Numerical investigation of nonequilibrium electron effects on the collisional ionization rate in the collisional-radiative model.

The interplay of kinetic electron physics and atomic processes in ultrashort laser-plasma interactions provides a comprehensive understanding of the impact of the electron energy distribution on plasma properties. Notably, nonequilibrium electrons play a vital role in collisional ionization, influencing ionization degrees and spectra. This paper introduces a computational model that integrates the physics of kinetic electrons and atomic processes, utilizing a Boltzmann equation for nonequilibrium electrons and a collisional-radiative model for atomic state populations. The model is used to investigate the influence of nonequilibrium electrons on collisional ionization rates and its effect on the population distribution, as observed in a widely known experiment [Young et al., Nature (London) 466, 56 (2010)0028-083610.1038/nature09177]. The study reveals a significant nonequilibrium electron presence during XFEL-matter interactions, profoundly affecting collisional ionization rates in the gas plasma, thereby necessitating careful consideration of the Collisional-Radiative model applied to such systems.

Motional Squeezing for Trapped Ion Transport and Separation.

Transport, separation, and merging of trapped ion crystals are essential operations for most large-scale quantum computing architectures. In this Letter, we develop a theoretical framework that describes the dynamics of ions in time-varying potentials with a motional squeeze operator, followed by a motional displacement operator. Using this framework, we develop a new, general protocol for trapped ion transport, separation, and merging. We show that motional squeezing can prepare an ion wave packet to enable transfer from the ground state of one trapping potential to another. The framework and protocol are applicable if the potential is harmonic over the extent of the ion wave packets at all times. As illustrations, we discuss two specific operations: changing the strength of the confining potential for a single ion and separating same-species ions with their mutual Coulomb force. Both of these operations are, ideally, free of residual motional excitation.

Optimal choice of multiple line-of-sight measurements determining plasma hotspot velocity at the National Ignition Facility.

The measurement of plasma hotspot velocity provides an important diagnostic of implosion performance for inertial confinement fusion experiments at the National Ignition Facility. The shift of the fusion product neutron mean kinetic energy as measured along multiple line-of-sight time-of-flight spectrometers provides velocity vector components from which the hotspot velocity is inferred. Multiple measurements improve the hotspot velocity inference; however, practical considerations of available space, operational overhead, and instrumentation costs limit the number of possible line-of-sight measurements. We propose a solution to this classical "experiment design" problem that optimizes the precision of the velocity inference for a limited number of measurements.

A genetic algorithm approach for reconstructing spectral content from filtered x-ray diode array spectrometers.

Filtered diode array spectrometers are routinely employed to infer the temporal evolution of spectral power from x-ray sources, but uniquely extracting spectral content from a finite set of broad, spectrally overlapping channel spectral sensitivities is decidedly nontrivial in these under-determined systems. We present the use of genetic algorithms to reconstruct a probabilistic spectral intensity distribution and compare to the traditional approach most commonly found in the literature. Unlike many of the previously published models, spectral reconstructions from this approach are neither limited by basis functional forms nor do they require a priori spectral knowledge. While the original intent of such measurements was to diagnose the temporal evolution of spectral power from quasi-blackbody radiation sources-where the exact details of spectral content were not thought to be crucial-we demonstrate that this new technique can greatly enhance the utility of the diagnostic by providing more physical spectra and improved robustness to hardware configuration for even strongly non-Planckian distributions.

Impact of a deep learning assistant on the histopathologic classification of liver cancer.

Artificial intelligence (AI) algorithms continue to rival human performance on a variety of clinical tasks, while their actual impact on human diagnosticians, when incorporated into clinical workflows, remains relatively unexplored. In this study, we developed a deep learning-based assistant to help pathologists differentiate between two subtypes of primary liver cancer, hepatocellular carcinoma and cholangiocarcinoma, on hematoxylin and eosin-stained whole-slide images (WSI), and evaluated its effect on the diagnostic performance of 11 pathologists with varying levels of expertise. Our model achieved accuracies of 0.885 on a validation set of 26 WSI, and 0.842 on an independent test set of 80 WSI. Although use of the assistant did not change the mean accuracy of the 11 pathologists (p = 0.184, OR = 1.281), it significantly improved the accuracy (p = 0.045, OR = 1.499) of a subset of nine pathologists who fell within well-defined experience levels (GI subspecialists, non-GI subspecialists, and trainees). In the assisted state, model accuracy significantly impacted the diagnostic decisions of all 11 pathologists. As expected, when the model's prediction was correct, assistance significantly improved accuracy (p = 0.000, OR = 4.289), whereas when the model's prediction was incorrect, assistance significantly decreased accuracy (p = 0.000, OR = 0.253), with both effects holding across all pathologist experience levels and case difficulty levels. Our results highlight the challenges of translating AI models into the clinical setting, and emphasize the importance of taking into account potential unintended negative consequences of model assistance when designing and testing medical AI-assistance tools.

Missed diagnosis and misdiagnosis of infectious diseases in hematopoietic cell transplant recipients: an autopsy study.

Hematopoietic cell transplantation (HCT) is potentially curative for patients with hematologic disorders, but carries significant risks of infection-related morbidity and mortality. Infectious diseases are the second most common cause of death in HCT recipients, surpassed only by progression of underlying disease. Many infectious diseases are difficult to diagnose and treat, and may only be first identified by autopsy. However, autopsy rates are decreasing despite their value. The clinical and autopsy records of adult HCT recipients at our center who underwent autopsy between 1 January 2000 and 31 December 2017 were reviewed. Discrepancies between premortem clinical diagnoses and postmortem autopsy diagnoses were evaluated. Of 185 patients who underwent autopsy, 35 patients (18.8%) had a total of 41 missed infections. Five patients (2.7%) had >1 missed infection. Of the 41 missed infections, 18 (43.9%) were viral, 16 (39.0%) were fungal, 5 (12.2%) were bacterial, and 2 (4.9%) were parasitic. According to the Goldman criteria, 31 discrepancies (75.6%) were class I, 5 (12.2%) were class II, 1 (2.4%) was class III, and 4 (9.8%) were class IV. Autopsies of HCT recipients frequently identify clinically significant infectious diseases that were not suspected premortem. Had these infections been suspected, a change in management might have improved patient survival in many of these cases. Autopsy is underutilized and should be performed regularly to help improve infection-related morbidity and mortality. Illustrative cases are presented and the lessons learned from them are also discussed.

Versatile laser-free trapped-ion entangling gates.

We present a general theory for laser-free entangling gates with trapped-ion hyperfine qubits, using either static or oscillating magnetic-field gradients combined with a pair of uniform microwave fields symmetrically detuned about the qubit frequency. By transforming into a 'bichromatic' interaction picture, we show that either σ ^ ϕ ⊗ σ ^ ϕ or σ ^ z ⊗ σ ^ z geometric phase gates can be performed. The gate basis is determined by selecting the microwave detuning. The driving parameters can be tuned to provide intrinsic dynamical decoupling from qubit frequency fluctuations. The σ ^ z ⊗ σ ^ z gates can be implemented in a novel manner which eases experimental constraints. We present numerical simulations of gate fidelities assuming realistic parameters.

The curli regulator CsgD mediates stationary phase counter-silencing of csgBA in Salmonella Typhimurium.

Integration of horizontally acquired genes into transcriptional networks is essential for the regulated expression of virulence in bacterial pathogens. In Salmonella enterica, expression of such genes is repressed by the nucleoid-associated protein H-NS, which recognizes and binds to AT-rich DNA. H-NS-mediated silencing must be countered by other DNA-binding proteins to allow expression under appropriate conditions. Some genes that can be transcribed by RNA polymerase (RNAP) associated with the alternative sigma factor σS or the housekeeping sigma factor σ70 in vitro appear to be preferentially transcribed by σS in the presence of H-NS, suggesting that σS may act as a counter-silencer. To determine whether σS directly counters H-NS-mediated silencing and whether co-regulation by H-NS accounts for the σS selectivity of certain promoters, we examined the csgBA operon, which is required for curli fimbriae expression and is known to be regulated by both H-NS and σS . Using genetics and in vitro biochemical analyses, we found that σS is not directly required for csgBA transcription, but rather up-regulates csgBA via an indirect upstream mechanism. Instead, the biofilm master regulator CsgD directly counter-silences the csgBA promoter by altering the DNA-protein complex structure to disrupt H-NS-mediated silencing in addition to directing the binding of RNAP.

Salmonella enterica causes more severe inflammatory disease in C57/BL6 Nramp1G169 mice than Sv129S6 mice.

Salmonella enterica serovar Typhimurium (S. Typhimurium) causes systemic inflammatory disease in mice by colonizing cells of the mononuclear leukocyte lineage. Mouse strains resistant to S. Typhimurium, including Sv129S6, have an intact Nramp1 (Slc11a1) allele and survive acute infection, whereas C57/BL6 mice, homozygous for a mutant Nramp1 allele, Nramp1(G169D) , develop lethal infections. Restoration of Nramp1 (C57/BL6 Nramp1(G169) ) reestablishes resistance to S. Typhimurium; mice survive at least 3 to 4 weeks postinfection. Since many transgenic mouse strains are on a C57/BL6 genetic background, C57/BL6 Nramp1(G169) mice provide a model to examine host genetic determinants of resistance to infection. To further evaluate host immune response to S. Typhimurium, we performed comparative analyses of Sv129S6 and C57/BL6 Nramp1(G169) mice 3 weeks following oral S. Typhimurium infection. C57/BL6 Nramp1(G169) mice developed more severe inflammatory disease with splenic bacterial counts 1000-fold higher than Sv129S6 mice and relatively greater splenomegaly and blood neutrophil and monocyte counts. Infected C57/BL6 Nramp1(G169) mice developed higher proinflammatory serum cytokine and chemokine responses (interferon-γ, tumor necrosis factor-α, interleukin [IL]-1ß, and IL-2 and monocyte chemotactic protein-1 and chemokine [C-X-C motif] ligand 1, respectively) and marked decreases in anti-inflammatory serum cytokine concentrations (IL-10, IL-4) compared with Sv129S6 mice postinfection. Splenic dendritic cells and macrophages in infected compared with control mice increased to a greater extent in C57/BL6 Nramp1(G169) mice than in Sv129S6 mice. Overall, data show that despite the Nramp1 gene present in both strains, C57/BL6 Nramp1(G169) mice develop more severe, Th1-skewed, acute inflammatory responses to S. Typhimurium infection compared with Sv129S6 mice. Both strains are suitable model systems for studying inflammation in the context of adaptive immunity.

Severe neuropsychiatric reaction in a deployed military member after prophylactic mefloquine.

Recent studies of military personnel who have deployed to Iraq and Afghanistan have reported a number of combat-related psychiatric disorders such as posttraumatic stress disorder, depression, and traumatic brain injury. This case report involves a 27-year-old male active-duty US military service member who developed severe depression, psychotic hallucinations, and neuropsychological sequelae following the prophylactic use of the antimalarial medication mefloquine hydrochloride. The patient had a recent history of depression and was taking antidepressant medications at the time of his deployment to the Middle East. Psychiatrists and other health care providers should be aware of the possible neuropsychiatric side effects of mefloquine in deployed military personnel and should consider the use of other medications for malaria prophylaxis in those individuals who may be at increased risk for side effects.

Klebsiella pneumoniae bacteraemia in a region of Canada.

The second case of magA+ rmpA+ hypermucoviscosity phenotype Klebsiella pneumoniae infection was documented in Canada, in an immigrant from Algeria. To ascertain whether this represented recent importation of the strain or local transmission within Canada, a retrospective study of K. pneumoniae bacteraemia was conducted in the region, from 1997 to 2007, and 411 episodes were identified. No epidemiological evidence for local transmission of this strain was found. However, for the first time, the population incidence of K. pneumoniae bacteraemia was determined, which increased by 82% between 1997 and 2007, from 10.2 to 18.7 per 100 000 inhabitants. Incidence increased dramatically with age and with the presence of diabetes, but remained stable over time within each stratum. The proportion of patients with K. pneumoniae bacteraemia who were diabetic increased from 26% (1997-2004) to 42% (2005-2007). The rising incidence of K. pneumoniae bacteraemia may represent an unexpected consequence of the expanding population of adult diabetics.

Genioplasty distraction osteogenesis and hyoid advancement for correction of upper airway obstruction in patients with Treacher Collins and Nager syndromes.

BACKGROUND: Treacher Collins and Nager syndromes may present with mandibular hypoplasia that causes posterior collapse of the tongue base and a decreased oropharyngeal airway. Mandibular distraction and orthognathic advancement are effective treatments to correct the airway, but failure may occur despite achieving class I occlusion. For this select population, the authors propose a novel procedure of genioplasty distraction and hyoid advancement to optimize epiglottal positioning. METHODS: Patients diagnosed with Treacher Collins (n = 5) or Nager syndrome (n = 3) with obstructive sleep apnea or tracheostomy dependency (n = 8) underwent genioplasty distraction and hyoid advancement. Airway outcome was assessed by preoperative and 1-year follow-up comparison of (1) laryngobronchoscopy, (2) sleep studies, and (3) tracheostomy dependency. For genioplasty outcome, three groups were used: group I (distraction genioplasty, syndromic) (n = 8), group II (acute genioplasty, syndromic) (n = 7), and group III (acute genioplasty, nonsyndromic) (n = 10). Lateral cephalogram measurements were used in the preoperative, postoperative, and follow-up periods to assess horizontal and vertical advancement and relapse. RESULTS: Epiglottal position was optimized by the procedure in all patients based on direct endoscopic assessment. All five patients with obstructive sleep apnea had resolution of symptoms, and two of three patients achieved removal of their tracheostomy. Mean advancement for groups I, II, and III was 25, 14, and 8 mm, respectively. Follow-up horizontal advancement for groups I, II, and III were 18, 4, and 6 mm, respectively. Cephalometric measurements showed a horizontal relapse for groups I, II, and III of 10, 62, and 11 percent, respectively. CONCLUSIONS: Data suggest that genioplasty distraction allows for a greater advancement and decreased relapse rate than acute procedures alone; and genioplasty distraction with hyoid advancement is a useful technique for resolution of obstructive sleep apnea or to achieve tracheostomy removal in those syndromic patients who have already undergone mandibular advancement into a class I occlusion.

Improved outcomes in cleft patients with severe maxillary deficiency after Le Fort I internal distraction.

BACKGROUND: Correction of severe maxillary deficiency in cleft lip-cleft palate patients often results in undercorrection, relapse, and need for secondary corrective procedures. Le Fort I internal distraction osteogenesis offers an alternative to one-step orthognathic advancement, with advantages of gradual lengthening through scar and earlier treatment in growing patients. METHODS: Patients with cleft lip-cleft palate deformities and maxillary deficiency were divided into three groups treated by Le Fort I advancement: group 1, mild to moderate deficiency (< 10 mm) with conventional orthognathic procedure; group 2, severe deficiency (> or = 10 mm) with conventional orthognathic procedure; and group 3, distraction procedure for severe deficiency (> or = 10 mm) (n = 51). Preoperative, postoperative, and follow-up (> 1 year) lateral cephalogram measurements were compared including angular (SNA and SNB) and linear (Deltax = horizontal and Deltay = vertical) changes. The Pittsburgh Speech Score was used to assess for velopharyngeal insufficiency (score > 3). RESULTS: Results demonstrated that group 1 patients had a mean SNA change from preoperatively (78.7) to postoperatively (83.8), and a horizontal change of 5.0 mm, with no relapse. Group 2 patients had a mean SNA change from preoperatively (76.3) to postoperatively (82.0) and a horizontal change of 7.2 mm, with 63 percent relapse. Group 3 patients had a mean SNA change from preoperatively (74.1) to postoperatively (84.9) and a horizontal change of 16.5 mm, with 15 percent relapse. Thus, for severe maxillary deficiency, the distraction group had 48 percent less relapse than the conventional Le Fort I group. Postoperative speech evaluation showed velopharyngeal insufficiency in the following: group 1, four of 20 patients (20 percent); group 2, nine of 11 patients (82 percent); and group 3, nine of 20 patients (45 percent). CONCLUSION: These data suggest that Le Fort I internal distraction for severe cleft maxillary deficiency leads to better dental occlusion, less relapse, and better speech results.

Who has life-sustaining therapy withdrawn after injury?

BACKGROUND: Trauma scoring systems have been developed to help surgeons predict who will die after injury. However, some patients may not actually die of their injuries but may undergo withdrawal of life-sustaining therapy (WLST). The goal of this study was to determine which factors were associated with WLST among older patients who died. We hypothesized that patients with comorbid illnesses, higher injury severity scores (ISS), complications, and existing advanced directives (AD) would be more likely to have WLST and that patients having WLST would receive more medication for symptom relief in the 24 hours before death. METHODS: Data were collected via a retrospective chart review of patients age 55 years and older admitted to the intensive care unit after injury who subsequently died. In addition to demographic and injury information, documentation of family discussions regarding care wishes and formal ADs were evaluated. Patients dying despite curative attempts were compared with those who died after WLST by Student's t test and chi test where appropriate. RESULTS: In a 3-year period, of 330 patients age 55 and older admitted to the intensive care unit, 66 (20%) died. Complete records were available for 64 patients. More than half of those who died (n = 35, 54.7%) had WLST. ADs were available for 15 patients (23.4%), and 11 (17.2%) patients had expressed to their families desires to not undergo aggressive curative care. Family discussions were documented for 50 (78%) cases. Comorbid illnesses were present in 46 (71.9%) patients and 35 (54.7%) developed at least one complication. Among people with ADs, 73% had WLST versus 49% of people without ADs (p = 0.09). WLST was independent of comorbid illnesses (p = 0.3), complications (p = 0.8), age (p = 0.5), and ISS (p = 0.2). Patients for whom there was documentation of a family discussion were more likely to have WLST than those without (91.4% versus 62.1%, p = 0.005). Morphine and benzodiazepine dosing in the 24 hours preceding death were greater in the WLST group than the curative therapy group (p = 0.02 and p = 0.05, respectively). CONCLUSIONS: Expected associations with WLST such as age, ISS, comorbidities, and complications were not present in this population. Although trends may exist regarding patient wishes and ADs, larger studies are needed to corroborate these findings. Given the percentage of patients having supportive care withdrawn, trauma registries and scoring systems should include WLST.

In vitro and in vivo assessment of Salmonella enterica serovar Typhimurium DT104 virulence.

Multidrug-resistant Salmonella enterica serovar Typhimurium phage type DT104 has become a widespread cause of human and other animal infection worldwide. The severity of clinical illness in S. enterica serovar Typhimurium DT104 outbreaks has led to the suggestion that this strain possesses enhanced virulence. In the present study, in vitro and in vivo virulence-associated phenotypes of several clinical isolates of S. enterica serovar Typhimurium DT104 were examined and compared to S. enterica serovar Typhimurium ATCC 14028s. The ability of these DT104 isolates to survive within murine peritoneal macrophages, invade cultured epithelial cells, resist antimicrobial actions of reactive oxygen and nitrogen compounds, and cause lethal infection in mice were assessed. Our results failed to demonstrate that S. enterica serovar Typhimurium DT104 isolates are more virulent than S. enterica serovar Typhimurium ATCC 14028s.

Fis, a DNA nucleoid-associated protein, is involved in Salmonella typhimurium SPI-1 invasion gene expression.

The ability of Salmonella enterica serovar Typhimurium to cause disease depends upon the co-ordinated expression of many genes located around the Salmonella chromosome. Specific pathogenicity loci, termed Salmonella pathogenicity islands, have been shown to be crucial for the invasion and survival of Salmonella within host cells. Salmonella pathogenicity island 1 (SPI-1) harbours the genes required for the stimulation of Salmonella uptake across the intestinal epithelia of the infected host. Regulation of SPI-1 genes is complex, as invasion gene expression responds to a number of different signals, presumably signals similar to those found within the environment of the intestinal tract. As a result of our continued studies of SPI-1 gene regulation, we have discovered that the nucleoid-binding protein Fis plays a pivotal role in the expression of HilA and InvF, two activators of SPI-1 genes. A S. typhimurium fis mutant demonstrates a two- to threefold reduction in hilA:Tn5lacZY and a 10-fold reduction in invF:Tn5lacZY expression, as well as a 50-fold decreased ability to invade HEp-2 tissue culture cells. This decreased expression of hilA and invF resulted in an altered secreted invasion protein profile in the fis mutant. Furthermore, the virulence of a S. typhimurium fis mutant is attenuated 100-fold when administered orally, but has wild-type virulence when administered intraperitoneally. Expression of hilA:Tn5lacZY and invF:Tn5lacZY in the fis mutant could be restored by introducing a plasmid containing the S. typhimurium fis gene or a plasmid containing hilD, a gene encoding an AraC-like regulator of Salmonella invasion genes.

Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice.

A20 is a cytoplasmic zinc finger protein that inhibits nuclear factor kappaB (NF-kappaB) activity and tumor necrosis factor (TNF)-mediated programmed cell death (PCD). TNF dramatically increases A20 messenger RNA expression in all tissues. Mice deficient for A20 develop severe inflammation and cachexia, are hypersensitive to both lipopolysaccharide and TNF, and die prematurely. A20-deficient cells fail to terminate TNF-induced NF-kappaB responses. These cells are also more susceptible than control cells to undergo TNF-mediated PCD. Thus, A20 is critical for limiting inflammation by terminating TNF-induced NF-kappaB responses in vivo.

The Salmonella virulence plasmid spv genes are required for cytopathology in human monocyte-derived macrophages.

The pathogenesis of serious systemic Salmonella infections is characterized by survival and proliferation of bacteria inside macrophages. Infection of human monocyte-derived macrophages in vitro with S. typhimurium or S. dublin produces cytopathology characterized by detachment of cells that contain large numbers of proliferating bacteria. This cytopathology is dependent on the expression of the bacterial spv genes, a virulence locus previously shown to markedly enhance the ability of Salmonella to produce systemic disease. After 24 h of infection, macrophage cultures contain two populations of bacteria: (i) proliferating organisms present in a detached cell fraction; and (ii) a static bacterial population in macrophages remaining attached to the culture well. Mutations in either the essential transcriptional activator SpvR or the key SpvB protein markedly reduce the cytopathic effect of Salmonella infection. The spv-dependent cytopathology in macrophages exhibits characteristics of apoptosis, with release of nucleosomes into the cytoplasm, nuclear condensation and DNA fragmentation. The current findings suggest that the mechanism of the spv effect is through induction of increased cytopathology in host macrophages.

Differential regulation of enteric and systemic salmonellosis by slyA.

Mutation of slyA, which reduces Salmonella typhimurium virulence in mice, caused only minor attenuation of S. typhimurium virulence in orally inoculated calves. This correlated with modest reductions in intestinal invasion and enteropathogenic responses in bovine ligated ileal loops. slyA appears to regulate virulence genes involved in systemic, but not enteric, salmonellosis.