Photobiomodulation in the infrared spectrum reverses the expansion of circulating natural killer cells and brain microglial activation in Sanfilippo mice.

Sanfilippo syndrome results from inherited mutations in genes encoding lysosomal enzymes that catabolise heparan sulfate (HS), leading to early childhood-onset neurodegeneration. This study explores the therapeutic potential of photobiomodulation (PBM), which is neuroprotective and anti-inflammatory in several neurodegenerative diseases; it is also safe and PBM devices are readily available. We investigated the effects of 10-14 days transcranial PBM at 670 nm (2 or 4 J/cm2/day) or 904 nm (4 J/cm2/day) in young (3 weeks) and older (15 weeks) Sanfilippo or mucopolysaccharidosis type IIIA (MPS IIIA) mice. Although we found no PBM-induced changes in HS accumulation, astrocyte activation, CD206 (an anti-inflammatory marker) and BDNF expression in the brains of Sanfilippo mice, there was a near-normalisation of microglial activation in older MPS IIIA mice by 904 nm PBM, with decreased IBA1 expression and a return of their morphology towards a resting state. Immune cell immunophenotyping of peripheral blood with mass cytometry revealed increased pro-inflammatory signalling through pSTAT1 and p-p38 in NK and T cells in young but not older MPS IIIA mice (5 weeks of age), and expansion of NK, B and CD8+ T cells in older affected mice (17 weeks of age), highlighting the importance of innate and adaptive lymphocytes in Sanfilippo syndrome. Notably, 670 and 904 nm PBM both reversed the Sanfilippo-induced increase in pSTAT1 and p-p38 expression in multiple leukocyte populations in young mice, while 904 nm reversed the increase in NK cells in older mice. In conclusion, this is the first study to demonstrate the beneficial effects of PBM in Sanfilippo mice. The distinct reduction in microglial activation and NK cell pro-inflammatory signalling and number suggests PBM may alleviate neuroinflammation and lymphocyte activation, encouraging further investigation of PBM as a standalone, or complementary therapy in Sanfilippo syndrome.

Distinct Inflammatory Phenotypes are associated with subclinical and clinical Cardiovascular disease in People living with HIV.

Despite inflammation being implicated in cardiovascular disease (CVD) in people with HIV (PWH), considerable heterogeneity within populations of PWH exists. Stratifying CVD risk based on inflammatory phenotype could play an important role. Using principal component analyses and unsupervised hierarchical clustering, we examined 38 biomarkers to identify inflammatory phenotypes in two independent cohorts of PWH. We identified three distinct inflammatory clusters present in both cohorts that associated with altered risk of both subclinical CVD (cohort 1) and prevalent clinical CVD (cohort 2) after adjusting for CVD risk factors. These data support precision medicine approaches to enhance CVD risk assessment in PWH.

The increasing burden of the 2-week wait colorectal cancer pathway in a single centre: the impact of faecal immunochemical tests.

INTRODUCTION: Two-week wait (TWW) volume and colorectal cancer (CRC) detection pose an increasing challenge for NHS cancer services. Primary aims were to assess the introduction of faecal immunochemical tests (FIT) into clinical practice at our centre, the impact on TWW referral volume and CRC diagnoses, and to provide an update to previously published work. A secondary aim was to correlate FIT value and investigation. METHODS: TWW CRC data following incorporation of FIT into clinical practice were analysed (1 June 2019-31 July 2021). Parameters assessed were monthly referral volume, CRC detection, primary care FIT volume and secondary care investigations. Referrals and CRC detection rates were compared with previously published data (2009-2019). Data relating to primary care FIT were collated from Berkshire and Surrey Pathology Services. RESULTS: TWW referrals increased 360% (2009-2020). CRC incidence decreased from 8.87% to 3.24%. Following incorporation into clinical practice, primary care FIT requests have increased to >450/month and accompanied 1,722/4,796 referrals. CRC incidence is static (3-4%). Patients with FIT <10µg Hb/g faeces undergo radiological imaging more commonly, whereas FIT-positive patients are more likely to undergo endoscopy, although the difference is not statistically significant. CONCLUSIONS: No significant change in CRC diagnosis was observed, despite increasing TWW referrals. Increasing utilisation of FIT in both primary and secondary care has helped maintain CRC detection while avoiding diagnostic delay. This study supports growing evidence highlighting the value of FIT in triage, referral and TWW investigation. FIT appears increasingly important for allocating secondary care resources (endoscopy), while guiding primary care referral. Additional low-cost strategies to determine prioritisation or reassurance (e.g. repeat FIT) require further evaluation.

Loss, resilience and recovery of kelp forests in a region of rapid ocean warming.

BACKGROUND AND AIMS: Changes in kelp abundances on regional scales have been highly variable over the past half-century owing to strong effects of local and regional drivers. Here, we assess patterns and dominant environmental variables causing spatial and interspecific variability in kelp persistence and resilience to change in Nova Scotia over the past 40 years. METHODS: We conducted a survey of macrophyte abundance at 251 sites spanning the Atlantic coast of Nova Scotia from 2019 to 2022. We use this dataset to describe spatial variability in kelp species abundances, compare species occurrences to surveys conducted in 1982 and assess changes in kelp abundance over the past 22 years. We then relate spatial and temporal patterns in abundance and resilience to environmental metrics. KEY RESULTS: Our results show losses of sea urchins and the cold-tolerant kelp species Alaria esculenta, Saccorhiza dermatodea and Agarum clathratum in Nova Scotia since 1982 in favour of the more warm-tolerant kelps Saccharina latissima and Laminaria digitata. Kelp abundances have increased slightly since 2000, and Saccharina latissima and L. digitata are widely abundant in the region today. The highest kelp cover occurs on wave-exposed shores and at sites where temperatures have remained below thresholds for growth (21 °C) and mortality (23 °C). Moreover, kelp has recovered from turf dominance following losses at some sites during a warm period from 2010 to 2012. CONCLUSIONS: Our results indicate that dramatic changes in kelp community composition and a loss of sea urchin herbivory as a dominant driver of change in the system have occurred in Nova Scotia over the past 40 years. However, a broad-scale shift to turf-dominance has not occurred, as predicted, and our results suggest that resilience and persistence are still a feature of kelp forests in the region despite rapid warming over the past several decades.

Gastric outlet obstruction secondary to a wandering spleen: systematic review and surgical management of a case.

INTRODUCTION: A wandering spleen occurs when laxity or absence of the suspensory ligaments allows migration throughout the abdomen. Gastric outlet obstruction resulting from this abnormality is rare. We present a systematic literature search and a case that was managed successfully with surgical intervention at our centre. METHODS: A systematic search of the PubMed, Embase™, Medline® and Google Scholar™ databases was carried out employing the combined search terms "gastric outlet obstruction" AND "wandering spleen". Six results were included for final analysis. RESULTS: All six search results described a single case each. Patients underwent surgical management (open or laparoscopic) after initial investigation utilising a range of modalities. There were no mortalities reported at 90 days. The single case we present was complicated by gastric perforation; the patient made a successful recovery following open splenopexy and stapled wedge resection of the stomach. CONCLUSIONS: A wandering spleen is a rare diagnosis and there are only six reported cases of gastric outlet obstruction secondary to a wandering spleen in the literature. None report associated gastric perforation. There are a variety of presenting symptoms, intraoperative findings and operative techniques used to address the gastrosplenic abnormality. The case reported by our centre adds to this limited evidence base and demonstrates a successful outcome from definitive surgical management. We highlight the need to seek early gastro-oesophageal expertise if any gastric pathology is found together with anatomical abnormality of the spleen.

Long-term results of ablation index guided atrial fibrillation ablation: insights after 5+ years of follow-up from the MPH AF Ablation Registry.

Background: Catheter ablation (CA) for symptomatic atrial fibrillation (AF) offers the best outcomes for patients. Despite the benefits of CA, a significant proportion of patients suffer a recurrence; hence, there is scope to potentially improve outcomes through technical innovations such as ablation index (AI) guidance during AF ablation. We present real-world 5-year follow-up data of AI-guided pulmonary vein isolation. Methods: We retrospectively followed 123 consecutive patients who underwent AI-guided CA shortly after its introduction to routine practice. Data were collected from the MPH AF Ablation Registry with the approval of the institutional research board. Results: Our patient cohort was older, with higher BMI, greater CHA2DS2-VASc scores, and larger left atrial sizes compared to similar previously published cohorts, while gender balance and other characteristics were similar. The probability of freedom from atrial arrhythmia with repeat procedures is as follows: year 1: 0.95, year 2: 0.92, year 3: 0.85, year 4: 0.79, and year 5: 0.72. Age >75 years (p = 0.02, HR: 2.7, CI: 1.14-6.7), BMI >35 kg/m2 (p = 0.0009, HR: 4.6, CI: 1.8-11.4), and left atrial width as measured on CT in the upper quartile (p = 0.04, HR: 2.5, CI: 1-5.7) were statistically significant independent predictors of recurrent AF. Conclusion: AI-guided CA is an effective treatment for AF, with 95.8% of patients remaining free from atrial arrhythmia at 1 year and 72.3% at 5 years, allowing for repeat procedures. It is safe with a low major complication rate of 1.25%. Age >75 years, BMI >35 kg/m2, and markedly enlarged atria were associated with higher recurrence rates.

A 300-fold conductivity increase in microbial cytochrome nanowires due to temperature-induced restructuring of hydrogen bonding networks.

Although proteins are considered as nonconductors that transfer electrons only up to 1 to 2 nanometers via tunneling, Geobacter sulfurreducens transports respiratory electrons over micrometers, to insoluble acceptors or syntrophic partner cells, via nanowires composed of polymerized cytochrome OmcS. However, the mechanism enabling this long-range conduction is unclear. Here, we demonstrate that individual nanowires exhibit theoretically predicted hopping conductance, at rate (>1010 s-1) comparable to synthetic molecular wires, with negligible carrier loss over micrometers. Unexpectedly, nanowires show a 300-fold increase in their intrinsic conductance upon cooling, which vanishes upon deuteration. Computations show that cooling causes a massive rearrangement of hydrogen bonding networks in nanowires. Cooling makes hemes more planar, as revealed by Raman spectroscopy and simulations, and lowers their reduction potential. We find that the protein surrounding the hemes acts as a temperature-sensitive switch that controls charge transport by sensing environmental perturbations. Rational engineering of heme environments could enable systematic tuning of extracellular respiration.

Protein nanowires with tunable functionality and programmable self-assembly using sequence-controlled synthesis.

Advances in synthetic biology permit the genetic encoding of synthetic chemistries at monomeric precision, enabling the synthesis of programmable proteins with tunable properties. Bacterial pili serve as an attractive biomaterial for the development of engineered protein materials due to their ability to self-assemble into mechanically robust filaments. However, most biomaterials lack electronic functionality and atomic structures of putative conductive proteins are not known. Here, we engineer high electronic conductivity in pili produced by a genomically-recoded E. coli strain. Incorporation of tryptophan into pili increased conductivity of individual filaments >80-fold. Computationally-guided ordering of the pili into nanostructures increased conductivity 5-fold compared to unordered pili networks. Site-specific conjugation of pili with gold nanoparticles, facilitated by incorporating the nonstandard amino acid propargyloxy-phenylalanine, increased filament conductivity ~170-fold. This work demonstrates the sequence-defined production of highly-conductive protein nanowires and hybrid organic-inorganic biomaterials with genetically-programmable electronic functionalities not accessible in nature or through chemical-based synthesis.

Temporal trends of perfluoroalkyl substances in an Australian wastewater treatment plant: A ten-year retrospective investigation.

Per- and poly-fluoroalkyl substances (PFAS) are a problematic group of chemicals used in various industrial and household products. They have been extensively detected in wastewater as a result of day-to-day product usage. Due to concerns about their safety, voluntary and regulatory action to limit the manufacture and use of some individual PFAS has occurred since the year 2000. The impact that this intervention has had on the use and potential exposure of Australians has not been measured. Wastewater serves as a powerful tool to assess the chemical use or consumption patterns of a population over time. We accessed a ten-year wastewater archiving program to conduct a temporal analysis of PFAS trends in an urban Australian population between the years 2010 and 2020. Results showed a decline in the concentrations for most PFAS, and a change in the PFAS profile from perfluorosulfonic acids and long-chain perfluorocarboxylic acids, to the short-chain perfluorocarboxylic acids and PFOS-replacement degradation products such as 5:3 FTCA. Intermittent pulses of PFAS that were significantly higher than 'background' levels (i.e., representing the PFAS input from primarily households) were observed, suggesting continuing industrial PFAS input within the wastewater catchment. This study highlights the long-term consequences of the diffuse use of persistent chemicals in products, and their ability to continue to enter the wastewater stream for decades.

Occult alloimmunization to the D antigen (RhD) related to graft versus host disease and its treatment.

Alloimmunization to red blood cell (RBC) antigens post-allogeneic stem cell transplantation (allo-SCT) appears to be quite rare. The D antigen (RhD) is considered the most immunogenic RBC antigen with possibly a third of RhD-negative individuals exposed to RhD-positive RBC transfusions becoming alloimmunized. Though variable, most are detectable within a year of exposure, and the median time between exposure and detection is estimated to be about a month. We report the detection of anti-D in an allogeneic bone marrow transplant (allo-BMT) recipient about five years following last exposure to RhD-positive RBC.

Decoding the conductance of disordered nanostructures: a quantum inverse problem.

Obtaining conductance spectra for a concentration of disordered impurities distributed over a nanoscale device with sensing capabilities is a well-defined problem. However, to do this inversely, i.e., extracting information about the scatters from the conductance spectrum alone, is not an easy task. In the presence of impurities, even advanced techniques of inversion can become particularly challenging. This article extends the applicability of a methodology we proposed capable of extracting composition information about a nanoscale sensing device using the conductance spectrum. The inversion tool decodes the conductance spectrum to yield the concentration and nature of the disorders responsible for conductance fluctuations in the spectra. We present the method for simple one-dimensional systems like an electron gas with randomly distributed delta functions and a linear chain of atoms. We prove the generality and robustness of the method using materials with complex electronic structures like hexagonal boron nitride, graphene nanoribbons, and carbon nanotubes. We also go on to probe distribution of disorders on the sublattice structure of the materials using the proposed inversion tool.

Structure of Geobacter pili reveals secretory rather than nanowire behaviour.

Extracellular electron transfer by Geobacter species through surface appendages known as microbial nanowires1 is important in a range of globally important environmental phenomena2, as well as for applications in bio-remediation, bioenergy, biofuels and bioelectronics. Since 2005, these nanowires have been thought to be type 4 pili composed solely of the PilA-N protein1. However, previous structural analyses have demonstrated that, during extracellular electron transfer, cells do not produce pili but rather nanowires made up of the cytochromes OmcS2,3 and OmcZ4. Here we show that Geobacter sulfurreducens binds PilA-N to PilA-C to assemble heterodimeric pili, which remain periplasmic under nanowire-producing conditions that require extracellular electron transfer5. Cryo-electron microscopy revealed that C-terminal residues of PilA-N stabilize its copolymerization with PilA-C (to form PilA-N-C) through electrostatic and hydrophobic interactions that position PilA-C along the outer surface of the filament. PilA-N-C filaments lack π-stacking of aromatic side chains and show a conductivity that is 20,000-fold lower than that of OmcZ nanowires. In contrast with surface-displayed type 4 pili, PilA-N-C filaments show structure, function and localization akin to those of type 2 secretion pseudopili6. The secretion of OmcS and OmcZ nanowires is lost when pilA-N is deleted and restored when PilA-N-C filaments are reconstituted. The substitution of pilA-N with the type 4 pili of other microorganisms also causes a loss of secretion of OmcZ nanowires. As all major phyla of prokaryotes use systems similar to type 4 pili, this nanowire translocation machinery may have a widespread effect in identifying the evolution and prevalence of diverse electron-transferring microorganisms and in determining nanowire assembly architecture for designing synthetic protein nanowires.

Stable expression of the human dopamine transporter in N27 cells as an in vitro model for dopamine cell trafficking and metabolism.

Dopamine (DA) metabolism and cell trafficking are critical for the proper functioning of DA neurons. Disruption of these DA processes can yield toxic products and is implicated in neurological conditions including Parkinson's disease (PD). To investigate pathogenic mechanisms involving DA neurons, in vitro models that recapitulate DA metabolism and trafficking in vivo are crucial. N27 cells are a widely used model for PD; however, these cells exhibit little expression of the DA transporter (DAT) confounding studies of DA uptake and metabolism. This lack of adequate DAT expression calls into question the use of this cell line as a model to study DA cell trafficking and metabolism. To overcome this problem, we stably expressed the human DAT (hDAT) in N27 cells to develop cells that we named N27-BCD. This approach allows for characterization of toxicants that may alter DA metabolism, trafficking, and/or interactions with DAT. N27-BCD cells are more sensitive to the neurotoxins 1-methyl-4-phenylpyridinium (MPTP/MPP+) and 6-hydroxydopamine (6-OHDA). N27-BCD cells allowed for clear observation of DA metabolism, whereas N27 cells did not. Here, we propose that stable expression of hDAT in N27 cells yields a useful model of DA neurons to study the impact of altered DA cell trafficking and metabolism.

Quantifying Recruitment Source and Participant Communication Preferences for Alzheimer's Disease Prevention Research.

BACKGROUND: Evidence on effective engagement of diverse participants in AD prevention research is lacking. OBJECTIVES: To quantify recruitment source in relation to race, ethnicity, and retention. DESIGN: Prospective cohort study. SETTING: University lab. PARTICIPANTS: Participants included older adults (N=1170) who identified as White (86%), Black (8%), and Hispanic/Latino ethnicity (6%). MEASUREMENTS: The Cognitive Aging Lab Marketing Questionnaire assessed recruitment source, social media use, and research opportunity communication preferences. RESULTS: Effective recruitment methods and communication preferences vary by race and ethnicity. The most common referral sources were postcards for racial minorities, friend/family referrals for Hispanic/Latinos, and the newspaper for Whites. Whereas Whites preferred email communications, Hispanic/Latinos preferred texts. CONCLUSIONS: Recruiting diverse samples in AD prevention research is clinically relevant given high AD-risk of minorities and that health disparities are propagated by their under-representation in research. Our questionnaire and these results may be applied to facilitate effective research engagement.

Introduction of an assessment toolkit associated with increased rate of DLB diagnosis.

BACKGROUND: Dementia with Lewy bodies (DLB) and dementia in Parkinson's disease (PDD) are recognised to be under-recognised in clinical practice in the UK, with only one third to a half of expected cases diagnosed. We aimed to assess whether clinical diagnostic rates could be increased by the introduction of a structured assessment toolkit for clinicians. METHODS: We established baseline diagnostic rates for DLB and PDD in four memory clinics and three movement disorder/Parkinson's disease (PD) clinics in two separate geographical regions in the UK. An assessment toolkit specifically developed to assist with the recognition and diagnosis of DLB and PDD was then introduced to the same clinical teams and diagnostic rates for DLB and PDD were reassessed. For assessing DLB diagnosis, a total of 3820 case notes were reviewed before the introduction of the toolkit, and 2061 case notes reviewed after its introduction. For PDD diagnosis, a total of 1797 case notes were reviewed before the introduction of the toolkit and 3405 case notes after it. Mean values and proportions were analysed using Student's t test for independent samples and χ2 test, respectively. RESULTS: DLB was diagnosed in 4.6% of dementia cases prior to the introduction of the toolkit, and 6.2% of dementia cases afterwards, an absolute rise of 1.6%, equal to a 35% increase in the number of DLB cases diagnosed when using the toolkit (χ2 = 4.2, P = 0.041). The number of PD patients diagnosed with PDD was not found overall to be significantly different when using the toolkit: 9.6% of PD cases before and 8.2% of cases after its introduction (χ2 = 1.8, P = 0.18), though the ages of PD patients assessed after the toolkit's introduction were lower (73.9 years vs 80.0 years, t = 19.2, p < 0.001). CONCLUSION: Introduction of the assessment toolkit was associated with a significant increase in the rate of DLB diagnosis, suggesting that a structured means of assessing symptoms and clinical features associated with DLB can assist clinicians in recognising cases. The assessment toolkit did not alter the overall rate of PDD diagnosis, suggesting that alternate means may be required to improve the rate of diagnosis of dementia in Parkinson's disease.

Cardiac 123I-MIBG normal uptake values are population-specific: Results from a cohort of controls over 60 years of age.

PURPOSE: Cardiac 123I-MIBG image interpretation is affected by population differences and technical factors. We recruited older adults without cognitive decline and compared their cardiac MIBG uptake with results from the literature. METHODS: Phantom calibration confirmed that cardiac uptake results from Japan could be applied to our center. We recruited 31 controls, 17 individuals with dementia with Lewy bodies (DLB) and 15 with Alzheimer's disease (AD). Images were acquired 20 minutes and four hours after injection using Siemens cameras with medium-energy low-penetration (MELP) collimators. Local normal heart-to-mediastinum (HMR) ratios were compared to Japanese results. RESULTS: Siemens gamma cameras with MELP collimators should give HMRs very close to the calibrated values used in Japan. However, our cut-offs with controls were lower at 2.07 for early and 1.86 for delayed images. Applying our lower cut-off to the dementia patients may increase the specificity of cardiac MIBG imaging for DLB diagnosis in a UK population without reducing sensitivity. CONCLUSIONS: Our local HMR cut-off values are lower than in Japan, higher than in a large US study but similar to those found in another UK center. UK centers using other cameras and collimators may need to use different cut-offs to apply our results.

The effect of ego depletion on challenge and threat evaluations during a potentially stressful public speaking task.

It has been well established that challenge and threat evaluations affect the performance of potentially stressful tasks. However, the factors that influence these evaluations have rarely been examined. Objective: This study examined the effects of ego depletion on challenge and threat evaluations during a public speaking task. Method: 262 participants (150 males, 112 females; Mage = 20.5, SD = 4.3) were randomly assigned to either an ego depletion or control group. Participants then completed self-report measures of trait self-control. The ego depletion group performed a written transcription task requiring self-control, while the control group transcribed the text normally. Before the public speaking task, participant's challenge and threat evaluations and subjective ratings of performance were assessed via self-report items. Results: The results of independent t-tests supported the effectiveness of the self-control manipulation. There were no significant differences between the ego depletion and control groups in terms of challenge and threat evaluations or subjective performance. Additional correlation analyses revealed that trait measures of self-control were significantly and negatively related to challenge and threat evaluations and subjective performance. Conclusion: Findings suggest that ego depletion might not influence appraisals of potentially stressful tasks, and thus add to recent evidence questioning the ego-depletion phenomenon.