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SummaryApproximately half of individuals with hypophosphatasemia (low levels of serum alkaline phosphatase) have hypophosphatasia, a rare genetic disease in which patients may have stress fractures, bone and joint pain, or premature tooth loss. We developed a predictive model based on specific biomarkers of this disease to better diagnose this condition.IntroductionHypophosphatasemia is a condition in which low levels of alkaline phosphatase (ALP) are detected in the serum. Some individuals presenting with this condition may have a rare genetic disease called hypophosphatasia (HPP), which involves mineralization of the bone and teeth. Lack of awareness of HPP and its nonspecific symptoms make this genetic disease difficult to diagnose. We developed a predictive model based on biomarkers of HPP such as ALP and pyridoxal 5′-phosphate (PLP), because clinical manifestations sometimes are not recognized as symptoms of HPP.MethodsWe assessed 325,000 ALP results between 2010 and 2015 to identify individuals suspected of having HPP. We performed univariate and multivariate analyses to characterize the relationship between hypophosphatasemia and HPP. Using several machine learning algorithms, we developed several models based on biomarkers and compared their performance to determine the best model.ResultsThe final cohort included 45 patients who underwent a genetic test. Half (23 patients) showed a mutation of the ALPL gene that encodes the tissue-nonspecific ALP enzyme. ALP (odds ratio [OR] 0.61, 95% confidence interval [CI] 0.3–0.8, p = 0.01) and PLP (OR 1.06, 95% CI 1.01–1.15, p = 0.04) were the only variables significantly associated with the presence of HPP. Support vector machines and logistic regression were the machine learning algorithms that provided the best predictive models in terms of classification (area under the curve 0.936 and 0.844, respectively).ConclusionsGiven the high probability of a misdiagnosis, its nonspecific symptoms, and a lack of awareness of serum ALP levels, it is difficult to make a clinical diagnosis of HPP. Predictive models based on biomarkers are necessary to achieve a proper diagnosis. Our proposed machine learning approaches achieved reasonable performance compared to traditional statistical methods used in biomedicine, increasing the likelihood of properly diagnosing such a rare disease as HPP.

Purpose The purpose of this study is to investigate the drivers of business-to-business (B2B) sales success and the role of digitalization, in a selling and sales management landscape being disrupted by COVID-19. Design/methodology/approach The methodology follows a discovery-oriented grounded theory approach, which consists of a two-stage qualitative study with sales professionals in Chile, and a fuzzy-set qualitative comparative analysis (fsQCA). Findings This research shows that interfunctional coordination, agility in the selling process and business customer engagement are critical determinants of B2B sales success, whereas digitalization moderates these relationships. Originality/value This research responds to a call for more research on the impact of digitalization on business relationships in different contexts and perspectives. The authors study the Chilean context, through a two-stage qualitative study, and a fsQCA analysis, which constitutes a novel combination in this stream of research.

The electrical control and readout of single two-level state defects in a defective oxide film grown directly on the channel of a thin-film FET allow for the extraction of individual long relaxation times. Electronic defect states at material interfaces provide highly deleterious sources of noise in solid-state nanostructures, and even a single trapped charge can qualitatively alter the properties of short one-dimensional nanowire field-effect transistors (FET) and quantum bit (qubit) devices 1 , 2 , 3 , 4 , 5 . Understanding the dynamics of trapped charge is thus essential for future nanotechnologies, but their direct detection and manipulation is rather challenging 2 , 4 , 5 . Here, a transistor-based set-up is used to create and probe individual electronic defect states that can be coherently driven with microwave (MW) pulses. Strikingly, we resolve a large number of very high quality ( Q ∼ 1 × 10 5 ) resonances in the transistor current as a function of MW frequency and demonstrate both long decoherence times (∼1 μs—40 μs) and coherent control of the defect-induced dynamics. Efficiently characterizing over 800 individually addressable resonances across two separate defect-hosting materials, we propose that their properties are consistent with weakly driven two-level systems.

Background Hypophosphatasia (HPP) is a rare and underdiagnosed condition characterized by deficient bone and teeth mineralization. The aim of this study was first, to evaluate the diagnostic utility of employing alkaline phosphatase (ALP) threshold levels to identify adults with variants in ALPL among individuals with persistently low ALP levels and second, to determine the value of also including its substrates (serum pyridoxal-5′-phosphate—PLP—and urinary phosphoetanolamine-PEA) for this purpose in order to create a biochemical algorithm that could facilitate the diagnostic work-up of HPP. Results The study population comprised 77 subjects with persistent hypophosphatasaemia. They were divided into two groups according to the presence (+GT) or absence (−GT) of pathogenic ALPL variants: 40 +GT and 37 −GT. Diagnostic utility measures were calculated for different ALP thresholds and Receiver Operating Characteristic (ROC) curves were employed to determine PLP and PEA optimal cut-off levels to predict the presence of variants. The optimal threshold for ALP was 25 IU/L; for PLP, 180 nmol/L and for PEA, 30 µmol/g creatinine. Biochemical predictive models were assessed using binary logistic regression analysis and bootstrapping machine learning technique and results were then validated. For ALP < 25 UI/L (model 1), the area under curve (AUC) and the 95% confidence intervals (CI) was 0.68 (95% CI 0.63–0.72) and it improved to 0.87 (95% CI 0.8–0.9), when PEA or PLP threshold levels were added (models 2 and 3), reaching 0.94 (0.91–0.97) when both substrates were included (model 4). The internal validation showed that the addition of serum PLP threshold levels to the model just including ALP improved significantly sensitivity (S) and negative predictive value (NPV) − 100%, respectively- with an accuracy (AC) of 93% in comparison to the inclusion of urinary PEA (S: 71%; NPV 75% and AC: 79%) and similar diagnostic utility measures as those observed in model 3 were detected when both substrates were added. Conclusions In this study, we propose a biochemical predictive model based on the threshold levels of the main biochemical markers of HPP (ALP < 25 IU/L and PLP > 180 nmol/L) that when combined, seem to be very useful to identify individuals with ALPL variants.

PurposeThis research serves to determine causal configurations of corporate social responsibility (CSR) conditions that best influences grassroots football club stakeholders to meet a sponsor's goals through promotional activity.Design/methodology/approachThe research uses a case study of the Essex Alliance League, a local amateur football league in England. Firstly, semi-structured interviews were held with multiple stakeholders to understand the ecosystem of grassroots football. From here, further semi-structured interviews were held with club sponsors to identify the conditions of CSR. This allowed the research to then issue a survey from which results were analysed and discussed using fuzzy set Qualitative Comparative Analysis (fsQCA).FindingsThe ecosystem of grassroots football is formed by a myriad of stakeholders operating at a national level, all the way to more local governance structures within which the business-club relationship exists. Sponsors identified three main conditions of CSR: shared values, self-congruity, and happiness. However, following fsQCA, two pathways were found: (1) presence of shared values, and (2) presence of happiness with the absence of self-congruity.Practical implicationsFor practitioners, adaptations can be made for clubs to attract and maintain sponsorship as businesses seek to use grassroots sport as a channel for their own CSR objectives. To attract long term sponsorship, club managers are recommended to maintain long-term relationships with business owners especially in relation to personal values, fit, and happiness. As such, the responsibility of the club to ensure its stakeholders engage in promotional activity on behalf of their sponsor will help in maximising the financial value over multiple seasons.Originality/valueWhere fertile ground for academic analysis in grassroots football is present, this research investigates CSR activity at this level of football, where most research is more concerned with professional levels of the game. Furthermore, this research reaches into the sport ecosystem through an understanding of co-created values between organisations in this exchange of shared values to meet common objectives.

Background Hypophosphatasia (HPP) is an inborn error of metabolism characterized by low levels of serum alkaline phosphatase (ALP). Scarce evidence exists about features that should signal the potential association between hypophosphatasaemia and HPP in adults. The aim of this study is to estimate the prevalence of ALPL variants in subjects with persistent hypophosphatasaemia and determine the associated clinical and laboratory features. For this cross-sectional study, laboratory records of 386,353 subjects were screened by measurement of ALP activity. A total of 85 (0.18%) subjects with persistent hypophosphatasaemia (≥2 serum alkaline phosphatase–ALP–measurements ≤35 IU/L and none > 45 IU/L) were included (secondary causes previously discarded). ALPL genetic testing and a systematized questionnaire to retrieve demographic, clinical and laboratory data were performed. Descriptive analysis and logistic regression models were employed to identify the clinical and laboratory characteristics associated with ALPL variants. Results Forty subjects ( 47%) had a variant(s) in ALPL . With regard to clinical characteristics, the presence of an ALPL variant was significantly associated only with musculoskeletal pain (OR: 7.6; 95% IC: 1.9–30.9). Nevertheless, a trend to present more dental abnormalities (OR: 3.6; 95% IC: 0.9–13.4) was observed. Metatarsal stress fractures were also more frequent (4 vs 0; p  < 0.05) in this group. Regarding laboratory features, median ALP levels were lower in subjects with ALPL variants (26 vs 29 IU/L; p  < 0.005). Interestingly, the threshold of ALP levels < 25 IU/L showed a specificity, positive predictive value and positive likelihood ratio of 97.8, 94.4% and 19.8 to detect a positive ALPL test, respectively. Conclusions In subjects with persistent hypophosphatasaemia –secondary causes excluded– one out of two presented ALPL variants. Musculoskeletal pain and ALP levels < 25 IU/L are associated with this variant(s). In this scenario, ALP levels < 25 IU/L seem to be very useful to identify individuals with the presence of an ALPL variant.

The venom duct transcriptomes and proteomes of the cryptic cone snail species Virroconus ebraeus and Virroconus judaeus were obtained and compared. The most abundant and shared conotoxin precursor superfamilies in both species were M, O1, and O2. Additionally, three new putative conotoxin precursor superfamilies (Virro01-03) with cysteine pattern types VI/VII and XVI were identified. The most expressed conotoxin precursor superfamilies were SF-mi2 and M in V. ebraeus, and Cerm03 and M in V. judaeus. Up to 16 conotoxin precursor superfamilies and hormones were differentially expressed between both species, and clustered into two distinct sets, which could represent adaptations of each species to different diets. Finally, we predicted, with machine learning algorithms, the 3D structure model of selected venom proteins including the differentially expressed Cerm03 and SF-mi2, an insulin type 3, a Gastridium geographus GVIA-like conotoxin, and an ortholog to the Pionoconus magus omega-conotoxin MVIIA (Ziconotide).

The transcriptomes of the venom glands of two individuals of the magician’s cone, Pionoconus magus, from Okinawa (Japan) were sequenced, assembled, and annotated. In addition, RNA-seq raw reads available at the SRA database from one additional specimen of P. magus from the Philippines were also assembled and annotated. The total numbers of identified conotoxin precursors and hormones per specimen were 118, 112, and 93. The three individuals shared only five identical sequences whereas the two specimens from Okinawa had 30 sequences in common. The total number of distinct conotoxin precursors and hormones for P. magus was 275, and were assigned to 53 conotoxin precursor and hormone superfamilies, two of which were new based on their divergent signal region. The superfamilies that had the highest number of precursors were M (42), O1 (34), T (27), A (18), O2 (17), and F (13), accounting for 55% of the total diversity. The D superfamily, previously thought to be exclusive of vermivorous cones was found in P. magus and contained a highly divergent mature region. Similarly, the A superfamily alpha 4/3 was found in P. magus despite the fact that it was previously postulated to be almost exclusive of the genus Rhombiconus. Di erential expression analyses of P. magus compared to Chelyconus ermineus, the only fish-hunting cone from the Atlantic Ocean revealed that M and A2 superfamilies appeare

Malignant neoplasms of any anatomical site, along with their treatments, can significantly affect the oral health of paediatric and adolescent populations, potentially influencing their oral health-related quality of life (OHRQoL). This systematic review sought to evaluate how cancer, regardless of tumour location, impacts the OHRQoL of children and adolescents. Electronic searches were conducted in PubMed, Scopus, EMBASE, Web of Science and LILACS, as well as grey literature, up to October 2023. Clinical studies reporting on OHRQoL in patients aged 0-19 years with cancer were included. Two reviewers independently performed study selection, data extraction and risk of bias assessment using the Joanna Briggs Institute tools. Certainty of evidence was evaluated using the GRADE approach. Of 27,684 records, four studies (three cross-sectional and one randomised clinical trial) met the inclusion criteria, encompassing 253 paediatric patients. OHRQoL was assessed using OHIP-14 and ECOHIS instruments. Most studies reported a weak impact of oral health on quality of life. However, methodological limitations and very low certainty of evidence were identified. Although a weak impact of oral health on quality of life was observed among children and adolescents with malignant neoplasms, the limited number and quality of available studies prevent firm conclusions. High-quality research with robust methodology is needed to better understand this relationship and draw robust conclusions and guide clinical decision-making.

Golgi phosphoprotein 3 (GOLPH3) has been implicated in the development of carcinomas in many human tissues, and is currently considered a bona fide oncoprotein. Importantly, several tumor types show overexpression of GOLPH3, which is associated with tumor progress and poor prognosis. However, the underlying molecular mechanisms that connect GOLPH3 function with tumorigenicity are poorly understood. Experimental evidence shows that depletion of GOLPH3 abolishes transformation and proliferation of tumor cells in GOLPH3-overexpressing cell lines. Conversely, GOLPH3 overexpression drives transformation of primary cell lines and enhances mouse xenograft tumor growth in vivo. This evidence suggests that overexpression of GOLPH3 could result in distinct features of GOLPH3 in tumor cells compared to that of non-tumorigenic cells. GOLPH3 is a peripheral membrane protein mostly localized at the trans-Golgi network, and its association with Golgi membranes depends on binding to phosphatidylinositol-4-phosphate. GOLPH3 is also contained in a large cytosolic pool that rapidly exchanges with Golgi-associated pools. GOLPH3 has also been observed associated with vesicles and tubules arising from the Golgi, as well as other cellular compartments, and hence it has been implicated in several membrane trafficking events. Whether these and other features are typical to all different types of cells is unknown. Moreover, it remains undetermined how GOLPH3 acts as an oncoprotein at the Golgi. Therefore, to better understand the roles of GOLPH3 in cancer cells, we sought to compare some of its biochemical and cellular properties in the human breast cancer cell lines MCF7 and MDA-MB-231 with that of the non-tumorigenic breast human cell line MCF 10A. We found unexpected differences that support the notion that in different cancer cells, overexpression of GOLPH3 functions in diverse fashions, which may influence specific tumorigenic phenotypes.