The UK Biobank: A Shining Example of Genome-Wide Association Study Science with the Power to Detect the Murky Complications of Real-World Epidemiology.

Genome-wide association studies (GWASs) have successfully identified thousands of genetic variants that are reliably associated with human traits. Although GWASs are restricted to certain variant frequencies, they have improved our understanding of the genetic architecture of complex traits and diseases. The UK Biobank (UKBB) has brought substantial analytical opportunity and performance to association studies. The dramatic expansion of many GWAS sample sizes afforded by the inclusion of UKBB data has improved the power of estimation of effect sizes but, critically, has done so in a context where phenotypic depth and precision enable outcome dissection and the application of epidemiological approaches. However, at the same time, the availability of such a large, well-curated, and deeply measured population-based collection has the capacity to increase our exposure to the many complications and inferential complexities associated with GWASs and other analyses. In this review, we discuss the impact that UKBB has had in the GWAS era, some of the opportunities that it brings, and exemplar challenges that illustrate the reality of using data from this world-leading resource.

Divergent functions of histone acetyltransferases KAT2A and KAT2B in keratinocyte self-renewal and differentiation.

The mammalian epidermis undergoes constant renewal, replenished by a pool of stem cells and terminal differentiation of their progeny. This is accompanied by changes in gene expression and morphology that are orchestrated, in part, by epigenetic modifiers. Here, we define the role of the histone acetyltransferase KAT2A in epidermal homeostasis and provide a comparative analysis that reveals key functional divergence with its paralog KAT2B. In contrast to the reported function of KAT2B in epidermal differentiation, KAT2A supports the undifferentiated state in keratinocytes. RNA-seq analysis of KAT2A- and KAT2B- depleted keratinocytes revealed dysregulated epidermal differentiation. Depletion of KAT2A led to premature expression of epidermal differentiation genes in the absence of inductive signals, whereas loss of KAT2B delayed differentiation. KAT2A acetyltransferase activity was indispensable in regulating epidermal differentiation gene expression. The metazoan-specific N terminus of KAT2A was also required to support its function in keratinocytes. We further showed that the interplay between KAT2A- and KAT2B-mediated regulation was important for normal cutaneous wound healing in vivo. Overall, these findings reveal a distinct mechanism in which keratinocytes use a pair of highly homologous histone acetyltransferases to support divergent functions in self-renewal and differentiation processes.

Mentoring as a complex adaptive system - a systematic scoping review of prevailing mentoring theories in medical education.

BACKGROUND: Effective mentorship is an important component of medical education with benefits to all stakeholders. In recent years, conceptualization of mentorship has gone beyond the traditional dyadic experienced mentor-novice mentee relationship to include group and peer mentoring. Existing theories of mentorship do not recognize mentoring's personalized, evolving, goal-driven, and context-specific nature. Evidencing the limitations of traditional cause-and-effect concepts, the purpose of this review was to systematically search the literature to determine if mentoring can be viewed as a complex adaptive system (CAS). METHODS: A systematic scoping review using Krishna's Systematic Evidence-Based Approach was employed to study medical student and resident accounts of mentoring and CAS in general internal medicine and related subspecialties in articles published between 1 January 2000 and 31 December 2023 in PubMed, Embase, PsycINFO, ERIC, Google Scholar, and Scopus databases. The included articles underwent thematic and content analysis, with the themes identified and combined to create domains, which framed the discussion. RESULTS: Of 5,704 abstracts reviewed, 134 full-text articles were evaluated, and 216 articles were included. The domains described how mentoring relationships and mentoring approaches embody characteristics of CAS and that mentorship often behaves as a community of practice (CoP). Mentoring's CAS-like features are displayed through CoPs, with distinct boundaries, a spiral mentoring trajectory, and longitudinal mentoring support and assessment processes. CONCLUSION: Recognizing mentorship as a CAS demands the rethinking of the design, support, assessment, and oversight of mentorship and the role of mentors. Further study is required to better assess the mentoring process and to provide optimal training and support to mentors.

The societal cost of modifiable risk factors in Singapore.

BACKGROUND: Singapore is one of the most rapidly ageing populations in the world. Nearly half of all disease burdens in Singapore are attributable to modifiable risk factors. This indicates that many illnesses are preventable by modifying behaviours such as increasing physical activity levels or maintaining a healthy diet. Prior cost-of-illness studies have estimated the cost of selected modifiable risk factors. However, no local study has compared costs between groups of modifiable risks. This study aims to estimate the societal cost attributable to a comprehensive list of modifiable risks in Singapore. METHODS: Our study builds on the comparative risk assessment framework from the Global Burden of Disease (GBD) 2019 study. A top-down prevalence-based cost-of-illness approach was undertaken to estimate the societal cost of modifiable risks in 2019. These include healthcare costs from inpatient hospitalisation and productivity losses from absenteeism and premature mortality. RESULTS: Metabolic risks had the highest total cost of US$1.62 billion (95% uncertainty interval [UI] US$1.51-1.84 billion), followed by lifestyle risks of US$1.40 billion (95% UI US$1.36-1.66 billion) and substance risks of US$1.15 billion (95% UI US$1.10-1.24 billion). Across the risk factors, the costs were driven by productivity losses, heavily skewed towards the older working-age group and among males. Most of the costs were driven by cardiovascular diseases. CONCLUSION: This study provides evidence of the high societal cost of modifiable risks and highlights the importance of developing holistic public health promotion programmes. As modifiable risks often do not occur in isolation, implementing effective population-based programmes targeting multiple modifiable risks has a strong potential to manage the cost of the rising disease burden in Singapore.

Revising the Pragmatics Profile using a modified Delphi methodology to meet the assessment needs of current speech-language therapists.

BACKGROUND: Non-standardized assessment tools are preferred when assessing communication of individuals with developmental disabilities. Currently, there are limited tools available for assessing this population. Informant report tools such as the Pragmatics Profile (PP) of Everyday Communication Skills are beneficial in gathering a representative view of an individual's communication. However, the PP is out of print and outdated, requiring revisions to meet contemporary assessment needs of speech-language therapists (SLTs). AIMS: To seek consensus from an international panel regarding revising the Pragmatic Profile by (1) updating language and terminology, and (2) development of an online tool. METHODS & PROCEDURES: A total of 13 experienced SLTs and researchers in the disability field participated in a modified Delphi study including an initial online meeting followed by an anonymous four-round survey. Participants reviewed the relevance and wording of questions in the original preschool, school-age and adult versions to create a single combined version of the PP. In each Delphi round, the level of consensus was calculated and qualitative comments were analysed using thematic analysis. OUTCOMES & RESULTS: A revised online version of the PP was created including 64 questions. Qualitative analysis illuminated key concepts in the creation of a revised form including the need for plain and age-neutral language, which is inclusive of all communication modalities and physical impairments, and identifies behaviours that have the potential to be communicative acts. Using conditional logic, users are navigated to the appropriate questions based on the intentionality level of the individual rather than their age. CONCLUSIONS & IMPLICATIONS: This study resulted in the revision of a valued assessment tool appropriate for current disability service provision that identifies communication along the continuum of intentionality rather than age. WHAT THIS PAPER ADDS: What is already known on this subject Non-standardized tools are appropriate when assessing communication of individuals with developmental disabilities. However, there are limited published tools suitable for this population with several of them out of print, making it difficult to conduct a holistic assessment. What this study adds to the existing knowledge This study resulted in the creation of an online PP based on experts' opinion. The revised PP modified the primary focus of the tool from age- to skill-based whereby questions are targeted according to intentionality level. Revisions included plain language, and inclusion of all communication modalities and physical impairments via a series of prompts to ensure that the information provided by informants is accurate and relevant. What are the potential or actual clinical implications of this work? The revised PP adds to the toolkit of an SLT working with individuals with a developmental disability and allows for accurate reporting of functional communication. Guided by experts' opinion, the revised PP is likely to be highly valued in the increasingly technological world in which we live.

Genetically proxied therapeutic inhibition of antihypertensive drug targets and risk of common cancers: A mendelian randomization analysis.

BACKGROUND: Epidemiological studies have reported conflicting findings on the potential adverse effects of long-term antihypertensive medication use on cancer risk. Naturally occurring variation in genes encoding antihypertensive drug targets can be used as proxies for these targets to examine the effect of their long-term therapeutic inhibition on disease outcomes. METHODS AND FINDINGS: We performed a mendelian randomization analysis to examine the association between genetically proxied inhibition of 3 antihypertensive drug targets and risk of 4 common cancers (breast, colorectal, lung, and prostate). Single-nucleotide polymorphisms (SNPs) in ACE, ADRB1, and SLC12A3 associated (P < 5.0 × 10-8) with systolic blood pressure (SBP) in genome-wide association studies (GWAS) were used to proxy inhibition of angiotensin-converting enzyme (ACE), ß-1 adrenergic receptor (ADRB1), and sodium-chloride symporter (NCC), respectively. Summary genetic association estimates for these SNPs were obtained from GWAS consortia for the following cancers: breast (122,977 cases, 105,974 controls), colorectal (58,221 cases, 67,694 controls), lung (29,266 cases, 56,450 controls), and prostate (79,148 cases, 61,106 controls). Replication analyses were performed in the FinnGen consortium (1,573 colorectal cancer cases, 120,006 controls). Cancer GWAS and FinnGen consortia data were restricted to individuals of European ancestry. Inverse-variance weighted random-effects models were used to examine associations between genetically proxied inhibition of these drug targets and risk of cancer. Multivariable mendelian randomization and colocalization analyses were employed to examine robustness of findings to violations of mendelian randomization assumptions. Genetically proxied ACE inhibition equivalent to a 1-mm Hg reduction in SBP was associated with increased odds of colorectal cancer (odds ratio (OR) 1.13, 95% CI 1.06 to 1.22; P = 3.6 × 10-4). This finding was replicated in the FinnGen consortium (OR 1.40, 95% CI 1.02 to 1.92; P = 0.035). There was little evidence of association of genetically proxied ACE inhibition with risk of breast cancer (OR 0.98, 95% CI 0.94 to 1.02, P = 0.35), lung cancer (OR 1.01, 95% CI 0.92 to 1.10; P = 0.93), or prostate cancer (OR 1.06, 95% CI 0.99 to 1.13; P = 0.08). Genetically proxied inhibition of ADRB1 and NCC were not associated with risk of these cancers. The primary limitations of this analysis include the modest statistical power for analyses of drug targets in relation to some less common histological subtypes of cancers examined and the restriction of the majority of analyses to participants of European ancestry. CONCLUSIONS: In this study, we observed that genetically proxied long-term ACE inhibition was associated with an increased risk of colorectal cancer, warranting comprehensive evaluation of the safety profiles of ACE inhibitors in clinical trials with adequate follow-up. There was little evidence to support associations across other drug target-cancer risk analyses, consistent with findings from short-term randomized controlled trials for these medications.

Identifying molecular mediators of the relationship between body mass index and endometrial cancer risk: a Mendelian randomization analysis.

BACKGROUND: Endometrial cancer is the most common gynaecological cancer in high-income countries. Elevated body mass index (BMI) is an established modifiable risk factor for this condition and is estimated to confer a larger effect on endometrial cancer risk than any other cancer site. However, the molecular mechanisms underpinning this association remain unclear. We used Mendelian randomization (MR) to evaluate the causal role of 14 molecular risk factors (hormonal, metabolic and inflammatory markers) in endometrial cancer risk. We then evaluated and quantified the potential mediating role of these molecular traits in the relationship between BMI and endometrial cancer using multivariable MR. METHODS: Genetic instruments to proxy 14 molecular risk factors and BMI were constructed by identifying single-nucleotide polymorphisms (SNPs) reliably associated (P < 5.0 × 10-8) with each respective risk factor in previous genome-wide association studies (GWAS). Summary statistics for the association of these SNPs with overall and subtype-specific endometrial cancer risk (12,906 cases and 108,979 controls) were obtained from a GWAS meta-analysis of the Endometrial Cancer Association Consortium (ECAC), Epidemiology of Endometrial Cancer Consortium (E2C2) and UK Biobank. SNPs were combined into multi-allelic models and odds ratios (ORs) and 95% confidence intervals (95% CIs) were generated using inverse-variance weighted random-effects models. The mediating roles of the molecular risk factors in the relationship between BMI and endometrial cancer were then estimated using multivariable MR. RESULTS: In MR analyses, there was strong evidence that BMI (OR per standard deviation (SD) increase 1.88, 95% CI 1.69 to 2.09, P = 3.87 × 10-31), total testosterone (OR per inverse-normal transformed nmol/L increase 1.64, 95% CI 1.43 to 1.88, P = 1.71 × 10-12), bioavailable testosterone (OR per natural log transformed nmol/L increase: 1.46, 95% CI 1.29 to 1.65, P = 3.48 × 10-9), fasting insulin (OR per natural log transformed pmol/L increase: 3.93, 95% CI 2.29 to 6.74, P = 7.18 × 10-7) and sex hormone-binding globulin (SHBG, OR per inverse-normal transformed nmol/L increase 0.71, 95% CI 0.59 to 0.85, P = 2.07 × 10-4) had a causal effect on endometrial cancer risk. Additionally, there was suggestive evidence that total serum cholesterol (OR per mg/dL increase 0.90, 95% CI 0.81 to 1.00, P = 4.01 × 10-2) had an effect on endometrial cancer risk. In mediation analysis, we found evidence for a mediating role of fasting insulin (19% total effect mediated, 95% CI 5 to 34%, P = 9.17 × 10-3), bioavailable testosterone (15% mediated, 95% CI 10 to 20%, P = 1.43 × 10-8) and SHBG (7% mediated, 95% CI 1 to 12%, P = 1.81 × 10-2) in the relationship between BMI and endometrial cancer risk. CONCLUSIONS: Our comprehensive MR analysis provides insight into potential causal mechanisms linking BMI with endometrial cancer risk and suggests targeting of insulinemic and hormonal traits as a potential strategy for the prevention of endometrial cancer.

Does testosterone mediate the relationship between vitamin D and prostate cancer progression? A systematic review and meta-analysis.

PURPOSE: Observational studies and randomized controlled trials (RCTs) have shown an association between vitamin D levels and prostate cancer progression. However, evidence of direct causality is sparse and studies have not examined biological mechanisms, which can provide information on plausibility and strengthen the evidence for causality. METHODS: We used the World Cancer Research Fund International/University of Bristol two-stage framework for mechanistic systematic reviews. In stage one, both text mining of published literature and expert opinion identified testosterone as a plausible biological mechanism. In stage two, we performed a systematic review and meta-analysis to assess the evidence from both human and animal studies examining the effect of vitamin D on testosterone, and testosterone on advanced prostate cancer (diagnostic Gleason score of ≥ 8, development of metastasis) or prostate cancer-specific mortality. RESULTS: A meta-analysis of ten human RCTs showed evidence of an effect of vitamin D on total testosterone (standardised mean difference (SMD) = 0.133, 95% CI = - 0.003-0.269, I2 = 0.0%, p = 0.056). Five human RCTs showed evidence of an effect of vitamin D on free testosterone (SMD = 0.173, 95% CI = - 0.104-0.450, I2 = 52.4%, p = 0.220). Three human cohort studies of testosterone on advanced prostate cancer or prostate cancer-specific mortality provided inconsistent results. In one study, higher levels of calculated free testosterone were positively associated with advanced prostate cancer or prostate cancer-specific mortality. In contrast, higher levels of dihydrotestosterone were associated with lowering prostate cancer-specific mortality in another study. No animal studies met the study eligibility criteria. CONCLUSION: There is some evidence that vitamin D increases levels of total and free testosterone, although the effect of testosterone levels within the normal range on prostate cancer progression is unclear. The role of testosterone as a mechanism between vitamin D and prostate cancer progression remains inconclusive.

The blood metabolome of incident kidney cancer: A case-control study nested within the MetKid consortium.

BACKGROUND: Excess bodyweight and related metabolic perturbations have been implicated in kidney cancer aetiology, but the specific molecular mechanisms underlying these relationships are poorly understood. In this study, we sought to identify circulating metabolites that predispose kidney cancer and to evaluate the extent to which they are influenced by body mass index (BMI). METHODS AND FINDINGS: We assessed the association between circulating levels of 1,416 metabolites and incident kidney cancer using pre-diagnostic blood samples from up to 1,305 kidney cancer case-control pairs from 5 prospective cohort studies. Cases were diagnosed on average 8 years after blood collection. We found 25 metabolites robustly associated with kidney cancer risk. In particular, 14 glycerophospholipids (GPLs) were inversely associated with risk, including 8 phosphatidylcholines (PCs) and 2 plasmalogens. The PC with the strongest association was PC ae C34:3 with an odds ratio (OR) for 1 standard deviation (SD) increment of 0.75 (95% confidence interval [CI]: 0.68 to 0.83, p = 2.6 × 10-8). In contrast, 4 amino acids, including glutamate (OR for 1 SD = 1.39, 95% CI: 1.20 to 1.60, p = 1.6 × 10-5), were positively associated with risk. Adjusting for BMI partly attenuated the risk association for some-but not all-metabolites, whereas other known risk factors of kidney cancer, such as smoking and alcohol consumption, had minimal impact on the observed associations. A mendelian randomisation (MR) analysis of the influence of BMI on the blood metabolome highlighted that some metabolites associated with kidney cancer risk are influenced by BMI. Specifically, elevated BMI appeared to decrease levels of several GPLs that were also found inversely associated with kidney cancer risk (e.g., -0.17 SD change [ßBMI] in 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2) levels per SD change in BMI, p = 3.4 × 10-5). BMI was also associated with increased levels of glutamate (ßBMI: 0.12, p = 1.5 × 10-3). While our results were robust across the participating studies, they were limited to study participants of European descent, and it will, therefore, be important to evaluate if our findings can be generalised to populations with different genetic backgrounds. CONCLUSIONS: This study suggests a potentially important role of the blood metabolome in kidney cancer aetiology by highlighting a wide range of metabolites associated with the risk of developing kidney cancer and the extent to which changes in levels of these metabolites are driven by BMI-the principal modifiable risk factor of kidney cancer.

Los teléfonos móviles como potencial vehículo de infección en un entorno hospitalario.

ResumenEl objetivo de este artículo es investigar el posible papel desempeñado por los teléfonos móviles como depósitos de colonización bacteriana y los factores de riesgo que ésta conlleva en un ambiente hospitalario. Entre enero de 2013 y marzo de 2014 examinamos a 226 miembros del personal de un hospital regional de Australia (146 médicos y 80 estudiantes de medicina). Los principales resultados de interés se relacionaron con los tipos de microorganismos y la cantidad de contaminación encontrados en los teléfonos móviles. Este estudio mostró la existencia de un alto nivel de contaminación bacteriana (n = 168/226, 74%) en los teléfonos móviles de los funcionarios de un hospital de atención terciaria, aislándose organismos similares en la mano dominante del personal y en sus teléfonos móviles. Mientras que la mayoría de los organismos aislados pertenecía a la flora cutánea normal, un pequeño porcentaje era potencialmente patógeno (n = 12/226, 5%). Además, se encontró que ser miembro subalterno del personal médico constituía un factor de riesgo para un importante crecimiento microbiano (OR 4.00, 95% CI 1.54, 10.37). Sólo 31% (70/226) de los participantes en el estudio informó que limpiaba sus teléfonos regularmente y sólo 21% (47/226) reportó que usa toallitas con alcohol para la limpieza de su teléfono. Este estudio demuestra que los teléfonos móviles son potenciales vehículos de bacterias patógenas en un ambiente hospitalario. Sólo una minoría de participantes informó que limpia su teléfono regularmente. Deberían elaborarse y aplicarse directrices de desinfección utilizando toallitas con alcohol.

Differential kynurenine pathway metabolism in highly metastatic aggressive breast cancer subtypes: beyond IDO1-induced immunosuppression.

BACKGROUND: Immunotherapy has recently been proposed as a promising treatment to stop breast cancer (BrCa) progression and metastasis. However, there has been limited success in the treatment of BrCa with immune checkpoint inhibitors. This implies that BrCa tumors have other mechanisms to escape immune surveillance. While the kynurenine pathway (KP) is known to be a key player mediating tumor immune evasion and while there are several studies on the roles of the KP in cancer, little is known about KP involvement in BrCa. METHODS: To understand how KP is regulated in BrCa, we examined the KP profile in BrCa cell lines and clinical samples (n = 1997) that represent major subtypes of BrCa (luminal, HER2-enriched, and triple-negative (TN)). We carried out qPCR, western blot/immunohistochemistry, and ultra-high pressure liquid chromatography on these samples to quantify the KP enzyme gene, protein, and activity, respectively. RESULTS: We revealed that the KP is highly dysregulated in the HER2-enriched and TN BrCa subtype. Gene, protein expression, and KP metabolomic profiling have shown that the downstream KP enzymes KMO and KYNU are highly upregulated in the HER2-enriched and TN BrCa subtypes, leading to increased production of the potent immunosuppressive metabolites anthranilic acid (AA) and 3-hydroxylanthranilic acid (3HAA). CONCLUSIONS: Our findings suggest that KMO and KYNU inhibitors may represent new promising therapeutic targets for BrCa. We also showed that KP metabolite profiling can be used as an accurate biomarker for BrCa subtyping, as we successfully discriminated TN BrCa from other BrCa subtypes.

Sequence tube maps: making graph genomes intuitive to commuters.

MOTIVATION: Compared to traditional haploid reference genomes, graph genomes are an efficient and compact data structure for storing multiple genomic sequences, for storing polymorphisms or for mapping sequencing reads with greater sensitivity. Further, graphs are well-studied computer science objects that can be efficiently analyzed. However, their adoption in genomic research is slow, in part because of the cognitive difficulty in interpreting graphs. RESULTS: We present an intuitive graphical representation for graph genomes that re-uses well-honed techniques developed to display public transport networks, and demonstrate it as a web tool. AVAILABILITY AND IMPLEMENTATION: Code: https://github.com/vgteam/sequenceTubeMap. DEMONSTRATION: https://vgteam.github.io/sequenceTubeMap/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Defects in optineurin- and myosin VI-mediated cellular trafficking in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder primarily affecting motor neurons. Mutations in optineurin cause a small proportion of familial ALS cases, and wild-type (WT) optineurin is misfolded and forms inclusions in sporadic ALS patient motor neurons. However, it is unknown how optineurin mutation or misfolding leads to ALS. Optineurin acts an adaptor protein connecting the molecular motor myosin VI to secretory vesicles and autophagosomes. Here, we demonstrate that ALS-linked mutations p.Q398X and p.E478G disrupt the association of optineurin with myosin VI, leading to an abnormal diffuse cytoplasmic distribution, inhibition of secretory protein trafficking, endoplasmic reticulum (ER) stress and Golgi fragmentation in motor neuron-like NSC-34 cells. We also provide further insight into the role of optineurin as an autophagy receptor. WT optineurin associated with lysosomes and promoted autophagosome fusion to lysosomes in neuronal cells, implying that it mediates trafficking of lysosomes during autophagy in association with myosin VI. However, either expression of ALS mutant optineurin or small interfering RNA-mediated knockdown of endogenous optineurin blocked lysosome fusion to autophagosomes, resulting in autophagosome accumulation. Together these results indicate that ALS-linked mutations in optineurin disrupt myosin VI-mediated intracellular trafficking processes. In addition, in control human patient tissues, optineurin displayed its normal vesicular localization, but in sporadic ALS patient tissues, vesicles were present in a significantly decreased proportion of motor neurons. Optineurin binding to myosin VI was also decreased in tissue lysates from sporadic ALS spinal cords. This study therefore links several previously described pathological mechanisms in ALS, including defects in autophagy, fragmentation of the Golgi and induction of ER stress, to disruption of optineurin function. These findings also indicate that optineurin-myosin VI dysfunction is a common feature of both sporadic and familial ALS.

Does milk intake promote prostate cancer initiation or progression via effects on insulin-like growth factors (IGFs)? A systematic review and meta-analysis.

PURPOSE: To establish whether the association between milk intake and prostate cancer operates via the insulin-like growth factor (IGF) pathway (including IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3). METHODS: Systematic review, collating data from all relevant studies examining associations of milk with IGF, and those examining associations of IGF with prostate cancer risk and progression. Data were extracted from experimental and observational studies conducted in either humans or animals, and analyzed using meta-analysis where possible, with summary data presented otherwise. RESULTS: One hundred and seventy-two studies met the inclusion criteria: 31 examining the milk-IGF relationship; 132 examining the IGF-prostate cancer relationship in humans; and 10 animal studies examining the IGF-prostate cancer relationship. There was moderate evidence that circulating IGF-I and IGFBP-3 increase with milk (and dairy protein) intake (an estimated standardized effect size of 0.10 SD increase in IGF-I and 0.05 SD in IGFBP-3 per 1 SD increase in milk intake). There was moderate evidence that prostate cancer risk increased with IGF-I (Random effects meta-analysis OR per SD increase in IGF-I 1.09; 95% CI 1.03, 1.16; n = 51 studies) and decreased with IGFBP-3 (OR 0.90; 0.83, 0.98; n = 39 studies), but not with other growth factors. The IGFBP-3 -202A/C single nucleotide polymorphism was positively associated with prostate cancer (pooled OR for A/C vs. AA = 1.22; 95% CI 0.84, 1.79; OR for C/C vs. AA = 1.51; 1.03, 2.21, n = 8 studies). No strong associations were observed for IGF-II, IGFBP-1 or IGFBP-2 with either milk intake or prostate cancer risk. There was little consistency within the data extracted from the small number of animal studies. There was additional evidence to suggest that the suppression of IGF-II can reduce tumor size, and contradictory evidence with regards to the effect of IGFBP-3 suppression on tumor progression. CONCLUSION: IGF-I is a potential mechanism underlying the observed associations between milk intake and prostate cancer risk.

Mobile Phones as a Potential Vehicle of Infection in a Hospital Setting.

The objective of this article is to investigate the potential role of mobile phones as a reservoir for bacterial colonization and the risk factors for bacterial colonization in a hospital setting. We screened 226 staff members at a regional Australian hospital (146 doctors and 80 medical students) between January 2013 and March 2014. The main outcomes of interest were the types of microorganisms and the amount of contamination of the mobile phones. This study found a high level of bacterial contamination (n = 168/226, 74%) on the mobile phones of staff members in a tertiary hospital, with similar organisms isolated from the staff member's dominant hand and mobile phones. While most of the isolated organisms were normal skin flora, a small percentage were potentially pathogenic (n = 12/226, 5%). Being a junior medical staff was found to be a risk factor for heavy microbial growth (OR 4.00, 95% CI 1.54, 10.37). Only 31% (70/226) of our participants reported cleaning their phones routinely, and only 21% (47/226) reported using alcohol containing wipes on their phones. This study demonstrates that mobile phones are potentially vehicles for pathogenic bacteria in a hospital setting. Only a minority of our participants reported cleaning their phones routinely. Disinfection guidelines utilizing alcohol wipes should be developed and implemented.

Pre-operative high resolution computed tomography scans for cholesteatoma: has anything changed?

OBJECTIVE: CT temporal bone scans are often performed to aid in surgical planning and management of cholesteatomas. With improvements in the resolution of CT scans today, it is now possible to obtain more information from these scans than before. The aim of this study is to compare findings on high resolution CT (HRCT) temporal bone scans to intra-operative findings, so as to determine how well various middle ear structures are assessed by HRCT scanning. STUDY DESIGN: Retrospective study. SETTING: Otology clinic of a tertiary otolaryngology centre. SUBJECTS AND METHODS: 32 mastoidectomies performed by a single otologist for clinically confirmed cholesteatoma were included. Correlation of CT and intra-operative findings on the status of structures including the ossicles, semicircular canals, facial canal and tegmen was analysed using kappa and AC1 statistics. RESULTS: In all patients, a soft tissue mass with bony erosion in keeping with a cholesteatoma was seen on CT. Radiosurgical agreement was excellent for the presence of semicircular canal erosion (k=0.89, AC1=0.96), facial canal dehiscence (k=0.74, AC1=0.76), tegmen erosion (k=0.76, AC1=0.92) and malleus erosion (k=0.76, AC1=0.85). It was good for incus erosion (k=0.71, AC1=0.92) and stapes erosion (k=0.63, AC1=0.73). CONCLUSION: There was good to excellent radiosurgical agreement in the assessment of the status of various middle ear structures. Improvement in radiosurgical agreement from existing studies in the literature was noted. This was especially true for features such as facial canal dehiscence. With technological advancements, CT temporal bone scans appear even more valuable for evaluation of patients prior to cholesteatoma surgery.

Impact of COVID-19 national response on primary care utilisation in Singapore: an interrupted time-series analysis.

Since the start of the pandemic, many national responses, such as nationwide lockdowns, have been implemented to curb the spread of COVID-19. We aim to assess the impact of Singapore's national responses on primary care utilisation. We performed an interrupted time series using acute and chronic primary care data of 3 168 578 visits between 1 September 2019 and 31 August 2020 over four periods: before any measures were put in place, during Disease Outbreak Response System Condition (DORSCON) Orange, when Circuit Breaker was instituted, and when Circuit Breaker was lifted. We found significant mean reductions in acute and chronic primary care visits immediately following DORSCON Orange and Circuit Breaker. DORSCON Orange was associated with - 2020 mean daily visits (95% CI - 2890 to - 1150). Circuit Breaker was associated with a further - 2510 mean daily visits (95% CI - 3660 to - 1360). Primary care utilisation for acute visits remained below baseline levels even after the Circuit Breaker was lifted. These significant reductions were observed in both acute and chronic visits, with acute visits experiencing a steeper drop during DORSCON Orange. Understanding the impact of COVID-19 measures on primary care utilisation will be useful for future public health planning.

Developing a production workflow for 3D-printed temporal bone surgical simulators.

INTRODUCTION: 3D-printed temporal bone models enable the training and rehearsal of complex otological procedures. To date, there has been no consolidation of the literature regarding the developmental process of 3D-printed temporal bone models. A brief review of the current literature shows that many of the key surgical landmarks of the temporal bone are poorly represented in models. This study aims to propose a novel design and production workflow to produce high-fidelity 3D-printed temporal bone models for surgical simulation. METHODS: Developmental phases for data extraction, 3D segmentation and Computer Aided Design (CAD), and fabrication are outlined. The design and fabrication considerations for key anatomical regions, such as the mastoid air cells and course of the facial nerve, are expounded on with the associated strategy and design methods employed. To validate the model, radiological measurements were compared and a senior otolaryngologist performed various surgical procedures on the model. RESULTS: Measurements between the original scans and scans of the model demonstrate sub-millimetre accuracy of the model. Assessment by the senior otologist found that the model was satisfactory in simulating multiple surgical procedures. CONCLUSION: This study offers a systematic method for creating accurate 3D-printed temporal bone models for surgical training. Results show high accuracy and effectiveness in simulating surgical procedures, promising improved training and patient outcomes.