Tumor resistance to anti-mesothelin CAR-T cells caused by binding to shed mesothelin is overcome by targeting a juxtamembrane epitope.

Despite many clinical trials, CAR-T cells are not yet approved for human solid tumor therapy. One popular target is mesothelin (MSLN) which is highly expressed on the surface of about 30% of cancers including mesothelioma and cancers of the ovary, pancreas, and lung. MSLN is shed by proteases that cleave near the C terminus, leaving a short peptide attached to the cell. Most anti-MSLN antibodies bind to shed MSLN, which can prevent their binding to target cells. To overcome this limitation, we developed an antibody (15B6) that binds next to the membrane at the protease-sensitive region, does not bind to shed MSLN, and makes CAR-T cells that have much higher anti-tumor activity than a CAR-T that binds to shed MSLN. We have now humanized the Fv (h15B6), so the CAR-T can be used to treat patients and show that h15B6 CAR-T produces complete regressions in a hard-to-treat pancreatic cancer patient derived xenograft model, whereas CAR-T targeting a shed epitope (SS1) have no anti-tumor activity. In these pancreatic cancers, the h15B6 CAR-T replicates and replaces the cancer cells, whereas there are no CAR-T cells in the tumors receiving SS1 CAR-T. To determine the mechanism accounting for high activity, we used an OVCAR-8 intraperitoneal model to show that poorly active SS1-CAR-T cells are bound to shed MSLN, whereas highly active h15B6 CAR-T do not contain bound MSLN enabling them to bind to and kill cancer cells.

Association of Pharmacist Interventions With Adverse Drug Events and Potential Adverse Drug Events.

BACKGROUND: Adverse drug events (ADEs) are a frequent cause of injury in patients. Our aim was to assess whether pharmacist interventions compared with no pharmacist intervention results in reduced ADEs and potential adverse drug events (PADEs). METHODS: We searched MEDLINE, Embase, and two other databases through September 19, 2022 for any RCT assessing the effect of a pharmacist intervention compared with no pharmacist intervention and reporting on ADEs or PADEs. The risk of bias was assessed using the Cochrane tool for RCTs. A random-effects model was used to pool summary results from individual RCTs. RESULTS: Fifteen RCTs met the inclusion criteria. The pooled results showed a statistically significant reduction in ADE associated with pharmacist intervention compared with no pharmacist intervention (RR = 0.86; [95% CI 0.80-0.94]; p = 0.0005) but not for PADEs (RR = 0.79; [95% CI 0.47-1.32]; p = 0.37). The heterogeneity was insignificant (I2 = 0%) for ADEs and substantial (I2 = 77%) for PADEs. Patients receiving a pharmacist intervention were 14% less likely for ADE than those who did not receive a pharmacist intervention. The estimated number of patients needed to prevent one ADE across all patient locations was 33. CONCLUSIONS: To our knowledge, this is the first systematic review and meta-analysis of RCTs seeking to understand the association of pharmacist interventions with ADEs and PADEs. The risk of having an ADE is reduced by a seventh for patients receiving a pharmacist care intervention versus no such intervention. The estimated number of patients needed to be followed across all patient locations to prevent one preventable ADE across all patient locations is 33.

Identifying factors associated with post-hospital falls in older patients: a territory-wide cohort study.

OBJECTIVES: Post-hospital falls impose a substantial healthcare burden on older adults, yet contributing factors remain inadequately examined. This study aimed to investigate underinvestigated factors associated with post-hospital falls. STUDY DESIGN: Retrospective territory-wide cohort study. METHODS: We examined the electronic medical records of patients aged ≥65 who were discharged from public hospitals in Hong Kong (2007-2018). During the 12 months following discharge, participants were monitored to identify falls based on diagnosis codes or clinical notes from inpatient episodes, the emergency department (ED) visits, and death records. Falls were categorized into two groups: those only requiring ED visits and those requiring hospitalizations. Binary logistic and multinomial logistic regressions examined the associated factors for post-hospital falls and subcategories of falls, respectively. RESULTS: Among 606,392 older patients, 28,593 (4.71%; 95% CI = 4.66%-4.77%) experienced falls within 12 months after discharge. Of those, 8438 (29.5%) only required ED visits, and 20,147 (70.5%) required hospitalizations. Discharge from non-surgical wards, length of stay over two weeks, receiving the Geriatric Day Hospital and Rehabilitation Day Program, advancing age, being female, having more comorbidities, taking more fall risk increasing drugs, previous admission for falls, and living in Hong Kong Island were associated with increased fall risk. Receiving allied health service or nurse service was associated with reduced risk. The same factors were more associated with falls requiring hospitalizations rather than falls only requiring ED visits. CONCLUSIONS: Older patients with identified factors were particularly vulnerable to post-hospital falls leading to rehospitalizations. Fall risk assessment and tailored prevention should prioritize this group.

Improved responsiveness to change in joint space width over 24-month follow-up: comparison of 3D JSW on weight-bearing CT vs 2D JSW on radiographs in the MOST study.

OBJECTIVE: Radiographic joint space width (JSW) has been a standard for measuring knee osteoarthritis (OA) structural change. Limitations in the responsiveness of this approach might be overcome by instead measuring 3D JSW on weight-bearing CT (WBCT). This study compared the responsiveness of 3D JSW measurements using WBCT with the responsiveness of radiographic 2D JSW. DESIGN: Standing, fixed-flexion knee radiographs (XR) and WBCT were acquired ancillary to the 144- and 168-month Multicenter Osteoarthritis Study visits. Tibiofemoral JSW was measured on both XR and WBCT. Responsiveness to change was defined by the standardized response mean (SRM) for change in JSW (1) at predetermined mediolateral locations (JSWx) on both modalities and (2) in the following subregions measured on WBCT images: central medial and lateral femur (CMF/CLF) and tibia (CMT/CLT), and anterior and posterior tibia (AMT/ALT, PMT/MLT). RESULTS: Baseline and 24-month follow-up JSWx measurements were completed for 265 participants (58.1% women). Responsiveness of 3D JSWx for medial tibiofemoral compartment on coronal WBCT (SRM range: -0.18, -0.24) exceeded that for 2D JSWx (-0.10, -0.16). Responsiveness of 3D JSW subregional mean (-0.06, -0.36) and maximal (-1.14, -1.75) CMF and CMT and maximal CLF/CLT 3D JSW changes were statistically significantly greater in comparison with respective medial and lateral 2D JSWx (P ≤ 0.002). CONCLUSIONS: Subregional 3D JSW on WBCT is substantially more responsive to 24-month changes in tibiofemoral joint structure compared to radiographic measurements. Use of subregional 3D JSW on WBCT could enable improved detection of OA structural progression over a 24-month duration in comparison with measurements made on XR.

Role of foetal kidney size on kidney function in childhood: the born in bradford cohort renal study.

BACKGROUND: Foetal and early childhood development contributes to the risk of adult non-communicable diseases such as hypertension and cardiovascular disease. We aimed to investigate whether kidney size at birth is associated with markers of kidney function at 7-11 years. METHODS: Foetal kidney dimensions were measured using ultrasound scans at 34 weeks gestation and used to derive kidney volume (cm3) in 1802 participants in the Born in Bradford (BiB) birth cohort. Blood and urine samples were taken from those who participated in the BiB follow-up at 7-11 years (n = 630) and analysed for serum creatinine, cystatin C, urea, and urinary albumin to creatinine ratio (ACR), protein to creatinine ratio (PCR) and retinol binding protein (RBP). Estimated glomerular filtration rate (eGFR) was calculated using Schwartz creatinine only and combined with cystatin C, and cystatin C only Zappitelli and Filler equations. Linear regression was used to examine the association between foetal kidney volume and eGFR, ACR, PCR and blood pressure, unadjusted and adjusted for confounders. RESULTS: Kidney volume was positively associated in adjusted models with eGFR calculated using Schwartz combined (0.64 ml/min diff per unit increase in volume, 95% CI 0.25 to 1.02), Zappitelli (0.79, 95% CI 0.38 to 1.20) and Filler (2.84, 95% CI 1.40 to 4.28). There was an association with the presence of albuminuria but not with its level, or with other urinary markers or with blood pressure. CONCLUSION: Foetal kidney volume was associated with small increases in eGFR in mid-childhood. Longitudinal follow-up to investigate the relationship between kidney volume and markers of kidney function as children go through puberty is required.

Comparison of United Kingdom and United States screening criteria for detecting retinopathy of prematurity in Hong Kong.

INTRODUCTION: We examined whether the United Kingdom (UK) or the United States (US) screening criteria are more appropriate for retinopathy of prematurity (ROP) screening in Hong Kong, in terms of sensitivity for detecting type 1 ROP and the number of infants requiring screening. METHODS: In this retrospective cohort study, we reviewed the medical records of all infants who underwent ROP screening from 2009 to 2018 at a tertiary hospital in Hong Kong. During this period, all infants born at gestational age (GA) ≤31 weeks and 6 days or birth weight (BW) <1501 g (ie, the UK screening criteria) underwent ROP screening. We determined the number of infants requiring screening and the number of type 1 ROP cases that would have been missed if the US screening criteria (GA ≤30 weeks & 0 days or BW ≤1500 g) had been used. RESULTS: Overall, 796 infants were screened using the UK screening criteria. If the US screening criteria had been used, the number of infants requiring screening would have decreased by 21.1%; all type 1 ROP cases would have been detected (38/38, 100% sensitivity). Of the 168 infants who would not have been screened using the US screening criteria, only four of them (2.4%) had developed ROP (all maximum stage 1 only). CONCLUSION: In our population, the use of the US screening criteria could reduce the number of infants screened without compromising sensitivity for the detection of type 1 ROP requiring treatment. We suggest narrowing the GA criterion for consistency with the US screening criteria during ROP screening in Hong Kong.

The effect of polymorphisms in FSHR gene on late follicular phase progesterone and estradiol serum levels in predicted normoresponders.

STUDY QUESTION: Does the presence of FSHR single-nucleotide polymorphisms (SNPs) affect late follicular phase progesterone and estradiol serum levels in predicted normoresponders treated with rFSH? SUMMARY ANSWER: The presence of FSHR SNPs (rs6165, rs6166, rs1394205) had no clinically significant impact on late follicular phase serum progesterone and estradiol levels in predicted normoresponders undergoing a GnRH antagonist protocol with a fixed daily dose of 150 IU rFSH. WHAT IS KNOWN ALREADY: Previous studies have shown that late follicular phase serum progesterone and estradiol levels are significantly correlated with the magnitude of ovarian response. Several authors have proposed that individual variability in the response to ovarian stimulation (OS) could be explained by variants in FSHR. However, so far, the literature is scarce on the influence of this genetic variability on late follicular phase steroidogenic response. Our aim is to determine whether genetic variants in the FSHR gene could modulate late follicular phase serum progesterone and estradiol levels. STUDY DESIGN, SIZE, DURATION: In this multicenter multinational prospective study conducted from November 2016 to June 2019, 366 patients from Vietnam, Belgium and Spain (166 from Europe and 200 from Asia) underwent OS followed by oocyte retrieval in a GnRH antagonist protocol with a fixed daily dose of 150 IU rFSH. All patients were genotyped for 3 FSHR SNPs (rs6165, rs6166, rs1394205) and had a serum progesterone and estradiol measurement on the day of trigger. PARTICIPANTS/MATERIALS, SETTING, METHODS: Included patients were predicted normal responder women <38 years old undergoing their first or second OS cycle. The prevalence of late follicular phase progesterone elevation (PE), as well as mean serum progesterone and estradiol levels on the day of trigger were compared between the different FSHR SNPs genotypes. PE was defined as >1.50 ng/ml. MAIN RESULTS AND THE ROLE OF CHANCE: The overall prevalence of PE was 15.8% (n = 58). No significant difference was found in the prevalence of PE in Caucasian and Asian patients (17.5% versus 14.5%). Estradiol levels on the day of trigger and the number of retrieved oocytes were significantly higher in patients with PE (4779 ± 6236.2 versus 3261 ± 3974.5 pg/ml, P = 0.003, and 16.1 ± 8.02 versus 13.5 ± 6.66, P = 0.011, respectively). Genetic model analysis, adjusted for patient age, body mass index, number of retrieved oocytes and continent (Asia versus Europe), revealed a similar prevalence of PE in co-dominant, dominant and recessive models for variants FSHR rs6166, rs6165 and rs1394205. No statistically significant difference was observed in the mean late follicular phase progesterone serum levels according to the genotypes of FSHR rs6166 (P = 0.941), rs6165 (P = 0.637) and rs1394205 (P = 0.114) in the bivariate analysis. Also, no difference was found in the genetic model analysis regarding mean late follicular phase progesterone levels across the different genotypes. Genetic model analysis has also revealed no statistically significant difference regarding mean estradiol levels on the day of trigger in co-dominant, dominant and recessive models for variants FSHR rs6166, rs6165 and rs1394205. Haplotype analysis revealed a statistically significant lower estradiol level on the day of trigger for rs6166/rs6165 haplotypes GA, AA and GG when compared to AG (respectively, estimated mean difference (EMD) -441.46 pg/ml (95% CI -442.47; -440.45), EMD -673.46 pg/ml (95% CI -674.26; -672.67) and EMD -582.10 pg/ml (95% CI -584.92; -579.28)). No statistically significant differences were found regarding the prevalence of PE nor late follicular phase progesterone levels according to rs6166/rs6165 haplotypes. LIMITATIONS, REASONS FOR CAUTION: Results refer to a population of predicted normal responders treated with a normal/low fixed dose of 150 IU rFSH throughout the whole OS. Consequently, caution is needed before generalizing our results to all patient categories. WIDER IMPLICATIONS OF THE FINDINGS: Based on our results, FSHR SNPs rs6165, rs6166 and rs1394205 do not have any clinically significant impact neither on late follicular phase serum progesterone nor on estradiol levels in predicted normal responders. These findings add to the controversy in the literature regarding the impact of individual genetic susceptibility in response to OS in this population. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by an unrestricted grant by Merck Sharp & Dohme (MSD, IISP56222). N.P.P. reports grants and/or personal fees from MSD, Merck Serono, Roche Diagnostics, Ferring International, Besins Healthcare, Gedeon Richter, Organon, Theramex and Institut Biochimique SA (IBSA). C.A. reports conference fees from Merck Serono, Medea and Event Planet. A.R.N., C.B., C.S., P.Q.M.M., H.T., C.B., N.L.V., M.T.H. and S.G. report no conflict of interests related to the content of this article. TRIAL REGISTRATION NUMBER: NCT03007043.

The effect of polymorphisms in FSHR and FSHB genes on ovarian response: a prospective multicenter multinational study in Europe and Asia.

STUDY QUESTION: Does the presence of single nucleotide polymorphisms (SNPs) in the FSH receptor gene (FSHR) and/or FSH beta subunit-encoding gene (FSHB) influence ovarian response in predicted normal responders treated with rFSH? SUMMARY ANSWER: The presence of FSHR SNPs (rs6165, rs6166, rs1394205) has a statistically significant impact in ovarian response, although this effect is of minimal clinical relevance in predicted normal responders treated with a fixed dose of 150 IU rFSH. WHAT IS KNOWN ALREADY: Ovarian reserve markers have been a breakthrough in response prediction following ovarian stimulation. However, a significant percentage of patients show a disproportionate lower ovarian response, as compared with their actual ovarian reserve. Studies on pharmacogenetics have demonstrated a relationship between FSHR or FSHB genotyping and drug response, suggesting a potential effect of individual genetic variability on ovarian stimulation. However, evidence from these studies is inconsistent, due to the inclusion of patients with variable ovarian reserve, use of different starting gonadotropin doses, and allowance for dose adjustments during treatment. This highlights the necessity of a well-controlled prospective study in a homogenous population treated with the same fixed protocol. STUDY DESIGN, SIZE, DURATION: We conducted a multicenter multinational prospective study, including 368 patients from Vietnam, Belgium, and Spain (168 from Europe and 200 from Asia), from November 2016 until June 2019. All patients underwent ovarian stimulation followed by oocyte retrieval in an antagonist protocol with a fixed daily dose of 150 IU rFSH until triggering. Blood sampling and DNA extraction was performed prior to oocyte retrieval, followed by genotyping of four SNPs from FSHR (rs6165, rs6166, rs1394205) and FSHB (rs10835638). PARTICIPANTS/MATERIALS, SETTING, METHODS: Eligible were predicted normal responder women <38 years old undergoing their first or second ovarian stimulation cycle. Laboratory staff and clinicians were blinded to the clinical results and genotyping, respectively. The prevalence of hypo-responders, the number of oocytes retrieved, the follicular output rate (FORT), and the follicle to oocyte index (FOI) were compared between different FSHR and FSHB SNPs genotypes. MAIN RESULTS AND THE ROLE OF CHANCE: The prevalence of derived allele homozygous SNPs in the FSHR was rs6166 (genotype G/G) 15.8%, rs6165 (genotype G/G) 34.8%, and rs1394205 (genotype A/A) 14.1%, with significant differences between Caucasian and Asian women (P < 0.001). FSHB variant rs10835638 (c.-211 G>T) was very rare (0.5%). Genetic model analysis revealed that the presence of the G allele in FSHR variant rs6166 resulted in less oocytes retrieved when compared to the AA genotype (13.54 ± 0.46 vs 14.81 ± 0.61, estimated mean difference (EMD) -1.47 (95% CI -2.82 to -0.11)). In FSHR variant rs1394205, a significantly lower number of oocytes was retrieved in patients with an A allele when compared to G/G (13.33 ± 0.41 vs 15.06 ± 0.68, EMD -1.69 (95% CI -3.06 to -0.31)). A significantly higher prevalence of hypo-responders was found in patients with the genotype A/G for FSHR variant rs6166 (55.9%, n = 57) when compared to A/A (28.4%, n = 29), ORadj 1.87 (95% CI 1.08-3.24). No significant differences were found regarding the FORT across the genotypes for FSHR variants rs6166, rs6165, or rs1394205. Regarding the FOI, the presence of the G allele for FSHR variant rs6166 resulted in a lower FOI when compared to the A/A genotype, EMD -13.47 (95% CI -22.69 to -4.24). Regarding FSHR variant rs6165, a lower FOI was reported for genotype A/G (79.75 ± 3.35) when compared to genotype A/A (92.08 ± 6.23), EMD -13.81 (95% CI -25.41 to -2.21). LIMITATIONS, REASONS FOR CAUTION: The study was performed in relatively young women with normal ovarian reserve to eliminate biases related to age-related fertility decline; thus, caution is needed when extrapolating results to older populations. In addition, no analysis was performed for FSHB variant rs10835638 due to the very low prevalence of the genotype T/T (n = 2). WIDER IMPLICATIONS OF THE FINDINGS: Based on our results, genotyping FSHR SNPs rs6165, rs6166, rs1394205, and FSHB SNP rs10835638 prior to initiating an ovarian stimulation with rFSH in predicted normal responders should not be recommended, taking into account the minimal clinical impact of such information in this population. Future research may focus on other populations and other genes related to folliculogenesis or steroidogenesis. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by an unrestricted grant by Merck Sharp & Dohme (MSD). N.P.P. reports grants and/or personal fees from MSD, Merck Serono, Roche Diagnostics, Ferring International, Besins Healthcare, Gedeon Richter, Theramex, and Institut Biochimique SA (IBSA). N.L.V. and M.T.H. report consultancy and conference fees from Merck, Ferring, and MSD, outside the submitted work. P.D. has received honoraria for lecturing and/or research grants from MSD, Ferring International, and Merck. D.S. reports grants and/or personal fees from MSD, Ferring International, Merck Serono, Cook, and Gedeon Richter. A.R.N., B.A.M., C.S., J.M., L.H.L., P.Q.M.M., H.T., and S.G. report no conflict of interests. TRIAL REGISTRATION NUMBER: NCT03007043.

Clinical and molecular characterization study of Chinese Kabuki syndrome in Hong Kong.

Kabuki syndrome (OMIM #147920 and 300867) is a rare genetic disorder characterized by a distinctive facial gestalt, intellectual disability and multiple congenital anomalies. We summarized the clinical features and molecular findings of the Kabuki syndrome (KS) patients diagnosed in Hong Kong between January 1991 and December 2019. There were 21 molecularly confirmed KS. Twenty of them were due to pathogenic KMT2D variants and one patient had KDM6A deletion. Nine KMT2D variants were novel. The clinical phenotype of our Chinese KS patients was largely comparable with that reported in patients of other ethnicities. This study expands the mutation spectrum but also provide important natural history information of Chinese KS in literature.

Impact of weight management nutrition interventions on dietary outcomes in children and adolescents with overweight or obesity: a systematic review with meta-analysis.

BACKGROUND: The impact of obesity interventions on dietary intake in children and adolescents with overweight or obesity is unclear. This systematic review aimed to investigate the impact of the dietary component of weight management interventions on the change in diet in children and adolescents with overweight or obesity. METHODS: Eligible randomised controlled trials (RCTs) published between 1975 and 2020 were identified by a systematic search following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Meta-analyses of eligible study outcomes were performed using statistical software. A multilevel random effects model was used with three significant random effects fitted using restricted maximum likelihood estimation. RESULTS: This review identified 109 RCTs, including 95 that reported at least one statistically significant dietary outcome change and 14 reporting no significant dietary change. Results from the meta-analyses (n = 29 studies) indicated that, compared to control groups, intervention groups achieved significantly greater reductions in mean total energy intake at ≤6 months (-194 kcal day-1 , 95% confidence interval = -275.80 to -112.90 kcal day-1 , P < 0.001) and up to 12 months (-112 kcal day-1 95% confidence interval = -218.92 to -5.83 kcal day-1 ) P = 0.038), increases in fruit and/or vegetable intakes over 2-12 months (n = 34, range +0.6 to +1.5 servings day-1 ) and reductions in consumption of sugar-sweetened beverages (n = 28, range -0.25 to -1.5 servings day-1 ) at 4-24 months follow-up. CONCLUSIONS: Obesity interventions with a dietary component have a modest but sustained impact on reducing total energy intake and improving intakes of specific food groups in children and adolescents with overweight or obesity. High quality RCTs that are powered to detect change in diet as a primary outcome are warranted.

Noisy Preprocessing Facilitates a Photonic Realization of Device-Independent Quantum Key Distribution.

Device-independent quantum key distribution provides security even when the equipment used to communicate over the quantum channel is largely uncharacterized. An experimental demonstration of device-independent quantum key distribution is however challenging. A central obstacle in photonic implementations is that the global detection efficiency, i.e., the probability that the signals sent over the quantum channel are successfully received, must be above a certain threshold. We here propose a method to significantly relax this threshold, while maintaining provable device-independent security. This is achieved with a protocol that adds artificial noise, which cannot be known or controlled by an adversary, to the initial measurement data (the raw key). Focusing on a realistic photonic setup using a source based on spontaneous parametric down conversion, we give explicit bounds on the minimal required global detection efficiency.

Phenotypic and mutational spectrum of 21 Chinese patients with Alström syndrome.

Alström syndrome (AS) is a monogenic syndromic ciliopathy caused by mutations in the ALMS1 (Alström Syndrome 1) gene. A total of 21 subjects with AS from 20 unrelated Chinese families were recruited. Our cohort consists of 9 females and 12 males, between 5 months and 20 years old. The first symptom(s) appeared between 3 and 24 months. They were recorded to be either visual impairments (83%) or dilated cardiomyopathy (17%). Median time from symptom onset to seeking medical attention was 6 months (3-36 months) and the median time needed to reach the final molecular diagnosis is 54 months (6-240 months). System involvement at the time of the survey was as follows: visual symptoms (100%), hearing Impairment (67%), endocrine symptoms (43%), neurological symptoms (19%), hepatic symptoms (14%), and renal Involvement (14%). These findings are comparable to data reported in the literature. However, the proportion of subjects with cognitive impairment (33%) and behavioral problems (19%) were higher. Thirty-three unique mutations were identified in the ALMS1 gene, of which 18 are novel mutations classified as pathogenic/likely pathogenic according to the American College of Medical Genetics (ACMG) guideline. Four recurrent mutations were identified in the cohort, in particular; c.2084C>A, p. (Ser695Ter), is suggestive to be a founder mutation in people of Chinese ancestry. The participation of AS subjects of differing ethnicities is essential to improve the algorithm in facial recognition/phenotyping, as well as to understand the mutation spectrum beyond than just those of European ancestry.

National risk prediction model for perioperative mortality in non-cardiac surgery.

BACKGROUND: Many multivariable models to calculate mortality risk after surgery are limited by insufficient sample size at development or by application to cohorts distinct from derivation populations. The aims of this study were to validate the Surgical Outcome Risk Tool (SORT) for a New Zealand population and to develop an extended NZRISK model to calculate 1-month, 1-year and 2-year mortality after non-cardiac surgery. METHODS: Data from the New Zealand National Minimum Data Set for patients having surgery between January 2013 and December 2014 were used to validate SORT. A random 75 per cent split of the data was used to develop the NZRISK model, which was validated in the other 25 per cent of the data set. RESULTS: External validation of SORT in the 360 140 patients who underwent surgery in the study period showed good discrimination (area under the receiver operating characteristic curve (AUROC) value of 0·906) but poor calibration (McFadden's pseudo-R2 0·137, calibration slope 5·32), indicating it was invalid in this national surgical population. Internal validation of the NZRISK model, which incorporates sex and ethnicity in addition to the variables used in SORT for 1-month, 1-year and 2-year outcomes, demonstrated excellent discrimination with AUROC values of 0·921, 0·904 and 0·895 respectively, and excellent calibration (McFadden's pseudo-R2 0·275, 0·308 and 0·312 respectively). Calibration slopes were 1·12, 1·02 and 1·02 respectively. CONCLUSION: The SORT performed poorly in this national population. However, inclusion of sex and ethnicity in the NZRISK model improved performance. Calculation of mortality risk beyond 30 days after surgery adds to the utility of this tool for shared decision-making.

ANTECEDENTES: Muchos modelos multivariados de estimación del riesgo de mortalidad después de la cirugía están limitados por haberse desarrollado a partir de tamaños muestrales insuficientes o por haberse aplicados a cohortes distintas de las poblaciones de derivación. Los objetivos de este estudio fueron validar el Surgical Outcome Risk Tool (SORT) para una población de Nueva Zelanda y desarrollar un modelo NZRISK extendido para calcular la mortalidad al mes y a los 1 y 2 años de una cirugía no cardíaca. MÉTODOS: Para validar el SORT se utilizó el Conjunto Mínimo Básico de Datos de Nueva Zelanda para los pacientes sometidos a cirugía entre enero de 2013 y diciembre de 2014. Se realizó una división aleatoria del 75% de los datos para desarrollar el modelo NZRISK que, posteriormente, se validó en el otro 25% del conjunto de datos. RESULTADOS: La validación externa de SORT en 360.140 pacientes intervenidos en el periodo analizado mostró una buena discriminación (área bajo las curvas de característica operativa del receptor (area under the receiver-operator characteristic curves (AUROC) 0,906)) pero con una mala calibración (pseudo-R2 de McFaddens 0,137 y pendiente de calibración 5,32), lo que indicaba que SORT no era válido para esta población quirúrgica nacional. La validación interna del modelo NZRISK, que incorpora el género y la etnia además de las variables utilizadas en el SORT, para los resultados al mes y a los 1 y 2 años demostró una excelente capacidad de discriminación con una AUROC de 0,921, 0,904, 0,895 respectivamente y una calibración excelente, con una pseudo-R2 de McFaddens de 0,275, 0,308 y 0,312 respectivamente. Las pendientes de calibración fueron de 1,12, 1,02 y 1,02, respectivamente. CONCLUSIÓN: El SORT no fue útil en esta población nacional. Sin embargo, la inclusión del género y la etnia en el modelo NZRISK mejoró sus resultados. El cálculo del riesgo de mortalidad más allá de 30 días después de la cirugía añade utilidad a esta herramienta para la toma de decisiones compartida.

Lycopene and tomato and risk of cardiovascular diseases: A systematic review and meta-analysis of epidemiological evidence.

BACKGROUND AND AIMS: Worldwide, cardiovascular diseases (CVDs) remains as the main cause of mortality. Observational studies supports an association between intake of tomato products or lycopene with a reduced CVDs risk. Our aim was to undertake a systematic review and meta-analysis of the evidence on the topic. METHODS: Medline, Web of Science, and Scopus were searched from inception until July 2017. We included longitudinal and cross-sectional studies reporting associations between lycopene and tomato consumption and cardiovascular morbidity and mortality among adult subjects. Random-effects models were used to determine the pooled effect sizes. RESULTS: Twenty-eight publications met our inclusion criteria and 25 studies provided quantitative data for meta-analysis. Results showed that individuals in the highest consumption category of, or with the highest serum concentration of, lycopene had significantly lower risk of stroke (hazard ratio (HR) 0.74, 0.62-0.89, p = 0.02; I2 = 32) and CVDs (HR 0.86, 0.77-0.95, p = 0.003; I2 = 0). In addition, individuals categorised in the highest serum concentration of lycopene also had significantly lower risk of mortality (HR 0.63, 0.49-0.81, p<0.001; I2 = 46). Lycopene was not significantly associated with myocardial infarction, while scarce evidence on the association of lycopene with atherosclerosis, congestive heart failure, or atrial fibrillation was evident. Evidence from three studies suggested that higher intakes of tomato were associated with non-significantly lower stroke, CVDs and CHD. CONCLUSIONS: This comprehensive meta-analysis suggests that high-intakes or high-serum concentration of lycopene are associated with significant reductions in the risk of stroke (26%), mortality (37%) and CVDs (14%).

Hierarchical measurement structure in the Women's Health Questionnaire: a confirmatory factor analysis.

Purpose: This study conducted confirmatory factor analysis (CFA) to examine the measurement structure of the Women's Health Questionnaire (WHQ) and how its components were organized. Methods: Participants were 448 postmenopausal women, with a mean age of 63.3 years. CFA was conducted to test how well several proposed measurement models fit the data. Results: The single-factor model performed poorly, indicating the presence of multiple factors. The model with seven correlated factors fit the data well, although the varying degrees of inter-factor correlations suggested grouping of similar factors. The hierarchical measurement structure, with seven first-order factors organized under two second-order factors of physical health and mental health functioning, demonstrated a good fit with the data (χ2(367) = 694.05, p < 0.001; root mean square error of approximation = 0.05; comparative fit index = 0.95) and a meaningful pattern. The Mental Health factor was represented by Depressed Mood, Anxiety/Fear, Memory/Concentration Problems, and Sleep Problems. The Physical Health factor was manifested mainly by Somatic Symptoms, Menstrual Symptoms, and Vasomotor Symptoms, and, to a lesser extent, also by Sleep Problems and Memory/Concentration Problems. Conclusion: Findings suggested that, in addition to a global index and subscale scores, the WHQ may produce summary scores of physical health and mental health functioning in evaluation of well-being among postmenopausal women.

Adults with autism are less proficient in identifying biological motion actions portrayed with point-light displays.

BACKGROUND: Whether individuals with autism spectrum disorder (ASD) have impairments with biological motion perception has been debated. The present study examined the ability to identify point-light-displayed (PLD) human actions in neurotypical (NT) adults and adults with ASD. METHOD: Twenty-seven adults with ASD (mean age = 28.36) and 30 NT adults (mean age = 22.45) were tested. Both groups viewed 10 different biological motion actions contacting an object/tool and 10 without making contact. Each action was presented twice, and participant's naming responses and reaction times were recorded. RESULTS: The ASD group had a significantly lower total number of correct items (M = 29.30 ± 5.08 out of 40) and longer response time (M = 4550 ± 1442 ms) than NT group (M = 32.77 ± 2.78; M = 3556 ± 1148 ms). Both groups were better at naming the actions without objects (ASD group: 17.33 ± 2.30, NT group: 18.67 ± 1.30) than those with objects (ASD group: 11.96 ± 3.57, NT group: 14.10 ± 1.97). Correlation analyses showed that individuals with higher Autism-spectrum Quotient scale scores tended to make more errors and responded more slowly. CONCLUSION: Adults with ASD were able to identify human point-light display biological motion actions much better than chance; however, they were less proficient compared with NT adults in terms of accuracy and speed, regardless of action type.

An automated quantitative DNA image cytometry system detects abnormal cells in cervical cytology with high sensitivity.

OBJECTIVE: To evaluate the performance of an automated DNA-image-cytometry system as a tool to detect cervical carcinoma. METHODS: Of 384 liquid-based cervical cytology samples with available biopsy follow-up were analyzed by both the Imager System and a high-risk HPV test (Cobas). RESULTS: The sensitivity and specificity of Imager System for detecting biopsy proven high-grade squamous intraepithelial lesion (HSIL, cervical intraepithelial neoplasia [CIN]2-3) and carcinoma were 89.58% and 56.25%, respectively, compared to 97.22% and 23.33% of HPV test but additional HPV 16/18 genotyping increased the specificity to 69.58%. The sensitivity and specificity of the Imager System for predicting HSIL+ (CIN2-3+) lesions among atypical squamous cells of undetermined significance samples were 80.00% and 70.53%, respectively, compared to 100% and 11.58% of HPV test whilst the HPV 16/18 genotyping increased the specificity to 77.89%. Among atypical squamous cells-cannot exclude HSIL, the sensitivity and specificity of Imager System for predicting HSIL+ (CIN2-3+) lesions upon follow up were 82.86% and 33.33%%, respectively, compared to 97.14% and 4.76% of HPV test and the HPV 16/18 genotyping increased the specificity to 19.05%. Among low-grade squamous intraepithelial lesion cases, the sensitivity and specificity of the Imager System for predicting HSIL+ (CIN2-3+) lesions were 66.67% and 35.71%%, respectively, compared to 66.67% and 29.76% of HPV test while HPV 16/18 genotyping increased the specificity to 79.76%. The overall results of imager and high-risk HPV test agreed in 69.43% (268) of all samples. CONCLUSIONS: The automated imager system and HPV 16/18 genotyping can enhance the specificity of detecting HSIL+ (CIN2-3+) lesions.

Paediatric case series of drug reaction with eosinophilia and systemic symptoms (DRESS): 12-year experience at a single referral centre in Hong Kong and the first reported use of infliximab.

Summary: DRESS (drug reaction with eosinophilia and systemic symptoms) is a rare but potentially life-threatening disorder characterized by fever, skin eruption, haematological abnormalities and multi-organ dysfunction after drug exposure. The pathophysiology is thought to be related to interactions between culprit drugs, viral reactivation and T-lymphocytes activation. We report 4 paediatric patients with DRESS who were treated at our centre over the past 12 years. Most cases improved after corticosteroids. Other immunosuppressive medications were attempted in refractory cases with varied outcomes. Patient 3 was the first reported case that involved the use of infliximab, a TNF-α inhibitor, for DRESS. Although clinical efficacy was not observed for this one patient, a previous study demonstrated that patients with DRESS, disease progression and HHV-6 reactivation had elevated pre-treatment TNF- α and IL-6 levels. Further research is needed to explore the role of these cytokines in DRESS.

The effects of global warming on allergic diseases.

Global warming is a public health emergency. Substantial scientific evidence indicates an unequivocal rising trend in global surface temperature that has caused higher atmospheric levels of moisture retention leading to more frequent extreme weather conditions, shrinking ice volume, and gradually rising sea levels. The concomitant rise in the prevalence of allergic diseases is closely related to these environmental changes because warm and moist environments favour the proliferation of common allergens such as pollens, dust mites, molds, and fungi. Global warming also stresses ecosystems, further accelerating critical biodiversity loss. Excessive carbon dioxide, together with the warming of seawater, promotes ocean acidification and oxygen depletion. This results in a progressive decline of phytoplankton and fish growth that in turn promotes the formation of larger oceanic dead zones, disrupting the food chain and biodiversity. Poor environmental biodiversity and a reduction in the microbiome spectrum are risk factors for allergic diseases in human populations. While climate change and the existence of an allergy epidemic are closely linked according to robust international research, efforts to mitigate these have encountered strong resistance because of vested economic and political concerns in different countries. International collaboration to establish legally binding regulations should be mandatory for forest protection and energy saving. Lifestyle and behavioural changes should also be advocated at the individual level by focusing on low carbon living; avoiding food wastage; and implementing the 4Rs: reduce, reuse, recycle, and replace principles. These lifestyle measures are entirely consistent with the current recommendations for allergy prevention. Efforts to mitigate climate change, preserve biodiversity, and prevent chronic diseases are interdependent disciplines.