Invited review: Modeling milk stability.

Novel insights into the stability of milk and milk products during storage and processing result from describing caseins near neutral pH as hydrophilic, intrinsically disordered, proteins. Casein solubility is strongly influenced by pH and multivalent ion binding. Solubility is high at neutral pH or above but decreases as casein net charge approaches zero, allowing a condensed casein phase or gel to form then increases at lower pH. Of particular importance for casein micelle stability near neutral pH is the proportion of free caseins in the micelle (i.e., caseins not bound directly to nanoclusters of calcium phosphate). Free caseins are more soluble and better able to act as molecular chaperones (to prevent casein and whey protein aggregation) than bound caseins. Some free caseins are highly phosphorylated and can also act as mineral chaperones to inhibit the growth of calcium phosphate phases and prevent mineralized deposits from forming on membranes or heat exchangers. Thus, casein micelle stability is reduced when free caseins bind to amyloid fibrils, destabilized whey proteins or calcium phosphate. The multivalent-binding model of the casein micelle quantitatively describes these and other factors affecting the stability of milk and milk protein products during manufacture and storage.

Tirzepatide attenuates mammary tumor progression in diet-induced obese mice.

We report for the first time an anticancer benefit of tirzepatide-a dual glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide receptor agonist-in a model of obesity and breast cancer in female mice. Long-term tirzepatide treatment induced weight loss, mitigated obesity-driven changes in circulating metabolic hormone levels, and suppressed orthotopic E0771 mammary tumor growth. Relative to tirzepatide, chronic calorie restriction, an established anticancer intervention in preclinical models, promoted even greater weight loss, systemic hormonal regulation, and tumor suppression. We conclude that tirzepatide represents a promising pharmacologic approach for mitigating the procancer effects of obesity. Moreover, strategies promoting greater weight loss than achieved with tirzepatide alone may augment the anticancer benefits of tirzepatide.

Microbiomes of microscopic marine invertebrates do not reveal signatures of phylosymbiosis.

Animals and microorganisms often establish close ecological relationships. However, much of our knowledge about animal microbiomes comes from two deeply studied groups: vertebrates and arthropods. To understand interactions on a broader scale of diversity, we characterized the bacterial microbiomes of close to 1,000 microscopic marine invertebrates from 21 phyla, spanning most of the remaining tree of metazoans. Samples were collected from five temperate and tropical locations covering three marine habitats (sediment, water column and intertidal macroalgae) and bacterial microbiomes were characterized using 16S ribosomal RNA gene sequencing. Our data show that, despite their size, these animals harbour bacterial communities that differ from those in the surrounding environment. Distantly related but coexisting invertebrates tend to share many of the same bacteria, suggesting that guilds of microorganisms preferentially associated with animals, but not tied to any specific host lineage, are the main drivers of the ecological relationship. Host identity is a minor factor shaping these microbiomes, which do not show the same correlation with host phylogeny, or 'phylosymbiosis', observed in many large animals. Hence, the current debate on the varying strength of phylosymbiosis within selected lineages should be reframed to account for the possibility that such a pattern might be the exception rather than the rule.

Assessing functional recovery following total knee replacement surgery using objective classification of level gait data and patient-reported outcome measures.

BACKGROUND: Patient recovery can be quantified objectively, via gait analysis, or subjectively, using patient reported outcome measures. Association between these measures would explain the level of disability reported in patient reported outcome measures and could assist with therapeutic decisions. METHODS: Total knee replacement outcome was assessed using objective classification and patient-reported outcome measures (Knee Outcome Survey and Oxford Knee Scores). A classifier was trained to distinguish between healthy and osteoarthritic characteristics using knee kinematics, ground reaction force and temporal gait data, combined with anthropometric data from 32 healthy and 32 osteoarthritis knees. For the osteoarthritic cohort, classification of 20 subjects quantified changes at up to 3 timepoints post-surgery. FINDINGS: Osteoarthritic classification was reduced for 17 subjects when comparing pre- to post-operative assessments, however only 6 participants achieved non-pathological classification and only 4 of these were classified as non-pathological at 12 months. In 15 cases, the level of osteoarthritic classification did not decrease between every post-operative assessment. For an individual's recovery, classification outputs correlated (r > 0.5) with knee outcome survey for 75% of patients and oxford knee score for 78% of patients (based on 20 and 9 subjects respectively). Classifier outputs from all visits of the combined total knee replacement sample correlated moderately with knee outcome survey (r > 0.4) and strongly with oxford knee score (r > 0.6). INTERPRETATION: Biomechanical deficits existed in most subjects despite improvements in Patient Reported Outcome Measures, with larger changes reported subjectively as compared to measured objectively. Objective Classification provides additional insight alongside Patient Reported Outcomes when reporting recovered outcomes.

Recruitment to higher specialty training in anaesthesia in the UK during the COVID-19 pandemic: a national survey.

There were more applications for higher specialty training posts in anaesthesia in the UK starting in August 2021 than in previous years, with approximately two-thirds being unsuccessful. We surveyed applicants to investigate their experience of the recruitment process (response rate 536/1056; 51%). Approximately 61% of respondents were not offered ST3 posts (n = 326). We enquired about their career plans for the next 12-24 months. Most respondents (79%) intended to take up a post equivalent to a third year of core training or a clinical fellow post from August 2021. Other options considered included: pursuing work abroad (17%); embarking on career breaks (16%); taking up higher training posts in intensive care medicine (15%); and permanently leaving medicine (9%). Nine per cent of respondents also expressed plans to pursue training in another medical specialty. Some expressed an intention to pursue further education or research (10%). A large proportion (42%) expressed a lack of confidence in being able to achieve the training requirements to later apply for a higher training post. The majority reported not feeling confident in achieving specialist registration in anaesthesia in the future without a training number (75%), and noted disruption to their wider life plans from the impending time out of training (78%). Sentiment analysis of free-text responses indicated generally negative sentiment about the recruitment process. Themes elicited included: feeling the recruitment process was unfair; burnout and negative impact on well-being; difficulties in making life plans; and feeling undervalued and abandoned. These results suggest that junior anaesthetic doctors in the UK negatively perceived postgraduate training structures and changes to the postgraduate curriculum and experienced difficulties in securing higher training.

A seafood risk tool for assessing and mitigating chemical and pathogen hazards in the aquaculture supply chain.

Intricate links between aquatic animals and their environment expose them to chemical and pathogenic hazards, which can disrupt seafood supply. Here we outline a risk schema for assessing potential impacts of chemical and microbial hazards on discrete subsectors of aquaculture-and control measures that may protect supply. As national governments develop strategies to achieve volumetric expansion in seafood production from aquaculture to meet increasing demand, we propose an urgent need for simultaneous focus on controlling those hazards that limit its production, harvesting, processing, trade and safe consumption. Policies aligning national and international water quality control measures for minimizing interaction with, and impact of, hazards on seafood supply will be critical as consumers increasingly rely on the aquaculture sector to supply safe, nutritious and healthy diets.

Decrease in cardiac catheterization and MI during COVID pandemic.

The consequences of severe acute viral respiratory syndrome (COVID 19) pandemic include collateral effects, one of which has been the significant reduction in routine hospital work. With widespread reports indicating reduction of cardiac procedures including MI presentation to hospitals, we aimed to analyze the local data over a 10-week period during lockdown in a tertiary cardiac centre Catheter Laboratory in England. METHODS: We conducted a retrospective review of the coronary catheterisation procedures and admissions with MI over the peak COVID-19 pandemic 10-week period (23rd March-30th May) in 2020, compared with the same 10-week period (25th March-2nd June) in 2019. RESULTS: In 2019, 539 patients were admitted to the Cath lab for coronary catheterisation (M = 385:F = 154; mean age 65 years; STEMI = 186, NSTEMI = 192, elective = 161). In 2020, during peak period of COVID19 pandemic in England, a total of 278 patients were admitted for coronary catheterisation over the 10-week period (M = 201:F = 77; mean age 60.5 years; STEMI = 132, NSTEMI = 118, elective = 28). During peak COVID19 pandemic, this represents a 48.4% drop in all coronary catheterisations. The reduction in STEMI was 29% (54 less), in NSTEMI was 38.9% (74 less) and elective procedures dropped by 83% (133 less). CONCLUSION: During peak COVID hospital admission period in England, we report a 48.5% reduction in coronary catheterisation in our tertiary hospital. These results are consistent with reports from other countries, and highlight the worrying potential consequences for these patients arising from delays in presentation with MI, and the challenges for restoring services post-pandemic.

Circulating lectin pathway proteins do not predict short-term cardiac outcomes after myocardial infarction.

Despite improvements in treatment, coronary artery disease is still responsible for one-third of all deaths globally, due predominantly to myocardial infarction (MI) and stroke. There is an important potential in developing new strategies for treatment of patients with these conditions. Inflammation, and in particular the actions of the complement system, has emerged as part of the pathogenesis in reperfusion injury in patients with MI. To further qualify this, we examined the association between the plasma levels of lectin pathway proteins and myocardial end-points, left ventricular ejection fraction (LVEF) and infarct size in a cohort of patients with ST-elevation myocardial infarction (STEMI). A blood sample was drawn the day after percutaneous coronary intervention from 73 patients with STEMI. The primary end-points, LVEF and infarct size, were measured with magnetic resonance imaging 6-9 days after the infarct. Complement pattern-recognition molecules of the lectin pathway (mannan-binding lectin, H-ficolin, L-ficolin and M-ficolin) were analysed along with soluble membrane attack complex (sMAC) and C-reactive protein (CRP) in plasma with immunofluorometric assays <50%. CRP correlated negatively with LVEF, regression coefficient = -0·17 (P = 0·01). None of the lectin pathway proteins correlated to LVEF or infarct size, nor did soluble membrane attack complex (sMAC). There were no differences in plasma levels of these complement proteins when comparing patients with ejection fraction <50% to patients with ejection fraction <50%. Pattern-recognition molecules of the lectin pathway and sMAC do not predict short-term cardiac outcomes after MI.

Correlations between patient-perceived outcome and objectively-measured biomechanical change following Total Knee Replacement.

BACKGROUND: Total Knee Replacement (TKR) surgery is being utilised in a younger, more active population with greater functional expectations. Understanding whether patient-perceived measures of function reflect objective biomechanical measures is critical in understanding whether functional limitations can be adequately captured within a clinical setting. RESEARCH QUESTION: Do changes in objective gait biomechanics measures reflect patient-reported outcome measures at approximately 12 months following TKR surgery? METHODS: Three-dimensional gait analysis was performed on 41 patients with OA who were scheduled for TKR surgery, 22 of which have returned for a (9-24 month) follow-up assessment. Principal Component Analysis was used to define features of variation between OA subjects and an additional 31 non-pathological control subjects. These were used to train the Cardiff Classifier, an objective classification technique, and subsequently quantify changes following TKR surgery. Patient-perceived changes were also assessed using the Oxford Knee Score (OKS), Knee Outcome Survey (KOS), and Pain Audit Collection System scores (PACS). Pearson and Spearman correlation coefficients were calculated to establish the relationship between changes in objectively-measured and perceived outcome. RESULTS: Objective measures of biomechanical change were strongly correlated to changes in OKS(r=-0.695, p < 0.001) and KOS(r=-.810, p < 0.001) assessed outcomes. Pain (PACS) was only related to biomechanical function post-operatively (r=-.623, p = 0.003). SIGNIFICANCE: In this biomechanics study, the relationship between changes in objective function and patient-reported measures pre to post TKR surgery is stronger than in studies which did not include biomechanics metrics. Quality of movement may hold more significance for a patient's perception of improvement than functional measures which consider only the time taken or distance travelled during functional activities.

Maternal antenatal mood and child development: an exploratory study of treatment effects on child outcomes up to 5 years.

Effective treatment of maternal antenatal depression may ameliorate adverse neurodevelopmental outcomes in offspring. We performed two follow-up rounds of children at age 2 and age 5 whose mothers had received either specialized cognitive-behavioural therapy or routine care for depression while pregnant. Of the original cohort of 54 women, renewed consent was given by 28 women for 2-year follow-up and by 24 women for 5-year follow-up. Child assessments at the 2-year follow-up included the Parenting Stress Index (PSI), Bayley Scales of Infant Development (BSID-III) and the Child Behaviour Checklist (CBCL). The 5-year follow-up included the Wechsler Preschool and Primary Scales of Intelligence (WPPSI-III) and again the CBCL. Treatment during pregnancy showed significant benefits for children's development at age 2, but not at age 5. At 2 years, intervention effects were found with lower scores on the PSI Total score, Parent Domain and Child domain (d=1.44, 1.47, 0.96 respectively). A non-significant trend favoured the intervention group on most subscales of the CBCL and the BSID-III (most notably motor development: d =0.52). In contrast, at 5-year follow-up, no intervention effects were found. Also, irrespective of treatment allocation, higher depression or anxiety during pregnancy was associated with higher CBCL and lower WPPSI-III scores at 5 years. This is one of the first controlled studies to evaluate the long-term effect of antenatal depression treatment on infant neurodevelopmental outcomes, showing some benefit. Nevertheless, caution should be taken interpreting the results because of a small sample size, and larger studies are warranted.

Automated Assessment of Movement Impairment in Huntington's Disease.

Quantitative assessment of movement impairment in Huntington's disease (HD) is essential to monitoring of disease progression. This paper aimed to develop and validate a novel low cost, objective automated system for the evaluation of upper limb movement impairment in HD in order to eliminate the inconsistency of the assessor and offer a more sensitive, continuous assessment scale. Patients with genetically confirmed HD and healthy controls were recruited to this observational study. Demographic data, including age (years), gender, and unified HD rating scale total motor score (UHDRS-TMS), were recorded. For the purposes of this paper, a modified upper limb motor impairment score (mULMS) was generated from the UHDRS-TMS. All participants completed a brief, standardized clinical assessment of upper limb dexterity while wearing a tri-axial accelerometer on each wrist and on the sternum. The captured acceleration data were used to develop an automatic classification system for discriminating between healthy and HD participants and to automatically generate a continuous movement impairment score (MIS) that reflected the degree of the movement impairment. Data from 48 healthy and 44 HD participants was used to validate the developed system, which achieved 98.78% accuracy in discriminating between healthy and HD participants. The Pearson correlation coefficient between the automatic MIS and the clinician rated mULMS was 0.77 with a p-value < 0.01. The approach presented in this paper demonstrates the possibility of an automated objective, consistent, and sensitive assessment of the HD movement impairment.

Investigating the Nature of Late-Time High-Energy GRB Emission Through Joint Fermi /Swift Observations.

We use joint observations by the Neil Gehrels Swift X-ray Telescope (XRT) and the Fermi Large Area Telescope (LAT) of gamma-ray burst (GRB) afterglows to investigate the nature of the long-lived high-energy emission observed by Fermi LAT. Joint broadband spectral modeling of XRT and LAT data reveal that LAT non-detections of bright X-ray afterglows are consistent with a cooling break in the inferred electron synchrotron spectrum below the LAT and/or XRT energy ranges. Such a break is sufficient to suppress the high-energy emission so as to be below the LAT detection threshold. By contrast, LAT-detected bursts are best fit by a synchrotron spectrum with a cooling break that lies either between or above the XRT and LAT energy ranges. We speculate that the primary difference between GRBs with LAT afterglow detections and the non-detected population may be in the type of circumstellar environment in which these bursts occur, with late-time LAT detections preferentially selecting GRBs that occur in low wind-like circumburst density profiles. Furthermore, we find no evidence of high-energy emission in the LAT-detected population significantly in excess of the flux expected from the electron synchrotron spectrum fit to the observed X-ray emission. The lack of excess emission at high energies could be due to a shocked external medium in which the energy density in the magnetic field is stronger than or comparable to that of the relativistic electrons behind the shock, precluding the production of a dominant synchrotron self-Compton (SSC) component in the LAT energy range. Alternatively, the peak of the SSC emission could be beyond the 0.1-100 GeV energy range considered for this analysis.

Regional gastrointestinal contractility parameters using the wireless motility capsule: inter-observer reproducibility and influence of age, gender and study country.

BACKGROUND: The wireless motility capsule concurrently measures temperature, pH and pressure as it traverses the gastrointestinal tract. AIMS: To describe normative values for motility/contractility parameters across age, gender and testing centres. METHODS: Healthy participants underwent a standardised wireless motility capsule assessment following an overnight fast and consumption of a meal of known nutritional content. Traces were divided into regions of interest and analysed using 2 software packages (MotiliGI and GIMS Data Viewer). Inter-observer agreement was independently assessed by 2 investigators. RESULTS: Normative data for motility/contractility parameters (maximum amplitude, mean peak amplitude, contraction frequency and motility index) are presented for 107 individuals (62 male, median age 40 years, range 18-78). MotiliGI-Gastric, small bowel and colonic maximal contraction amplitude correlated with age (r = .24, P = .01; r = .22, P = .02; and r = .2, P = .04 respectively). Small bowel motility index was higher in females than males (150.4 ± 12 vs 122 ± 7.6, P = .04). Inter-observer agreement was excellent for transit times, pH and contractility/motility parameters. GIMS Data viewer-Gastric, small bowel and colonic loge motility index correlated with the respective area under the contraction curve, total contractions, sum of amplitudes and contraction frequency (all r>.35, P < .0003) but not with transit times. CONCLUSIONS: Our analysis provides normative data for motility/contractility parameters. Log motility index summarises a number of measures. In future, the measurement of contractile activity with the wireless motility capsule may potentially aid in the diagnosis of disease states such as visceral myopathic disorders.

Abnormal loading and functional deficits are present in both limbs before and after unilateral knee arthroplasty.

Unilateral knee replacement is often followed by a contralateral replacement in time and the biomechanics of the other knee before and after knee replacement remains poorly understood. The aim of this paper is to distinguish the features of arthritic gait in the affected and unaffected legs relative to a normal population and to assess the objective recovery of gait function post-operatively, with the aim of defining patients at risk of poor post-operative function. Twenty patients with severe knee OA but no pain or deformity in any other lower limb joint were compared to twenty healthy subjects of the same age. Gait analysis was performed and quadriceps and hamstrings co-contraction was measured. Fifteen subjects returned 1year following knee arthroplasty. Moments and impulses were calculated, principal component analysis was used to analyse the waveforms and a classification technique (the Cardiff Classifier) was used to select the most discriminant data and define functional performance. Comparing pre-operative function to healthy function, classification accuracies for the affected and unaffected knees were 95% and 92.5% respectively. Post-operatively, the affected limb returned to the normal half of the classifier in 8 patients, and 7 of those patients returned to normal function in the unaffected limb. Recovery of normal gait could be correctly predicted 13 out of 15 times at the affected knee, and 12 out of 15 times at the unaffected knee based on pre-operative gait function. Focused rehabilitation prior to surgery may be beneficial to optimise outcomes and protect the other joints following knee arthroplasty.

Plasma levels of MASP-1, MASP-3 and MAp44 in patients with type 2 diabetes: influence of glycaemic control, body composition and polymorphisms in the MASP1 gene.

Mounting evidence indicates that adverse activation of the complement system plays a role in the development of diabetic vascular complications. Plasma levels of the complement proteins mannan-binding lectin (MBL) and its associated serine proteases (MASP-1 and MASP-2) are elevated in diabetes. We hypothesized that single nucleotide polymorphisms (SNPs) in the MASP1 gene may contribute to altered plasma levels of the belonging gene products; MASP-1, MASP-3 and mannan-binding lectin-associated protein of 44 kDa (MAp44) in patients with type 2 diabetes. To investigate this, we compared plasma levels of MASP-1, MASP-3 and MAp44 in 100 patients with type 2 diabetes and 100 sex- and age-matched controls. Ten carefully selected SNPs were analysed using TaqMan® genotyping assay. Additionally, we included a streptozotocin-induced diabetes mouse model to directly examine the effect of inducing diabetes on MASP-1 levels. MASP-1 levels were significantly higher among patients with type 2 diabetes compared with healthy controls (P = 0·017). Five SNPs (rs874603, rs72549254, rs3774275, rs67143992, rs850312) in the MASP1 gene were associated with plasma levels of MASP-1, MASP-3 and MAp44. In the diabetes mouse model, diabetic mice had significantly higher MASP-1 levels than control mice (P = 0·003). In conclusion, MASP-1 levels were higher among patients with type 2 diabetes and diabetic mice. The mechanism behind this increase remains elusive.

Combined effect of toe out gait and high tibial osteotomy on knee adduction moment in patients with varus knee deformity.

BACKGROUND: Gait adaptations, including toe out gait, have been proposed as treatments for knee osteoarthritis. The clinical application of toe out gait, however, is unclear. This study aims to identify the changes in Knee adduction moment in varus knee deformity assessing toe out gait as an alternative to high tibial osteotomy, and if any change in dynamic loading persists post operatively, when anatomical alignment is restored. METHODS: Three-dimensional motion analysis was performed on 17 patients with medial compartment knee osteoarthritis and varus deformity prior to undergoing high tibial osteotomy, 13 patients were assessed post-operatively, and results compared to 13 healthy controls. FINDINGS: Pre-operatively, there was no significant difference between natural and toe out gait for measures of knee adduction moment. Post high tibial osteotomy, first (2.70 to 1.51% BW·h) and second peak (2.28 to 1.21% BW·h) knee adduction moment were significantly reduced, as was knee adduction angular impulse (1.00 to 0.52% BW·h·s), to a healthy level. Adopting toe out gait post-operatively reduced the second peak further to a level below that of healthy controls. INTERPRETATION: Increasing the foot progression angle from 20° (natural) to 30° in isolation did not significantly alter the knee adduction moment or angular impulse. This suggests that adopting a toe out gait, in isolation, in an already high natural foot progression angle, is not of benefit. Adopting toe out gait post-operatively, however, resulted in a further reduction in the second peak to below that of the healthy control cohort, however, this may increase lateral compartment load.

Nanoscale Structure, Dynamics, and Aging Behavior of Metallic Glass Thin Films.

Scanning tunnelling microscopy observations resolve the structure and dynamics of metallic glass Cu100-xHfx films and demonstrate scanning tunnelling microscopy control of aging at a metallic glass surface. Surface clusters exhibit heterogeneous hopping dynamics. Low Hf concentration films feature an aged surface of larger, slower clusters. Argon ion-sputtering destroys the aged configuration, yielding a surface in constant fluctuation. Scanning tunnelling microscopy can locally restore the relaxed state, allowing for nanoscale lithographic definition of aged sections.

Dynamic footprint of sequestration in the molecular fluctuations of osteopontin.

The sequestration of calcium phosphate by unfolded proteins is fundamental to the stabilization of biofluids supersaturated with respect to hydroxyapatite, such as milk, blood or urine. The unfolded state of osteopontin (OPN) is thought to be a prerequisite for this activity, which leads to the formation of core-shell calcium phosphate nanoclusters. We report on the structures and dynamics of a native OPN peptide from bovine milk, studied by neutron spectroscopy and small-angle X-ray and neutron scattering. The effects of sequestration are quantified on the nanosecond- ångström resolution by elastic incoherent neutron scattering. The molecular fluctuations of the free phosphopeptide are in agreement with a highly flexible protein. An increased resilience to diffusive motions of OPN is corroborated by molecular fluctuations similar to those observed for globular proteins, yet retaining conformational flexibilities. The results bring insight into the modulation of the activity of OPN and phosphopeptides with a role in the control of biomineralization. The quantification of such effects provides an important handle for the future design of new peptides based on the dynamics-activity relationship.

The application of NCaRBS to the Trendelenburg test and total hip arthroplasty outcome.

This paper compares the frontal plane hip function of subject's known to have had hip arthroplasty via either the lateral (LA) or posterior (PA) surgical approaches and a group of subjects associated with no pathology (NP). This is investigated through the Trendelenburg test using 3D motion analysis and classification. Here, a recent development on the Classification and Ranking Belief Simplex (CaRBS) technique, able to undertake n-state classification, so termed NCaRBS is employed. The relationship between post-operative hip function measured during a Trendelenburg Test using three patient characteristics (pelvic obliquity, frontal plane hip moment and frontal plane hip power) of LA, PA and NP subjects are modelled together. Using these characteristics, the classification accuracy was 93.75% for NP, 57.14% for LA, 38.46% for PA. There was a clear distinction between NP and post-surgical function. 3/6 LA subjects and 6/8 PA subjects were misclassified as having NP function, implying that greater function is restored following the PA to surgery. NCaRBS achieved a higher accuracy (65.116%) than through a linear discriminant analysis (48.837%). A Neural Network with two-nodes achieved the same accuracy (65.116%) and as expected was further improved with three-nodes (69.767%). A valuable benefit to the employment of the NCaRBS technique is the graphical exposition of the contribution of patient characteristics to the classification analysis.