current screening recommendations.

Despite the current screening approach for Cushing syndrome (CS), delayed diagnosis is common due to broad spectrum of presentation, poor discriminant symptoms featured in diabetes and obesity, and low clinical index of suspicion. Even if initial tests are recommended to screen CS, divergent results are not infrequent. As global prevalence of type 2 diabetes and obesity increases, CS may not be frequent enough to back routine screening to avoid false-positive results. This represents a greater challenge in countries with limited health resources. The development of indexes incorporates clinical features and biochemical data that are largely used to provide a tool to predict the presence of disease. In clinical endocrinology, indexes have been used in Graves' ophthalmology, hirsutism, and hypothyroidism. The use of clinical risk scoring system may assist clinicians in discriminating CS in the context of at-risk populations and, thus, may provide a potential intervention to decrease time to diagnosis. Development and validation of clinical model to estimate pre-test probability of CS in different geographic source population may help to establish regional prediction model for CS. Here, we review on the latest progress in clinical risk scoring system for CS and attempt to raise awareness for the use, validation, and/or development of clinical risk scores in CS.