Dietary carbohydrate restriction augments weight loss-induced improvements in glycaemic control and liver fat in individuals with type 2 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: Lifestyle modification and weight loss are cornerstones of type 2 diabetes management. However, carbohydrate restriction may have weight-independent beneficial effects on glycaemic control. This has been difficult to demonstrate because low-carbohydrate diets readily decrease body weight. We hypothesised that carbohydrate restriction enhances the beneficial metabolic effects of weight loss in type 2 diabetes. METHODS: This open-label, parallel RCT included adults with type 2 diabetes, HbA1c 48-97 mmol/mol (6.5-11%), BMI >25 kg/m2, eGFR >30 ml min-1 [1.73 m]-2 and glucose-lowering therapy restricted to metformin or dipeptidyl peptidase-4 inhibitors. Participants were randomised by a third party and assigned to 6 weeks of energy restriction (all foods were provided) aiming at ~6% weight loss with either a carbohydrate-reduced high-protein diet (CRHP, percentage of total energy intake [E%]: CH30/P30/F40) or a conventional diabetes diet (CD, E%: CH50/P17/F33). Fasting blood samples, continuous glucose monitoring and magnetic resonance spectroscopy were used to assess glycaemic control, lipid metabolism and intrahepatic fat. Change in HbA1c was the primary outcome; changes in circulating and intrahepatic triacylglycerol were secondary outcomes. Data were collected at Copenhagen University Hospital (Bispebjerg and Herlev). RESULTS: Seventy-two adults (CD 36, CRHP 36, all white, 38 male sex) with type 2 diabetes (mean duration 8 years, mean HbA1c 57 mmol/mol [7.4%]) and mean BMI of 33 kg/m2 were enrolled, of which 67 (CD 33, CRHP 34) completed the study. Body weight decreased by 5.8 kg (5.9%) in both groups after 6 weeks. Compared with the CD diet, the CRHP diet further reduced HbA1c (mean [95% CI] -1.9 [-3.5, -0.3] mmol/mol [-0.18 (-0.32, -0.03)%], p = 0.018) and diurnal mean glucose (mean [95% CI] -0.8 [-1.2, -0.4] mmol/l, p < 0.001), stabilised glucose excursions by reducing glucose CV (mean [95% CI] -4.1 [-5.9, -2.2]%, p < 0.001), and augmented the reductions in fasting triacylglycerol concentration (by mean [95% CI] -18 [-29, -6]%, p < 0.01) and liver fat content (by mean [95% CI] -26 [-45, 0]%, p = 0.051). However, pancreatic fat content was decreased to a lesser extent by the CRHP than the CD diet (mean [95% CI] 33 [7, 65]%, p = 0.010). Fasting glucose, insulin, HOMA2-IR and cholesterol concentrations (total, LDL and HDL) were reduced significantly and similarly by both diets. CONCLUSIONS/INTERPRETATION: Moderate carbohydrate restriction for 6 weeks modestly improved glycaemic control, and decreased circulating and intrahepatic triacylglycerol levels beyond the effects of weight loss itself compared with a CD diet in individuals with type 2 diabetes. Concurrent differences in protein and fat intakes, and the quality of dietary macronutrients, may have contributed to these results and should be explored in future studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT03814694. FUNDING: The study was funded by Arla Foods amba, The Danish Dairy Research Foundation, and Copenhagen University Hospital Bispebjerg Frederiksberg.

Night-time heart rate variability identifies high-risk people among people with uncomplicated type 2 diabetes mellitus.

BACKGROUND: Low heart rate variability (HRV) reflects cardiac autonomic neuropathy, which is associated with increased cardiovascular mortality in people with type 2 diabetes mellitus (T2DM). Measuring HRV is challenged by environmental noise, mental stress and physical activity during daytime. Night-time HRV during sleep may be a more valid tool to measure cardiac autonomic neuropathy and therefore may improve prediction of cardiovascular (CV) events in low-risk people with T2DM. METHODS: Copenhagen Holter Study included 678 community-dwelling participants aged 55-75 years who were free of previous CV disease. Day and night-time HRV were available for 653 participants. The population included 133 people with well-controlled T2DM and newly recognized T2DM (mean HbA1c 55 mmol/mol [7.2%]). HRV is defined as standard deviation for the mean value of normal-to-normal complexes (SDNN). Night-time HRV measurements were pre-defined from 2:00 to 2:15 AM. Cardiovascular events were defined as CV death, myocardial infarction, stroke or coronary revascularization. RESULTS: Median follow-up time was 14.4 years. During this period, 245 death and 149 CV events (CV death 36, myocardial infarction 42, revascularisation procedures 46, stroke 70) occurred in total. Among people with T2DM, 41 CV events were observed (CV death 13, myocardial infarction 13, revascularisation procedures 17, stroke 18). Night-time SDNN was inversely associated with CV events in people with T2DM, (hazard ratio [HR]: 0.74 95% confidence interval [CI]:0.61-0.89) for each 10-millisecond increment in SDNN after adjustment for the conventional risk factors sex, age, LDL cholesterol, smoking, systolic blood pressure and by also including glucose CRP and NT-proBNP in adjustment. Twenty-four-hour HRV was not associated with CV events, but associated with all-cause mortality in people with T2DM. Conventional risk factors had a receiver operating characteristic (ROC) value of 0.704 (95% CI 0.602-0.806) to predict CV events in people with T2DM. The prediction of CV events by conventional risk factors was improved in people with T2DM by the addition of night-time SDNN; ROC 0.765 (95% CI 0.669-0.862), p = 0.037, but ROC was not improved by addition of CRP and NT-proBNP in the model. In people with T2DM and night-time SDNN ≤30 ms, the 10-year risk of CV death and CV event rate was 12% and 45%, respectively, which re-allocated them to a 'very high-risk' group according to current guidelines. CONCLUSION: Reduced night-time HRV predicts increased risk of CV events in people with well-controlled T2DM, thus night-time HRV may add to traditional risk factors in predicting CV events in people with T2DM.

A Highly Active Ylide-Functionalized Phosphine for Palladium-Catalyzed Aminations of Aryl Chlorides.

Ylide-functionalized phosphine ligands (YPhos) were rationally designed to fit the requirements of Buchwald-Hartwig aminations at room temperature. This ligand class combines a strong electron-donating ability comparable to NHC ligands with high steric demand similar to biaryl phosphines. The active Pd species are stabilized by agostic C-H⋅⋅⋅Pd rather than by Pd-arene interactions. The practical advantage of YPhos ligands arises from their easy and scalable synthesis from widely available, inexpensive starting materials. Benchmark studies showed that YPhos-Pd complexes are superior to the best-known phosphine ligands in room-temperature aminations of aryl chlorides. The utility of the catalysts was demonstrated by the synthesis of various arylamines in high yields within short reaction times.

Regiospecific ortho-C-H Allylation of Benzoic Acids.

A carboxylate-directed ortho-C-H functionalization has been developed and it allows the regiospecific introduction of allyl residues to benzoic acids. In the presence of a [Ru(p-cymene)Cl2 ]2 and K3 PO4 , benzoic acids react with allyl acetates at only 50 °C to give the corresponding ortho-allylbenzoic acids. The protocol is generally applicable to both electron-rich and electron-poor benzoic acids in combination with linear and branched allyl acetates. The products can be further functionalized in situ, for example, by double-bond migration, lactonization, or decarboxylation.

Synthesis of 3-Substituted 2-Arylpyridines via Cu/Pd-Catalyzed Decarboxylative Cross-Coupling of Picolinic Acids with (Hetero)Aryl Halides.

A decarboxylative cross-coupling of 3-substituted picolinic acids with (hetero)aryl halides is presented. In the presence of catalytic Cu2O and Pd(1,5-cyclooctadiene)Cl2 with 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl as the ligand, both electron-rich and electron-deficient aryl bromides and chlorides as well as heteroaryl bromides were successfully coupled with various picolinate salts under mild conditions in yields up to 96%. This protocol provides an efficient entry to 2-(hetero)arylpyridines, an attractive substance class in drug discovery.

Speaker identification in courtroom contexts - Part III: Groups of collaborating listeners compared to forensic voice comparison based on automatic-speaker-recognition technology.

Expert testimony is only admissible in common-law systems if it will potentially assist the trier of fact. In order for a forensic-voice-comparison expert's testimony to assist a trier of fact, the expert's forensic voice comparison should be more accurate than the trier of fact's speaker identification. "Speaker identification in courtroom contexts - Part I" addressed the question of whether speaker identification by an individual lay listener (such as a judge) would be more or less accurate than the output of a forensic-voice-comparison system that is based on state-of-the-art automatic-speaker-recognition technology. The present paper addresses the question of whether speaker identification by a group of collaborating lay listeners (such as a jury) would be more or less accurate than the output of such a forensic-voice-comparison system. As members of collaborating groups, participants listen to pairs of recordings reflecting the conditions of the questioned- and known-speaker recordings in an actual case, confer, and make a probabilistic consensus judgement on each pair of recordings. The present paper also compares group-consensus responses with "wisdom of the crowd" which uses the average of the responses from multiple independent individual listeners.

The role of technology use in food practices during the COVID-19 pandemic.

Over the last three years, COVID-19, with its lockdowns, social restrictions, and work from home structures, had a significant influence on our daily lives. The resulting changes in technology practices are likely to be explored in the years ahead. We will contribute to this exploration by looking specifically at the impact of COVID-19 on everyday food practices and the role of involved technology. To explore food practices and technology use, we conducted a qualitative interview study with 16 interviewees and delved into the underlying influencing factors behind them. Thereby we can better understand potential behavioral changes and technology usage by people to design not only for future pandemics and exceptional situations but to also for non-pandemic times.

Speaker identification in courtroom contexts - Part II: Investigation of bias in individual listeners' responses.

In "Speaker identification in courtroom contexts - Part I" individual listeners made speaker-identification judgements on pairs of recordings which reflected the conditions of the questioned-speaker and known-speaker recordings in a real case. The recording conditions were poor, and there was a mismatch between the questioned-speaker condition and the known-speaker condition. No contextual information that could potentially bias listeners' responses was included in the experiment condition - it was decontextualized with respect to case circumstances and with respect to other evidence that could be presented in the context of a case. Listeners' responses exhibited a bias in favour of the different-speaker hypothesis. It was hypothesized that the bias was due to the poor and mismatched recording conditions. The present research compares speaker-identification performance between: (1) listeners under the original Part I experiment condition, (2) listeners who were informed ahead of time that the recording conditions would make the recordings sound more different from one another than had they both been high-quality recordings, and (3) listeners who were presented with high-quality versions of the recordings. Under all experiment conditions, there was a substantial bias in favour of the different-speaker hypothesis. The bias in favour of the different-speaker hypothesis therefore appears not to be due to the poor and mismatched recording conditions.

The opacity myth: A response to Swofford & Champod (2022).

Swofford & Champod (2022) FSI Synergy article 100220 reports the results of semi-structured interviews that asked interviewees their views on probabilistic evaluation of forensic evidence in general, and probabilistic evaluation of forensic evidence performed using computational algorithms in particular. The interview protocol included a leading question based on the premise that machine-learning methods used in forensic inference are not understandable even to those who develop those methods. We contend that this is a false premise.

Speaker identification in courtroom contexts - Part I: Individual listeners compared to forensic voice comparison based on automatic-speaker-recognition technology.

Expert testimony is only admissible in common law if it will potentially assist the trier of fact to make a decision that they would not be able to make unaided. The present paper addresses the question of whether speaker identification by an individual lay listener (such as a judge) would be more or less accurate than the output of a forensic-voice-comparison system that is based on state-of-the-art automatic-speaker-recognition technology. Listeners listen to and make probabilistic judgements on pairs of recordings reflecting the conditions of the questioned- and known-speaker recordings in an actual case. Reflecting different courtroom contexts, listeners with different language backgrounds are tested: Some are familiar with the language and accent spoken, some are familiar with the language but less familiar with the accent, and others are less familiar with the language. Also reflecting different courtroom contexts: In one condition listeners make judgements based only on listening, and in another condition listeners make judgements based on both listening to the recordings and considering the likelihood-ratio values output by the forensic-voice-comparison system.

Validations of an alpha version of the E3 Forensic Speech Science System (E3FS3) core software tools.

This paper reports on validations of an alpha version of the E3 Forensic Speech Science System (E3FS3) core software tools. This is an open-code human-supervised-automatic forensic-voice-comparison system based on x-vectors extracted using a type of Deep Neural Network (DNN) known as a Residual Network (ResNet). A benchmark validation was conducted using training and test data (forensic_eval_01) that have previously been used to assess the performance of multiple other forensic-voice-comparison systems. Performance equalled that of the best-performing system with previously published results for the forensic_eval_01 test set. The system was then validated using two different populations (male speakers of Australian English and female speakers of Australian English) under conditions reflecting those of a particular case to which it was to be applied. The conditions included three different sets of codecs applied to the questioned-speaker recordings (two mismatched with the set of codecs applied to the known-speaker recordings), and multiple different durations of questioned-speaker recordings. Validations were conducted and reported in accordance with the "Consensus on validation of forensic voice comparison".

A strawman with machine learning for a brain: A response to Biedermann (2022) the strange persistence of (source) "identification" claims in forensic literature.

We agree wholeheartedly with Biedermann (2022) FSI Synergy article 100222 in its criticism of research publications that treat forensic inference in source attribution as an "identification" or "individualization" task. We disagree, however, with its criticism of the use of machine learning for forensic inference. The argument it makes is a strawman argument. There is a growing body of literature on the calculation of well-calibrated likelihood ratios using machine-learning methods and relevant data, and on the validation under casework conditions of such machine-learning-based systems.

Effects of Carbohydrate Restriction on Body Weight and Glycemic Control in Individuals with Type 2 Diabetes: A Randomized Controlled Trial of Efficacy in Real-Life Settings.

A fully provided, hypocaloric, carbohydrate-reduced high-protein (CRHP) diet compared to a hypocaloric conventional diabetes (CD) diet for 6 weeks improved glycemic control to a greater extent in face of an intended 6% weight loss in individuals with type 2 diabetes mellitus (T2DM). The present 24-week extension of that study reports on the efficacy of CRHP and CD diets in a real-life setting. Sixty-five individuals with T2DM who completed the initial 6-week fully provided diet period (% energy from carbohydrate, protein, and fat was 30/30/40 in CRHP, and 50/17/33 in CD) continued a free-living, dietician guided 24-week period of which 59 individuals completed. The CRHP compared to CD group reported a 4% lower carbohydrate intake and had higher urea excretion by 22% (both p ≤ 0.05) at week 30, suggesting less difference in carbohydrate and protein intake between groups during the 24-week extension compared to week 6. The loss of body weight during the initial 6 weeks was maintained in both groups during the 24-week extension (-5.5 ± 4.5 and -4.6 ± 4.8 kg) as well as HbA1c (-8.4 ± 6.2 and -8.4 ± 6.9 mmol/mol) with no significant differences between groups. The additional benefits on glucoregulation harnessed by carbohydrate restriction under full diet provision for 6 weeks combined with titrated weight loss could not be maintained in a real-life setting of self-prepared diet aiming on similar diets for 6 months.

Parasympathetic tonus in type 2 diabetes and pre-diabetes and its clinical implications.

Autonomic imbalance reflected by higher resting heart rate and reduced parasympathetic tone may be driven by low-grade inflammation (LGI) and impaired glycemic control in type 2 diabetes mellitus (T2DM) and pre-diabetes. We examined the interaction of parasympathetic components of heart rate variability (HRV), variables of LGI, and glucose metabolism in people with T2DM, pre-diabetes, and normal glucose metabolism (NGM). We recorded HRV by Holter (48 h) in 633 community-dwelling people of whom T2DM n = 131, pre-diabetes n = 372, and NGM n = 130 and mean HbA1c of 7.2, 6.0 and 5.3%, respectively. Age was 55-75 years and all were without known cardiovascular disease except from hypertension. Fasting plasma glucose, fasting insulin, HOMA-IR, HbA1c and LGI (CRP, Interleukin-18 (IL-18), and white blood cells) were measured. Root-mean-square-of-normal-to-normal-beats (RMSSD), and proportion of normal-to-normal complexes differing by more than 50 ms (pNN50) are accepted measures of parasympathetic activity. In univariate analyses, RMSSD and pNN50 were significantly inversely correlated with level of HbA1c and CRP among people with T2DM and pre-diabetes, but not among NGM. RMSSD and pNN50 remained significantly inversely associated with level of HbA1c after adjusting for age, sex, smoking, and BMI among people with T2DM (ß = - 0.22) and pre-diabetes (ß = - 0.11); adjustment for LGI, HOMA-IR, and FPG did not attenuate these associations. In backward elimination models, age and level of HbA1c remained associated with RMSSD and pNN50. In people with well controlled diabetes and pre-diabetes, a lower parasympathetic activity was more related to age and HbA1c than to markers of LGI. Thus, this study shows that the driver of parasympathetic tonus may be more the level of glycemic control than inflammation in people with prediabetes and well controlled diabetes.

Calculation of likelihood ratios for inference of biological sex from human skeletal remains.

It is common in forensic anthropology to draw inferences (e.g., inferences with respect to biological sex of human remains) using statistical models applied to anthropometric data. Commonly used models can output posterior probabilities, but a threshold is usually applied in order to obtain a classification. In the forensic-anthropology literature, there is some unease with this "fall-off-the-cliff" approach. Proposals have been made to exclude results that fall within a "zone of uncertainty", e.g., if the posterior probability for "male" is greater than 0.95 then the remains are classified as male, and if the posterior probability for "male" is less than 0.05 then the remains are classified as female, but if the posterior probability for "male" is between 0.05 and 0.95 the remains are not classified as either male or female. In the present paper, we propose what we believe is a simpler solution that is in line with interpretation of evidence in other branches of forensic science: implementation of the likelihood-ratio framework using relevant data, quantitative measurements, and statistical models. Statistical models that can implement this approach are already widely used in forensic anthropology. All that is required are minor modifications in the way those models are used and a change in the way practitioners and researchers think about the meaning of the output of those models. We explain how to calculate likelihood ratios using osteometric data and linear discriminant analysis, quadratic discriminant analysis, and logistic regression models. We also explain how to empirically validate likelihood-ratio models.

MedPath: A process-based modeling language for designing care pathways.

CONTEXT: Medical professionals and hospitals promote solutions like care pathways and Health Information Systems (HIS) to support medical conduct and improve the quality of medical care. PURPOSE: This study proposes MedPath: a Domain Specific Language (DSL) for modeling care pathways based on the paradigms of Model-Based Engineering (MBE) that can be integrated into software solutions. PROCEDURES: We have developed MedPath's abstract syntax with the Eclipse Modeling Framework by employing Ecore technology and concrete syntax with the Eclipse Sirius. FINDINGS: We have modeled over 85 care pathways that are in use in 45 hospitals in Brazil. MedPath-originated pathways have been used over 3.2 million times since October 2017. We conducted a survey among the professionals who used MedPath to evaluate user satisfaction. CONCLUSIONS: We believe MedPath can translate any care pathway into an action flow with its current abstractions. MedPath makes care pathways more easily integrated into HIS and electronic patient records, as it enables programmatic modeling and generates consumable artifacts.

Automated Verification of Care Pathways Using Constraint Programming.

Bad construction of modeled care pathways can lead to satisfiability problems during the pathway execution. These problems can ultimately result in medical errors and need to be checked as formally as possible. Therefore, this study proposes a set of algorithms using a free open-source library dedicated to constraint programming allied with a DSL to encode and verify care pathways, checking four possible problems: states in deadlock, non-determinism, inaccessible steps and transitions with logically equivalent guard conditions. We then test our algorithms in 84 real care pathways used both in hospitals and surgeries. Using our algorithms, we were able to find 200 problems taking less than 1 second to complete the verification on most pathways.

A scalable visualization environment for the correlation of radiological and histopathological data at multiple levels of resolution.

Until the introduction of non-invasive imaging techniques, the representation of anatomy and pathology relied solely on gross dissection and histological staining. Computerized Tomography (CT) and Magnetic Resonance Imaging (MRI) protocols allow for the clinical evaluation of anatomical images derived from complementary modalities, thereby increasing reliability of the diagnosis and the prognosis of disease. Despite the significant improvements in image contrast and resolution of MRI, autopsy and classical histopathological analysis are still indispensable for the correct diagnosis of specific disease. It is therefore important to be able to correlate multiple images from different modalities, in vivo and postmortem, in order to validate non-invasive imaging markers of disease. To that effect, we have developed a methodological pipeline and a visualization environment that allow for the concurrent observation of both macroscopic and microscopic image data relative to the same patient. We describe these applications and sample data relative to the study of the anatomy and disease of the Central Nervous System (CNS). The brain is approached as an organ with a complex 3-dimensional (3-D) architecture that can only be effectively studied combining observation and analysis at the system level as well as at the cellular level. Our computational and visualization environment allows seamless navigation through multiple layers of neurological data that are accessible quickly and simultaneously.

Ylide-Functionalized Phosphine (YPhos)-Palladium Catalysts: Selective Monoarylation of Alkyl Ketones with Aryl Chlorides.

Ylide-functionalized phosphine (YPhos) ligands allow the palladium-catalyzed α-arylation of alkyl ketones with aryl chlorides with record setting activity. Using a cyclohexyl-substituted YPhos ligand, a wide range of challenging ketone substrates was efficiently and selectively monoarylated under mild conditions. A newly designed YPhos ligand bearing tert-butyl groups on the coordinating phosphorus atom is already active at room temperature. The synthetic potential was demonstrated by gram-scale reactions and the succinct synthesis of ε-caprolactone derivatives.

Successful endovascular coil embolization of large pseudoaneurysm of ductus arteriosus diverticulum.

BACKGROUND: Pseudoaneurysm of the ductus arteriosus diverticulum, although rare in adults, may have catastrophic consequences if left untreated due to erosion and rupture of the pseudoaneurysm into adjacent thoracic structures. Although thoracic endovascular aortic repair (TEVAR) is the standard treatment method for aneurysm closure of the ductus arteriosus diverticulum, it was not possible in our patient secondary to marked aortoiliac access vessel tortuosity, significant vascular calcific burden, and an abdominal aortic aneurysm. We describe the first reported case of endovascular coil embolization being successfully used as the definite repair of a ductus arteriosus diverticulum pseudoaneurysm. CASE PRESENTATION: An 85-year-old man with history of severe coronary arterial disease presented with an enlarging pseudoaneurysm of a ductus arteriosus diverticulum. The diverticulum and thoracic aortic junction demonstrated the typical obtuse angles and wide neck, differentiating it from otherwise similar-appearing diagnostic considerations. Repair was attempted with conventional aortic stent graft but the patient's infrarenal abdominal aortic aneurysm and his heavily calcified, tortuous iliac vessels could not accommodate the 24Fr introducer sheath necessary for stent graft placement. Therefore, endovascular coil embolization was successfully completed through a 4Fr directional catheter. The patient tolerated the procedure well and was discharged from the hospital in good condition on post-embolization day six. CONCLUSIONS: Endovascular coil embolization is an alternative treatment for ductus arteriosus diverticulum pseudoaneurysm closure in cases where the standard TEVAR method is unsuccessful. Instead of the wide entry point at the aorta we used the junction of the diverticulum and pseudoaneurysm as the "neck" for satisfactory and stable coil placement. Endovascular coil embolization alone may be a viable definitive therapy for occlusion of the ductus pseudoaneurysm component of the diverticulum in cases where complex anatomy or extensive vascular disease makes stent graft repair impractical if not impossible.