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Abstract Background Pulmonary rehabilitation (PR) is widely recommended for short-term benefits in chronic respiratory diseases, yet long-term outcomes remain uncertain. This retrospective cohort study addresses this gap, comparing 20-year mortality rates between PR participants and matched controls, and hypothesizing that the short-term benefits of PR contribute to improved long-term survival. Methods The 20-year mortality of stable chronic respiratory patients who participated in an outpatient PR program was compared with a matched control group based on the type of lung disease. Demographic and clinical variables, and the dates of deaths, were extracted and compared between two groups with two sample t-test and chi-square tests. Kaplan-Meier plots and Cox regression analyses were employed to evaluate survival differences. Results Between 2000 and 2002, 238 individuals enrolled in a pulmonary rehabilitation (PR) program (58% male, mean age ± SD: 69 ± 8 years, mean FEV1% predicted ± SD: 46 ± 21%). An equal number of people with comparable lung disease were selected as controls (88% COPD, 5% ILD). Controls had lower FEV1% predicted values (mean ± SD: 39 ± 17%, P

Sponges (Phylum Porifera) are aquatic sessile metazoans found worldwide in marine and freshwater environments. They are significant in the animal tree of life as one of the earliest-branching metazoan lineages and as filter feeders play crucial ecological roles, particularly in coral reefs, but are susceptible to the effects of climate change. In the face of the current biodiversity crisis, genomic data is crucial for species conservation efforts and predicting their evolutionary potential in response to environmental changes. However, there is a limited availability of culturable sponge species with annotated high-quality genomes to further comprehensive insights into animal evolution, function, and their response to the ongoing global change. Despite the publication of a few high-quality annotated sponge genomes, there remains a gap in resources for culturable sponge species. To address this gap, we provide high quality draft genomes of the two congeneric aquarium species Tethya wilhelma and Tethya minuta, small ball-shaped demosponges that are easily maintained long-term in ex situ culture. As such, they offer promising opportunities as laboratory models to contribute to advancing our understanding of sponge biology and provide valuable resources for studying animal evolution, function, and responses to environmental challenges.

Objective The primary goal of this study is to evaluate the relationship between Body Mass Index (BMI) and muscle atrophy in individuals with rotator cuff tears.Methods This study consists of patients with rotator cuff tears identified by MRI from two independent cohorts, the Rotator Cuff Outcomes Workgroup (ROW) and the Multicenter Orthopaedic Outcomes Network (MOON). Presence of atrophy (yes/no) and severity of atrophy (as an ordinal variable) were assessed on MRI by expert physicians. We used multivariable regression models to evaluate the relationship between BMI and muscle atrophy while adjusting for age and sex in each study, conducted sensitivity analyses for full-thickness tear and combined results using inverse variance-weighted meta-analysis.Results A total of 539 patients (MOON=395, ROW=144) from the combined cohorts had MRI data available on muscle atrophy. Among these patients, 246 (46%) had atrophy of at least one of the muscles of the rotator cuff and 282 (52%) had full-thickness tears. In meta-analysis across both cohorts, each 5 kg/m2 increase in BMI was associated with a 21% (aOR=1.21, 95% CI=1.02, 1.43) increased odds of having muscle atrophy among individuals with any tear size, and 36% (aOR=1.36, 95% CI=1.01–1.81) increased odds among individuals with full-thickness tear.Conclusions Higher BMI was associated with significantly higher odds of muscle atrophy in patiens with rotator cuff tears. More study is needed to unders1tand why and how this relationship exists, as well as whether interventions to reduce BMI may help improve outcomes for these patients.Level of Evidence III.

A low level of Neurotrophins (NTs), their Tyrosine Kinase Receptors (Trks), Vascular Endothelial Growth Factors (VEGFs) and their receptors, mainly VEGFR1 and VEGFR2, characterizes AD brains. The use of NTs and VEGFs as drugs presents different issues due to their low permeability of the blood−brain barrier, the poor pharmacokinetic profile, and the relevant side effects. To overcome these issues, different functional and structural NT mimics have been employed. Being aware that the N-terminus domain as the key domain of NTs for the binding selectivity and activation of Trks and the need to avoid or delay proteolysis, we herein report on the mimicking ability of two cyclic peptide encompassing the N-terminus of Brain Derived Growth Factor (BDNF), (c-[HSDPARRGELSV-]), cBDNF(1-12) and of Neurotrophin3 (NT3), (c-[YAEHKSHRGEYSV-]), cNT3(1-13). The two cyclic peptide features were characterized by a combined thermodynamic and spectroscopic approach (potentiometry, NMR, UV-vis and CD) that was extended to their copper(II) ion complexes. SH-SY5Y cell assays show that the Cu2+ present at the sub-micromolar level in the complete culture media affects the treatments with the two peptides. cBDNF(1-12) and cNT3(1-13) act as ionophores, induce neuronal differentiation and promote Trks and CREB phosphorylation in a copper dependent manner. Consistently, both peptide and Cu2+ stimulate BDNF and VEGF expression as well as VEGF release; cBDNF(1-12) and cNT3(1-13) induce the expression of Trks and VEGFRs.

Breast cancer metastasis is initiated by invasion of tumor cells into the collagen type I-rich stroma to reach adjacent blood vessels. Prior work has identified that metabolic plasticity is a key requirement of tumor cell invasion into collagen. However, it remains largely unclear how blood vessels affect this relationship. Here, we developed a microfluidic platform to analyze how tumor cells invade collagen in the presence and absence of a microvascular channel. We demonstrate that endothelial cells secrete pro-migratory factors that direct tumor cell invasion toward the microvessel. Analysis of tumor cell metabolism using metabolic imaging, metabolomics, and computational flux balance analysis revealed that these changes are accompanied by increased rates of glycolysis and oxygen consumption caused by broad alterations of glucose metabolism. Indeed, restricting glucose availability decreased endothelial cell-induced tumor cell invasion. Our results suggest that endothelial cells promote tumor invasion into the stroma due, in part, to reprogramming tumor cell metabolism.

Background. Organ donors supported by extracorporeal membrane oxygenation (ECMO) have historically been considered high-risk and are judiciously utilized. This study examines transplant outcomes using renal allografts from donors supported on ECMO for nondonation purposes. Methods. Retrospective review of the Gift of Life (Pennsylvania, New Jersey, Delaware) organ procurement organization database, cross-referenced to the Organ Procurement and Transplantation Network database, assessed kidney transplants using donors supported on venoarterial (VA) and venovenous (VV) ECMO for nondonation purposes. Transplants using VA- and VV-ECMO donors were compared with Kidney Donor Profile Index (KDPI)-stratified non-ECMO donors. Regression modeling of the entire ECMO and non-ECMO populations assessed ECMO as predictive of graft survival. Additional regression of the ECMO population alone assessed for donor features associated with graft survival. Results. Seventy-eight ECMO donors yielded 128 kidney transplants (VA: 80, VV: 48). Comparing outcomes using these donors to kidney transplants using organs from KDPI-stratified non-ECMO donors, VA- and VV-ECMO donor grafts conferred similar rates of delayed graft function and posttransplant renal function to KDPI-matched non-ECMO counterparts. VA-ECMO kidneys demonstrated superior graft survival compared with the lowest-quality (KDPI 86%–100%) non-ECMO kidneys and similar graft survival to KDPI

Ultrasonic dental scalers are indispensable instruments for efficient dental cleaning through the generation of cavitation. To gain valuable insights and enhance the cavitation cleaning effects, a numerical investigation is conducted using the finite element method via ABAQUS. Numerical results are compared with the experimental cavitation image for a scaler undergoes vibrations near a wall. We then analyse how the amplitude, frequency, and cross-sectional shape of the scaler affect cavitation generation. Numerical results indicate that cavitation is more pronounced for a scaler oscillating near a nearly rigid boundary than a soft boundary. It increases with the vibration amplitude because of higher ultrasonic energy transferring to the liquid and generating stronger pressure waves. The resonant frequency of the scaler coincides with the maximum cavitation and scaler tip amplitude. Reducing the dimension of the cross-section of the scaler in its oscillation direction increases both the scaler tip amplitude and the cavitation generated. This finding offers a potential design approach for enhancing the scaler cavitation and its cleaning effects. These insights provide practical guidance for optimising dental scaler settings, which can improve oral hygiene and prevent complications related to dental implants.

Summary: Background: Systemic sclerosis is a heterogenous disease in which little is known about patterns of patient-reported symptom clusters. We aimed to identify classes of individuals with similar anxiety, depression, fatigue, sleep disturbance, and pain symptoms and to evaluate associated sociodemographic and disease-related characteristics. Methods: This multi-centre cross-sectional study used baseline data from Scleroderma Patient-centered Intervention Network Cohort participants enrolled from 2014 to 2020. Eligible participants completed the PROMIS-29 v2.0 measure. Latent profile analysis was used to identify homogeneous classes of participants based on patterns of anxiety, depression, fatigue, sleep disturbance, and pain scores. Sociodemographic and disease-related characteristics were compared across classes. Findings: Among 2212 participants, we identified five classes, including four classes with “Low” (565 participants, 26%), “Normal” (651 participants, 29%), “High” (569 participants, 26%), or “Very High” (193 participants, 9%) symptom levels across all symptoms. Participants in a fifth class, “High Fatigue/Sleep/Pain and Low Anxiety/Depression” (234 participants, 11%) had similar levels of fatigue, sleep disturbance, and pain as in the “High” class but low anxiety and depression symptoms. There were significant and substantive trends in sociodemographic characteristics (age, education, race or ethnicity, marital or partner status) and increasing disease severity (diffuse disease, tendon friction rubs, joint contractures, gastrointestinal symptoms) across severity-based classes. Disease severity and sociodemographic characteristics of “High Fatigue/Sleep/Pain and Low Anxiety/Depression” class participants were similar to the “High” severity class. Interpretation: Most people with systemic sclerosis can be classified by levels of patient-reported symptoms, which are consistent across symptoms and highly associated with sociodemographic and disease-related variables, except for one group which reports low mental health symptoms despite high levels of other symptoms and substantial disease burden. Studies are needed to better understand resilience in systemic sclerosis and to identify and facilitate implementation of cognitive and behavioural strategies to improve coping and overall quality of life. Funding: National Institute of Nursing Research (F31NR019007), Canadian Institutes of Health Research, Arthritis Society Canada, the Lady Davis Institute for Medical Research, the Jewish General Hospital Foundation, McGill University, Scleroderma Society of Ontario, Scleroderma Canada, Sclérodermie Québec, Scleroderma Manitoba, Scleroderma Atlantic, Scleroderma Association of BC, Scleroderma SASK, Scleroderma Australia, Scleroderma New South Wales, Scleroderma Victoria, and Scleroderma Queensland.

PURPOSEThe study reports on the current perception of medical and radiation oncologists regarding teleconsultation in the Philippines. Before the COVID-19 pandemic, the adoption of telemedicine was not widespread. With movement restrictions imposed during the pandemic, physicians were compelled to use telemedicine. It is uncertain whether physicians will still adopt its use in practice in the post–COVID-19 era. This study gives insight into the possible adaptation of this mode of consultation in the future, especially in areas with limited health care resources.MATERIALS AND METHODSWe conducted a national survey among medical oncologists and radiation oncologists in the Philippines. A 43-item online survey was developed, validated, and administered to the oncologists. The demographics and data from categorical questions were reported as frequencies and percentages.RESULTSA total of 142 responses were gathered from 82 medical oncologists and 60 radiation oncologists. There was agreement among participants that, during the pandemic, teleconsultation could be used for the first visit, diagnostic workup request, treatment explanation, follow-up care, and chronic disease management. There was disagreement whether cancer diagnosis disclosure and cancer prognosis revelation could be performed via teleconsultation, and there was agreement that emergency consultation and physical examination would warrant a face-to-face consultation. After the COVID-19 pandemic, 78.7% intend to continue using teleconsultation except for emergency consultations, first visits, physical examination, diagnosis disclosure, and cancer prognosis revelation.CONCLUSIONTeleconsultation was perceived by oncologists as an acceptable method of providing cancer care during and after the COVID-19 pandemic. Oncologists also intend to use teleconsultation in the post–COVID-19 era in certain aspects of patient care.

Well-annotated and contiguous genomes are an indispensable resource for understanding the evolution, development, and metabolic capacities of organisms. Sponges, an ecologically important non-bilaterian group of primarily filter-feeding sessile aquatic organisms, are underrepresented with respect to available genomic resources. Here we provide a high-quality and well-annotated genome of Aphrocallistes vastus, a glass sponge (Porifera: Hexactinellida) that forms large reef structures off the coast of British Columbia (Canada). We show that its genome is approximately 80 Mb, small compared to most other metazoans, and contains nearly 2500 nested genes, more than other genomes. Hexactinellida is characterized by a unique skeletal architecture made of amorphous silicon dioxide (SiO2), and we identified 419 differentially expressed genes between the osculum, i.e. the vertical growth zone of the sponge, and the main body. Among the upregulated ones, mineralization-related genes such as glassin, as well as collagens and actins, dominate the expression profile during growth. Silicateins, suggested being involved in silica mineralization, especially in demosponges, were not found at all in the A. vastus genome and suggests that the underlying mechanisms of SiO2 deposition in the Silicea sensu stricto (Hexactinellida + Demospongiae) may not be homologous.

We present follow-up spectroscopy and a detailed model atmosphere analysis of 29 wide double white dwarfs, including eight systems with a crystallized C/O core member. We use the state-of-the-art evolutionary models to constrain the physical parameters of each star, including the total age. Assuming that the members of wide binaries are coeval, any age difference between the binary members can be used to test the cooling physics for white dwarf stars, including potential delays due to crystallization and ^22 Ne distillation. We use our control sample of 14 wide binaries with noncrystallized members to show that this method works well; the control sample shows an age difference of only ΔAge = −0.03 ± 0.15 Gyr between its members. For the eight crystallized C/O core systems we find a cooling anomaly of ΔAge = ${1.13}_{-1.07}^{+1.20}$ Gyr. Even though our results are consistent with a small additional cooling delay (∼1 Gyr) from ^22 Ne distillation and other neutron-rich impurities, the large uncertainties make this result not statistically significant. Nevertheless, we rule out cooling delays longer than 3.6 Gyr at the 99.7% (3 σ ) confidence level for 0.6–0.9 M _⊙ white dwarfs. Further progress requires larger samples of wide binaries with crystallized massive white dwarf members. We provide a list of subgiant + white dwarf binaries that could be used for this purpose in the future.

We present a detailed model atmosphere analysis of massive white dwarfs with M > 0.9 M _⊙ and T _eff ≥ 11,000 K in the Montreal White Dwarf Database 100 pc sample and the Pan-STARRS footprint. We obtained follow-up optical spectroscopy of 109 objects with no previous spectral classification in the literature. Our spectroscopic follow-up is now complete for all 204 objects in the sample. We find 118 normal DA white dwarfs, including 45 massive DAs near the ZZ Ceti instability strip. There are no normal massive DBs: the six DBs in the sample are strongly magnetic and/or rapidly rotating. There are 20 massive DQ white dwarfs in our sample, and all are found in the crystallization sequence. In addition, 66 targets are magnetic (32% of the sample). We use magnetic white dwarf atmosphere models to constrain the field strength and geometry using offset dipole models. We also use magnetism, kinematics, and rotation measurements to constrain the fraction of merger remnant candidates among this population. The merger fraction of this sample increases from 25% for 0.9–1 M _⊙ white dwarfs to 49% for 1.2–1.3 M _⊙ . However, this fraction is as high as ${78}_{-7}^{+4}$ % for 1.1–1.2 M _⊙ white dwarfs. Previous works have demonstrated that 5%–9% of high-mass white dwarfs stop cooling for ∼8 Gyr due to the ^22 Ne distillation process, which leads to an overdensity of Q-branch stars in the solar neighborhood. We demonstrate that the overabundance of the merger remnant candidates in our sample is likely due to the same process.

Four years after the discovery of a unique DAQ white dwarf with a hydrogen-dominated and carbon-rich atmosphere, we report the discovery of four new DAQ white dwarfs, including two that were not recognized properly in the literature. We find all five DAQs in a relatively narrow mass and temperature range of M = 1.14–1.19 M _⊙ and T _eff = 13,000–17,000 K. In addition, at least two show photometric variations due to rapid rotation with ≈10 minute periods. All five are also kinematically old, but appear photometrically young, with estimated cooling ages of about 1 Gyr based on standard cooling tracks, and their masses are roughly twice the mass of the most common white dwarfs in the solar neighborhood. These characteristics are smoking gun signatures of white dwarf merger remnants. Comparing the DAQ sample with warm DQ white dwarfs, we demonstrate that there is a range of hydrogen abundances among the warm DQ population and that the distinction between DAQ and warm DQ white dwarfs is superficial. We discuss the potential evolutionary channels for the emergence of the DAQ subclass, suggesting that DAQ white dwarfs are trapped on the crystallization sequence and may remain there for a significant fraction of the Hubble time.

Abstract Objectives These data were collected to generate a novel reference metagenome for the sponge Halichondria panicea and its microbiome for subsequent differential expression analyses. Data description These data include raw sequences from four separate sequencing runs of the metagenome of a single individual of Halichondria panicea—one Illumina MiSeq (2 × 300 bp, paired-end) run and three Oxford Nanopore Technologies (ONT) long-read sequencing runs, generating 53.8 and 7.42 Gbp respectively. Comparing assemblies of Illumina, ONT and an Illumina-ONT hybrid revealed the hybrid to be the ‘best’ assembly, comprising 163 Mbp in 63,555 scaffolds (N50: 3084). This assembly, however, was still highly fragmented and only contained 52% of core metazoan genes (with 77.9% partial genes), so it was also not complete. However, this sponge is an emerging model species for field and laboratory work, and there is considerable interest in genomic sequencing of this species. Although the resultant assemblies from the data presented here are suboptimal, this data note can inform future studies by providing an estimated genome size and coverage requirements for future sequencing, sharing additional data to potentially improve other suboptimal assemblies of this species, and outlining potential limitations and pitfalls of the combined Illumina and ONT approach to novel genome sequencing.

Abstract Background The Scleroderma Patient-centered Intervention Network (SPIN) developed an online self-management program (SPIN-SELF) designed to improve disease-management self-efficacy in people with systemic sclerosis (SSc, or scleroderma). The aim of this study was to evaluate feasibility aspects for conducting a full-scale randomized controlled trial (RCT) of the SPIN-SELF Program. Methods This feasibility trial was embedded in the SPIN Cohort and utilized the cohort multiple RCT design. In this design, at the time of cohort enrollment, cohort participants consent to be assessed for trial eligibility and randomized prior to being informed about the trial. Participants in the intervention arm are informed and provide consent, but not the control group. Forty English-speaking SPIN Cohort participants from Canada, the USA, or the UK with low disease-management self-efficacy (Self-Efficacy for Managing Chronic Disease Scale [SEMCD] score ≤ 7) who were interested in using an online self-management program were randomized (3:2 ratio) to be offered the SPIN-SELF Program or usual care for 3 months. Program usage was examined via automated usage logs. User satisfaction was assessed with semi-structured interviews. Trial personnel time requirements and implementation challenges were logged. Results Of 40 SPIN Cohort participants randomized, 26 were allocated to SPIN-SELF and 14 to usual care. Automated eligibility and randomization procedures via the SPIN Cohort platform functioned properly, except that two participants with SEMCD scores > 7 (scores of 7.2 and 7.3, respectively) were included, which was caused by a system programming error that rounded SEMCD scores. Of 26 SPIN Cohort participants offered the SPIN-SELF Program, only 9 (35%) consented to use the program. Usage logs showed that use of the SPIN-SELF Program was low: 2 of 9 users (22%) logged into the program only once (median = 3), and 4 of 9 (44%) accessed none or only 1 of the 9 program’s modules (median = 2). Conclusions The results of this study will lead to substantial changes for the planned full-scale RCT of the SPIN-SELF Program that we will incorporate into a planned additional feasibility trial with progression to a full-scale trial. These changes include transitioning to a conventional RCT design with pre-randomization consent and supplementing the online self-help with peer-facilitated videoconference-based groups to enhance engagement. Trial registration clinicaltrials.gov , NCT03914781 . Registered 16 April 2019.

Abstract Background Systemic sclerosis (scleroderma; SSc) is a rare autoimmune connective tissue disease. We completed an initial feasibility trial of an online self-administered version of the Scleroderma Patient-centered Intervention Network Self-Management (SPIN-SELF) Program using the cohort multiple randomized controlled trial (RCT) design. Due to low intervention offer uptake, we will conduct a new feasibility trial with progression to full-scale trial, using a two-arm parallel, partially nested RCT design. The SPIN-SELF Program has also been revised to include facilitator-led videoconference group sessions in addition to online material. We will test the group-based intervention delivery format, then evaluate the effect of the SPIN-SELF Program on disease management self-efficacy (primary) and patient activation, social appearance anxiety, and functional health outcomes (secondary). Methods This study is a feasibility trial with progression to full-scale RCT, pending meeting pre-defined criteria, of the SPIN-SELF Program. Participants will be recruited from the ongoing SPIN Cohort ( http://www.spinsclero.com/en/cohort ) and via social media and partner patient organizations. Eligible participants must have SSc and low to moderate disease management self-efficacy (Self-Efficacy for Managing Chronic Disease (SEMCD) Scale score ≤ 7.0). Participants will be randomized (1:1 allocation) to the group-based SPIN-SELF Program or usual care for 3 months. The primary outcome in the full-scale trial will be disease management self-efficacy based on SEMCD Scale scores at 3 months post-randomization. Secondary outcomes include SEMCD scores 6 months post-randomization plus patient activation, social appearance anxiety, and functional health outcomes at 3 and 6 months post-randomization. We will include 40 participants to assess feasibility. At the end of the feasibility portion, stoppage criteria will be used to determine if the trial procedures or SPIN-SELF Program need important modifications, thereby requiring a re-set for the full-scale trial. Otherwise, the full-scale RCT will proceed, and outcome data from the feasibility portion will be utilized in the full-scale trial. In the full-scale RCT, 524 participants will be recruited. Discussion The SPIN-SELF Program may improve disease management self-efficacy, patient activation, social appearance anxiety, and functional health outcomes in people with SSc. SPIN works with partner patient organizations around the world to disseminate its programs free-of-charge. Trial registration ClinicalTrials.gov NCT04246528 . Registered on 27 January 2020

Periodontal pockets are spaces or holes surrounded by teeth under the gum line. These pockets can become filled with infection-causing bacteria resulting in tissue, bone, and tooth loss. Cavitation produced by the oscillating tip of dental ultrasonic scalers plays a significant role in routine periodontal therapy to clean these areas. Numerical studies were conducted for a scaler vibrating in a periodontal pocket which was simplified to a hole, using ABAQUS based on the finite element method. The simulations consider the three-dimensional, nonlinear, and transient interaction between the vibration and deformation of the scaler tip, the water flow around the scaler and the cavitation formation. The numerical model was validated by comparing results with experimental data for a scaler vibrating in an unbounded liquid, the displacement at the free end of the scaler and the cavitation pattern near the scaler tip displaying excellent agreement. A parametric study for a scaler vibrating in a hole has been carried out in terms of the volume of the hole, the taper ratio (the radius ratio between the circular opening and bottom of the hole), and the immersion depth of the scaler tip in the hole. The amount of cavitation generated is evaluated by the cavitation density (or the void fraction) which is the ratio of the volume of the cavitation occupied in the hole to the total volume of the hole. Numerical results indicate that the cavitation density in the hole increases with the decreasing hole volume and the increasing taper ratio. It is inferred that cleaning effects could be increased if some modifications to the scaler design could be made to increase the blocking effect of the hole during the cleaning process. Cavitation is observed in the hole even if the scaler is placed above the hole and increases with the immersion depth.

The SARS-CoV-2 pandemic demonstrated the need for potent and broad-spectrum vaccines. This study reports the development and testing of a lumpy skin disease virus (LSDV)-vectored vaccine against SARS-CoV-2, utilizing stabilized spike and conserved nucleocapsid proteins as antigens to develop robust immunogenicity. Construction of the vaccine (LSDV-SARS2-S,N) was confirmed by polymerase chain reaction (PCR) amplification and sequencing. In vitro characterization confirmed that cells infected with LSDV-SARS2-S,N expressed SARS-CoV-2 spike and nucleocapsid protein. In BALB/c mice, the vaccine elicited high magnitude IFN-γ ELISpot responses (spike: 2808 SFU/106 splenocytes) and neutralizing antibodies (ID50 = 6552). Testing in hamsters, which emulate human COVID-19 disease progression, showed the development of high titers of neutralizing antibodies against the Wuhan and Delta SARS-CoV-2 variants (Wuhan ID50 = 2905; Delta ID50 = 4648). Additionally, hamsters vaccinated with LSDV-SARS2-S,N displayed significantly less weight loss, lung damage, and reduced viral RNA copies following SARS-CoV-2 infection with the Delta variant as compared to controls, demonstrating protection against disease. These data demonstrate that LSDV-vectored vaccines display promise as an effective SARS-CoV-2 vaccine and as a potential vaccine platform for communicable diseases in humans and animals. Further efficacy testing and immune response analysis, particularly in non-human primates, are warranted.

Purpose The Scleroderma Patient-centered Intervention Network (SPIN) online hand exercise program (SPIN-HAND), is an online self-help program of hand exercises designed to improve hand function for people with scleroderma. The objective of this feasibility trial was to evaluate aspects of feasibility for conducting a full-scale randomized controlled trial of the SPIN-HAND program. Materials and Methods The feasibility trial was embedded in the SPIN cohort and utilized the cohort multiple randomized controlled trial (cmRCT) design. In the cmRCT design, at the time of cohort enrollment, cohort participants consent to be assessed for trial eligibility and randomized prior to being informed about trials conducted using the cohort. When trials were conducted in the cohort, participants randomized to the intervention were informed and consented to access the intervention. Participants randomized to control were not informed that they have not received an intervention. All participants eligible and randomized to participate in the trial were included in analyses on an intent-to-treat basis. Cohort participants with a Cochin Hand Function Scale score ≥ 3/90 and an interest in using an online hand-exercise intervention were randomized (1:1 ratio) to be offered as usual care plus the SPIN-HAND Program or usual care for 3 months. User satisfaction was assessed with semi-structured interviews. Results Of the 40 randomized participants, 24 were allocated to SPIN-HAND and 16 to usual care. Of 24 participants randomized to be offered SPIN-HAND, 15 (63%) consented to use the program. Usage of SPIN-HAND content among the 15 participants who consented to use the program was low; only five (33%) logged in more than twice. Participants found the content relevant and easy to understand (satisfaction rating 8.5/10, N = 6). Automated eligibility and randomization procedures via the SPIN Cohort platform functioned properly. The required technical support was minimal. Conclusions Trial methodology functioned as designed, and the SPIN-HAND Program was feasibly delivered; however, the acceptance of the offer and use of program content among accepters were low. Adjustments to information provided to potential participants will be implemented in the full-scale SPIN-HAND trial to attempt to increase offer acceptance.

Reconstructing the early molecular evolution of animals requires genomic resources for non-bilaterian animals. Here, the authors present the chromosome-level genome of a freshwater sponge together with analyses of its genome architecture, methylation, developmental gene expression, and microbiome.

IntroductionSmoking and chronic obstructive pulmonary disease (COPD) are associated with an increased risk of post-operative pulmonary complications (PPCs) following lung cancer resection. It remains unclear whether smoking cessation reduces this risk.MethodsRetrospective review of a large, prospectively collected database of over 1000 consecutive resections for lung cancer in a quaternary lung cancer centre over a 23-year period.ResultsOne thousand and thirteen patients underwent curative-intent lobectomy or pneumonectomy between 1995 and 2018. Three hundred and sixty-two patients (36%) were ex-smokers, 314 (31%) were current smokers and 111 (11%) were never smokers. A pre-operative diagnosis of COPD was present in 57% of current smokers, 57% of ex-smokers and 20% of never smokers. Just over 25% of patients experienced a PPC. PPCs were more frequent in current smokers compared to never smokers (27% vs 17%, p = 0.036), however, no difference was seen between current and ex-smokers (p = 0.412) or between never and ex-smokers (p = 0.113). Those with a diagnosis of COPD, independent of smoking status, had a higher frequency of both PPCs (65% vs 35%, pConclusionSmoking and COPD are both associated with a higher rate of PPCs post lung cancer resection. COPD, independent of smoking status, is also associated with an increased overall post-operative complication rate and length of hospital stay. An emphasis on COPD treatment optimisation, rather than smoking cessation in isolation, may help improve post-operative outcomes.

We present the results from our ongoing spectroscopic survey targeting low-mass white dwarf binaries, focusing on the southern sky. We used a Gaia DR2- and eDR3-based selection and identified 28 new binaries, including 19 new extremely low-mass (ELM) white dwarfs, one short period, likely eclipsing, DABZ, and two potential LISA binaries. We present the orbital and atmospheric parameters for each new binary based on our spectroscopic follow up. Four of our new binaries show periodic photometric variability in TESS 2 minutes cadence data, including one new eclipsing double-lined spectroscopic binary. Three others show periodic photometric variability in ZTF, including one new eclipsing binary. We provide estimates for the inclinations and scaled component radii for these ZTF variables, based on light-curve modeling of our high-speed photometric follow-up observations. Our observations have increased the sample of ELM Survey binaries identified in the southern sky to 41, an increase of 64%. Future time domain surveys, such as BlackGEM and the Vera C. Rubin Observatory Legacy Survey of Space and Time, will efficiently identify photometric variables in the southern sky and significantly increase the population of southern sky low-mass white dwarf binaries, leading to a more complete all-sky population of these systems.

AbstractHere, we present a karyotype, a chromosome-scale genome assembly, and a genome annotation from the ctenophore Hormiphora californensisPleurobrachia bacheiH. californensis and P. bachein

Traumatic brain injury (TBI) is a major risk factor for several neurodegenerative disorders, including Parkinson’s disease (PD) and Alzheimer’s disease (AD). Neuroinflammation is a cause of later secondary cell death following TBI, has the potential to aggravate the initial impact, and provides a therapeutic target, albeit that has failed to translate into clinical trial success. Thalidomide-like compounds have neuroinflammation reduction properties across cellular and animal models of TBI and neurodegenerative disorders. They lower the generation of proinflammatory cytokines, particularly TNF-α which is pivotal in microglial cell activation. Unfortunately, thalidomide-like drugs possess adverse effects in humans before achieving anti-inflammatory drug levels. We developed F-3,6′-dithiopomalidomide (F-3,6′-DP) as a novel thalidomide-like compound to ameliorate inflammation. F-3,6′-DP binds to cereblon but does not efficiently trigger the degradation of the transcription factors (SALL4, Ikaros, and Aiolos) associated with the teratogenic and anti-proliferative responses of thalidomide-like drugs. We utilized a phenotypic drug discovery approach that employed cellular and animal models in the selection and development of F-3,6’-DP. F-3,6′-DP significantly mitigated LPS-induced inflammatory markers in RAW 264.7 cells, and lowered proinflammatory cytokine/chemokine levels in the plasma and brain of rats challenged with systemic LPS. We subsequently examined immunohistochemical, biochemical, and behavioral measures following controlled cortical impact (CCI) in mice, a model of moderate TBI known to induce inflammation. F-3,6′-DP decreased CCI-induced neuroinflammation, neuronal loss, and behavioral deficits when administered after TBI. F-3,6′-DP represents a novel class of thalidomide-like drugs that do not lower classical cereblon-associated transcription factors but retain anti-inflammatory actions and possess efficacy in the treatment of TBI and potentially longer-term neurodegenerative disorders.

Background: The coexistence of cervical cancer and pelvic organ prolapse represents a rare clinical scenario. Small cell neuroendocrine histology likewise represents only 0.9–1.5% of all invasive cervical cancers. There is no consensus regarding the optimal management of patients with concomitant locally advanced cervical cancer and pelvic organ prolapse. Case summary: The patient was a 32-year old woman with an 8-cm fungating cervical mass extruding from the introitus. Biopsy was consistent with small cell neuroendocrine carcinoma. Examination showed stage IIIC1r cervical cancer with stage IV pelvic organ prolapse. After manual reduction, a pessary was used to optimize target volume reproducibility during definitive chemoradiation. The patient was treated using cisplatin and etoposide chemotherapy with intensity modulated radiation therapy followed by intracavitary brachytherapy. The patient had no clinical evidence of disease and recurrence of symptomatic prolapse one year after treatment completion. Conclusion: This is the first reported case of a cervical neuroendocrine carcinoma in a prolapsed uterus, and the youngest patient in literature to have concomitant cervical cancer and pelvic organ prolapse. The use of a pessary for optimizing target volume reproducibility during definitive chemoradiation is a viable option in managing this rare case scenario.

PURPOSE: The objectives of this study were to report the oncologic outcomes and the treatment-related toxicities after reirradiation (re-RT) for recurrent nasopharyngeal carcinoma (rNPC) at our institution and to apply a recently published prognostic model for survival in rNPC in our cohort. PATIENTS AND METHODS: Thirty-two patients with rNPC treated at the authors' institution with re-RT were retrospectively reviewed. Treatment modalities for re-RT were intensity-modulated radiotherapy (n = 14), three-dimensional conformal radiotherapy (n = 9), single-fraction stereotactic radiosurgery (n = 6), fractionated stereotactic radiotherapy (n = 2), and high dose rate intracavitary brachytherapy (n = 1). Twenty-seven patients received re-RT with curative intent, whereas five patients were treated palliatively. RESULTS: Median follow-up time was 15.5 months (range, 1 to 123 months) for the entire cohort and 20 months (range, 3 to 123 months) for patients treated with curative intent. For the entire cohort, median locoregional recurrence-free survival (LRRFS) was 14 months, with actuarial 1- and 2-year LRRFS estimates of 67.5% and 44.0%, respectively. Median overall survival (OS) time was 38 months, with actuarial 1- and 2-year estimates of 74.2% and 57.2%, respectively. For patients treated with curative intent, median LRRFS was not reached. Actuarial 1- and 2-year LRRFS estimates were 68.2% and 54.5%, respectively. Median OS time after curative intent re-RT was 42 months, with actuarial 1- and 2-year estimates of 75.4% and 63.8%, respectively. One- and 2-year OS estimates based on risk stratification were 68.6% for high risk compared with 80.8% for low risk and 34.3% for high risk compared with 70.7% for low risk, respectively (P = .223). Three patients (9.4%) developed symptomatic temporal lobe necrosis. There was no reported grade 5 treatment-related toxicity. CONCLUSION: Results of the study suggest that re-RT is an effective and safe salvage treatment strategy for rNPC. Re-RT to a maximum equivalent dose in 2-Gy fractions of 60 Gy may yield good LRRFS and translate to prolonged OS.

Background: Ankle fractures are one of the most common injuries managed by orthopedic surgeons. Although the etiology of posttraumatic osteoarthritis in anatomically reduced ankle fractures is not completely known, several studies suggest that undetected intra-articular pathology at the time of injury may play a role. The purpose of this study is to report the operative findings of ankle arthroscopy as an adjunct to ankle fracture open reduction and internal fixation. Methods: A retrospective review was performed of all ankle fractures treated consecutively at our institution by a single surgeon from August 2010 to October 2019, which were found using Current Procedural Terminology codes. A total of 84 patients met our inclusion criteria for whom patient demographics and clinical history were collected. Pre- and postoperative diagnoses from every operative report were noted as well as intra-articular intervention made during the time of arthroscopy. Results: The study included 49 men (58.3%) and 35 women (41.7%), with a mean age of 39.0 (range, 12-69; SD = 15.0) years. Sixty-three patients (75%) had new diagnoses detected by the addition of ankle arthroscopy. The most common new pathology seen arthroscopically were osteochondral lesions (n = 36, 41.9%) and posterior malleolus fractures (n = 28, 32.6%). Thirty-four patients had a total of 40 additional arthroscopic procedures in conjunction with their fracture management. Complications were noted in 13 patients, with hardware removal (n = 8) being the most common (62%). Conclusion: Ankle arthroscopy can act as a significant diagnostic and prognostic tool and can help address intra-articular injuries without adding considerable cost or serious adverse events. Level of Evidence: Level IV, retrospective case series.

Traumatic brain injury (TBI) is the most common cause of morbidity among trauma patients; however, an effective pharmacological treatment has not yet been approved. Individuals with TBI are at greater risk of developing neurological illnesses such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). The approval process for treatments can be accelerated by repurposing known drugs to treat the growing number of patients with TBI. This review focuses on the repurposing of N-acetyl cysteine (NAC), a drug currently approved to treat hepatotoxic overdose of acetaminophen. NAC also has antioxidant and anti-inflammatory properties that may be suitable for use in therapeutic treatments for TBI. Minocycline (MINO), a tetracycline antibiotic, has been shown to be effective in combination with NAC in preventing oligodendrocyte damage. (−)-phenserine (PHEN), an anti-acetylcholinesterase agent with additional non-cholinergic neuroprotective/neurotrophic properties initially developed to treat AD, has demonstrated efficacy in treating TBI. Recent literature indicates that NAC, MINO, and PHEN may serve as worthwhile repositioned therapeutics in treating TBI.

Sea surface fugacity of carbon dioxide (fCO2ssw) was measured across the Weddell gyre and the eastern sector in the Atlantic Southern Ocean in autumn. During the occupation between February and April 2019, the region of the study transect was a potential ocean CO2 sink. A net CO2 flux (FCO2) of −6.2 (± 8; sink) mmol m–2 d–1 was estimated for the entire study region, with the largest average CO2 sink of −10.0 (± 8) mmol m–2 d–1 in the partly ice-covered Astrid Ridge (AR) region near the coast at 68°S and −6.1 (± 8) mmol m–2d–1 was observed in the Maud Rise (MR) region. A CO2 sink was also observed south of 66°S in the Weddell Sea (WS). To assess the main drivers describing the variability of fCO2ssw, a correlation model using fCO2 and oxygen saturation was considered. Spatial distributions of the fCO2 saturation/O2 saturation correlations, described relative to the surface water properties of the controlling variables (chlorophyll a, apparent oxygen utilization (AOU), sea surface temperature, and sea surface salinity) further constrained the interplay of the processes driving the fCO2ssw distributions. Photosynthetic CO2 drawdown significantly offsets the influence of the upwelling of CO2-rich waters in the central Weddell gyre and enhanced the CO2 sink in the region. FCO2 of −6.9 mmol m–2 d–1 estimated for the Weddell gyre in this study was different from FCO2 of −2.5 mmol m–2 d–1 in autumn estimated in a previous study. Due to low CO2 data coverage during autumn, limited sea-air CO2 flux estimates from direct sea-surface CO2 observations particularly for the Weddell gyre region are available with which to compare the values estimated in this study. This highlights the importance of increasing seasonal CO2 observations especially during autumn/winter to improving the seasonal coverage of flux estimates in the seasonal sea ice-covered regions of the Southern Ocean.

Introduction. Hepatitis A infection (HAV) is generally characterized by an acute icteric illness or may have a subclinical self-limited course, although rarely, can result in fulminant hepatitis and death. In 2019, the City of Philadelphia declared a public health emergency due to an HAV outbreak. We are reporting a series of four cases of acute liver failure (ALF) requiring liver transplantation (LT) due to acute HAV. Methods. Chart review and case descriptions of four patients with acute HAV-related ALF who were expeditiously evaluated, listed as Status 1A, and who underwent LT between August 2019 and October 2019 at Thomas Jefferson University Hospital. Results. All four patients presented with acute hepatocellular jaundice and had a positive HAV IgM, and all other causes of ALF were excluded. All four cases met the American Association for the Study of Liver Diseases (AASLD) criteria for ALF. Three of the four cases met King’s College Criteria of poor prognosis for nonacetaminophen-induced ALF. All four patients underwent successful LT and were discharged six to twelve days postoperatively. One patient died of disseminated Aspergillus infection five months after LT, while the others have had excellent clinical outcomes shown by one-year follow-ups. All four explants had remarkably similar histological changes, revealing acute hepatitis with massive necrosis accompanied by a prominent lymphoplasmacytic inflammatory infiltrate and bile ductular proliferation. Conclusion. Although rare, patients presenting with acute HAV need close monitoring as they may rapidly progress to ALF. Early referral to a transplant center afforded timely access to LT and yielded overall good one-year survival. Widespread HAV vaccination for high-risk individuals is an essential strategy for preventing disease and curbing such future outbreaks.

(1) Background: An important concomitant of stroke is neuroinflammation. Pomalidomide, a clinically available immunomodulatory imide drug (IMiD) used in cancer therapy, lowers TNF-α generation and thus has potent anti-inflammatory actions. Well-tolerated analogs may provide a stroke treatment and allow evaluation of the role of neuroinflammation in the ischemic brain. (2) Methods: Two novel pomalidomide derivatives, 3,6′-dithiopomalidomide (3,6′-DP) and 1,6′-dithiopomalidomide (1,6′-DP), were evaluated alongside pomalidomide in a rat middle cerebral artery occlusion (MCAo) stroke model, and their anti-inflammatory actions were characterized. (3) Results: Post-MCAo administration of all drugs lowered pro-inflammatory TNF-α and IL1-β levels, and reduced stroke-induced postural asymmetry and infarct size. Whereas 3,6′- and 1,6′-DP, like pomalidomide, potently bound to cereblon in cellular studies, 3,6′-DP did not lower Ikaros, Aiolos or SALL4 levels—critical intermediates mediating the anticancer/teratogenic actions of pomalidomide and IMiDs. 3,6′-DP and 1,6′-DP lacked activity in mammalian chromosome aberration, AMES and hERG channel assays –critical FDA regulatory tests. Finally, 3,6′- and 1,6′-DP mitigated inflammation across rat primary dopaminergic neuron and microglia mixed cultures challenged with α-synuclein and mouse LPS-challenged RAW 264.7 cells. (4) Conclusion: Neuroinflammation mediated via TNF-α plays a key role in stroke outcome, and 3,6′-DP and 1,6′-DP may prove valuable as stroke therapies and thus warrant further preclinical development.

Objectives The Social Appearance Anxiety Scale (SAAS) is a 16-item questionnaire developed to evaluate fear of appearance-based evaluation by others. The primary objective of this research was to investigate the existence of differential item functioning (DIF) for the 16 SAAS items, comparing patients who completed the SAAS in English and French, either to confirm that scores are comparable or provide guidance on calculating comparable scores. A secondary research objective was to investigate the existence of DIF based on sex and disease status. A tertiary research objective was to assess DIF related to language, sex, and disease status on the recently developed SAAS-5.Design This was a cross-sectional analysis using baseline data from patients enrolled in the Scleroderma Patient-centred Intervention Network (SPIN).Setting SPIN patients included in the present study were enrolled at 43 centres in Canada, USA, UK, France and Australia, with questionnaires completed in April 2014 to July 2019.Participants 1640 SPIN patients completed the SAAS in French (n=600) or English (n=1040).Primary and secondary measures The SAAS was collected along with demographic and disease characteristics.Results Six items were identified with statistically significant language-based DIF, four with sex-based DIF and one with disease type-based DIF. However, factor scores before and after accounting for DIF were similar (Pearson correlation >0.99), and individual score differences were small. This was true for both the full and shortened versions of the SAAS.Conclusion SAAS and SAAS-5 scores are comparable across language, sex, and disease-type, despite small differences in how patients respond to some items.

The history of animal evolution, and the relative placement of extant animal phyla in this history is, in principle, testable from phylogenies derived from molecular sequence data. Though datasets have increased in size and quality in the past years, the contribution of individual genes (and ultimately amino acid sites) to the final phylogeny is unequal across genes. Here we demonstrate that removing a small fraction of sites strongly favoring one topology can produce a highly-supported tree of an alternate topology. We explore this approach using a dataset for animal phylogeny, and create a highly-supported tree with a monophyletic group of sponges and ctenophores, a topology not usually recovered. Because of the high sensitivity of such an analysis to gene selection, and because most gene sets are neither standardized nor representative of the entire genome, researchers should be diligent about making intermediate analyses available with their phylogenetic studies. Effort is needed to ensure these datasets are maximally informative, by ensuring all genes are systematically sampled across relevant species. From there, it could be determined whether any gene or gene sets introduce bias, and then deal with those biases appropriately.

Impairments in social interaction in Autism Spectrum Disorder (ASD) differ greatly across individuals and vary throughout an individual’s lifetime. Yet, an important marker of ASD in infancy is deviations in social-visual engagement, such as the reliably detectable early deviations in attention to the eyes or to biological movement (Klin et al., 2015). Given the critical nature of these early developmental periods, understanding its neurobehavioral underpinnings by means of a nonhuman primate model will be instrumental to understanding the pathophysiology of ASD. Like humans, rhesus macaques 1) develop in rich and complex social behaviors, 2) progressively develop social skills throughout infancy, and 3) have high similarities with humans in brain anatomy and cognitive functions (Machado and Bachevalier, 2003). In this study, male infant rhesus macaques living with their mothers in complex social groups were eye-tracked longitudinally from birth to 6 months while viewing full-faced videos of unfamiliar rhesus monkeys differing in age and sex. The results indicated a critical period for the refinement of social skills around 4–8 weeks of age in rhesus macaques. Specifically, infant monkeys’ fixation to the eyes shows an inflection in developmental trajectory, increasing from birth to 8 weeks, decreasing slowly to a trough between 14–18 weeks, before increasing again. These results parallel the developmental trajectory of social visual engagement published in human infants (Jones & Klin, 2013) and suggest the presence of a switch in the critical networks supporting these early developing social skills that is highly conserved between rhesus macaque and human infant development.

To date, five ctenophore species’ mitochondrial genomes have been sequenced, and each contains open reading frames (ORFs) that if translated have no identifiable orthologs. ORFs with no identifiable orthologs are called unidentified reading frames (URFs). If truly protein-coding, ctenophore mitochondrial URFs represent a little understood path in early-diverging metazoan mitochondrial evolution and metabolism. We sequenced and annotated the mitochondrial genomes of three individuals of the beroid ctenophore Beroe forskalii and found that in addition to sharing the same canonical mitochondrial genes as other ctenophores, the B. forskalii mitochondrial genome contains two URFs. These URFs are conserved among the three individuals but not found in other sequenced species. We developed computational tools called pauvre and cuttlery to determine the likelihood that URFs are protein coding. There is evidence that the two URFs are under negative selection, and a novel Bayesian hypothesis test of trinucleotide frequency shows that the URFs are more similar to known coding genes than noncoding intergenic sequence. Protein structure and function prediction of all ctenophore URFs suggests that they all code for transmembrane transport proteins. These findings, along with the presence of URFs in other sequenced ctenophore mitochondrial genomes, suggest that ctenophores may have uncharacterized transmembrane proteins present in their mitochondria.

Objective There is conflicting and limited literature on the effect of intraoperative resident involvement on surgical outcomes. Our study assessed effects of resident involvement on outcomes in patients undergoing neurosurgery. Methods We identified 33,977 adult neurosurgical cases from 374 hospitals in the 2006–2012 National Surgical Quality Improvement Program, a prospectively collected national database with established reproducibility and validity. Outcomes were compared according to resident involvement before and after 1:1 matching on procedure and perioperative risk factors. Results Resident involvement was documented in 13,654 cases. We matched 10,170 resident-involved cases with 10,170 attending-alone. In the matched sample, resident involvement was associated with increased surgery duration (average, 34 minutes) and slight increases in odds for prolonged hospital stay (odds ratio, 1.2; 95% confidence interval [CI], 1.2–1.3) and complications (odds ratio, 1.2; 95% CI, 1.1–1.3) including infections (odds ratio, 1.4; 95% CI, 1.2–1.7). Increased risk for infections persisted after controlling for surgery duration (odds ratio, 1.3; 95% CI, 1.1–1.5). The majority of cases were spine surgeries, and resident involvement was not associated with morbidity or mortality for malignant tumor and aneurysm patients. Training level of residents was not associated with differences in outcomes. Conclusion Resident involvement was more common in sicker patients undergoing complex procedures, consistent with academic centers undertaking more complex cases. After controlling for patient and intraoperative characteristics, resident involvement in neurosurgical cases continued to be associated with longer surgical duration and slightly higher infection rates. Longer surgery duration did not account for differences in infection rates.

Abstract Objective: Ecological models have been applied to investigate multiple domains influencing physical activity behaviour, including individual, social, organisational, community, environmental and policy factors. With regard to the built environment, research to date has been limited to small geographical areas and/or small samples of participants. This study examined the geographical association between provision of sport facilities and participation in sport across an entire Australian state, using objective total enumerations of both, for a group of sports, with adjustment for the effect of socioeconomic status (SES). Methods: De‐identified membership registration data were obtained from state sport governing bodies of four popular team sports. Associations between participation rate, facility provision rate and SES were investigated using correlation and regression methods. Results: Participation rate was positively associated with provision of facilities, although this was complicated by SES and region effects. The non‐metropolitan region generally had higher participation rates and better provision of facilities than the metropolitan region. Conclusions: Better provision of sports facilities is generally associated with increased sport participation, but SES and region are also contributing factors. Implications for public health: Community‐level analysis of the population, sport participation and provision of facilities should be used to inform decisions of investments in sports facilities.

The Takai olefination (or Takai reaction) is a method for the conversion of aldehydes to vinyl iodides, and has seen widespread implementation in organic synthesis. The reaction is usually noted for its high (E)-selectivity; however, herein we report the highly (Z)-selective Takai olefination of salicylaldehyde derivatives. Systematic screening of related substrates led to the identification of key factors responsible for this surprising inversion of selectivity, and enabled the development of a modified mechanistic model to rationalise these observations.