Unconventional post-translational modifications in immunological signaling.

The activity of a cell is governed by the signals it receives from the extracellular milieu, which are 'translated' into the appropriate biological output, such as activation, survival, proliferation, migration or differentiation. Signaling pathways are responsible for converting environmental cues into discrete intracellular events. The alteration of existing proteins by post-translational modification (PTM) is a key feature of signal-transduction pathways that allows the modulation of protein function. Research into PTMs has long been dominated by the investigation of protein phosphorylation; other PTMs, such as methylation of lysine and arginine residues, acetylation, and nitrosylation of thiol groups and tyrosine residues, have received comparatively little attention. This Review aims to present an overview of these PTMs, with an emphasis on their role in cells of the immune system.

Single Live Cell Monitoring of Protein Turnover Reveals Intercellular Variability and Cell-Cycle Dependence of Degradation Rates.

Cells need to reliably control their proteome composition to maintain homeostasis and regulate growth. How protein synthesis and degradation interplay to control protein expression levels remains unclear. Here, we combined a tandem fluorescent timer and pulse-chase protein labeling to disentangle how protein synthesis and degradation control protein homeostasis in single live mouse embryonic stem cells. We discovered substantial cell-cycle dependence in protein synthesis rates and stabilization of a large number of proteins around cytokinesis. Protein degradation rates were highly variable between cells, co-varied within individual cells for different proteins, and were positively correlated with synthesis rates. This suggests variability in proteasome activity as an important source of global extrinsic noise in gene expression. Our approach paves the way toward understanding the complex interplay of synthesis and degradation processes in determining protein levels of individual mammalian cells.

Methylphenidate differentially alters corticostriatal connectivity after traumatic brain injury.

Traumatic brain injury commonly impairs attention and executive function, and disrupts the large-scale brain networks that support these cognitive functions. Abnormalities of functional connectivity are seen in corticostriatal networks, which are associated with executive dysfunction and damage to neuromodulatory catecholaminergic systems caused by head injury. Methylphenidate, a stimulant medication that increases extracellular dopamine and noradrenaline, can improve cognitive function following TBI. In this experimental medicine add-on study to a randomised, double-blind, placebo-controlled clinical trial, we test whether administration of methylphenidate alters corticostriatal network function and influences drug response. 43 moderate-severe traumatic brain injury patients received 0.3 mg/kg of methylphenidate or placebo twice a day in 2-week blocks. 28 patients were included in the neuropsychological and functional imaging analysis (4 females, mean age 40.9±12.7, range 20-65) and underwent functional MRI and neuropsychological assessment after each block. 123I-Ioflupane SPECT Dopamine Transporter (DAT) scans were performed, and specific binding ratios were extracted from caudate subdivisions. Functional connectivity and the relationship to cognition was compared between drug and placebo conditions. Methylphenidate increased caudate to anterior cingulate cortex functional connectivity compared to placebo and decreased connectivity from the caudate to default mode network. Connectivity within the default mode network was also decreased by methylphenidate administration and there was a significant relationship between caudate functional connectivity and DAT binding during methylphenidate administration. Methylphenidate significantly improved executive function in TBI patients, and this was associated with alterations in the relationship between executive function and right anterior caudate functional connectivity. Functional connectivity is strengthened to brain regions including the anterior cingulate that are activated when attention is focused externally. These results show that methylphenidate alters caudate interactions with cortical brain networks involved in executive control. In contrast, caudate functional connectivity reduces to default mode network regions involved in internally focused attention and that deactivate during tasks that require externally focused attention. These results suggest that the beneficial cognitive effects of methylphenidate may be mediated through its impact on the caudate. Methylphenidate differentially influences how the caudate interacts with large-scale functional brain networks that exhibit co-ordinated but distinct patterns of activity required for attentionally demanding tasks.

Antibiotic Prescribing Patterns for Respiratory Tract Illnesses Following the Conclusion of an Education and Feedback Intervention in Primary Care.

BACKGROUND: A study previously conducted in primary care practices found that implementation of an educational session and peer comparison feedback was associated with reduced antibiotic prescribing for respiratory tract diagnoses (RTDs). Here, we assess the long-term effects of this intervention on antibiotic prescribing following cessation of feedback. METHODS: RTD encounters were grouped into tiers based on antibiotic prescribing appropriateness: tier 1, almost always indicated; tier 2, possibly indicated; and tier 3, rarely indicated. A χ2 test was used to compare prescribing between 3 time periods: pre-intervention, intervention, and post-intervention (14 months following cessation of feedback). A mixed-effects multivariable logistic regression analysis was performed to assess the association between period and prescribing. RESULTS: We analyzed 260 900 RTD encounters from 29 practices. Antibiotic prescribing was more frequent in the post-intervention period than in the intervention period (28.9% vs 23.0%, P < .001) but remained lower than the 35.2% pre-intervention rate (P < .001). In multivariable analysis, the odds of prescribing were higher in the post-intervention period than the intervention period for tier 2 (odds ratio [OR], 1.19; 95% confidence interval [CI]: 1.10-1.30; P < .05) and tier 3 (OR, 1.20; 95% CI: 1.12-1.30) indications but was lower compared to the pre-intervention period for each tier (OR, 0.66; 95% CI: 0.59-0.73 tier 2; OR, 0.68; 95% CI: 0.61-0.75 tier 3). CONCLUSIONS: The intervention effects appeared to last beyond the intervention period. However, without ongoing provider feedback, there was a trend toward increased prescribing. Future studies are needed to determine optimal strategies to sustain intervention effects.

Risk of COVID-19 death for people with a pre-existing cancer diagnosis prior to COVID-19-vaccination: A systematic review and meta-analysis.

While previous reviews found a positive association between pre-existing cancer diagnosis and COVID-19-related death, most early studies did not distinguish long-term cancer survivors from those recently diagnosed/treated, nor adjust for important confounders including age. We aimed to consolidate higher-quality evidence on risk of COVID-19-related death for people with recent/active cancer (compared to people without) in the pre-COVID-19-vaccination period. We searched the WHO COVID-19 Global Research Database (20 December 2021), and Medline and Embase (10 May 2023). We included studies adjusting for age and sex, and providing details of cancer status. Risk-of-bias assessment was based on the Newcastle-Ottawa Scale. Pooled adjusted odds or risk ratios (aORs, aRRs) or hazard ratios (aHRs) and 95% confidence intervals (95% CIs) were calculated using generic inverse-variance random-effects models. Random-effects meta-regressions were used to assess associations between effect estimates and time since cancer diagnosis/treatment. Of 23 773 unique title/abstract records, 39 studies were eligible for inclusion (2 low, 17 moderate, 20 high risk of bias). Risk of COVID-19-related death was higher for people with active or recently diagnosed/treated cancer (general population: aOR = 1.48, 95% CI: 1.36-1.61, I2 = 0; people with COVID-19: aOR = 1.58, 95% CI: 1.41-1.77, I2 = 0.58; inpatients with COVID-19: aOR = 1.66, 95% CI: 1.34-2.06, I2 = 0.98). Risks were more elevated for lung (general population: aOR = 3.4, 95% CI: 2.4-4.7) and hematological cancers (general population: aOR = 2.13, 95% CI: 1.68-2.68, I2 = 0.43), and for metastatic cancers. Meta-regression suggested risk of COVID-19-related death decreased with time since diagnosis/treatment, for example, for any/solid cancers, fitted aOR = 1.55 (95% CI: 1.37-1.75) at 1 year and aOR = 0.98 (95% CI: 0.80-1.20) at 5 years post-cancer diagnosis/treatment. In conclusion, before COVID-19-vaccination, risk of COVID-19-related death was higher for people with recent cancer, with risk depending on cancer type and time since diagnosis/treatment.

High level of immunoglobulin G targeting mycoplasma or cytomegalovirus in the newborn increases risk of ADHD.

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder typically detected in childhood. Although ADHD has been demonstrated to have a strong genetic component, environmental risk factors, such as maternal infections during pregnancy, may also play a role. We therefore measured the immunological response to 5 abundant microorganisms (Toxoplasmosis Gondii, cytomegalovirus (CMV), Herpes Simplex Virus 1, Epstein Barr Virus and mycoplasma pneumoniae) in newborn heel prick samples of 1679 ADHD cases and 2948 matching controls as part of the iPSYCH Danish case-cohort study. We found an association between high anti-CMV (OR 1.30, 95 % CI [1.09,1.55], p = 0.015) and anti-mycoplasma (OR 1.30, 95 % CI [1.07,1.59], p = 0.037) signal and those newborns later being diagnosed with ADHD. The risk estimate remained increased when controlling for ADHD polygenic risk score as well as penicillin prescriptions. We saw a dose-response association with the amount of positive anti-microorganism titers increasing the risk of being diagnosed with ADHD later in life (p = 0.01 for the trend), suggesting that the more activated the immune system is prior to or at birth, the higher the risk is for a later diagnosis with ADHD. If the associations are causal, they emphasize the importance of a healthy life style during pregnancy to reduce the risk of infections when pregnant and the associated risks for the child.

Guided versus non-guided digital psychological interventions for cancer patients: A systematic review and meta-analysis of engagement and efficacy.

OBJECTIVE: To evaluate engagement with and efficacy of guided versus non-guided digital interventions targeting psychological symptoms of cancer via a systematic review of current evidence. METHODS: PubMed, Scopus, PsychINFO, MEDLINE, and CINAHL databases were searched. Eligible publications were randomised controlled trials of guided or non-guided digital psychological interventions used in cancer settings reporting intervention efficacy and/or engagement. Study methodological quality was assessed using the Cochrane risk of bias (RoB) tool. Random effects meta-analyses were performed on outcomes with sufficient data, with sub-group analyses of intervention type and follow-up period. RESULTS: Forty-three studies were included. Studies varied by level of guidance, type of technology used, duration, and outcomes assessed. Most studies had a high overall RoB. Meta-analysis indicated that guided interventions significantly reduced distress, anxiety, and fatigue, while non-guided did not. For depression and quality of life, both guided and non-guided interventions produced significant improvements. Guided interventions reported higher levels of intervention engagement than non-guided. CONCLUSIONS: Guided digital psychological interventions were likely to be more effective than non-guided ones for cancer patients, particularly in reducing distress, anxiety, and fatigue. Whilst both types were found to improve depression and life quality, guided interventions were associated with higher patient engagement. These findings suggest digital interventions could supplement traditional cancer care, warranting further research concerning long-term effects and cost-efficiency.

Effect of a smartphone-based physical intervention on depression, fitness factors and movement characteristics in adults.

BACKGROUND: Physical activity has been shown to correlate with mental health and a reduction in symptoms of depression. However, the majority of research has focused only on the effects of either aerobic or nonaerobic exercise on depressive symptoms, while the use of novel technological innovations such as mobile phone-based activity programs and their effects on movement characteristics are underrepresented. This study had two objectives: (1) to investigate how effectively 4 weeks of mobile phone-based physical activity can affect depressive scores (CES-10-D and PHQ) and fitness levels and (2) to investigate the whether 4 weeks of mobile phone-based physical activity affected participants' movement characteristics. METHODS: A total of 31 participants were included and divided into an exercise group (n = 21) and a control group (n = 10). The exercise group was instructed to use a mobile phone-based exercise program 5 times per week for 4 weeks. Pre- and post-exercise, the participants' depression score (CES-10-D, PHQ9), fitness level (YMCA, grip strength) and movement characteristics (postural sway, movement ROM, movement speeds, etc.) for three Azure Kinect physical activity games based on different fitness factors (balance game, cardiovascular game, reaction game) were measured. RESULTS: Mixed model ANOVA revealed significant differences between pre- and post-intervention depression scores on the PHQ9 (P = .001) and CES-10-D (P < .001) in both the exercise group and the control group, but not between groups. In terms of movement characteristics, there was an increase in body sway (P = .045) and vertical head movement (P = .02) in the cardiovascular game jogging condition for the exercise group. In the reaction game, the exercise group showed a significant reduction in the number of mistakes (P = .03). There were no other significant differences for the other variables. CONCLUSION: The results revealed no differences in the reduction in depression scores between the exercise group and the control group. However, this study showed that a mobile phone-based physical activity intervention affects in-game movement characteristics such as body sway and vertical head movement and therefore may show the potential of using activity-promoting mobile games for improving movement.

Effect of exercise interventions on hospital length of stay and admissions during cancer treatment: a systematic review and meta-analysis.

OBJECTIVE: To assess the effect of participating in an exercise intervention compared with no exercise during cancer treatment on the duration and frequency of hospital admissions. DESIGN: Systematic review and meta-analysis. DATA SOURCES: MEDLINE, EMBASE, PEDro and Cochrane Central Registry of Randomized Controlled Trials. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised studies published until August 2023 evaluating exercise interventions during chemotherapy, radiotherapy or stem cell transplant regimens, compared with usual care, and which assessed hospital admissions (length of stay and/or frequency of admissions). STUDY APPRAISAL AND SYNTHESIS: Study quality was assessed using the Cochrane Risk-of-Bias tool and Grading of Recommendations Assessment, Development and Evaluation assessment. Meta-analyses were conducted by pooling the data using random-effects models. RESULTS: Of 3918 screened abstracts, 20 studies met inclusion criteria, including 2635 participants (1383 intervention and 1252 control). Twelve studies were conducted during haematopoietic stem cell transplantation regimens. There was a small effect size in a pooled analysis that found exercise during treatment reduced hospital length of stay by 1.40 days (95% CI: -2.26 to -0.54 days; low-quality evidence) and lowered the rate of hospital admission by 8% (difference in proportions=-0.08, 95% CI: -0.13 to -0.03, low-quality evidence) compared with usual care. CONCLUSION: Exercise during cancer treatment can decrease hospital length of stay and admissions, although a small effect size and high heterogeneity limits the certainty. While exercise is factored into some multidisciplinary care plans, it could be included as standard practice for patients as cancer care pathways evolve.

Cervical Auscultation for Detecting Oropharyngeal Aspiration in Paediatric and Adult Populations: A Systematic Review and Meta-Analysis.

BACKGROUND: Cervical auscultation (CA) involves listening to swallowing and respiratory sounds and/or vibrations to detect oropharyngeal aspiration (OPA). CA has shown promising diagnostic test accuracy when used with the clinical swallowing examination and is gaining popularity in clinical practise. There has not been a review to date analysing the accuracy of CA in paediatric and adult populations with meta-analyses. OBJECTIVES: To determine the accuracy of CA in detecting OPA in paediatric and adult populations, when compared to instrumental assessments. SEARCH METHODS: Databases searched included MEDLINE, PubMed, Embase, CINAHL, AustHealth, Cochrane and Web of Science. The search was restricted between 01 October 2012 and 01 October 2022. SELECTION CRITERIA: Inclusion criteria included (a) all clinical populations of all ages, (b) who have had an instrumental assessment and (c) CA. All study types were included. DATA COLLECTION AND ANALYSIS: Studies were reviewed independently by two authors. The methodological quality of the studies was analysed using the QUADAS-2. MAIN RESULTS: Ten studies met the inclusion criteria for this review and meta-analyses. The pooled diagnostic performance of CA in detecting OPA was 0.91 for sensitivity and 0.79 for specificity. The area under the curve summary receiver operating curve (sROC) was estimated to be 0.86, thereby indicating good discrimination of OPA. Most studies scored high for risk of bias in at least one domain in the QUADAS-2, likely attributed to a lack of high-quality prospectively designed studies. CONCLUSIONS: There are promising diagnostic test accuracies for the use of CA in detection of OPA. Future research could include using CA in specific clinical populations and settings, and identifying standardised criteria for CA.

Determinants of Bladder Care at Night in a Subacute Ward for Aged Patients: An Observational Study.

PURPOSE: The purpose of this study was to evaluate how bladder care at night correlates to patients' mobility status. DESIGN: This was an observational study. SUBJECTS AND SETTING: The sample comprises 63 aged care subacute patients who were observed over 3 consecutive nights in an inpatient subacute aged care ward located in Melbourne, Australia. Half of the participants were female; their mean age was 82.0 (standard deviation 8.2) years. Data were collected from December 2020 to March 2021. METHODS: Outcome variables included demographic and pertinent clinical characteristics, type and timing of toileting and/or bladder care provided, and mobility classification. Descriptive statistics were used to summarize the frequency of nocturnal bladder care provided each night and as a mean over the 3 nights. The relationship between the type of care units provided and other variables was explored using a 1-way analysis of variance; values ≤.05 were deemed statistically significant. RESULTS: Findings indicate that 27% (n = 17), 41% (n = 26), and 48% (n = 30) of participants required assistance to move in bed, sit up in bed, and stand from sitting, respectively. Care episodes for both incontinence and assistance with voiding were significantly associated with functional mobility in bed ( F = 5.52, P < .001; F = 2.14, P = .02) and with ambulation independence ( F = 3.52, P = .001; F = 2.04, P = .03) but not with age or ambulation distance. CONCLUSIONS: Care provided for urinary incontinence during the night was related to the need for physical support of ambulation and poor mobility in bed. Targeted input from a multidisciplinary team is warranted to facilitate change of practice at night.

Evaluation of an Opt-Out Protocol for Antibiotic De-Escalation in Patients With Suspected Sepsis: A Multicenter, Randomized, Controlled Trial.

BACKGROUND: Sepsis guidelines recommend daily review to de-escalate or stop antibiotics in appropriate patients. This randomized, controlled trial evaluated an opt-out protocol to decrease unnecessary antibiotics in patients with suspected sepsis. METHODS: We evaluated non-intensive care adults on broad-spectrum antibiotics despite negative blood cultures at 10 US hospitals from September 2018 through May 2020. A 23-item safety check excluded patients with ongoing signs of systemic infection, concerning or inadequate microbiologic data, or high-risk conditions. Eligible patients were randomized to the opt-out protocol vs usual care. Primary outcome was post-enrollment antibacterial days of therapy (DOT). Clinicians caring for intervention patients were contacted to encourage antibiotic discontinuation using opt-out language. If continued, clinicians discussed the rationale for continuing antibiotics and de-escalation plans. To evaluate those with zero post-enrollment DOT, hurdle models provided 2 measures: odds ratio of antibiotic continuation and ratio of mean DOT among those who continued antibiotics. RESULTS: Among 9606 patients screened, 767 (8%) were enrolled. Intervention patients had 32% lower odds of antibiotic continuation (79% vs 84%; odds ratio, 0.68; 95% confidence interval [CI], .47-.98). DOT among those who continued antibiotics were similar (ratio of means, 1.06; 95% CI, .88-1.26). Fewer intervention patients were exposed to extended-spectrum antibiotics (36% vs 44%). Common reasons for continuing antibiotics were treatment of localized infection (76%) and belief that stopping antibiotics was unsafe (31%). Thirty-day safety events were similar. CONCLUSIONS: An antibiotic opt-out protocol that targeted patients with suspected sepsis resulted in more antibiotic discontinuations, similar DOT when antibiotics were continued, and no evidence of harm. CLINICAL TRIALS REGISTRATION: NCT03517007.

Genetic liability to posttraumatic stress disorder and its association with postpartum depression.

BACKGROUND: Childbirth may be a traumatic experience and vulnerability to posttraumatic stress disorder (PTSD) may increase the risk of postpartum depression (PPD). We investigated whether genetic vulnerability to PTSD as measured by polygenic score (PGS) increases the risk of PPD and whether a predisposition to PTSD in PPD cases exceeds that of major depressive disorder (MDD) outside the postpartum period. METHODS: This case-control study included participants from the iPSYCH2015, a case-cohort of all singletons born in Denmark between 1981 and 2008. Restricting to women born between 1981 and 1997 and excluding women with a first diagnosis other than depression (N = 22 613), 333 were identified with PPD. For each PPD case, 999 representing the background population and 993 with MDD outside the postpartum were matched by calendar year at birth, cohort selection, and age. PTSD PGS was calculated from summary statistics from the Psychiatric Genomics Consortium with LDpred2-auto. Odds ratios (ORs) were estimated using conditional logistic regression adjusted for parental psychiatric history and country of origin, PGS for MDD and age at first birth, and the first 10 principal components. RESULTS: The PTSD PGS was significantly associated with PPD (OR 1.42, 95% CI 1.20-1.68 per standard deviation increase in PTSD PGS) compared to healthy female controls. Genetic PTSD vulnerability in PPD cases did not exceed that of matched female depression cases outside the postpartum period (OR 1.10, 95% CI 0.94-1.30 per standard deviation increase). CONCLUSIONS: Genetic vulnerability to PTSD increased the risk of PPD but did not differ between PPD cases and women with depression at other times.

Effects of antimicrobial therapy duration and class on risk of antimicrobial-resistant Gram-negative bacillus bloodstream infection in patients with AML.

BACKGROUND: Antimicrobial-resistant Gram-negative bacilli (ARGNB) bloodstream infection (BSI) has been associated with prior antibiotic exposure among hematologic malignancy patients. The relationships between days of therapy (DOT), antimicrobial class, and ARGNB BSI risk are poorly understood. METHODS: This is a single-center, case-control study of acute myeloid leukemia (AML) patients including 115 cases with ARGNB BSI and 230 matched controls with non-ARGNB BSI between January 1, 2007 and December 31, 2018. Fixed- and mixed-effects logistic regression was used to examine relationships between antibiotic DOT and risk of ARGNB BSI. Admission to an intensive care unit (ICU) within 7 days, 30-day mortality, and Pitt Bacteremia Score (PBS) were secondary outcomes. RESULTS: Prior isolation of a antimicrobial-resistant organism (ARO) (OR 4.45 95% CI 1.46, 13.54), surgery within 90 days (OR 3.71, 95% CI 1.57, 8.73), aminoglycoside DOT (OR 1.14, 95% CI 1.05, 1.23), cefepime DOT (OR 1.09, 95% CI 1.05, 1.13), and carbapenem DOT (OR 1.10, 95% CI 1.05, 1.16) were associated with increased odds of ARGNB BSI. Days since last antibiotic administration (OR 0.98, 95% CI 0.97, 0.99) and inpatient days within 90 days (OR 0.95, 95% CI 0.93, 0.98) showed reduced odds of ARGNB BSI. Total antimicrobial DOT regardless of class was not associated with ARGNB BSI. ARGNB BSI was associated with increased 30-day mortality (OR 2.86, 95% CI 1.57, 5.22) CONCLUSIONS: Among AML patients with GNB BSI, greater DOT of aminoglycosides, cefepime, and carbapenems in the 90 days prior to BSI were associated with increased odds of ARGNB BSI.

Analgesic effect of oral paracetamol 1000 mg/ibuprofen 400 mg, paracetamol 1000 mg/codeine 60 mg, paracetamol 1000 mg/ibuprofen 400 mg/codeine 60 mg, or placebo on acute postoperative pain: a single-dose, randomized, and double-blind study.

PURPOSE: Combining analgesics with different mechanisms of action may increase the analgesic efficacy. The multidimensional pharmacodynamic profiles of ibuprofen 400 mg/paracetamol 1000 mg, ibuprofen 400 mg/paracetamol 1000 mg/codeine 60 mg, and paracetamol 1000 mg/codeine 60 mg and placebo were compared. METHODS: A randomized, double-blind, placebo-controlled, parallel-group, single-centre, outpatient, and single-dose study used 200 patients of both sexes and homogenous ethnicity after third molar surgery (mean age 24 years, range 19-30 years). Primary outcome was sum pain intensity over 6 h (SPI). Secondary outcomes were time to analgesic onset, duration of analgesia, time to rescue drug intake, number of patients taking rescue drug, sum pain intensity difference (SPID), maximum pain intensity difference, time to maximum pain intensity difference, number needed to treat, prevent remedication and harm values, adverse effects, and patient-reported outcome measure (PROM). RESULTS: Analgesia following ibuprofen and paracetamol combination with or without codeine was comparable. Both were better than paracetamol combined with codeine. Secondary variables supported this finding. Post hoc analysis of SPI and SPID revealed a sex/drug interaction trend in the codeine-containing groups where females experienced less analgesia. PROM showed a significant sex/drug interaction in the paracetamol and codeine group, but not in the other codeine-containing group. Especially females reported known and mild side effects in the codeine-containing groups. CONCLUSION: Codeine added to ibuprofen/paracetamol does not seem to add analgesia in a sex-mixed study population. Sex may be a confounding factor when testing weak opioid analgesics such as codeine. PROM seems to be more sensitive than traditional outcome measures. TRIAL REGISTRATION: ClinicalTrials.gov June 2009 NCT00921700.

Thirsty? Choose Water! A regional perspective to promoting water consumption in secondary school students.

OBJECTIVE: Adolescents are high consumers of sugar-sweetened beverages (SSB), which contribute to overweight and obesity - a significant public health issue. Evidence suggests that replacing SSB with water and school-based interventions can reduce consumption. This study examines the acceptability of a previously trialled intervention (Thirsty? Choose Water!) in regional and remote secondary schools. DESIGN: An open-label randomised controlled trial using a two-by-two factorial design tested the outcomes of a behavioural and/or environmental intervention on SSB and water consumption. SETTING: Regional and remote secondary schools (public, catholic and independent) within the boundaries of two regional Local Health Districts within New South Wales. PARTICIPANTS: Twenty-four schools participated in the study. The target group was year 7 students (n 1640) - 72 % of eligible students completed baseline data. The study followed students into year 8 (n 1188) - 52 % of eligible students completed post-intervention data. Forty teachers undertook training to deliver the intervention. RESULTS: Interventions showed high levels of acceptability. Students demonstrated changes in knowledge, attitudes and consumption behaviours. Multivariable ordinal logression analysis demonstrated that all interventions increased the odds of students increasing their water consumption (though not statistically significant). Conversely, the combined (OR: 0·75; 95 % CI: 0·59, 0·97) or environmental intervention (OR: 0·68; 95 % CI: 0·51, 0·90) had greater odds of reducing SSB consumption and was statistically significant. CONCLUSIONS: This study builds on recent Australian evidence regarding the impact of school-based interventions on water and SSB consumption. In this study, despite a minor intervention change, and the impacts of fires, floods and COVID-19 on study implementation, the interventions were highly regarded by the school communities with positive outcomes.

Natural history of pituitary apoplexy: a long-term follow-up study.

BACKGROUND AND AIMS: Pituitary apoplexy (PA) is a rare neurosurgical emergency, associated with deficiency of one or more pituitary hormones. Few studies have explored the relative outcomes associated with conservative and neurosurgical intervention. METHODS: A retrospective evaluation of all patients with PA reviewed at Morriston Hospital was undertaken and diagnosis was obtained from Morriston database (Leicester Clinical Workstation database) between 1998 and 2019 from clinic letters and discharge summaries. RESULTS: Thirty-nine patients with PA were identified with a mean age of 74.5 years and 20 (51.3%) patients were women. Patients were followed up for a mean±SD 68.1±61.7 months. Twenty-three (59.0%) patients had a known pituitary adenoma. Commoner clinical presentations of PA were ophthalmoplegia or visual field loss. Following PA, 34 (87.2%) patients were noted to have a non-functioning pituitary adenoma (either pre-existing or new), while 5 (12.8%) patients had a pre-existing functional macroadenoma. Neurosurgical intervention was taken in 15 (38.5%) patients of which 3 (20.0%) patients also received radiotherapy, 2 (13.3%) patients had radiotherapy alone and the remainder managed conservatively. External ophthalmoplegia recovered in all cases. Visual loss remained in all cases. One (2.6%) patient with chromophobe adenoma had a significant second episode of PA requiring repeat surgery. CONCLUSION: PA often occurs in patients with undiagnosed adenoma. Hypopituitarism commonly occurred following conservative or surgical treatment. External ophthalmoplegia resolved in all cases, however, visual loss did not recover. Pituitary tumour recurrence and further PA episodes are rare.

The history of resection prosthesis.

INTRODUCTION: The purpose of this historical review is to highlight the progression and development of prosthetic reconstruction with a focus on the modular distal femur with hinged total knee arthroplasty. METHOD: Scientific literature was searched for descriptions of endoprosthetic reconstruction of the extremities to provide a thorough overview of the subject, focusing the research on the evolution of limb salvage of the distal femur. RESULTS: After the first works of Gluck and Giordano, with ivory and metal and the pioneer shoulder prosthesis by Pean in the late 1890s, a great advancement was brought by reconstructions performed for injured soldiers of the Great War. By the 1940s, replacement of all the main joints had been attempted, and documented. DISCUSSION: Walldius in the 1950s developed a fully constrained hinge knee, offering for the first time a consistent and replicable method of substituting the joint. In 1953, Shiers' prosthesis allowed for good flexion and extension. Stanmore and GUEPAR group prosthesis in the 1960s were the first to have a different right and left side model. The rotating hinge was developed in 1978 by Walker, with the innovative concept of six degrees of freedom. Between 1979 and 1982, Kotz developed the modular segmental replacement that, added to a fixed hinge knee, permitted the revolutionary creation of the modern distal femur replacement. CONCLUSION: The study of the materials and mechanical solutions that was brought to the modern distal femur resection prosthesis is a good example of a virtuous multidisciplinary teamwork between orthopaedic surgeons, anatomists, and biomechanical engineers.

Staphylococcus aureus Genomic Analysis and Outcomes in Patients with Bone and Joint Infections: A Systematic Review.

Many studies have been published assessing the association between the presence of S. aureus genes and outcomes in patients with bone and joint infections (BJI), but it is not known if they have had similar findings. A systematic literature review was performed. All available data on studies in Pubmed between January 2000 to October 2022 reporting the genetic characteristics of S. aureus and the outcomes of BJIs were analyzed. BJI included prosthetic joint infection (PJI), osteomyelitis (OM), diabetic foot infection (DFI), and septic arthritis. Because of the heterogeneity of studies and outcomes, no meta-analysis was performed. With the search strategy, 34 articles were included: 15 articles on children and 19 articles on adults. In children, most BJI studied were OM (n = 13) and septic arthritis (n = 9). Panton Valentine leucocidin (PVL) genes were associated with higher biological inflammatory markers at presentation (n = 4 studies), more febrile days (n = 3), and more complicated/severe infection (n = 4). Other genes were reported anecdotally associated with poor outcomes. In adults, six studies reported outcomes in patients with PJI, 2 with DFI, 3 with OM, and 3 with various BJI. Several genes were associated with a variety of poor outcomes in adults, but studies found contradictory results. Whereas PVL genes were associated with poor outcomes in children, no specific genes were reported similarly in adults. Additional studies with homogenous BJI and larger sample sizes are needed.

The Genes-Stemness-Secretome Interplay in Malignant Pleural Mesothelioma: Molecular Dynamics and Clinical Hints.

MPM has a uniquely poor somatic mutational landscape, mainly driven by environmental selective pressure. This feature has dramatically limited the development of effective treatment. However, genomic events are known to be associated with MPM progression, and specific genetic signatures emerge from the exceptional crosstalk between neoplastic cells and matrix components, among which one main area of focus is hypoxia. Here we discuss the novel therapeutic strategies focused on the exploitation of MPM genetic asset and its interconnection with the surrounding hypoxic microenvironment as well as transcript products and microvesicles representing both an insight into the pathogenesis and promising actionable targets.