A Neural Network Approach for Inertial Measurement Unit-Based Estimation of Three-Dimensional Spinal Curvature.

The spine is an important part of the human body. Thus, its curvature and shape are closely monitored, and treatment is required if abnormalities are detected. However, the current method of spinal examination mostly relies on two-dimensional static imaging, which does not provide real-time information on dynamic spinal behaviour. Therefore, this study explored an easier and more efficient method based on machine learning and sensors to determine the curvature of the spine. Fifteen participants were recruited and performed tests to generate data for training a neural network. This estimated the spinal curvature from the readings of three inertial measurement units and had an average absolute error of 0.261161 cm.

Prognostic implication of the neoadjuvant rectal score and other biomarkers of clinical outcome in Hong Kong Chinese patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiotherapy.

BACKGROUND: Neoadjuvant chemoradiotherapy is a standard treatment for locally advanced rectal cancer, for which pathological complete response is typically used as a surrogate survival endpoint. Neoadjuvant rectal score is a new biomarker that has been shown to correlate with survival. The main objectives of this study were to investigate factors contributing to pathological complete response, to validate the prognostic significance of neoadjuvant rectal score, and to investigate factors associated with a lower neoadjuvant rectal score in a cohort of Hong Kong Chinese. METHODS: Data of patients with locally advanced rectal cancer who received neoadjuvant chemoradiotherapy from August 2006 to October 2018 were retrieved from hospital records and retrospectively analysed. RESULTS: Of 193 patients who had optimal response to neoadjuvant chemoradiotherapy and surgery, tumour down-staging was the only independent prognostic factor that predicted pathological complete response (P<0.0001). Neoadjuvant rectal score was associated with overall survival (hazard ratio [HR]=1.042, 95% confidence interval [CI]=1.021-1.064; P<0.0001), disease-free survival (HR=1.042, 95% CI=1.022-1.062; P<0.0001), locoregional recurrence-free survival (HR=1.070, 95% CI=1.039-1.102; P<0.0001) and distant recurrence-free survival (HR=1.034, 95% CI=1.012-1.056; P=0.002). Patients who had pathological complete response were associated with a lower neoadjuvant rectal score (P<0.0001), but pathological complete response was not associated with survival. For patients with intermediate neoadjuvant rectal scores, late recurrences beyond 72 months from diagnosis were observed. CONCLUSION: Neoadjuvant rectal score is an independent prognostic marker of survival and disease recurrence in a cohort of Hong Kong Chinese patients who received neoadjuvant chemoradiotherapy for locally advanced rectal cancer.

New developments in defecatory studies based on biomechatronics.

Introduction: Defecation is a complex process that is difficult to study and analyze directly. In anorectal disease conditions, the defecation process may be disturbed, resulting in symptoms including fecal incontinence and constipation. Current state-of-the-art technology measures various aspects of anorectal function but detailed analysis is impossible because they are stand-alone tests rather than an integrated multi-dimensional test. Objectives: The need for physiologically-relevant and easy-to-use diagnostic tests for identifying underlying mechanisms is substantial. We aimed to advance the field with integrated technology for anorectal function assessment. Methods: We developed a simulated stool named Fecobionics that integrates several tests to assess defecation pressures, dimensions, shape, orientation and bending during evacuation. A novelty is that pressures are measured in axial direction, i.e. in the direction of the trajectory. Using this novel tool, we present new analytical methods to calculate physiologically relevant parameters during expulsion in normal human subjects. Results: Data are reported from 28 human subjects with progressively more advanced versions of Fecobionics. A new concept utilizes the rear-front pressure (preload-afterload) diagram for computation of novel defecation indices. Fecobionics obtained physiological data that cannot be obtained with current state-of-the-art technologies. Conclusion: Fecobionics measures well known parameters such as expulsion time and pressures as well as new metrics including defecation indices. The study suggests that Fecobionics is effective in evaluation of key defecatory parameters and well positioned as an integrated technology for assessment of anorectal function and dysfunction.

First nosocomial cluster of COVID-19 due to the Delta variant in a major acute care hospital in Singapore: investigations and outbreak response.

OBJECTIVES: The first large nosocomial cluster of coronavirus disease 2019 (COVID-19) in Singapore in April 2021 led to partial closure of a major acute care hospital. This study examined factors associated with infection among patients, staff and visitors; investigated the possible role of aerosol-based transmission; evaluated the effectiveness of BNT162.b2 and mRNA1273 vaccines; and described the successful containment of the cluster. METHODS: Close contacts of patients with COVID-19 and the affected ward were identified and underwent surveillance for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Patient, staff and visitor cohorts were constructed and factors associated with infection were evaluated. Phylogenetic analysis of patient samples was performed. Ward air exhaust filters were tested for SARS-CoV-2. RESULTS: In total, there were 47 cases, comprising 29 patients, nine staff, six visitors and three household contacts. All infections were of the Delta variant. Ventilation studies showed turbulent air flow and swabs from air exhaust filters were positive for SARS-CoV-2. Vaccine breakthrough infections were seen in both patients and staff. Among patients, vaccination was associated with a 79% lower odds of infection with COVID-19 (adjusted odds ratio 0.21, 95% confidence interval 0.05-0.95). CONCLUSIONS: This cluster occurred despite enhancement of infection control measures that the hospital had undertaken at the onset of the COVID-19 pandemic. It was brought under control rapidly through case isolation, extensive contact tracing and quarantine measures, and led to enhanced use of hospital personal protective equipment, introduction of routine rostered testing of inpatients and staff, and changes in hospital infrastructure to improve ventilation within general wards.

Fecobionics assessment of the effect of position on defecatory efficacy in normal subjects.

BACKGROUND: Defecation is a complex process and up to 25% of the population suffer from symptoms of defecatory dysfunction. For functional testing, diagnostics, and therapy of anorectal disorders, it is important to know the optimal defecation position. is The aim of this study was to evaluate defecation pressure patterns in side lying, seated and squatting defecation positions in normal subjects using a simulated stool device called Fecobionics. METHODS: The Fecobionics expulsion parameters were assessed in an interventional study design conducted from May 29 to December 9 2019. Subjects were invited to participate in the study through advertisement at The Chinese University of Hong Kong. The Fecobionics device consisted of a core containing pressure sensors at the front (caudal end) and rear (cranial end) and a polyester-urethane bag spanning most of the core length which also contained sensors. The Fecobionics bag was distended to 50 ml in the rectum of normal subjects (no present and past symptoms of defecatory disorders, no prior abdominal surgery, medication or chronic diseases). Studies were done in side lying (left lateral recumbent position), seated (hip flexed 90°) and squatting position (hip flexed 25°). Pressure endpoints including the rear-front pressure diagram and defecation indices were compared between positions. RESULTS: Twelve subjects (6 females/6 males, mean age 26.3 ± 2.6 [19.0-48.0] years) were included and underwent the planned procedures. The resting anal pressure for side lying and seated positions were 33.1 ± 4.1 cmH2O and 37.1 ± 4.0 cmH2O (p > 0.3). The anal squeeze pressure for side lying and seated positions were 98.4 ± 6.9 cmH2O and 142.3 ± 16.4 cmH2O (p < 0.05). The expulsion duration for the side lying, seated and squatting positions were 108.9 ± 8.3 s, 15.0 ± 2.1 s and 16.1 ± 2.9 s, respectively (p < 0.01 between lying and the two other positions). The maximum evacuation pressure for seated and squatting were 130.1 ± 12.4 cmH2O and 134.0 ± 11.1 cmH2O (p > 0.5). Rear-front pressure diagrams and distensibility indices demonstrated distinct differences in pressure patterns between the side lying position group and the other positions. CONCLUSIONS: The delay in expelling the Fecobionics device in the lying position was associated with dyssynergic pressure patterns on the device. Quantitative differences were not found between the seated and squatting position. Trial Registration http://www.clinicaltrials.gov Identifier: NCT03317938.

Influenza vaccine failure in the tropics: a retrospective cohort study of waning effectiveness.

Influenza vaccine effectiveness (VE) wanes over the course of a temperate climate winter season but little data are available from tropical countries with year-round influenza virus activity. In Singapore, a retrospective cohort study of adults vaccinated from 2013 to 2017 was conducted. Influenza vaccine failure was defined as hospital admission with polymerase chain reaction-confirmed influenza infection 2-49 weeks after vaccination. Relative VE was calculated by splitting the follow-up period into 8-week episodes (Lexis expansion) and the odds of influenza infection in the first 8-week period after vaccination (weeks 2-9) compared with subsequent 8-week periods using multivariable logistic regression adjusting for patient factors and influenza virus activity. Records of 19 298 influenza vaccinations were analysed with 617 (3.2%) influenza infections. Relative VE was stable for the first 26 weeks post-vaccination, but then declined for all three influenza types/subtypes to 69% at weeks 42-49 (95% confidence interval (CI) 52-92%, P = 0.011). VE declined fastest in older adults, in individuals with chronic pulmonary disease and in those who had been previously vaccinated within the last 2 years. Vaccine failure was significantly associated with a change in recommended vaccine strains between vaccination and observation period (adjusted odds ratio 1.26, 95% CI 1.06-1.50, P = 0.010).

Beyond neurotransmission: acetylcholine in immunity and inflammation.

Acetylcholine (ACh) is best known as a neurotransmitter and was the first such molecule identified. ACh signalling in the neuronal cholinergic system has long been known to regulate numerous biological processes (reviewed by Beckmann and Lips). In actuality, ACh is a ubiquitous signalling molecule that is produced by numerous non-neuronal cell types and even by some single-celled organisms. Within multicellular organisms, a non-neuronal cholinergic system that includes the immune system functions in parallel with the neuronal cholinergic system. Several immune cell types both respond to ACh signals and can directly produce ACh. Recent work from our laboratory has demonstrated that the capacity to produce ACh is an intrinsic property of T cells responding to viral infection, and that this ability to produce ACh is dependent upon IL-21 signalling to the T cells. Furthermore, during infection this immune-derived ACh is necessary for the T cells to migrate into infected tissues. In this review, we will discuss the various sources of ACh that are relevant during immune responses and describe how ACh acts on immune cells to influence their functions. We will also address the clinical implications of this fascinating aspect of immunity, focusing on ACh's role in the migration of T cells during infection and cancer.

Poisoning by toxic plants in Hong Kong: a 15-year review.

INTRODUCTION: Hong Kong has a great diversity of plants, many of which are toxic to humans. The aim of this study was to identify the plant species most commonly involved in cases of plant poisoning in Hong Kong and to provide clinicians with a reference tool for the diagnosis and management of plant poisoning. METHODS: We retrospectively reviewed all plant poisoning cases referred to the Hospital Authority Toxicology Reference Laboratory from 1 January 2003 to 31 December 2017. Demographics, clinical presentation, laboratory findings, treatment and outcomes of patients, as well as morphological identification and analytical testing of the plant specimens, were investigated. RESULTS: A total of 62 cases involving 26 poisonous plant species were identified, among which Alocasia macrorrhizos (Giant Alocasia), Gelsemium elegans (Graceful Jessamine), and Rhododendron (Azalea) species were the three most commonly encountered. Gastrointestinal toxicity (n=30, 48%), neurological toxicity (n=22, 35%), and hepatotoxicity (n=6, 10%) were the three most common clinical problems. Forty-nine (79%) and eight (13%) patients had mild and moderate toxicity, respectively; they all recovered shortly with supportive treatment. The remaining five (8%) patients experienced severe toxicity requiring intensive care support. Most patients (n=61, 98%) used the plants intentionally: as a medicinal herb (n=31), as food (n=29), and for attempting suicide (n=1). Reasons for using the poisonous plants included misidentification (n=34, 55%), unawareness of the toxicity (n=20, 32%), and contamination (n=6, 10%). CONCLUSIONS: Although most plant exposure resulted in a self-limiting disease, severe poisonings were encountered. Epidemiology of plant poisonings is geographically specific. Clinicians should be aware of local poisonous plants and their toxicities.

Targeting the cell cycle in breast cancer: towards the next phase.

Deregulation of the cell cycle is a hallmark of cancer that enables limitless cell division. To support this malignant phenotype, cells acquire molecular alterations that abrogate or bypass control mechanisms in signaling pathways and cellular checkpoints that normally function to prevent genomic instability and uncontrolled cell proliferation. Consequently, therapeutic targeting of the cell cycle has long been viewed as a promising anti-cancer strategy. Until recently, attempts to target the cell cycle for cancer therapy using selective inhibitors have proven unsuccessful due to intolerable toxicities and a lack of target specificity. However, improvements in our understanding of malignant cell-specific vulnerabilities has revealed a therapeutic window for preferential targeting of the cell cycle in cancer cells, and has led to the development of agents now in the clinic. In this review, we discuss the latest generation of cell cycle targeting anti-cancer agents for breast cancer, including approved CDK4/6 inhibitors, and investigational TTK and PLK4 inhibitors that are currently in clinical trials. In recognition of the emerging population of ER+ breast cancers with acquired resistance to CDK4/6 inhibitors we suggest new therapeutic avenues to treat these patients. We also offer our perspective on the direction of future research to address the problem of drug resistance, and discuss the mechanistic insights required for the successful implementation of these strategies.

Disruption of the anaphase-promoting complex confers resistance to TTK inhibitors in triple-negative breast cancer.

TTK protein kinase (TTK), also known as Monopolar spindle 1 (MPS1), is a key regulator of the spindle assembly checkpoint (SAC), which functions to maintain genomic integrity. TTK has emerged as a promising therapeutic target in human cancers, including triple-negative breast cancer (TNBC). Several TTK inhibitors (TTKis) are being evaluated in clinical trials, and an understanding of the mechanisms mediating TTKi sensitivity and resistance could inform the successful development of this class of agents. We evaluated the cellular effects of the potent clinical TTKi CFI-402257 in TNBC models. CFI-402257 induced apoptosis and potentiated aneuploidy in TNBC lines by accelerating progression through mitosis and inducing mitotic segregation errors. We used genome-wide CRISPR/Cas9 screens in multiple TNBC cell lines to identify mechanisms of resistance to CFI-402257. Our functional genomic screens identified members of the anaphase-promoting complex/cyclosome (APC/C) complex, which promotes mitotic progression following inactivation of the SAC. Several screen candidates were validated to confer resistance to CFI-402257 and other TTKis using CRISPR/Cas9 and siRNA methods. These findings extend the observation that impairment of the APC/C enables cells to tolerate genomic instability caused by SAC inactivation, and support the notion that a measure of APC/C function could predict the response to TTK inhibition. Indeed, an APC/C gene expression signature is significantly associated with CFI-402257 response in breast and lung adenocarcinoma cell line panels. This expression signature, along with somatic alterations in genes involved in mitotic progression, represent potential biomarkers that could be evaluated in ongoing clinical trials of CFI-402257 or other TTKis.

Fundamental movement skills and balance of children with Down syndrome.

BACKGROUND: Conclusive evidence supports the importance of fundamental movement skills (FMS) proficiency in promoting physical activity and countering obesity. In children with Down Syndrome (DS), FMS development is delayed, which has been suggested to be associated with balance deficits. This study therefore examined the relationship between FMS proficiency and balance ability in children with DS, with the aim of contributing evidence to programmes that address FMS delay. METHODS: Participants consisted of 20 children with DS (7.1 ± 2.9 years old) and an age-matched control group of children with typical development (7.25 ± 2.5 years). In the first part of the study, FMS (i.e. locomotor and object control) proficiency of the children was tested using the Test of Gross Motor Development-2. Balance ability was assessed using a force platform to measure centre of pressure average velocity (AV; mm/sec), path length (mm), medio-lateral standard deviation (mm) and antero-posterior standard deviation (mm). In the second part of the study, children with DS participated in 5 weeks of FMS training. FMS proficiency and balance ability were tested post-training and compared to pre-training scores. Verbal and visuo-spatial short-term memory capacities were measured at pre-training to verify the role of working memory in skill learning. RESULTS: FMS proficiency was associated with centre of pressure parameters in children with DS but not in children with typical development. After controlling for age, AV was found to predict significant variance in locomotor (R2  = 0.61, P < 0.001) and object control (R2  = 0.69, P < 0.001) scores. FMS proficiency and mastery improved after FMS training, as did AV, path length and antero-posterior standard deviation (all P < 0.05). Verbal and visuo-spatial short-term memory did not interact with the effects of training. CONCLUSIONS: Children with DS who have better balance ability tend to have more proficient FMS. Skill-specific training improved not only FMS sub-skills but static balance stability as well. Working memory did not play a role in the changes caused by skills training. Future research should examine the causal relationship between balance and FMS.

Inhibition of the spindle assembly checkpoint kinase Mps-1 as a novel therapeutic strategy in malignant mesothelioma.

Malignant mesothelioma (MM) is an aggressive malignancy, highly resistant to current medical and surgical therapies, whose tumor cells characteristically show a high level of aneuploidy and genomic instability. We tested our hypothesis that targeting chromosomal instability in MM would improve response to therapy. Thr/Tyr kinase (TTK)/monopolar spindle 1 kinase (Mps-1) is a kinase of the spindle assembly checkpoint that controls cell division and cell fate. CFI-402257 is a novel, selective inhibitor of Mps-1 with antineoplastic activity. We found that CFI-402257 suppresses MM growth. We found that Mps-1 is overexpressed in MM and that its expression correlates with poor patients' outcome. In vitro, CFI-402257-mediated inhibition of Mps-1 resulted in abrogation of the mitotic checkpoint, premature progression through mitosis, marked aneuploidy and mitotic catastrophe. In vivo, CFI-402257 reduced MM growth in an orthotopic, syngeneic model, when used as a single agent, and more so when used in combination with cisplatin+pemetrexed, the current standard of care. Our preclinical findings indicate that CFI-402257 is a promising novel therapeutic agent to improve the efficacy of the current chemotherapeutic regimens for MM patients.

Robotic transanal surgery (RTAS) with utilization of a next-generation single-port system: a cadaveric feasibility study.

PURPOSE: Transanal surgery remains both an innovative approach to rectal pathology and a demonstrated technical challenge. Improved technology using a single-port system robotic platform (SPS) offers a promising option for this surgery. METHODS: SPS robotic system was utilized to perform submucosal, full-thickness and cylindrical excision on four cadavers. Operative performance and surgeon fatigue were measured. RESULTS: On all types of resections, the SPS system performed well. There were no piecemeal or fragmented resections. Closure was judged to be good to excellent in all cases. Surgeon assessment of setup and performance of the SPS was excellent in all cases. CONCLUSIONS: SPS robotic transanal surgery represents an exciting new option for transanal surgery.

MOB1-YAP1/TAZ-NKX2.1 axis controls bronchioalveolar cell differentiation, adhesion and tumour formation.

Mps One Binder Kinase Activator (MOB)1A/1B are core components of the Hippo pathway. These proteins, which coactivate LArge Tumour Suppressor homologue kinases, are also tumour suppressors. To investigate MOB1A/B's roles in normal physiology and lung cancer, we generated doxycycline (Dox)-inducible, bronchioalveolar epithelium-specific, null mutations of MOB1A/B in mice (SPC-rtTA/(tetO)7-Cre/Mob1aflox/flox/Mob1b-/-; termed luMob1DKO mice). Most mutants (70%) receiving Dox in utero (luMob1DKO (E6.5-18.5) mice) died of hypoxia within 1 h post-birth. Their alveolar epithelial cells showed increased proliferation, impaired YAP1/TAZ-dependent differentiation and decreased surfactant protein production, all features characteristic of human respiratory distress syndrome. Intriguingly, mutant mice that received Dox postnatally (luMob1DKO (P21-41) mice) did not develop spontaneous lung adenocarcinomas, and urethane treatment-induced lung tumour formation was decreased (rather than increased). Lungs of luMob1DKO (P21-41) mice exhibited increased detachment of bronchiolar epithelial cells and decreased numbers of the bronchioalveolar stem cells thought to initiate lung adenocarcinomas. YAP1/TAZ-NKX2.1-dependent expression of collagen XVII, a key hemidesmosome component, was also reduced. Thus, a MOB1-YAP1/TAZ-NKX2.1 axis is essential for normal lung homeostasis and expression of the collagen XVII protein necessary for alveolar stem cell maintenance in the lung niche.

MALT1 is an intrinsic regulator of regulatory T cells.

Regulatory T cells (Tregs) are crucial for the maintenance of immunological self-tolerance and their absence or dysfunction can lead to autoimmunity. However, the molecular pathways that govern Treg biology remain obscure. In this study, we show that the nuclear factor-κB signalling mediator mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is an important novel regulator of both Tregs originating in the thymus ('natural' or nTregs) and Tregs induced to differentiate from naive thymocyte helper (Th) cells in the periphery ('induced' or iTregs). Our examination of mice deficient for MALT1 revealed that these mutants have a reduced number of total Tregs. In young Malt1-/- mice, nTregs are totally absent and iTreg are diminished in the periphery. Interestingly, total Treg numbers increase in older Malt1-/- mice as well as in Malt1-/- mice subjected to experimentally induced inflammation. iTregs isolated from WT and Malt1-/- mice were indistinguishable with respect to their ability to suppress the activities of effector T cells, but Malt1-/- iTregs expressed higher levels of Toll-like receptor (TLR) 2. Treatment of WT and Malt1-/- Th cells in vitro with the TLR2 ligand Pam3Cys strongly enhanced the induction and proliferation of Malt1-/- iTregs. Our data suggest that MALT1 supports nTreg development in the thymus but suppresses iTreg induction in the periphery during inflammation. Our data position MALT1 as a key molecule that contributes to immune tolerance at steady-state while facilitating immune reactivity under stress conditions.

Urban food consumption and associated water resources: The example of Dutch cities.

Full self-sufficiency in cities is a major concern. Cities import resources for food, water and energy security. They are however key to global sustainability, as they concentrate a rapidly increasing and urbanising population (or number of consumers). In this paper, we analysed the dependency of urban inhabitants on the resource water for food consumption, by means of Dutch cities. We found that in extremely urbanised municipalities like Amsterdam and Rotterdam, people eat more meat and cereals and less potatoes than in other Dutch municipalities. Their current water footprint (WF) related to food consumption is therefore higher (3245l/cap/day) than in strongly urbanised cities (3126l/cap/day). Dutch urban citizens who eat too many animal products, crop oils and sugar can reduce their WF (with 29 to 32%) by shifting to a healthier diet. Recommended less meat consumption has the largest impact on the total WF reduction. A shift to a pesco-vegetarian or vegetarian diet would require even less water resources, where the WF can be reduced by 36 to 39% and 40 to 42% respectively. Dutch cities such as Amsterdam have always scored very high in international sustainability rankings for cities, partly due to a long history in integrated (urban) water management in the Netherlands. We argue that such existing rankings only show a certain - undoubtedly very important - part of urban environmental sustainability. To communicate the full picture to citizens, stakeholders and policy makers, indicators on external resource usage need to be employed. The fact that external resource dependency can be altered through changing dietary behaviour should be communicated.