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In the lead-up to the Truth Matters conference in October, we will be focusing our attention on the sufficiency, authority, and clarity of Scripture. One of our previous blog series, Looking for Truth in All the Wrong Places, strongly emphasizes those doctrines. The following entry from that series originally appeared on June 12, 2017. -ed.

You have undoubtedly heard people say things like, “God is calling me to the mission field,” or “God led me to attend this college,” or “We feel God wants us to get married.” Perhaps you have even said such things yourself.

Christians who use expressions like those often mean they have had an impression or a strong feeling that they interpret as a disclosure of the divine will. Even people who believe prophecy and divine revelation have ceased sometimes fall into the trap of thinking God speaks directly to us through subjective means.

Normally people who make such claims have no intention of equating their mental impressions with divine revelation. They regard the subjective “leading of the Lord” as something far less than prophetic. Yet they believe God somehow communicates His will personally to individuals through inner promptings, signs, feelings of peace or uneasiness, strong impressions on the mind, or other similar means.

For reasons we shall examine, it is not wise to seek divine guidance through subjective impressions like these. Nowhere does Scripture encourage us to attempt to discern God’s will through such means. As we shall see, that sort of decision making can lead to confusion, disappointment, and sometimes spiritual tragedy.

And the truth is that treating subjective impressions as messages from the Holy Spirit is not really much different from claiming to receive divine revelation. Though most Christians who follow subjective impressions would not dream of listening to extrabiblical “prophecies,” in effect they are doing the same thing.

In fact, some advocates of modern prophetic revelation want to erase any distinction between subjective impressions and the gift of prophecy mentioned in 1 Corinthians 12–14. Professor Wayne Grudem, for example, who has produced the most thorough theological defense of the modern prophecy movement, believes God is giving revelation today chiefly through mental impressions. He even defines revelation as “something God brings to mind.” ^[1] Wayne Grudem, The Gift of Prophecy in the New Testament and Today (Wheaton, IL: Crossway Books, 1988), 42, 115. He suggests that when God providentially brings a thought to a believer’s mind, that is the New Testament gift of prophecy in operation. Thus he has elevated mental impressions to the level of prophetic revelation.

Grudem’s work has had widespread influence. And it is in many respects a fine study. He shows biblically why important distinctions must be made between Old Testament prophecy, apostolic prophecy, and the New Testament gift of prophecy. In places (but not everywhere) his exegesis of the pertinent texts is very helpful. He includes a crucial appendix on the sufficiency of Scripture which, if heeded by his friends in the modern prophecy movement, would provide a remedy against the serious abuses that have so plagued the movement. And he offers another important appendix showing that the canon of Scripture is closed.

But it is at this very point that Grudem’s position seems most inconsistent. If the canon of Scripture is really closed; if (as Grudem rightly suggests) “it is in Scripture alone that we are to search for God’s words to us”; ^[2] The Gift of Prophecy in the New Testament and Today, 299. and if, in his words, “the Bible is sufficient to equip us for living the Christian life” ^[3] The Gift of Prophecy in the New Testament and Today, 300. —then what point is there in seeking additional “revelations” like the prophetic messages Grudem advocates? It is unfortunate that Grudem relegated his thoughts on the canon of Scripture and the sufficiency of Scripture to the book’s final appendixes. If this had been the starting point for his study of prophecy, perhaps he would have reached very different conclusions.

Grudem’s defense of prophetic revelation has opened the door to a host of bizarre and misleading “prophecies” that have plagued evangelical Christianity over the past several years. Scores of churches worldwide have implemented Grudem’s theology and are encouraging people to share mere mental impressions as if they were prophetic messages from God. Ironically, Grudem’s work is frequently summoned to defend even the most outlandish aspects of a movement that has utterly ignored his many clear warnings against abuse of the prophetic gifts.

To his credit, Grudem appeals for a view of prophecy that “would still include a strong affirmation of the closing of the New Testament canon (so that no new words of equal authority are given today), of the sufficiency of Scripture, and of the supremacy and unique authority of the Bible in guidance.”^[4] The Gift of Prophecy in the New Testament and Today, 15. He writes, “I am asking that charismatics . . . stop calling [prophecy] ‘a word from the Lord’—simply because that label makes it sound exactly like the Bible in authority.” ^[5] The Gift of Prophecy in the New Testament and Today, 14. Elsewhere he writes, “Remember that what is spoken in any prophecy today is not the word of God, but is simply a human being reporting in merely human words something which God has brought to mind.” ^[6] The Gift of Prophecy in the New Testament and Today, 262. He also warns that modern prophecy

should not be thought of as “God’s very words,” nor should the speaker preface his or her remarks with words which would give that impression, such as, “Thus says the Lord,” or, “Hear the words of God,” etc.—those statements should be reserved for Scripture alone. Something like, “I think the Lord is showing me that . . .” or, “I think the Lord is indicating that . . .” or, “It seems that the Lord is putting on my heart a concern that . . .” would all be much more appropriate, and far less misleading. ^[7] The Gift of Prophecy in the New Testament and Today, 133.

If those warnings were consistently heeded, charismatic “prophets” could save their churches much grief and confusion.

But even in the denomination Grudem himself once identified with—the Association of Vineyard Churches—his words of caution are frequently ignored in the prophets’ actual practice.

James Ryle is himself a Vineyard pastor [Ryle passed away in 2015, Ed.]. He does give lip service to Grudem’s caution. He writes,

How often have you heard someone say casually, “The Lord spoke to me,” or “The Lord told me” to do this or that?

. . . Many within the church use these terms to justify their own desires and opinions. Possibly they feel that this puts what they are saying beyond challenge. After all, how does one argue with a “word from the Lord”?

In light of this problem I have found it a good policy to avoid such expressions and simply say, “It occurred to me” when I am sharing some insight which I’ve received in prayer or devotions. This removes unnecessary stumbling blocks and allows more people to hear the message without being distracted with the way the word is being presented. ^[8] James Ryle, Hippo in the Garden (Lake Mary, FL: Creation House, 1993), 30-31.

But note the significant difference between Grudem’s position and Ryle’s. Grudem believes prophecy is merely “something God brought to mind”—not “God’s very words.” He seems eager to avoid confusion on this point. Ryle’s perspective is markedly different. He says he employs terminology like “It occurred to me” to avoid “unnecessary stumbling blocks.” But he clearly does think of prophecy as God’s very words. After analyzing the dangers of saying things like “God spoke to me,” he states, “Nonetheless, the Lord does speak to us today.” In practice he cannot avoid placing modern words of prophecy on the same level with the written Word of God.

Ryle does this perhaps without even realizing it. He repeatedly cites Matthew 4:4 in defense of modern prophecy: “Man shall not live by bread alone, but by every word that proceedeth out of the mouth of God” ^[9] Hippo in the Garden, 32, 39, 62 (emphasis added).—taking a verse that clearly speaks of Scripture and applying it to modern words of prophecy.

Furthermore, despite his stated preference for expressions like, “It occurred to me,” Ryle never once uses that expression or any like it in his book. Instead, the book is filled with statements like, “I heard the voice of the Lord,” “The voice of the Lord spoke to me,” “God was speaking to me again,” “The Lord Himself was standing before me . . . speaking directly to me,” “Again I heard the voice of the Lord. . . . The Lord continued [speaking]. . . . The Lord seemed to pause. . . . Then He delivered the knockout blow,” “The Lord was saying to me,” “The Lord spoke to him, telling him to call [me],” “He speaks to me,” “I received a word from the Lord,” “I sensed the Holy Spirit say to me,” “I treasure these words from the Lord, holding them in my heart with the deepest regard,” “These were the exact words I was given,” “The prophetic word from the heart of the Lord was spoken,” “This is what the Holy Spirit showed me,” and similar expressions. ^[10] Hippo in the Garden, 13-14, 15, 18, 20, 25-29, 83, 91, 113, 115-116, 142. All Ryle’s interpretations of his own dreams and visions are stated with dogmatic conviction.

Ryle continually uses terminology that suggests he has canonized modern prophecy—at least in his own mind. “The Holy Spirit inspires us to speak through any number of means,” he says, referring to his prophecies as “inspired utterance.” ^[11] Hippo in the Garden, 99.] At the end of the book, Ryle suggests that when the hippo of modern prophecy comes into the garden of mainstream evangelicalism, “the church will be found in the midst of the world, speaking forth the words of God to a crooked and perverse generation, among whom we will shine as light, holding forth the word of life.” ^[12] Hippo in the Garden, 292 (emphasis added).

So in practice, Ryle finds it impossible not to equate his own prophecies with the words of Scripture, even though he appears to be trying to avoid this error. (In one place, Ryle says, “We must stop putting our own words in the Lord’s mouth. . . . Scripture alone is our sure foundation.” ^[13] Hippo in the Garden, 54-55. To that I add a hearty amen.)

He is not alone in this failing. Anyone who is truly convinced that God is speaking fresh words of revelation will inevitably view the later prophecies as somehow more relevant and more personal than the message of Scripture, which is more than two thousand years old. Inevitably, wherever personal prophecy has been stressed, Scripture has been deemphasized. Two thousand years of church history confirms that this is true.

(Adapted from Reckless Faith.)

Why pray to God if He sovereignly rules and reigns over our lives—isn’t His mind already made up? And if God is orchestrating every event in the universe for His glory, does that mean our choices and decisions are nothing more than pre-arranged manipulations by our Creator? Many Christians wrestle with these questions as they try to grasp the implications of God’s sovereignty over all that He has created.

The digital divide has become more pronounced than ever amid the global coronavirus lockdown, but experts are concerned that in the current circumstances this divide, where over 46 percent of the world’s population remain without technology or internet access, could grow wider — particularly among women.   “There were already deep divides in access to technologies […]

The post COVID-19: The Digital Divide Grows Wider Amid Global Lockdown appeared first on Inter Press Service.

ISLAMABAD: The Petroleum Division has admitted that it has violated the marginal gas policy guidelines 2013, and the terms of reference set by directorate general petroleum concessions , while...

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ISLAMABAD: The Petroleum Division has admitted that it has violated the marginal gas policy guidelines 2013, and the terms of reference set by directorate general petroleum concessions , while...

[[ This is a content summary only. Visit my website for full links, other content, and more! ]]

ISLAMABAD: The Petroleum Division has admitted that it has violated the marginal gas policy guidelines 2013, and the terms of reference set by directorate general petroleum concessions , while...

[[ This is a content summary only. Visit my website for full links, other content, and more! ]]

ADB has a vacancy for the position of Intern - Urban Development and Water Division, SERD - 2008 in the Southeast Asia Department. The deadline for submitting applications is on 15 September 2019.

ADB has a vacancy for the position of Intern - Solutions Delivery Division, OIST - 2012 in the Office of Information Systems and Technology. The deadline for submitting applications is on 15 September 2019.

Dentons has advised TSXV listed Bragg Gaming Group Inc., a next generation gaming group, on the sale of its online media division to SN&CK Media Limited. The sale follows a strategic review initiated by CEO, Dominic Mansour, and will allow Bragg to focus its efforts and resources on Oryx,  the group's rapidly growing B2B online gaming business.

MCHP Declares Dividend of 3670 Cents per Share

MCHP Declares Dividend of 3675 Cents per Share

KOLKATA: The state Public Works department (PWD) have divided all its circles into three zones – North, West and South for better supervision and monitoring of development projects of various government department entrusted to PWD all over the state. The PWD authorities were mulling on the plan to reorganise all its circles with the aim to implement the concept of coming up with three zones – North zone, West zone and South zone – so that the authorities can properly monitor and supervise all development projects that have been entrusted on them by the other departments. The PWD has several circles under the PWD road division, national highway and state […]

Some dividend fund managers are wading back into the shares of battered railroad stocks, energy companies and other economically sensitive, cyclical names, even as a host of companies have slashed...

STAMFORD, CT – May 4, 2020 – HARMAN, a wholly-owned subsidiary of Samsung Electronics Co. Ltd., focused on connected technologies for automotive, consumer and enterprise markets, announced today that it has entered into a multi-year, global partnership...

They’re safer than other kinds of road junction, require less energy for lights and result in less pollution from vehicles. But will they ever conquer the world?

Title: Healthy Heart in Middle Age Delivers Big Dividends
Category: Health News
Created: 5/1/2017 12:00:00 AM
Last Editorial Review: 5/2/2017 12:00:00 AM

ABSTRACT

Transporters belonging to the chromosomally encoded resistance-nodulation-division (RND) superfamily mediate multidrug resistance in Gram-negative bacteria. However, the cotransfer of large gene clusters encoding RND-type pumps from the chromosome to a plasmid appears infrequent, and no plasmid-mediated RND efflux pump gene cluster has yet been found to confer resistance to tigecycline. Here, we identified a novel RND efflux pump gene cluster, designated tmexCD1-toprJ1, on plasmids from five pandrug-resistant Klebsiella pneumoniae isolates of animal origin. TMexCD1-TOprJ1 increased (by 4- to 32-fold) the MICs of tetracyclines (including tigecycline and eravacycline), quinolones, cephalosporins, and aminoglycosides for K. pneumoniae, Escherichia coli, and Salmonella. TMexCD1-TOprJ1 is closely related (64.5% to 77.8% amino acid identity) to the MexCD-OprJ efflux pump encoded on the chromosome of Pseudomonas aeruginosa. In an IncFIA plasmid, pHNAH8I, the tmexCD1-toprJ1 gene cluster lies adjacent to two genes encoding site-specific integrases, which may have been responsible for its acquisition. Expression of TMexCD1-TOprJ1 in E. coli resulted in increased tigecycline efflux and in K. pneumoniae negated the efficacy of tigecycline in an in vivo infection model. Expression of TMexCD1-TOprJ1 reduced the growth of E. coli and Salmonella but not K. pneumoniae. tmexCD1-toprJ1-positive Enterobacteriaceae isolates were rare in humans (0.08%) but more common in chicken fecal (14.3%) and retail meat (3.4%) samples. Plasmid-borne tmexCD1-toprJ1-like gene clusters were identified in sequences in GenBank from Enterobacteriaceae and Pseudomonas strains from multiple continents. The possibility of further global dissemination of the tmexCD1-toprJ1 gene cluster and its analogues in Enterobacteriaceae via plasmids may be an important consideration for public health planning.

IMPORTANCE In an era of increasing concerns about antimicrobial resistance, tigecycline is likely to have a critically important role in the treatment of carbapenem-resistant Enterobacteriaceae, the most problematic pathogens in human clinical settings—especially carbapenem-resistant K. pneumoniae. Here, we identified a new plasmid-borne RND-type tigecycline resistance determinant, TMexCD1-TOprJ1, which is widespread among K. pneumoniae isolates from food animals. tmexCD1-toprJ1 appears to have originated from the chromosome of a Pseudomonas species and may have been transferred onto plasmids by adjacent site-specific integrases. Although tmexCD1-toprJ1 still appears to be rare in human clinical isolates, considering the transferability of the tmexCD1-toprJ1 gene cluster and the broad substrate spectrum of TMexCD1-TOprJ1, further dissemination of this mobile tigecycline resistance determinant is possible. Therefore, from a "One Health" perspective, measures are urgently needed to monitor and control its further spread. The current low prevalence in human clinical isolates provides a precious time window to design and implement measures to tackle this.

ABSTRACT

Cell division requires proper spatial coordination with the chromosome, which undergoes dynamic changes during chromosome replication and segregation. FtsZ is a bacterial cytoskeletal protein that assembles into the Z-ring, providing a platform to build the cell division apparatus. In the model bacterium Caulobacter crescentus, the cellular localization of the Z-ring is controlled during the cell cycle in a chromosome replication-coupled manner. Although dynamic localization of the Z-ring at midcell is driven primarily by the replication origin-associated FtsZ inhibitor MipZ, the mechanism ensuring accurate positioning of the Z-ring remains unclear. In this study, we showed that the Z-ring colocalizes with the replication terminus region, located opposite the origin, throughout most of the C. crescentus cell cycle. Spatial organization of the two is mediated by ZapT, a previously uncharacterized protein that interacts with the terminus region and associates with ZapA and ZauP, both of which are part of the incipient division apparatus. While the Z-ring and the terminus region coincided with the presence of ZapT, colocalization of the two was perturbed in cells lacking zapT, which is accompanied by delayed midcellular positioning of the Z-ring. Moreover, cells overexpressing ZapT showed compromised positioning of the Z-ring and MipZ. These findings underscore the important role of ZapT in controlling cell division processes. We propose that ZapT acts as a molecular bridge that physically links the terminus region to the Z-ring, thereby ensuring accurate site selection for the Z-ring. Because ZapT is conserved in proteobacteria, these findings may define a general mechanism coordinating cell division with chromosome organization.

IMPORTANCE Growing bacteria require careful tuning of cell division processes with dynamic organization of replicating chromosomes. In enteric bacteria, ZapA associates with the cytoskeletal Z-ring and establishes a physical linkage to the chromosomal replication terminus through its interaction with ZapB-MatP-DNA complexes. However, because ZapB and MatP are found only in enteric bacteria, it remains unclear how the Z-ring and the terminus are coordinated in the vast majority of bacteria. Here, we provide evidence that a novel conserved protein, termed ZapT, mediates colocalization of the Z-ring with the terminus in Caulobacter crescentus, a model organism that is phylogenetically distant from enteric bacteria. Given that ZapT facilitates cell division processes in C. crescentus, this study highlights the universal importance of the physical linkage between the Z-ring and the terminus in maintaining cell integrity.

We appreciate the readers' comments on the prevalence and impact of apathy on quality of life among individuals with Parkinson disease. In constructing our survey instrument, we discussed the inclusion of apathy as a symptom. However, we ultimately opted against inclusion because of concerns about the specificity of terminology in our online survey. Patients and care partners may not be familiar with the term "apathy,"and near-synonyms such as "reduced motivation" have substantial overlap with other nonmotor features. Still, as the readers point out, apathy is extremely common and under-recognized. Similar to many of the nonmotor symptoms identified in our study,¹ we agree that clinicians should be screening for apathy among those with Parkinson disease.

We read with great interest the study by Tarolli et al.,¹ which explored the burden of disease in Parkinson disease (PD) by evaluating the prevalence of nonmotor symptoms and their association with quality of life. The authors selected nonmotor symptoms based on literature review, expert opinions, and patient interviews. We note that apathy, which has major consequences for patients and carers, was not included as a relevant nonmotor symptom in their study. We performed a subcohort analysis of 60 patients from a study of pain in PD in 110 outpatients (PaCoMo-study, registered trial number: NL6311402917 [toetsingonline.nl]). We retrospectively reviewed the medical records to check whether the clinician identified apathy in these patients in the previous year, which was the case in 15% of the patients (n = 9). Blind to those results, patients were examined with the Apathy Scale (AS).² In total, 63.3% (n = 38) of the patients scored positive on the AS. Only 18.4% of the patients who scored positive on the AS were also classified or mentioned with apathy in the medical records by clinicians.

Annebelle C. M. Kok, Lisette van Kolfshoten, James A. Campbell, Alexander M. von Benda-Beckmann, Patrick J. O. Miller, Hans Slabbekoorn, and Fleur Visser

Group-living animals must communicate to stay in contact. In long-finned pilot whales, there is a trade-off between the benefits of foraging individually at depth and the formation of tight social groups at the surface. Using theoretical modelling and empirical data of tagged pairs within a group, we examined the potential of pilot whale social calls to reach dispersed group-members during foraging periods. Both theoretical predictions and empirical data of tag pairs showed a potential for communication between diving and non-diving group members over separation distances up to at least 385 m (empirical) and 1800 m (theoretical). These distances are at or exceeding pilot whale dive depths recorded across populations. Call characteristics and environmental characteristics were analysed to investigate determinants of call detectability. Longer calls with a higher sound pressure level (SPL) that were received in a quieter environment were more often detected than their shorter, lower SPL counterparts within a noisier environment. In a noisier environment, calls were louder and had a lower peak frequency, indicating mechanisms for coping with varying conditions. However, the vulnerability of pilot whales to anthropogenic noise is still of concern as the ability to cope with increasing background noise may be limited. Our study shows that combining propagation modelling and actual tag recordings provides new insights into the communicative potential for social calls in orientation and reunion with group members for deep-diving pilot whales.

BACKGROUND:Patients with cystic fibrosis develop decreased exercise capacity. However, the main factors responsible for this decline are still unclear. Thus, the objective of this study was to evaluate the factors influencing exercise capacity assessed with the modified shuttle test (MST) in individuals with cystic fibrosis.METHODS:A cross-sectional study was carried out in subjects with a diagnosis of cystic fibrosis who were 6–26 y old and were regularly monitored at 2 cystic fibrosis reference centers in Brazil. Individuals who were unable to perform the tests or who exhibited hemodynamic instability and exacerbation of respiratory symptoms were excluded. Anthropometric, clinical, and genotype data were collected. In addition, lung function and exercise capacity were evaluated with the MST.RESULTS:73 subjects (mean age 12.2 ± 4.9 y and FEV1 76.8 ± 23.3%) were included. The mean distance achieved in the MST was 765 ± 258 m (71.6% of predicted). The distance achieved on the MST correlated significantly with age (r = 0.49, P < .001), body mass index (r = 0.41, P < .001), resting heart rate (r = −0.51, P < .001), and FEV1 (r = 0.24, P = .042). Subjects with FEV1 > 67% of predicted (P = .02) and those with resting heart rate < 100 beats/min (P = .01) had a greater exercise capacity. Resting heart rate, age, and FEV1 (%) were found as significant variables to explain the distance achieved on the MST (R2 = 0.48, standard error = 191.0 m).CONCLUSIONS:The main determinants of exercise capacity assessed with the MST in individuals with cystic fibrosis were resting heart rate, age, and lung function.

¹⁸F-prostate-specific membrane antigen (PSMA)-1007 is excreted mainly through the liver. We benchmarked the performance of ¹⁸F-PSMA-1007 against 3 renally excreted PSMA tracers. Methods: Among 668 patients, we selected 27 in whom PET/CT results obtained with ⁶⁸Ga-PSMA-11, ¹⁸F-DCFPyL (2-(3-(1-carboxy-5-[(6-[¹⁸F]fluoro-pyridine-3-carbonyl)-amino]-pentyl)-ureido)-pentanedioic acid), or ¹⁸F-JK-PSMA-7 (JK, Juelich-Koeln) were interpreted as equivocal or negative or as oligometastatic disease (PET-1). Within 3 wk, a second PET scan with ¹⁸F-PSMA-1007 was performed (PET-2). The confidence in the interpretation of PSMA-positive locoregional findings was scored on a 5-point scale, first in routine diagnostics (reader 1) and then by an independent second evaluation (reader 2). Discordant PSMA-positive skeletal findings were examined by contrast-enhanced MRI. Results: For both readers, ¹⁸F-PSMA-1007 facilitated the interpretability of 27 locoregional lesions. In PET-2, the clinical readout led to a significantly lower number of equivocal locoregional lesions (P = 0.024), and reader 2 reported a significantly higher rate of suspected lesions that were falsely interpreted as probably benign in PET-1 (P = 0.023). Exclusively in PET-2, we observed a total of 15 PSMA-positive spots in the bone marrow of 6 patients (22%). None of the 15 discordant spots had a morphologic correlate on the corresponding CT scan or on the subsequent MRI scan. Thus, ¹⁸F-PSMA-1007 exhibits a significantly higher rate of unspecific medullary spots (P = 0.0006). Conclusion: ¹⁸F-PSMA-1007 may increase confidence in interpreting small locoregional lesions adjacent to the urinary tract but may decrease the interpretability of skeletal lesions.

OBJECTIVE

Most individuals with type 2 diabetes also have obesity, and treatment with some diabetes medications, including insulin, can cause further weight gain. No approved chronic weight management medications have been prospectively investigated in individuals with overweight or obesity and insulin-treated type 2 diabetes. The primary objective of this study was to assess the effect of liraglutide 3.0 mg versus placebo on weight loss in this population.

OBJECTIVE

The aim of this study was to quantify the excess risk of autoimmune hypothyroidism and hyperthyroidism, Addison disease, celiac disease, and atrophic gastritis in adults with type 1 diabetes (T1D) compared with nondiabetic individuals in Finland.

Pharmacokinetic-based prophylaxis of replacement factor VIII (FVIII) products has been encouraged in recent years, but the relationship between exposure (factor VIII activity) and response (bleeding frequency) remains unclear. The aim of this study was to characterize the relationship between FVIII dose, plasma FVIII activity, and bleeding patterns and individual characteristics in severe hemophilia A patients. Pooled pharmacokinetic and bleeding data during prophylactic treatment with BAY 81-8973 (octocog alfa) were obtained from the three LEOPOLD trials. The population pharmacokinetics of FVIII activity and longitudinal bleeding frequency, as well as bleeding severity, were described using non-linear mixed effects modeling in NONMEM. In total, 183 patients [median age 22 years (range, 1-61); weight 60 kg (11-124)] contributed with 1,535 plasma FVIII activity observations, 633 bleeds and 11 patient/study characteristics [median observation period 12 months (3.1-13.1)]. A parametric repeated time-to-categorical bleed model, guided by plasma FVIII activity from a 2-compartment population pharmacokinetic model, described the time to the occurrence of bleeds and their severity. Bleeding probability decreased with time of study, and a bleed was not found to affect the time of the next bleed. Several covariate effects were identified, including the bleeding history in the 12-month pre-study period increasing the bleeding hazard. However, unexplained inter-patient variability in the phenotypic bleeding pattern remained large (111%CV). Further studies to translate the model into a tool for dose individualization that considers the individual bleeding risk are required. Research was based on a post-hoc analysis of the LEOPOLD studies registered at clinicaltrials.gov identifiers: 01029340, 01233258 and 01311648.

Studies implicating sodium–glucose cotransporter 2 (SGLT2) inhibitors in glucagon secretion by pancreatic α-cells reported controversial results. We hypothesized that interindividual heterogeneity in SGLT2 expression and regulation may affect glucagon secretion by human α-cells in response to SGLT2 inhibitors. An unbiased RNA-sequencing analysis of 207 donors revealed an unprecedented level of heterogeneity of SLC5A2 expression. To determine heterogeneity of SGLT2 expression at the protein level, the anti-SGLT2 antibody was first rigorously evaluated for specificity, followed by Western blot and immunofluorescence analysis on islets from 10 and 12 donors, respectively. The results revealed a high interdonor variability of SGLT2 protein expression. Quantitative analysis of 665 human islets showed a significant SGLT2 protein colocalization with glucagon but not with insulin or somatostatin. Moreover, glucagon secretion by islets from 31 donors at low glucose (1 mmol/L) was also heterogeneous and correlated with dapagliflozin-induced glucagon secretion at 6 mmol/L glucose. Intriguingly, islets from three donors did not secrete glucagon in response to either 1 mmol/L glucose or dapagliflozin, indicating a functional impairment of the islets of these donors to glucose sensing and SGLT2 inhibition. Collectively, these data suggest that heterogeneous expression of SGLT2 protein and variability in glucagon secretory responses contribute to interindividual differences in response to SGLT2 inhibitors.

Treating malaria in HIV-coinfected individuals should consider potential drug-drug interactions. Artemether-lumefantrine is the most widely recommended treatment for uncomplicated malaria globally. Lumefantrine is metabolized by CYP3A4, an enzyme that commonly used antiretrovirals often induce or inhibit. A population pharmacokinetic meta-analysis was conducted using individual participant data from 10 studies with 6,100 lumefantrine concentrations from 793 nonpregnant adult participants (41% HIV-malaria-coinfected, 36% malaria-infected, 20% HIV-infected, and 3% healthy volunteers). Lumefantrine exposure increased 3.4-fold with coadministration of lopinavir-ritonavir-based antiretroviral therapy (ART), while it decreased by 47% with efavirenz-based ART and by 59% in the patients with rifampin-based antituberculosis treatment. Nevirapine- or dolutegravir-based ART and malaria or HIV infection were not associated with significant effects. Monte Carlo simulations showed that those on concomitant efavirenz or rifampin have 49% and 80% probability of day 7 concentrations <200 ng/ml, respectively, a threshold associated with an increased risk of treatment failure. The risk of achieving subtherapeutic concentrations increases with larger body weight. An extended 5-day and 6-day artemether-lumefantrine regimen is predicted to overcome these drug-drug interactions with efavirenz and rifampin, respectively.

Symmetric division of stem cells positive for gastrin receptor CCK2R is linked to gastric cancer.

Although they are usually not considered to be diabetes complications, musculoskeletal disorders (MSKDs) are common in individuals with type 1 or type 2 diabetes and can strongly interfere with daily diabetes care, especially in people using diabetes technologies. The authors of this retrospective study in a population of 140 patients with type 1 diabetes report the distribution of subtypes of MSKDs and speculate about the mechanisms involved. The authors emphasize the need for multidisciplinary care involving not only the diabetes care team but also orthopedic surgeons. This report should lead to large, prospective studies to increase knowledge about these under-studied complications.

If you didn’t feel challenged enough by Indivisible‘s main platforming and punching campaign, here’s some good news for ya. Lab Zero have released a new DLC for their turn-ish-based RPG today that promises the “forty specially crafted levels await to test your platforming and combat skills.” The Razmi’s Challenges DLC is available now, so you […]

Scientists set out to investigate a potential role of the gut microbiota in the development of cardio-metabolic diseases. They ended up identifying the common cholesterol-lowering drug statins as a potential microbiota-modulating therapeutic.

New research describes a new model for how the brain interprets patterns in complex networks. They found that the ability to detect patterns stems in part from the brain's desire to represent things in the simplest way possible and that the brain is constantly weighing the pressures of complexity and simplicity when making decisions.

Researchers have used a microbiome 'fingerprint' method to report that an individualized mosaic of microbial strains is transmitted to the infant gut microbiome from a mother giving birth through vaginal delivery. They detailed this transmission by analyzing existing metagenomic databases of fecal samples from mother-infant pairs, as well as analyzing mouse dam and pup transmission in a germ-free, or gnotobiotic, mouse model, where the dams were inoculated with human fecal microbes.

A week packed with U.S. economic data is likely to provide investors with more evidence of the extent to which the coronavirus pandemic has hit growth, sharpening the debate on whether a rebound in stocks has been justified amid an unprecedented slowdown.

Humans have proven themselves remarkably adept at learning to do what other animals can do naturally. We have taught ourselves to fly like birds, climb like monkeys and burrow like moles. But the one animal that has always proven beyond our reach is the fish.

Apple capitalized on the Federal Reserve's emergency measures in response to the coronavirus outbreak to issue its cheapest bonds in year

Team training facilities have been closed, other than for approved rehab, since the league suspended play March 12 due to the global pandemic.

'Why so much anti-Boris clips in a time when the country should be united?'