Brief Report: Risk of Recurrent Interstitial Lung Disease From Osimertinib Versus Erlotinib Rechallenge After Symptomatic Osimertinib-Induced Interstitial Lung Disease.

Introduction: Interstitial lung disease (ILD) is the most frequent cause of drug-related mortality from EGFR tyrosine kinase inhibitors (TKIs). Yet, for patients with symptomatic osimertinib-induced ILD, the risk of recurrent ILD associated with EGFR TKI rechallenge, either with osimertinib or another TKI, such as erlotinib, is unclear. Methods: Retrospective study of 913 patients who received osimertinib treatment for EGFR mutation-positive NSCLC. Clinical characteristics, ILD treatment history, and subsequent anticancer therapy of patients with symptomatic osimertinib-induced ILD were collated. The primary end point was to compare the incidence of recurrent ILD with osimertinib versus erlotinib rechallenge. Results: Of 913 patients, 35 (3.8%) had symptomatic osimertinib-induced ILD, of which 12 (34%), 15 (43%), and eight (23%) had grade 2, 3 to 4, and 5 ILD, respectively. On ILD recovery, 17 patients had EGFR TKI rechallenge with eight received osimertinib and nine received erlotinib. The risk of recurrent ILD was higher with osimertinib rechallenge than erlotinib (p = 0.0498). Of eight, five (63%) developed recurrent ILD on osimertinib rechallenge, including three patients with fatal outcomes. In contrast, only one of nine patients (11%) treated with erlotinib had recurrent ILD. Median time to second ILD occurrence was 4.7 (range 0.7-12) weeks. Median time-to-treatment failure of patients with erlotinib rechallenge was 13.2 months (95% confidence interval: 8.6-15.0). Conclusions: The risk of recurrent ILD was considerably higher with osimertinib rechallenge than erlotinib. Osimertinib rechallenge should be avoided, whereas erlotinib may be considered in patients with symptomatic osimertinib-induced ILD.

Perioperative gabapentin usage in pediatric patients: A scoping review.

BACKGROUND: There has been a recent focus among anesthesiologists on reducing the use of perioperative opioids in favor of multimodal analgesic regimens. Gabapentin has played an integral role in this evolution of practice. This comprehensive review assesses the current clinical evidence on the efficacy of perioperative gabapentin regarding postoperative pain and opioid requirements among the pediatric surgery population. DATA SOURCES: Pubmed, CINAHL, Embase, Scopus, and Web of Science Review. METHODS: This scoping review of the above databases includes all studies examining the use of gabapentin perioperatively in pediatric patients and its association with postoperative pain intensity and postoperative opioid consumption through July 2021. The inclusion criteria encompassed all studies evaluating gabapentin in the perioperative pediatric population through randomized controlled trials (RCTs) and retrospective studies. Relevant metadata from each study were abstracted and descriptive statistics were used to summarize the results. RESULTS: Fifteen papers met the inclusion criteria for this review, including 11 RCTs and 4 retrospective studies. Sample sizes ranged from 20 to 144 patients. Administered doses varied widely, mainly between 5 and 20 mg/kg. The studies included primarily orthopedic (10) and neck surgery cases (3). Seven papers had gabapentin provided preoperatively only, two postoperative only, and six both pre- and postoperatively. Of the studies assessing postoperative pain, 6/11 studies saw a decrease in postoperative pain in at least one period for the gabapentin group. Of the studies considering opioid requirements, 6/10 reported a reduction, 1/10 an increase, and 3/10 no difference in opioid requirements for the gabapentin groups. Yet, most of these pain and opioid requirement findings were only significant at one to two time points in the study follow-up periods, and the actual decreases had minimal clinical significance. CONCLUSIONS: The current data on perioperative gabapentin in pediatric patients are insufficient to support the routine use of gabapentin in pediatric patients. Additional high-quality RCTs with more standardized protocols for gabapentin administration and outcome measures are necessary to provide more definitive conclusions.

Are the relationships between mental health issues and being left-behind gendered in China: A systematic review and meta-analysis.

BACKGROUND: While most existing studies reveal left-behind children (LBC) are prone to suffering from mental health issues, some other literature fails to develop a statistical significance between being left-behind and facing mental health dilemmas. In further detail, it is noteworthy that suicide ideation is a gendered issue. Here girls, relative to their male counterparts, are more likely to experience emotional and affective challenges, alongside a higher risk of suicide ideation. Aside from suicide ideation, the rate of suicide attempts is also higher among Chinese female than among male LBC. However, Chang et al. counter-argue that, within the LBC cohorts, it is not statistically significant to state that girls were more likely for suicide attempts than boys. METHODS: In this paper, a systematic review of relevant literature and a meta-analysis of all qualified randomised controlled trial (RCT) studies were conducted. The authors aim to examine all relevant studies with similar methodologies to observe the nuanced relationships between being left-behind and mental health issues in Chinese contexts. Specifically, the authors will, grounded on the findings from the systematic review and meta-analysis, assess whether the relationship between mental health issues and being left-behind is gendered in Chinese contexts by analysing all relevant findings derived from similar methodologies and the same method (i.e., RCT). RESULTS: Aside from Wanjie et al.'s studies, it is noticeable that the rest of the studies share similar point estimates and their CIs overlapped to a large extent. As per the I2, given the presence of Wanjie et al.'s studies that demonstrate an observably higher degree of heterogeneity than the rest of the studies, the I2 values, each for the measurement of anxiety and depression, are 74.8 percent and 34.7 percent respectively. This shows that there is a considerable heterogeneity level for anxiety, while the heterogeneity level for depression is moderate. However, both p-values for the I2 statistics are larger than 0.05. Therefore, at the 0.05 significance level, it is statistically insignificant to reject the null hypothesis that there is no heterogeneity between individual studies in both the subgroups of anxiety and depression. Therefore, the concern of the potentially substantial heterogeneity should be irrelevant in this meta-analysis. Beyond the discussion from the forest plot, when looking at the single study addressing the relationship between being left-behind and having suicide attempts (note: LBC-OR is 1.22; 95 percent CI is 1.22 -and NLBC-OR is 1.42; 95 percent CI is 1.09-1.86 -at the p-value of 0.34), the findings demonstrate that such a relationship per se is not gendered at the 0.05 statistical significance level. However, when examining the relationship between being resilient and left-behind, such an association is gendered where the OR of female left-behind university students being resilient, relative to male left-behind university students, is slightly higher than that of female non-left-behind university students being resilient, relative to their male non-left-behind university student counterparts. It is noteworthy that this study focuses on studying left-behind and non-left-behind samples who entered universities. Since a raft of LBC are socially, educationally disadvantaged, they lack the opportunities to receive higher education. Therefore, the findings of this study might not be indicative of the LBC population at large. CONCLUSIONS: While the findings of this meta-analysis project fail to reflect any gendered issues statistically, the authors are aware of the fact that the data included in this project were collected based on perception. Here samples, or their parents and teachers, were responsible for answering the questions with respect to samples' mental health status and demographic details. In China, especially in less developed rural regions, the discourse on mental health challenges might continue to be seen as taboo, so individuals giving responses might, consciously or not, tend to give socially desirable answers to avoid any potential social stigmatisation. Therefore, there is some extent of reservation regarding the validity of the included studies' data.

Detection of antibody-coated Mucor in skin biopsy by direct immunofluorescence.

Cutaneous mucormycosis may be caused by direct inoculation or hematogenous spread of mucormycetes in immunocompromised patients. Skin biopsy is characterized by a deep fungal infection with frequent angioinvasion. The fungal hyphae can usually be identified on H&E stain. We report a case of cutaneous angioinvasive mucormycosis in which the fungi were also visualized on direct immunofluorescence. A 57-year-old patient with relapsed myelodysplastic syndrome status-post allogeneic hematopoietic cell transplant, diabetes mellitus, and graft-versus-host disease presented with painful, palpable, dark-red to violaceous retiform purpuric plaques. Light microscopy of punch biopsy revealed numerous broad, ribbon-like, pauci-septate hyphae in the dermis with angioinvasion, consistent with mucormycosis. Direct immunofluorescence performed on a concurrent biopsy to exclude immune complex vasculitis showed smooth IgG, IgA (weak), IgM (faint), and C3 deposition on the hyphal structures, compatible with antibody-coated fungi. Tissue culture subsequently confirmed Mucor species. Although mucormycosis was readily diagnosable on routine light microscopy in this case, recognition of the unique phenomenon of antibody-coated fungi can be crucial when the invasive fungi are sparse or only present in the direct immunofluorescence specimen.

An Investigation of the Impact of COVID-19 on Food Access and Security in Bexar County: A Mixed Methods Approach.

OBJECTIVES: To investigate the effect of COVID-19 on food access and security in Bexar County, located within San Antonio, TX. METHODS: To assess food insecurity levels and severity, we distributed a 10-min Qualtrics survey to San Antonio Food Bank (SAFB) clients. The survey was distributed between 19 October 2020 and 24 May 2021. Twenty-four survey respondents also participated in virtual focus group sessions over Zoom. Seven virtual focus group interviews were held between 15 January 2021 and 5 March 2021. RESULTS: Survey results revealed that following COVID-19, 20.2% of SAFB clients were newly food insecure. 31.3% of survey respondents reported reduced wages and 28.8% reported job loss. Households experiencing job disruption from COVID-19 were 7 times at greater odds of being food insecure (OR 7.05; 95% CI, 1.61-30.88), as compared to those with stable employment. Major subthemes across focus group interviews included "excessive amounts of a single food item distributed," "long wait times for food," and "not receiving the type of food needed." CONCLUSIONS: Our study found evidence to support early studies' findings that COVID-19 has negatively impacted food security for many Americans. 70% of all unique Bexar County zip codes appeared in our survey analysis. Even beyond COVID-19's effect on food security, many other major societal changes were identified such as the increased reliance on technology, decreased in-person social gatherings, and greater mental health needs.

Scalable true random number generator using adiabatic superconductor logic.

Alternative computing such as stochastic computing and bio-inspired computing holds promise for overcoming the limitations of von Neumann computers. However, one difficulty in the implementation of such alternative computing is the need for a large number of random bits at the same time. To address this issue, we propose a scalable true-random-number generating scheme that we refer to as XORing shift registers (XSR). XSR generates multiple uncorrelated true random bitstreams using only two true random number generators as entropy sources and can thus be implemented by a variety of logic devices. Toward superconducting alternative computing, we implement XSR using an energy-efficient superconductor logic family, adiabatic quantum-flux-parametron (AQFP) logic. Furthermore, to demonstrate its performance, we design and observe an AQFP-based XSR circuit that generates four random bitstreams in parallel. The results of the experiment confirm that the bitstreams generated by the XSR circuit exhibit no autocorrelation and that there is no correlation between the bitstreams.

Cell Reprogramming for Regeneration and Repair of the Nervous System.

A persistent barrier to the cure and treatment of neurological diseases is the limited ability of the central and peripheral nervous systems to undergo neuroregeneration and repair. Recent efforts have turned to regeneration of various cell types through cellular reprogramming of native cells as a promising therapy to replenish lost or diminished cell populations in various neurological diseases. This review provides an in-depth analysis of the current viral vectors, genes of interest, and target cellular populations that have been studied, as well as the challenges and future directions of these novel therapies. Furthermore, the mechanisms by which cellular reprogramming could be optimized as treatment in neurological diseases and a review of the most recent cellular reprogramming in vitro and in vivo studies will also be discussed.

Advances in Cutaneous Squamous Cell Carcinoma Management.

cSCC is increasing in prevalence due to increased lifespans and improvements in survival for conditions that increase the risk of cSCC. The absolute mortality of cSCC exceeds melanoma in the United States and approaches that of melanoma worldwide. This review presents significant changes in the management of cSCC, focusing on improvements in risk stratification, new treatment options, optimization of existing treatments, and prevention strategies. One major breakthrough in cSCC treatment is the advent of immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1), which have ushered in a renaissance in the treatment of patients with locally advanced and metastatic disease. These agents have offered patients with advanced disease decreased therapeutic toxicity compared to traditional chemotherapy agents, a more durable response after discontinuation, and improved survival. cSCC is an active field of research, and this review will highlight some of the novel and more developed clinical trials that are likely to impact cSCC management in the near future.

Advances in Management and Therapeutics of Cutaneous Basal Cell Carcinoma.

Basal cell carcinoma (BCC), the most common cancer in humans, is a malignant neoplasm of cells derived from the basal layer of the epidermis. Tumor characteristics such as histologic subtype, primary versus recurrent tumor, anatomic location, size, and patient attributes determine the risk level and acceptable treatment options. Surgical options offer histologic confirmation of tumor clearance. Standard excision provides post-treatment histologic assessment, while Mohs micrographic surgery (MMS) provides complete margin assessment intraoperatively. Additional treatment options may be employed in the correct clinical context. Small and low-risk BCCs, broad field cancerization, locally-advanced disease, metastatic disease, cosmetic concerns, or morbidity with surgical approaches raise consideration of other treatment modalities. We review herein a range of treatment approaches and advances in treatments for BCC, including standard excision, MMS, electrodesiccation and curettage, ablative laser treatment, radiation therapy, targeted molecular therapies, topical therapies, field therapies, immunotherapy, and experimental therapies.

Au nanoparticles for SERS: Temperature-controlled nanoparticle morphologies and their Raman enhancing properties.

Quasi-fractal gold nanoparticles can be synthesized via a modified and temperature controlled procedure initially used for the synthesis of star-like gold nanoparticles. The surface features of nanoparticles lead to improved enhancement of Raman scattering intensity of analyte molecules due to the increased number of sharp surface features possessing numerous localized surface plasmon resonances (LSPR). The LSPR is affected by the size and shape of surface features as well as inter-nanoparticle interactions, as these affect the oscillation modes of electrons on the nanoparticle surfaces. The effect of the particle morphologies on the localized surface plasmon resonance (LSPR) and on the surface-enhancing capabilities of these nanoparticles is explored by comparing different nanoparticle morphologies and concentrations. We show that in a fixed nanoparticle concentration regime, quasi-fractal gold nanoparticles (gold nanocaltrop) provide the highest level of surface enhancement, whereas spherical nanoparticles provide the largest enhancement in a fixed gold concentration regime. The presence of highly branched features enables these nanoparticles to couple with a laser wavelength, despite having no strong absorption band and hence no single surface plasmon resonance. This cumulative LSPR may allow these nanoparticles to be used in a variety of applications in which laser wavelength flexibility is beneficial, such as in medical imaging applications where fluorescence at short laser wavelengths may be coupled with non-fluorescing long laser wavelengths for molecular sensing.

Approval processes in evidence-based clinical practice guidelines sponsored by medical specialty societies.

OBJECTIVE: To determine the approval processes for evidence-based Clinical Practice Guidelines sponsored by medical specialty societies in the United States. STUDY DESIGN AND SETTING: Cross-sectional analysis of published Clinical Practice Guidelines and Guideline procedure manuals, sponsored by the 43 members of the Council of Medical Specialty Societies in the United States. Approval processes were measured by written evidence in the specialty society's guideline procedure manual or published guidelines, through May 2017. RESULTS: Among the 36 (of 43) specialty societies that published evidence-based Clinical Practice Guidelines, 27 (75%) required approval by a committee representing the society as a whole. None specified the criteria used for approval decisions. Six specialty societies (17%) required approval but included procedures to maintain some editorial independence for the guideline development group, such as approval by a guideline committee not an executive committee or approval dependent on fidelity to established guideline methodology, not content. One society required Board review, but not approval. The approval process was not reported by 2 (6%) of the specialty societies. CONCLUSIONS: Most medical specialty societies in the U.S. require approval of guidelines by a board that represents the society as whole. Since medical specialty societies have loyalties to the patients they serve and to their physician members, and because the interests of those two groups may differ, such an approval process introduces a potential conflict of interest into the guideline development process.

Adiabatic Quantum-Flux-Parametron: Towards Building Extremely Energy-Efficient Circuits and Systems.

Adiabatic Quantum-Flux-Parametron (AQFP) logic is an adiabatic superconductor logic family that has been proposed as a future technology towards building extremely energy-efficient computing systems. In AQFP logic, dynamic energy dissipation can be drastically reduced due to the adiabatic switching operations using AC excitation currents, which serve as both clock signals and power supplies. As a result, AQFP could overcome the power/energy dissipation limitation in conventional superconductor logic families such as rapid-single-flux-quantum (RSFQ). Simulation and experimental results show that AQFP logic can achieve an energy-delay-product (EDP) near quantum limit using practical circuit parameters and available fabrication processes. To shed some light on the design automation and guidelines of AQFP circuits, in this paper we present an automatic synthesis framework for AQFP and perform synthesis on 18 circuits, including 11 ISCAS-85 circuit benchmarks, 6 deep-learning accelerator components, and a 32-bit RISC-V ALU, based on our developed standard cell library of AQFP technology. Synthesis results demonstrate the significant advantage of AQFP technology. We forecast 9,313×, 25,242× and 48,466× energy-per-operation advantage, compared to the synthesis results of TSMC (Taiwan Semiconductor Manufacturing Company) 12 nm fin field-effect transistor (FinFET), 28 nm and 40 nm complementary metal-oxide-semiconductor (CMOS) technology nodes, respectively.

Surface-Enhanced Raman Spectroscopy Characterization of Breast Cell Phenotypes: Effect of Nanoparticle Geometry.

The use of surface-enhanced Raman spectroscopy (SERS) to delineate between the breast epithelial cell lines MCF10A, SK-BR-3, and MDA-MB-231 is explored utilizing varied morphologies of gold nanoparticles. The nanoparticles studied had spherical, star-like, and quasi-fractal (nanocaltrop) morphologies and possessed varying degrees of surface inhomogeneity and complexity. The efficacy of Raman enhancement of these nanoparticles was a function of their size, their surface morphology, and the associated density of "hot spots," as well as their cellular uptake. The spherical and star-like nanoparticles provided strong signal enhancement that allowed for the discernment among the three cell phenotypes based solely on the acquired Raman spectra. The presence of overlapping Raman band spectral regions, as well as unique spectral bands, suggests that the underlying biological differences between these cells can be accessed without the need for tagging the nanoparticles or for specific cell targeting, demonstrating the potential ubiquity of this technique in imaging any cancer. This work provides clear evidence for the potential application of SERS as a tool for mapping cancerous lesions, possibly during surgery and under histopathological analysis.

Impact of diabetes on heart failure incidence in adults with ischemic heart disease.

BACKGROUND: Ischemic heart disease (IHD) is the most potent risk factor for heart failure (HF). Our study aims to evaluate the incremental impact of diabetes on the incidence of HF in individuals with IHD. METHODS: Data from the NHANES Epidemiologic Follow-Up Study (Baseline: 1971 to 1974) were linked to the facility and mortality files up to 1992. Our analyses were restricted to patients with IHD without prevalent HF at baseline. The cumulative incidence of HF in patients with diabetes and IHD versus those with IHD alone was assessed using failure curves. Cox proportional hazards models were used to control for important covariates. All analyses incorporated the complex sample design by including the weights and clustering variables. RESULTS: Out of the 14,407 participants, 497 had IHD without prevalent HF and had information about diabetes status. Among these participants, the cumulative incidence of HF was 38.1% for those with diabetes (n=63) and 26.5% in those without diabetes (n=434) (log-rank p-value<0.005). The multivariate hazard ratio (adjusted for age, BMI, alcohol consumption, hypertension, high cholesterol, and smoking) for incident HF for people who had myocardial infarction (MI) and diabetes compared to people who had MI alone was 2.98 (95% CI 1.51, 5.88). CONCLUSION: Among participants with MI, those with diabetes had a substantially higher incidence of HF than those without diabetes. Based on these findings, practitioners should focus greater attention on patients with diabetes and previous MI in order to potentially prevent incident HF.

Systematic comparison of 2A peptides for cloning multi-genes in a polycistronic vector.

Cloning of multiple genes in a single vector has greatly facilitated both basic and translational studies that require co-expression of multiple factors or multi-units of complex protein. Many strategies have been adopted, among which 2A "self-cleaving" peptides have garnered increased interest for their polycistronic nature, small size and high "cleavage" efficiency. However, broad application of 2 A peptides is limited by the lack of systematic comparison of different 2As alone or in combination. Here we characterized the effect of varying gene position and 2As on the expression of proteins encoded in bi-, tri-, or quad-cistronic constructs. Using direct cardiac reprogramming as an example, we further determined the effect of varied 2As on the efficiency of fluorescent cell labeling and cell fate conversion. We found that the expression of fluorophores decreased as it was moved towards the end of the construct while reprogramming was most efficient with the fluorophore at the second position. Moreover, quad-cistronic TPE2A constructs resulted in more efficient reprogramming than 3P2A or PTE2A constructs. We expect that the bi-, tri-, and quad-cistronic vectors constructed here and our results on protein expression ratios from different 2A constructs could serve to guide future utilization of 2A peptides in basic research and clinical applications.

Verrucae Planae Within Previous Xenograft Sites of Burn Wounds.

Burn injuries are known to compromise host immune defenses through disruption of mucocutaneous barriers and suppression of cell-mediated immune responses, which may render patients with burn injuries susceptible to viral infections in the days to years after an initial insult. We report a case of verrucae planae developing as a secondary condition confined to former xenograft sites in a child, appearing more than 3.5 years after initial second-degree burn injuries. Only a few reports have previously described the development of verrucae in former burn sites, with most reporting latency to onset of verrucae appearance of months rather than years. Current hypotheses suggest that the postburn immune response shifts from an early proinflammatory to a late antiinflammatory response characterized by altered cytokine profiles and diminished cellular cytotoxicity mediated by cytotoxic T-lymphocytes, natural killer cells, and epidermal antigen-presenting cells, which together likely contribute to an enduring postburn regional immunosuppression that allows for the seeding and proliferation of viral agents.

Re-patterning of H3K27me3, H3K4me3 and DNA methylation during fibroblast conversion into induced cardiomyocytes.

Direct conversion of fibroblasts into induced cardiomyocytes (iCMs) offers an alternative strategy for cardiac disease modeling and regeneration. During iCM reprogramming, the starting fibroblasts must overcome existing epigenetic barriers to acquire the CM-like chromatin pattern. However, epigenetic dynamics along this reprogramming process have not been studied. Here, we took advantage of our recently generated polycistronic system and determined the dynamics of two critical histone marks, H3K27me3 and H3K4me3, in parallel with gene expression at a set of carefully selected cardiac and fibroblast loci during iCM reprogramming. We observed reduced H3K27me3 and increased H3K4me3 at cardiac promoters as early as day 3, paralleled by a rapid significant increase in their mRNA expression. In contrast, H3K27me3 at loci encoding fibroblast marker genes did not increase until day 10 and H3K4me3 progressively decreased along the reprogramming process; these changes were accompanied by a gradual decrease in the mRNA expression of fibroblast marker genes. Further analyses of fibroblast-enriched transcription factors revealed a similarly late deposition of H3K27me3 and decreased mRNA expression of Sox9, Twist1 and Twist2, three important players in epithelial-mesenchymal transition. Our data suggest early rapid activation of the cardiac program and later progressive suppression of fibroblast fate at both epigenetic and transcriptional levels. Additionally, we determined the DNA methylation states of representative cardiac promoters and found that not every single CpG was equally demethylated during early stages of iCM reprogramming. Rather, there are specific CpGs, whose demethylation states correlated tightly with transcription activation, that we propose are the major contributing CpGs. Our work thus reveals a differential re-patterning of H3K27me3, H3K4me3 at cardiac and fibroblast loci during iCM reprogramming and could provide future genome-wide epigenetic studies with important guidance such as the appropriate time window and loci to be utilized as positive and negative controls.

Direct Cardiac Reprogramming: Advances in Cardiac Regeneration.

Heart disease is one of the lead causes of death worldwide. Many forms of heart disease, including myocardial infarction and pressure-loading cardiomyopathies, result in irreversible cardiomyocyte death. Activated fibroblasts respond to cardiac injury by forming scar tissue, but ultimately this response fails to restore cardiac function. Unfortunately, the human heart has little regenerative ability and long-term outcomes following acute coronary events often include chronic and end-stage heart failure. Building upon years of research aimed at restoring functional cardiomyocytes, recent advances have been made in the direct reprogramming of fibroblasts toward a cardiomyocyte cell fate both in vitro and in vivo. Several experiments show functional improvements in mouse models of myocardial infarction following in situ generation of cardiomyocyte-like cells from endogenous fibroblasts. Though many of these studies are in an early stage, this nascent technology holds promise for future applications in regenerative medicine. In this review, we discuss the history, progress, methods, challenges, and future directions of direct cardiac reprogramming.