Describing endosymbiont-host interactions within the parasitism-mutualism continuum.

Endosymbionts are widespread in arthropods, living in host cells with effects that extend from parasitic to mutualistic. Newly acquired endosymbionts tend to be parasitic, but vertical transmission favors coevolution toward mutualism, with hosts sometimes developing dependency. Endosymbionts negatively affecting host fitness may still spread by impacting host reproductive traits, referred to as reproductive "manipulation," although costs for hosts are often assumed rather than demonstrated. For cytoplasmic incompatibility (CI) that involves endosymbiont-mediated embryo death, theory predicts directional shifts away from "manipulation" toward reduced CI strength; moreover, CI-causing endosymbionts need to increase host fitness to initially spread. In nature, endosymbiont-host interactions and dynamics are complex, often depending on environmental conditions and evolutionary history. We advocate for capturing this complexity through appropriate datasets, rather than relying on terms like "manipulation." Such imprecision can lead to the misclassification of endosymbionts along the parasitism-mutualism continuum.

Trends in reported outcomes and patient reported outcome measures (PROMs) in humeral shaft fracture literature: a systematic review.

PURPOSE: With a lack of standardization among outcome measures in fracture literature, cross-study comparisons remain limited. This systematic review aimed to identify trends in outcome measures reported by studies of the treatment of humeral shaft fractures. METHODS: A systematic review was performed of studies reporting clinical outcomes of humeral shaft fractures indexed in PubMed. Extracted data included demographics, fracture characteristics, treatment modalities, outcomes, patient reported outcome measures (PROMs), and journal characteristics. Cochran-Armitage tests and linear regressions were used to identify data trends. Pearson chi-square and Kruskal-Wallis tests were used for comparisons between studies. RESULTS: This review included 197 studies with outcomes of 15,445 humeral shaft fractures. 126 studies reported PROMs and 37 different PROMs were used. The Constant Score was most commonly reported (34% of studies), followed by ASES Score (21%), MEPS (21%), and DASH Score (20%). There was a significant increase in PROM usage over time (p = 0.016) and in articles using three or more PROMs (p = 0.005). The number of PROMs were significantly greater in prospective cohort studies and RCTs (p = 0.012) compared to retrospective cohort studies and case series (p = 0.044 for both). Post-treatment shoulder motion was reported in 43% of studies and 34% reported elbow motion. 86% of studies reported complications as an outcome parameter. Time to union and nonunion rate were published in 69% and 88% of studies, respectively. CONCLUSION: This study identified increasing PROM usage over time and disparities in the reporting of outcomes in humeral shaft fracture literature requiring further validation and standardization of available outcome measures.

The Effects of Unitizing Nail-Plate Constructs in Distal Femur Fractures: A Biomechanical Study.

OBJECTIVES: To assess the biomechanical differences between linked and unlinked constructs in young and osteoporotic cadavers in addition to osteoporotic sawbones. METHODS: Intraarticular distal femur fractures with comminuted metaphyseal regions were created in three young matched pair cadavers, three osteoporotic matched pair cadavers, and six osteoporotic sawbones. Precontoured distal femur locking plates were placed in addition to a standardized retrograde nail, with unitized constructs having one 4.5 mm locking screw placed distally through the nail. Nonunitized constructs had seven 4.5 mm locking screws placed through the plate around the nail, with one 5 mm distal interlock placed through the nail alone. Cadaveric specimens were subjected to axial fatigue loads between 150 and 1500 N (R Ratio = 10) with 1 Hx frequency for 10,000 cycles. Sawbones were axially loaded at 50% of the ultimate load for fatigue testing to achieve runout, with testing performed with 30 and 300 N (R Ratio = 10) loads with 1 Hz frequency for 10,000 cycles. RESULTS: In young cadavers, there was no difference in the mean cyclic displacement of the unitized constructs (1.51 ± 0.62mm) compared to the non-unitized constructs (1.34 ± 0.47mm) (Figure 4A), (p = 0.722). In osteoporotic cadavers, there was no difference in the mean cyclic displacement of the unitized constructs (2.46 ± 0.47mm) compared to the non-unitized constructs (2.91 ± 1.49mm) (p =0.639). There was statistically no significant difference in cyclic displacement between the unitized and non-unitized groups in osteoporotic sawbones(p = 0.181). CONCLUSIONS: Linked constructs did not demonstrate increased axial stiffness or decreased cyclical displacement in comparison to unlinked constructs in young cadaveric specimens, osteoporotic cadaveric specimens, or osteoporotic sawbones.

Long COVID Brain Fog Treatment: Findings from a Pilot Randomized Controlled Trial of Constraint-Induced Cognitive Therapy.

Purpose: Long COVID brain fog is often disabling. Yet, no empirically-supported treatments exist. This study's objectives were to evaluate feasibility and efficacy, provisionally, of a new rehabilitation approach, Constraint-Induced Cognitive Therapy (CICT), for post-COVID-19 cognitive sequelae. Design: Sixteen community-residents ≥ 3-months post-COVID-19 infection with mild cognitive impairment and dysfunction in instrumental activities of daily living (IADL) were enrolled. Participants were randomized to Immediate-CICT or treatment-as-usual (TAU) with crossover to CICT. CICT combined behavior change techniques modified from Constraint-Induced Movement Therapy with Speed of Processing Training, a computerized cognitive-training program. CICT was deemed feasible if (a) ≥80% of participants completed treatment, (b) the same found treatment highly satisfying and at most moderately difficult, and (c) <2 study-related, serious adverse-events occurred. The primary outcome was IADL performance in daily life (Canadian Occupational Performance Measure). Employment status and brain fog (Mental Clutter Scale) were also assessed. Results: Fourteen completed Immediate-CICT ( n =7) or TAU ( n =7); two withdrew from TAU before their second testing session. Completers were [ M (S D )]: 10 (7) months post-COVID; 51 (13) years old; 10 females, 4 males; 1 African American, 13 European American. All the feasibility benchmarks were met. Immediate-CICT, relative to TAU, produced very large improvements in IADL performance ( M =3.7 points, p<.001, d =2.6) and brain fog ( M =-4 points, p<.001, d =-2.9). Four of five non-retired Immediate-CICT participants returned-to-work post-treatment; no TAU participants did, p =.048. Conclusions: CICT has promise for reducing brain fog, improving IADL, and promoting returning-to-work in adults with Long COVID. Findings warrant a large-scale RCT with an active-comparison group. IMPACT: Brain fog in adults with Long COVID is often associated with dysfunction in everyday activities and unemployment. Yet, there are no empirically supported treatments targeting cognition in this population. Findings from this small-scale, pilot randomized controlled trial (RCT) suggest that a novel intervention, i.e., Constraint-Induced Cognitive Therapy, is a feasible cognitive rehabilitation method in adults with Long COVID cognitive sequelae with promise of (a) improving performance of cognition-based tasks in daily life and (b) promoting return-to-work. Further studies with larger sample sizes are warranted.Speed of Processing Training (SOPT) has been shown to increase processing speed in older adults without neurological disorders but has not been applied to adults with brain fog due to Long COVID, in whom slowing of cognitive processing speed is common. The results of this pilot RCT suggest that SOPT, in conjunction with behavior change techniques, may increase cognitive processing speed in this brain-injured population.

Optimal Management of Traumatic Abdominal Wall Hernias Remains Unclear.

High-energy, blunt force trauma to the abdomen results in an abdominal wall injury (AWI) in up to 9% of patients. In 1% of blunt abdominal trauma, they result in a traumatic abdominal wall hernia (TAWH). Optimal management of these injuries remains unclear. Because they are the result of a high-energy mechanism, concomitant serious abdominal organ injuries are common. This has prompted some to advocate that the presence of a TAWH on physical exam mandates exploratory laparotomy. However, delayed repairs have better outcomes and nontherapeutic celiotomy should be avoided. Similarly debated is the expanding use of minimally invasive techniques and the use of mesh for hernia repairs. Overall, the presence of a TAWH is likely not an absolute indication for emergency surgery. Rather, it is an indicator of high-energy impact and associated with a high rate of visceral injury. These patients require a close observation for clinical decline and development of typical indicators for laparotomy.

Comparative Effectiveness Systematic Review and Meta-analysis of Peripheral Nerve Repair Using Direct Repair and Connector-assisted Repair.

Background: This clinical literature systematic review and meta-analysis were performed to assess differences in outcomes between nerves repaired with direct repair (DR) and connector-assisted repair (CAR). Methods: A systematic literature review for DR and CAR was performed. Studies from 1980 through August 2023 were included if DR or CAR repairs were performed in upper extremities with nerve gaps less than 5 mm and reported sensory Medical Research Council Classification (MRCC) outcomes or equivalent. Comparative analyses were planned for meaningful recovery (MR) rate (at both S3 and S3+ or better), postsurgical neuroma, cold intolerance, altered sensation, pain, and revision rate. Results: There were significant differences in MR rates for CAR and DR. At the MRCC S3 threshold, 96.1% of CAR and 81.3% of DR achieved MR (P < 0.0001). At the MRCC S3+ threshold, 87.1% of CAR and 54.2% of DR achieved this higher threshold of MR (P < 0.0001). There were no differences in neuroma rate or pain scores in our dataset. Altered sensation (dysesthesia, paresthesia, hyperesthesia, or hypersensitivity) was not discussed in any CAR studies, so no analysis could be performed. The revision rate for both procedures was 0%. The proportion of patients with cold intolerance was 46.2% in the DR studies, which was significantly higher than the 10.7% of patients in the CAR group. Conclusions: Significantly more patients achieved sensory MR and fewer had cold intolerance when the CAR technique, instead of the DR technique, was performed to repair peripheral nerve injuries.

The Penn Electrophysiology of Encoding and Retrieval Study.

The Penn Electrophysiology of Encoding and Retrieval Study (PEERS) aimed to characterize the behavioral and electrophysiological (EEG) correlates of memory encoding and retrieval in highly practiced individuals. Across five PEERS experiments, 300+ subjects contributed more than 7,000 memory testing sessions with recorded EEG data. Here we tell the story of PEERS: its genesis, evolution, major findings, and the lessons it taught us about taking a big scientific approach in studying memory and the human brain. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

CNS Bridging Radiotherapy Achieves Rapid Cytoreduction Prior to CAR T Cell Therapy for Aggressive B-Cell Lymphoma.

CAR T-cell therapy (CAR T) for central nervous system lymphoma (CNSL) is a promising strategy, yet responses are frequently not durable. Bridging radiotherapy (BRT) is used for extra-cranial lymphoma where it can improve CAR T outcomes through cytoreduction of high-risk lesions. We hypothesized that BRT would achieve similar, significant cytoreduction prior to CAR T for CNSL (CNS-BRT). We identified CNSL patients with non-Hodgkin B-cell lymphoma who received CNS-BRT prior to commercial CAR T. Cytoreduction from CNS-BRT was calculated as change in lesion size prior to CAR T. Twelve patients received CNS-BRT, and the median follow up among survivors is 11.8 months (IQR: 8.5 - 21.9). Ten patients had CNSL (9 secondary, 1 primary) and 2 patients had epidural disease (evaluable for toxicity). All ten patients with CNSL had progressive disease at the time of CNS-BRT. 1/12 patients experienced grade ≥ 3 cytokine release syndrome (CRS), and 3/12 patients experienced grade ≥ 3 immune effector cell-associated neurotoxicity syndrome (ICANS). CNS-BRT achieved a 74.0% (95% confidence interval: 62.0 - 86.0) mean reduction in lesion size from baseline (p = 0.014) at a median of 12 days from BRT completion and prior to CAR T infusion. Best CNS response included 8 complete responses (CR), 1 partial response (PR), and 1 progressive disease (PD). Three patients experienced CNS relapse outside the BRT field. Preliminary data suggest CNS-BRT achieves rapid cytoreduction and is associated with a favorable CNS response and safety profile. These data support further study of BRT as a bridging modality for CNSL CAR T.

The Association Between Surgeon Volume and Dislocation After Total Hip Arthroplasty: A Nationwide Evaluation of 5,106 Orthopaedic Surgeons.

INTRODUCTION: The relationship between surgeon volume and risk of dislocation after total hip arthroplasty (THA) is debated. This study sought to characterize this association and assess patient outcomes using a nationwide patient and surgeon registry. METHODS: The Premier Healthcare Database was queried for adult primary elective THA patients from January 1, 2016, to December 31, 2019. Annual surgeon volume and 90-day risk of dislocation were modeled using multivariable logistic regression with restricted cubic splines. Bootstrap analysis identified a threshold annual case volume, corresponding to the maximum decrease in dislocation risk. Surgeons with an annual volume greater than the threshold were deemed high volume, and those with an annual volume less than the threshold were low volume. Each surgeon within a given year was treated as a unique entity (surgeon-year unit). 90-day complications of patients treated by high-volume and low-volume surgeons were compared. RESULTS: From 2016 to 2019, 352,131 THAs were performed by 5,106 surgeons. The restricted cubic spline model demonstrated an inverse relationship between risk of dislocation and surgeon volume (threshold: 109 cases per year). A total of 9,967 (87.8%) low-volume surgeon-year units had individual dislocation rates lower than the average of the entire surgeon cohort. Patients treated by high-volume surgeons had decreased risk of dislocation (adjusted odds ratio [aOR], 0.60; 95% CI, 0.54 to 0.67), periprosthetic fracture (aOR, 0.87; 95% CI, 0.76 to 0.99), periprosthetic joint infection (aOR, 0.63; 95% CI, 0.56 to 0.69), readmission (aOR, 0.70; 95% CI, 0.67 to 0.73), and in-hospital death (aOR, 0.60; 95% CI, 0.46 to 0.80). CONCLUSION: While most of the low-volume surgeons had dislocation rates lower than the cohort average, increasing annual surgeon case volume was associated with a reduction in risk of dislocation after primary elective THA. THERAPEUTIC LEVEL OF EVIDENCE: Level IV.

Role of allogeneic placental tissues in penile inversion vaginoplasty.

Background: The role of allogeneic placental tissue (APT) in genital gender-affirming surgery (GAS) is not well understood. Penile inversion vaginoplasty (PIV), the most common genital GAS, often results in tissue healing- or wound-related complications, including scarring and neovaginal stenosis. Surgical reoperation and revision vaginoplasty are common. The aim of this study was to evaluate the contribution of APT to postoperative outcomes in PIV. Methods: The authors performed a retrospective analysis of consecutive adult patients undergoing primary PIV during a 6-year period (September 1, 2014 to September 1, 2020). Subjects receiving intraoperative application of an APT biomaterial were compared to those undergoing primary PIV without APT. Postoperative outcomes-including wound healing morbidity and reoperation-were compared between groups. Short- and long-term complications were classified using Clavien-Dindo. Results: A total of 182 primary PIV cases were reviewed (115 conventional PIV; 67 PIV-APT). The postoperative follow-up time for the population averaged 12.7 months. All-cause and wound related complications were significantly lower amongst PIV-APT patients when compared to conventional PIV (P=0.002 and P=0.004, respectively). The rate of long-term complications was significantly lower in PIV-APT subjects: prolonged pain (P=0.001), prolonged swelling (P=0.047), and neovaginal stenosis (P<0.001). The PIV-APT group required significantly less reoperation for vaginal depth enhancement (P=0.007). Conclusions: Though its use in urogenital reconstruction has been limited, this study indicates that the placement of APT during PIV significantly lowered the risk of complications associated with poor wound healing. This supports a novel use for placental tissues in reducing complications in genital GAS.

Comparative analysis of Wolbachia maternal transmission and localization in host ovaries.

Many insects and other animals carry microbial endosymbionts that influence their reproduction and fitness. These relationships only persist if endosymbionts are reliably transmitted from one host generation to the next. Wolbachia are maternally transmitted endosymbionts found in most insect species, but transmission rates can vary across environments. Maternal transmission of wMel Wolbachia depends on temperature in natural Drosophila melanogaster hosts and in transinfected Aedes aegypti, where wMel is used to block pathogens that cause human disease. In D. melanogaster, wMel transmission declines in the cold as Wolbachia become less abundant in host ovaries and at the posterior pole plasm (the site of germline formation) in mature oocytes. Here, we assess how temperature affects maternal transmission and underlying patterns of Wolbachia localization across 10 Wolbachia strains diverged up to 50 million years-including strains closely related to wMel-and their natural Drosophila hosts. Many Wolbachia maintain high transmission rates across temperatures, despite highly variable (and sometimes low) levels of Wolbachia in the ovaries and at the developing germline in late-stage oocytes. Identifying strains like closely related wMel-like Wolbachia with stable transmission across variable environmental conditions may improve the efficacy of Wolbachia-based biocontrol efforts as they expand into globally diverse environments.

Systematic Review and Meta-Analysis of the Effect of Osteoporosis on Reoperation Rates and Complications after Surgical Management of Lumbar Degenerative Disease.

BACKGROUND: There is considerable heterogeneity in findings and a lack of consensus regarding the interplay between osteoporosis and outcomes in patients with lumbar degenerative spine disease. Therefore, the purpose of this systematic review and meta-analysis was to gather and analyze existing data on the effect of osteoporosis on radiographic, surgical, and clinical outcomes following surgery for lumbar degenerative spinal disease. METHODS: A systematic review was performed to determine the effect of osteoporosis on the incidence of adverse outcomes after surgical intervention for lumbar degenerative spinal diseases. The approach focused on the radiographic outcomes, reoperation rates, and other medical and surgical complications. Subsequently, a meta-analysis was performed on the eligible studies. RESULTS: The results of the meta-analysis suggested that osteoporotic patients experienced increased rates of adjacent segment disease (ASD; p=0.015) and cage subsidence (p=0.001) while demonstrating lower reoperation rates than non-osteoporotic patients (7.4% vs. 13.1%; p=0.038). The systematic review also indicated that the length of stay, overall costs, rates of screw loosening, and rates of wound and other medical complications may increase in patients with a lower bone mineral density. Fusion rates, as well as patient-reported and clinical outcomes, did not differ significantly between osteoporotic and non-osteoporotic patients. CONCLUSIONS: Osteoporosis was associated with an increased risk of ASD, cage migration, and possibly postoperative screw loosening, as well as longer hospital stays, incurring higher costs and an increased likelihood of postoperative complications. However, a link was not established between osteoporosis and poor clinical outcomes.

Practical Bayesian Inference in Neuroscience: Or How I Learned to Stop Worrying and Embrace the Distribution.

Typical statistical practices in the biological sciences have been increasingly called into question due to difficulties in the replication of an increasing number of studies, many of which are confounded by the relative difficulty of null significance hypothesis testing designs and interpretation of p-values. Bayesian inference, representing a fundamentally different approach to hypothesis testing, is receiving renewed interest as a potential alternative or complement to traditional null significance hypothesis testing due to its ease of interpretation and explicit declarations of prior assumptions. Bayesian models are more mathematically complex than equivalent frequentist approaches, which have historically limited applications to simplified analysis cases. However, the advent of probability distribution sampling tools with exponential increases in computational power now allows for quick and robust inference under any distribution of data. Here we present a practical tutorial on the use of Bayesian inference in the context of neuroscientific studies in both rat electrophysiological and computational modeling data. We first start with an intuitive discussion of Bayes' rule and inference followed by the formulation of Bayesian-based regression and ANOVA models using data from a variety of neuroscientific studies. We show how Bayesian inference leads to easily interpretable analysis of data while providing an open-source toolbox to facilitate the use of Bayesian tools.

A machine learning approach for potential Super-Agers identification using neuronal functional connectivity networks.

INTRODUCTION: Aging is often associated with cognitive decline. Understanding neural factors that distinguish adults in midlife with superior cognitive abilities (Positive-Agers) may offer insight into how the aging brain achieves resilience. The goals of this study are to (1) introduce an optimal labeling mechanism to distinguish between Positive-Agers and Cognitive Decliners, and (2) identify Positive-Agers using neuronal functional connectivity networks data and demographics. METHODS: In this study, principal component analysis initially created latent cognitive trajectories groups. A hybrid algorithm of machine learning and optimization was then designed to predict latent groups using neuronal functional connectivity networks derived from resting state functional magnetic resonance imaging. Specifically, the Optimal Labeling with Bayesian Optimization (OLBO) algorithm used an unsupervised approach, iterating a logistic regression function with Bayesian posterior updating. This study encompassed 6369 adults from the UK Biobank cohort. RESULTS: OLBO outperformed baseline models, achieving an area under the curve of 88% when distinguishing between Positive-Agers and cognitive decliners. DISCUSSION: OLBO may be a novel algorithm that distinguishes cognitive trajectories with a high degree of accuracy in cognitively unimpaired adults. Highlights: Design an algorithm to distinguish between a Positive-Ager and a Cognitive-Decliner.Introduce a mathematical definition for cognitive classes based on cognitive tests.Accurate Positive-Ager identification using rsfMRI and demographic data (AUC = 0.88).Posterior default mode network has the highest impact on Positive-Aging odds ratio.

Evaluation of Educational YouTube Videos for Distal Radius Fracture Treatment.

Purpose: Distal radius fractures (DRFs) are one of the most common fractures in adults. Adequate patient education is crucial for adherence to treatment. YouTube is a popular, accessible resource that has become a valuable tool for obtaining health information. The current study evaluated the top 50 YouTube videos on DRF treatment for patient education. Methods: A systematic search was conducted on YouTube using three searches to obtain 150 videos. Duplicate, nonrelevant, paid, and non-English videos were removed, and the top 50 rank-ordered videos were reviewed and characterized in terms of general (views, likes, video length, and publication date), source (publisher affiliation, presenter type, and target audience), and content (media type, topic coverage, advertisements, and bias) parameters. Results: Only 56% of videos were directed toward patients versus 40% for health care providers, highlighting a gap in patient-oriented educational content on YouTube. Most (86%) videos included effective visual aids, aligning with best practices for educational videos. Surgical management was overrepresented in 64% of the videos as opposed to nonsurgical management in 34% of videos. Only 31% of patient-oriented videos discussed surgical complications. Home exercises were emphasized in 75% of the videos discussing recovery topics. Conclusions: Although YouTube has the potential to be an effective resource for disseminating health information to patients, it has several limitations for education in DRF treatment including the lack of patient-oriented educational videos, overrepresentation of surgical treatment, and lack of information on surgical complications. Nonetheless, YouTube may have an important role as a supplementary resource, especially in certain topics such as guiding postoperative recovery with home exercises. Clinical relevance: This study allows health care providers and content creators to proactively address information gaps identified in educational YouTube videos on DRF treatment. It helps characterize the role of YouTube in supporting the treatment and recovery of patients experiencing DRFs.

Perioperative Dexamethasone is Associated With a Decreased Risk of Pulmonary Embolism and Deep Vein Thrombosis Following Total Joint Arthroplasty: An Analysis of 70,000 High-Risk Patients.

BACKGROUND: Dexamethasone (DEX) has demonstrated promise with respect to decreasing postoperative thromboembolic complications following total joint arthroplasty (TJA). Therefore, the aim of this study was to investigate the effects of perioperative intravenous DEX on rates of pulmonary embolism (PE) and deep vein thrombosis (DVT) after primary TJA in patients who have a history of venous thromboembolism (VTE). METHODS: Patients who have a history of VTE who underwent primary elective TJA from 2015 to 2021 were identified using a commercial health care database. Patients were divided based on receipt of perioperative intravenous DEX [DEX(+) versus DEX(-)] on the day of index TJA. Patient demographics and hospital factors were collected. The 90-day risk of postoperative complications, readmission, and in-hospital mortality were compared. RESULTS: Overall, 70,147 patients who had a history of VTE underwent TJA, of which 40,607 (57.89%) received DEX and 29,540 (42.11%) did not. The DEX(+) patients were younger (67 ± 9.8 versus 68 ± 9.9 years, P < .001) and had a significantly shorter length of stay compared to the DEX(-) patients (1.8 ± 1.6 versus 2.2 ± 1.8 days, P < .001). The DEX(+) patients demonstrated lower rates of PE (1.37 versus 1.75%, P < .001) and DVT (2.37 versus 3.01%, P < .001) compared to DEX(-) patients. The DEX(+) patients experienced a lower risk of PE (adjusted odds ratio: 0.78, 95% confidence interval: 0.66 to 0.93, P = .006) and DVT (adjusted odds ratio: 0.84, 95% confidence interval: 0.74 to 0.95, P = .006) compared to DEX(-) patients. The DEX(+) patients demonstrated no differences in the odds of surgical site infection, periprosthetic joint infection, or sepsis compared to the DEX(-) patients (P > .05). CONCLUSIONS: The administration of DEX was associated with a decreased risk of PE and DVT in patients who have a history of VTE who underwent TJA. These data warrant further study investigating the postoperative benefits of perioperative DEX administration for high-risk patients undergoing TJA. LEVEL OF EVIDENCE: Level III.

Discovery and Optimization of Tambjamines as a Novel Class of Antileishmanial Agents.

Leishmaniasis is a neglected tropical disease that is estimated to afflict over 12 million people. Current drugs for leishmaniasis suffer from serious deficiencies, including toxicity, high cost, modest efficacy, primarily parenteral delivery, and emergence of widespread resistance. We have discovered and developed a natural product-inspired tambjamine chemotype, known to be effective against Plasmodium spp, as a novel class of antileishmanial agents. Herein, we report in vitro and in vivo antileishmanial activities, detailed structure-activity relationships, and metabolic/pharmacokinetic profiles of a large library of tambjamines. A number of tambjamines exhibited excellent potency against both Leishmania mexicana and Leishmania donovani parasites with good safety and metabolic profiles. Notably, tambjamine 110 offered excellent potency and provided partial protection to leishmania-infected mice at 40 and/or 60 mg/kg/10 days of oral treatment. This study presents the first account of antileishmanial activity in the tambjamine family and paves the way for the generation of new oral antileishmanial drugs.

Recommendations for reporting tissue and circulating tumour (ct)DNA next-generation sequencing results in non-small cell lung cancer.

Non-small cell lung cancer is a heterogeneous disease and molecular characterisation plays an important role in its clinical management. Next-generation sequencing-based panel testing enables many molecular alterations to be interrogated simultaneously, allowing for comprehensive identification of actionable oncogenic drivers (and co-mutations) and appropriate matching of patients with targeted therapies. Despite consensus in international guidelines on the importance of broad molecular profiling, adoption of next-generation sequencing varies globally. One of the barriers to its successful implementation is a lack of accepted standards and guidelines specifically for the reporting and clinical annotation of next-generation sequencing results. Based on roundtable discussions between pathologists and oncologists, we provide best practice recommendations for the reporting of next-generation sequencing results in non-small cell lung cancer to facilitate its use and enable easy interpretation for physicians. These are intended to complement existing guidelines related to the use of next-generation sequencing (solid and liquid). Here, we discuss next-generation sequencing workflows, the structure of next-generation sequencing reports, and our recommendations for best practice thereof. The aim of these recommendations and considerations is ultimately to ensure that reports are fully interpretable, and that the most appropriate treatment options are selected based on robust molecular profiles in well-defined reports.