Rationale, aims, and objectives: Portenoy and Foley’s 1986 landmark study “Chronic use of opioid analgesics in non-malignant pain: report of 38 cases” has been reproached for opening the floodgates of opioid prescribing for chronic non-cancer pain and the attendant harms. This influential article has been cited over 500 times in the scientific literature over the last four decades. This study seeks to understand the impact of Portenoy and Foley’s article on subsequent discussions and research about opioids. Methods: We conducted a multi-method bibliometric analysis of all citations of this article from 1986 through 2019 using quantitative relational and qualitative content analysis to determine how uses and interpretations of this case series and associated prescribing guidance have changed over time, in relationship to the evolution of the North American opioid crises. Results: Using time series analysis, we identified three periods with distinct interpretations and uses of the index study. In the first “exploration” period (1986-1996), the index study was well-received by the scientific community and motivated further study of the effects of opioids. In the second “implementation” period (1997-2003, coinciding with the release of OxyContin®), this study was used as evidence to support widespread prescribing of opioid analgesics, even while it was recognized that long-term effects had not yet been evaluated. The third “reassessment” period (2004-2019) focused on how opioid-related harms had been overlooked, and in many cases these harms were directly attributed to this study. Conclusion: These changes in interpretation demonstrate shifting currents of the use and mobilization of evidence regarding pain and opioids, and how these currents both impact and are impacted by clinical practices and major sociohistorical phenomena such as the opioid crisis. Researchers and clinicians must account for these shifting dynamics when developing and interpreting scientific knowledge, including in the form of clinical practice guidelines.

Phylogenetic trees have been extensively used in community ecology. However, how the phylogenetic reconstruction affects ecological inferences is poorly understood. In this study, we reconstructed three different types of phylogenetic trees (a synthetic-tree generated using VPhylomaker, a barcode-tree generated using rbcL+matK+trnH-psbA and a genome-tree generated from plastid genomes) that represented an increasing level of phylogenetic resolution among 580 woody plant species from six dynamic plots in subtropical evergreen broadleaved forests of China. We then evaluated the performance of each phylogeny in estimations of community phylogenetic structure, turnover and phylogenetic signal in functional traits. As expected, the genome-tree was most resolved and most supported for relationships among species. For local phylogenetic structure, the three trees showed consistent results with Faith’s PD and MPD; however, only the synthetic-tree produced significant clustering patterns using MNTD for some plots. For phylogenetic turnover, contrasting results between the molecular trees and the synthetic-tree occurred only with nearest neighbor distance. The barcode-tree agreed more with the genome-tree than the synthetic-tree for both phylogenetic structure and turnover. For functional traits, both the barcode-tree and genome-tree detected phylogenetic signal in maximum height, but only the genome-tree detected signal in leaf width. This is the first study that uses plastid genomes in large-scale community phylogenetics. Our results highlight the outperformance of genome-trees over barcode-trees and synthetic-trees for the analyses studied here. Our results also point to the possibility of Type I and II errors in estimation of phylogenetic structure and turnover and detection of phylogenetic signal when using synthetic-trees.

Lifespan is a key attribute of a species’ life cycle and varies extensively among major lineages of animals. In fish, lifespan varies by several orders of magnitude, with reported values ranging from less than one year to approximately 400 years. Lifespan information is particularly useful for species management, as it can be used to estimate invasion potential, extinction risk and sustainable harvest rates. Despite its utility, lifespan is unknown for most fish species. This is due to the difficulties associated with accurately identifying the oldest individual(s) of a given species, and/or deriving lifespan estimates that are representative for an entire species. Recently it has been shown that CpG density in gene promoter regions can be used to predict lifespan in mammals and other vertebrates, with variable accuracy across taxa. To improve accuracy of lifespan prediction in a non-mammalian vertebrate, here we develop a fish-specific genomic lifespan predictor. Addressing previous issues of low sample size and sequence dissimilarity, we incorporate more than eight times the number of fish species used previously (n = 442) and use fish-specific gene promoters as reference sequences. Our model predicts fish lifespan from genomic CpG density alone (measured as CpG observed/expected ratio), explaining 64 % of the variance between known and predicted lifespans. The results demonstrate the value of promoter CpG density as a universal predictor of fish lifespan that can applied where empirical data are unavailable, or impracticable to obtain.

Background: ABVD, the standard-of-care in adult Hodgkin lymphoma (HL), has not been directly compared to ABVE-PC, a pediatric regimen designed to reduce late-effects. We aimed to compare the effectiveness and associated toxicities of these two regimens used in the same institution. Methods: This retrospective cohort study evaluated a total of 224 patients diagnosed with HL between 1999 and 2018 at Children’s Hospital Los Angeles (CHLA), of which 93 patients were eligible having received ABVD (n=46) or ABVE-PC (n=47) chemotherapy as their initial treatment. Descriptive analyses were performed using the Student’s t-test or Fisher’s exact test. Survival analysis used the Kaplan-Meier method. Events included: death, relapse, secondary malignancy, need for radiation therapy, pulmonary toxicity and cardiomyopathy determined by shortening fraction <29%. Analyses followed an intention-to-treat principle. Results: There was no difference in baseline characteristics between the patients receiving ABVE-PC or ABVD in regard for stage, risk group or prognostic variables, such as the presence or absence of “B” symptoms, bulky disease, and extra-nodal involvement. A greater proportion of patients treated with ABVE-PC received consolidating external beam radiation treatment (XRT) either by randomization or by response compared to ABVD (59.6% vs 32.6% respectively, p=0.01). While not statistically significant, response to therapy, assessed by PET/CT where available, mirrored the need for radiation (rapid response 58.3% vs 90.0%, n=34, p=0.11). There was no difference in event-free survival (p=0.63) or overall survival (p=0.37) with a median follow up length of 3.9 years. Conclusion: ABVD and ABVE-PC achieved similar survival outcomes in our single-institution cohort

We described eleven patients positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The younger age and female gender seem to contribute to poor outcomes possibly. Furthermore, the left ventricle ejection fraction and pro-BNP improvement within the first week of treatment might indicate a good prognosis.

Some of the most vexing problems of deep level relationship that remain in angiosperms involve the superrosids. The superrosid clade contains a quarter of all angiosperm species, with 18 orders in three subclades (Vitales, Saxifragales and core rosids) exhibiting remarkable morphological and ecological diversity. To help resolve deep-level relationships, we constructed a high-quality chromosome-level genome assembly for Tiarella polyphylla (Saxifragaceae) thus providing broader genomic representation of Saxifragales. Whole genome microsynteny analysis of superrosids showed that Saxifragales shared more synteny clusters with core rosids than Vitales, further supporting Saxifragales as more closely related with core rosids. To resolve the ordinal phylogeny of superrosids, we screened 122 single copy nuclear genes from genomes of 36 species, representing all 18 superrosid orders. Vitales were recovered as sister to all other superrosids (Saxifragales + core rosids). Our data suggest dramatic differences in relationships compared to earlier studies within core rosids. Fabids should be restricted to the nitrogen-fixing clade, while Picramniales, the Celastrales-Malpighiales (CM) clade, Huerteales, Oxalidales, Sapindales, Malvales and Brassicales formed an “expanded” malvid clade. The Celastrales-Oxalidales-Malpighiales (COM) clade (sensu APG IV) was not monophyletic. Crossosomatales, Geraniales, Myrtales and Zygophyllales did not belong to either of our well-supported malvids or fabids. There is strong discordance between nuclear and plastid phylogenetic hypotheses for superrosid relationships; we show that this is best explained by a combination of incomplete lineage sorting and ancient reticulation.

Silk is a fibrous protein, has been a part of human lives for centuries and was used as suture and textile material. Silk is mainly produced by members of certain arthropods such as spiders, butterflies, mites, and moths. However, recent biotechnological advances have revolutionized silk as a biomaterial for various applications ranging from diverse sensors to robust fibers. The biocompatibility, mechanical resilience, and biodegradability of the material make it a suitable candidate for biomaterials. Silk can also be easily converted into several morphological forms, including fibers, films, sponges, and hydrogels. Provided these abilities, silk has received excellent traction from scientists worldwide for various developments, one of them being its use as a bio-sensor. The diversity of silk materials offers various options, giving scientists the freedom to choose from and personalize them as per their needs. In this review, we foremost look upon the composition, production, properties, and various morphologies of silk. The numerous applications of silk and its derivatives for fabricating biosensors to detect small molecules, macromolecules, and cells have been explored comprehensively. Also, the data from various globally developed sensors using silk have been described into organized tables for each category of molecules, along with their important analytical details.

The peach fruit moth (PFM), Carposina sasakii Matsumura, is a major phytophagous orchard pest widely distributed across Northeast Asia. Here, we report the chromosome-level genome for the PFM, representing the first genome for the family Carposinidae, from the lepidopteran superfamily Copromorphoidea. The genome was assembled into 404.83 Mb sequences using PacBio long-read and Illumina short-read sequences, including 275 contigs, with a contig N50 length of 2.62 Mb. All contigs were assembled into 32 linkage groups assisted by the Hi-C technique, including 30 autosomes, a female-specific W chromosome and a Z chromosome. BUSCO analysis showed that 98.2% genes were complete and 0.4% of genes were fragmented, while 1.4% of genes were missing in the assembled genome. In total, 23,218 protein-coding genes were predicted, of which 82.72% were functionally annotated. Because of the importance of diapause triggered by photoperiod in PFM, five circadian genes in the PFM as well as in the other related species were annotated, and potential genes related to diapause and photoperiodic reaction were also identified from transcriptome sequencing. In addition, manual annotation of detoxification gene families was undertaken and showed a higher number of ABC and GST genes in PFM than in most other lepidopterans, in contrast to a lower number of UGT genes, suggesting different detoxication pathways in this moth. The high-quality genome provides a resource for comparative evolutionary studies of this moth and its relatives within the context of radiations across Lepidoptera.

As an essential micronutrient for many organisms, sodium plays an important role in ecological and evolutionary dynamics. Although plants mediate trophic fluxes of sodium, from substrates to higher trophic levels, we know relatively little about plants’ comparative growth and sodium accumulation responses to variation in substrate sodium. We carried out a systematic review to examine how plants respond to variation in substrate sodium concentrations. We compared growth and tissue-sodium responses among 107 populations (67 species in 20 plant families), broadly expanding beyond the agricultural and model taxa for which several generalizations previously have been made. We hypothesized a priori response models for each population’s growth and sodium accumulation responses as a function of increasing substrate NaCl. We used BIC to choose the best model. Additionally, using a phylogenetic signal analysis, we tested for phylogenetic patterning of growth and sodium accumulation responses across plant taxa. The influence of substrate sodium on growth differed across taxa, with most populations experiencing detrimental effects at high concentrations. Irrespective of growth response, tissue concentrations of sodium for most taxa increased as sodium concentrations in the substrate increased. We found no strong associations between growth and types of sodium accumulation responses across taxa. Our phylogenetic signal analyses found that evolutionary history helps predict the distribution of total plant growth responses across the phylogeny, but not sodium accumulation responses. Our study suggests that saltier plants in saltier soils may prove to be a broadly general pattern for sodium across plant taxa. Regardless of growth responses, sodium accumulation mostly followed an increasing trend and did not have any evident association with growth responses as substrate sodium levels increased. Finally, plant adaptations to substrate sodium vary with a degree of phylogenetic conservatism.

Hereditary disorders are frequently caused by genetic variants that affect pre-mRNA splicing. Whilst genetic variants in the canonical splice motifs are almost always disrupting splicing, the pathogenicity of variants in the non-canonical splice sites (NCSS) and deep intronic (DI) regions are difficult to predict. Multiple splice prediction tools have been developed for this purpose, with the latest tools employing deep learning algorithms. We benchmarked established and deep learning splice prediction tools on gold standard sets of variants in the ABCA4 and MYBPC3 genes associated with Stargardt disease (STGD1) and cardiomyopathy, respectively, with functional assessment in midigene and minigene splice assays. The best performing splice prediction tool for both NCSS and DI variants in ABCA4 was SpliceAI, whilst SpliceSiteFinder-like performed best for NCSS variants in MYBPC3. Overall, the performance in a real time clinical setting is much more modest than reported by the developers of the tools.

The mid-infrared (mid-IR) anisotropic optical response of a material probes vibrational fingerprints and absorption bands sensitive to order, structure and direction dependent stimuli. Such anisotropic properties play a fundamental role in catalysis, optoelectronic, photonic, polymer and biomedical research and applications. Infrared dual-comb polarimetry (IR-DCP) is introduced as a powerful new spectroscopic method for the analysis of complex dielectric functions and anisotropic samples in the mid-IR range. IR DCP enables novel hyperspectral and time-resolved applications far beyond the technical possibilities of classical Fourier-transform IR (FTIR) approaches. The method unravels structure–spectra relations at high spectral bandwidth (100 cm–1) and short integration times of 65 µs, with previously unattainable time resolutions for spectral IR polarimetric measurements for potential studies of noncyclic and irreversible processes. The polarimetric capabilities of IR-DCP are demonstrated by investigating an anisotropic inhomogeneous free-standing nanofiber scaffold for neural tissue applications. Polarization sensitive multi-angle dual-comb transmission amplitude and absolute phase measurements (separately for ss-, pp-, ps- and sp-polarized light) allow the in-depth probing of the samples’ orientation dependent vibrational absorption properties. Mid-IR anisotropies can be quickly identified by cross-polarized IR-DCP polarimetry.

Rationale and aims: Precision medicine (PM) raises a key question: How can we know what works when the number of people with a health problem becomes small or one (n=1)? We here present a formative case from Norway. The Norwegian Board of Health Supervision was faced with a cancer patient, who had improved after treatment with a drug in the private health sector but was refused continued treatment in the public health service due to lack of clinical trial evidence. The Board overturned this decision, arguing that the drug had been unambiguously documented to work in the individual case. We aim to provide an in-depth analysis of this case and The Board´s decision and thereby to illustrate and elucidate key epistemological and ethical issues and developments in PM. Method: We provide our analysis and discussion using tools of critical thinking and concepts from philosophy of science and medicine such as uncertainty, evidence, forms of inference and causation. We also examine the case in the light of the history of evidence-based medicine (EBM). Results and discussion: The case reflects an epistemological shift in medicine where PM puts greater emphasis on evidence that arises in individual patients after the treatment is provided over preexisting population-based evidence. PM may rely more heavily on abduction to decide what works and qualitative, rather than quantitative judgments. The case also illustrates a possible shift in the concept of causation from regularity accounts to mechanistic and process accounts. We discuss ethical implications of a shift from more “traditional” to “personalized EBM”. Conclusion: A framework that is more based on abductions and evidence arising in the individual case has problems in creating quantifiable, reliable, and generalizable evidence, and in promoting transparency and accountability. PM currently lacks clear criteria for deciding what works in an individual, posing ethical challenges.

Asthma is a chronic inflammatory airway disease resulting in airflow obstruction, which in part can become irreversible to conventional therapies, defining the concept of airway remodeling. The introduction of biologics in severe asthma has led in some patients to the complete normalization of previously considered irreversible airflow obstruction. This highlights the need to distinguish a “fixed” bronchial obstruction due to structural changes unresponsive to current therapies, from a “reversible” one as demonstrated by lung function normalization during biological therapies not previously obtained even with high dose systemic glucocorticoids. The mechanisms by which exposure to environmental factors initiates the inflammatory responses that trigger airway remodeling are still incompletely understood. Alarmins represent tissue-derived cytokines that initiate immunologic events leading to inflammatory airway remodeling. Biological therapies can improve airflow obstruction by addressing these airway inflammatory changes. In addition, biologics might prevent and possibly even revert “fixed” remodeling due to structural changes. Hence, it appears clinically important to separate the therapeutic effects (early and late) of biologics as a new paradigm to evaluate the effects of these drugs and future treatments on airway remodeling in severe asthma.

The core metabolic reactions of life drive electrons through a class of redox protein enzymes, the oxidoreductases. The energetics of electron flow is determined by the redox potentials of organic and inorganic cofactors as tuned by the protein environment. Understanding how protein structure affects oxidation-reduction energetics is crucial for studying metabolism, creating bioelectronic systems, and tracing the history of biological energy utilization on Earth. We constructed ProtReDox ([https://protein-redox-potential.web.app](https://protein-redox-potential.web.app)), a manually curated database of experimentally determined redox potentials. With over 500 measurements, we can begin to identify how proteins modulate oxidation-reduction energetics across the tree of life. By mapping redox potentials onto networks of oxidoreductase fold evolution, we can infer the evolution of electron transfer energetics over deep-time. ProtReDox is designed to include user-contributed submissions with the intention of making it a valuable resource for researchers in this field.

Since the start of the SARS-CoV-2 pandemic, it has been difficult to differentiate between SARS-CoV-2 re-infection and prolonged RNA shedding. In this report, we identified patients with positive rtPCR results for SARS-CoV-2 ≥70 days apart. Clinical and laboratory data were collected and criteria were applied to discern whether the presentation was consistent with SARS-CoV-2 re-infection or prolonged viral RNA shedding. Eleven individuals met the initial testing criteria, of which, seven met at least one criteria for re-infection and four were consistent with prolonged RNA shedding. These data demonstrate the need for criteria to differentiate SARS-CoV-2 re-infection from prolonged RNA shedding.

Background: Rapid advancement of stem cell (SC) therapies provides both opportunities and risks for patients and physicians alike. Physicians have a role in counseling patients about unproven SC therapies, requiring a basic level of knowledge and access to information about SCs. Objective: This study sought to assess SC-related knowledge of and attitudes among physicians in Jordan to elucidate areas of deficiency that can be addressed. Methods: A cross-sectional survey, comprising questions on demographics and SC knowledge and attitudes, was designed as a scoring system to evaluate physicians’ knowledge and attitudes. Participants were recruited from 10 major hospitals in Jordan over 3 months between February and April 2019. The internal consistency of the scoring scales was calculated using Cronbach’s alpha reliability coefficient. Gender differences were evaluated with an independent t-test. Results: 382 physicians in Jordan completed the survey (59.9% response rate). They demonstrated a low/moderate level of overall SC knowledge (51.3%), but most lacked confidence in their ability to answer patients’ questions about SC therapies (64.7%). However, the total attitude score was moderate/high positive (66.8%) and most were interested in learning more about SCs (80.8%). Male physicians reported significantly more knowledge than females (p<0.0001). Conclusions: This study reveals Jordanian physicians’ hesitancy to counsel patients about SC therapies, largely due to gaps in knowledge. However, overall attitudes toward SC research and therapies are positive. The results of this study demonstrate a need to cover SC-related information in medical curricula in Jordan, as well as to support initiatives to regulate SC tourism in Jordan.

Rheumatic heart disease is the most common cause of mitral valve stenosis. Left atrial appendage thrombus is associated with mitral stenosis, but in rare cases the thrombus can extend to the left atrial cavity. We present a case of a severe rheumatic mitral stenosis and associated large left atrial thrombus, with embolic sequelae.

We present clinical cases of ALS, accompanied by hydromyelia, where we tried to find out the causes of the cavities and its connection with the disease. Usually, MRI does not reveal any spinal cord alterations in ALS patients. We did not find any observable cause for cavity formation.