Cardiac nitric oxide scavenging: role of myoglobin and mitochondria.

Vascular production of nitric oxide (NO) regulates vascular tone. However, highly permeable NO entering the cardiomyocyte would profoundly impact metabolism and signalling without scavenging mechanisms. The purpose of this study was to establish mechanisms of cardiac NO scavenging. Quantitative optical studies of normoxic working hearts demonstrated that micromolar NO concentrations did not alter mitochondria redox state or respiration despite detecting NO oxidation of oxymyoglobin to metmyoglobin. These data are consistent with proposals that the myoglobin/myoglobin reductase (Mb/MbR) system is the major NO scavenging site. However, kinetic studies in intact hearts reveal a minor role (∼9%) for the Mb/MbR system in NO scavenging. In vitro, oxygenated mitochondria studies confirm that micromolar concentrations of NO bind cytochrome oxidase (COX) and inhibit respiration. Mitochondria had a very high capacity for NO scavenging, importantly, independent of NO binding to COX. NO is also known to quickly react with reactive oxygen species (ROS) in vitro. Stimulation of NO scavenging with antimycin and its inhibition by substrate depletion are consistent with NO interacting with ROS generated in Complex I or III under aerobic conditions. Extrapolating these in vitro data to the intact heart supports the hypothesis that mitochondria are a major site of cardiac NO scavenging. KEY POINTS: Cardiomyocyte scavenging of vascular nitric oxide (NO) is critical in maintaining normal cardiac function. Myoglobin redox cycling via myoglobin reductase has been proposed as a major NO scavenging site in the heart. Non-invasive optical spectroscopy was used to monitor the effect of NO on mitochondria and myoglobin redox state in intact beating heart and isolated mitochondria. These non-invasive studies reveal myoglobin/myoglobin reductase plays a minor role in cardiac NO scavenging. A high capacity for NO scavenging by heart mitochondria was demonstrated, independent of cytochrome oxidase binding but dependent on oxygen and high redox potentials consistent with generation of reactive oxygen species.

A phase 3b study of venetoclax and azacitidine or decitabine in an outpatient setting in patients with acute myeloid leukemia.

Venetoclax, a highly selective BCL-2 inhibitor, combined with hypomethylating agents (HMAs) azacitidine or decitabine, is approved for the treatment of newly diagnosed acute myeloid leukemia (ND AML) in patients who are ineligible to receive intensive chemotherapy. Previous clinical studies initiated venetoclax plus HMA in an inpatient setting owing to concerns of tumor lysis syndrome (TLS). This study (NCT03941964) evaluated the efficacy and safety of venetoclax plus HMA in a United States community-based outpatient setting in patients with ND AML (N = 60) who were treatment naïve for AML, ineligible to receive intensive chemotherapy, had no evidence of spontaneous TLS at screening, and were deemed as appropriate candidates for outpatient initiation of venetoclax plus HMA by the investigator. Patients received venetoclax in combination with azacitidine (75 mg/m2) or decitabine (20 mg/m2) for up to 6 cycles during the study. With a median time on study of 18.3 weeks, the best response rate of composite complete remission was 66.7%, and the overall post-baseline red blood cell (RBC) and platelet transfusion independence rate was 55.0%, consistent with results of studies in which treatment was initiated in an inpatient setting. Key adverse events included nausea, anemia, thrombocytopenia, neutropenia, and white blood cell count decrease of any grade (≥50% of patients). The observed safety profile was generally consistent with that of venetoclax plus HMA observed in inpatient AML studies. With close monitoring, 2 cases of TLS were identified, appropriately managed, and the patients were able to continue study treatment. CLINICAL TRIALS REGISTRATION: This study is registered at ClinicalTrials.gov. The registration identification number is NCT03941964.

Minimally invasive approach for retrorectal tumors above and below S3: a multicentric tertiary center retrospective study (MiaRT study).

BACKGROUND: Retrorectal tumors are uncommon lesions developed in the retrorectal space. Data on their minimally invasive resection are scarce and the optimal surgical approach for tumors below S3 remains debated. METHODS: We performed a retrospective review of consecutive patients who underwent minimally invasive resection of retrorectal tumors between 2005 and 2022 at two tertiary university hospital centers, by comparing the results obtained for lesions located above or below S3. RESULTS: Of over 41 patients identified with retrorectal tumors, surgical approach was minimally invasive for 23 patients, with laparoscopy alone in 19, with transanal excision in 2, and with combined approach in 2. Retrorectal tumor was above S3 in 11 patients (> S3 group) and below S3 in 12 patients (< S3 group). Patient characteristics and median tumor size were not significantly different between the two groups (60 vs 67 mm; p = 0.975). Overall median operative time was 131.5 min and conversion rate was 13% without significant difference between the two groups (126 vs 197 min and 18% vs 8%, respectively; p > 0.05). Final pathology was tailgut cyst (48%), schwannoma (22%), neural origin tumor (17%), gastrointestinal stromal tumor (4%), and other (19%). The 90-day complication rates were 27% and 58% in the > S3 and < S3 groups, respectively, without severe morbidity or mortality. After a median follow-up of 3.3 years, no recurrence was observed in both groups. Three patients presented chronic pain, three anal dysfunction, and three urinary dysfunction. All were successfully managed without reintervention. CONCLUSIONS: Minimally invasive surgery for retrorectal tumors can be performed safely and effectively with low morbidity and no mortality. Laparoscopic and transanal techniques alone or in combination may be recommended as the treatment of choice of benign retrorectal tumors, even for lesions below S3, in centers experienced with minimally invasive surgery.

Risk factors for severe morbidity and definitive stoma after elective surgery for sigmoid diverticulitis: a multicenter national cohort study.

BACKGROUND: In the decision to perform elective surgery, it is of great interest to have data about the outcomes of surgery to individualize patients who could safely undergo sigmoid resection. The aim of this study was to provide information on the outcomes of elective sigmoid resection for sigmoid diverticular disease (SDD) at a national level. METHODS: All consecutive patients who had elective surgery for SDD (2010-2021) were included in this retrospective, multicenter, cohort study. Patients were identified from institutional review board-approved databases in French member centers of the French Surgical Association. The endpoints of the study were the early and the long-term postoperative outcomes and an evaluation of the risk factors for 90-day severe postoperative morbidity and a definitive stoma after an elective sigmoidectomy for SDD. RESULTS: In total, 4617 patients were included. The median [IQR] age was 61 [18.0;100] years, the mean ± SD body mass index (BMI) was 26.8 ± 4 kg/m2, and 2310 (50%) were men. The indications for surgery were complicated diverticulitis in 50% and smoldering diverticulitis in 47.4%. The procedures were performed laparoscopically for 88% and with an anastomosis for 83.8%. The severe complication rate on postoperative day 90 was 11.7%, with a risk of anastomotic leakage of 4.7%. The independent risk factors in multivariate analysis were an American Society of Anesthesiologists (ASA) score ≥ 3, an open approach, and perioperative blood transfusion. Age, perioperative blood transfusion, and Hartmann's procedure were the three independent risk factors for a permanent stoma. CONCLUSIONS: This series provides a real-life picture of elective sigmoidectomy for SDD at a national level. TRIAL REGISTRATION: Comité National Information et Liberté (CNIL) (n°920361).

Hospitalization and hospital mortality rates during the first and second waves of the COVID-19 pandemic in Quebec: interrupted time series and decomposition analysis.

OBJECTIVES: We investigated hospitalization and hospital mortality rates by cause during the first year of the COVID-19 pandemic in Quebec, Canada. STUDY DESIGN: Interrupted time series and decomposition analysis. METHODS: We analyzed hospital mortality during the first (February 25-August 22, 2020) and second waves (August 23, 2020-March 31, 2021), compared with 2019. We identified the cause of death and examined trends using: 1) interrupted time series analysis; 2) log-binomial regression; and 3) decomposition of cause-specific mortality. RESULTS: Hospitalization rates decreased; however, the proportion of deaths increased from 27.0 per 1000 in 2019 to 35.0 per 1000 in the first wave, for an excess of 8.0 deaths per 1000 admissions. COVID-19 was the cause of a third of excess deaths (2.6 per 1000). Other drivers of excess deaths included respiratory conditions (1.6 deaths per 1000), circulatory disorders (0.6 deaths per 1000), and cancer (0.9 deaths per 1000). COVID-19 was the cause of 58% of excess deaths in the second wave. Interrupted time series regression indicated that the proportion of deaths increased at the outset of the first wave but returned to prepandemic levels before increasing again in the second wave. Compared with 2019, the first wave was associated with 1.31 times (95% confidence interval [CI] 1.28-1.33) and the second wave with 1.17 times (95% CI 1.15-1.19) the risk of death during hospitalization. CONCLUSIONS: The pandemic was associated with a greater risk of hospital mortality. Excess deaths were driven by COVID-19 but also other causes, including respiratory conditions, circulatory disorders, and cancer.

Doublecortin mutation leads to persistent defects in the Golgi apparatus and mitochondria in adult hippocampal pyramidal cells.

Human doublecortin (DCX) mutations are associated with severe brain malformations leading to aberrant neuron positioning (heterotopia), intellectual disability and epilepsy. DCX is a microtubule-associated protein which plays a key role during neurodevelopment in neuronal migration and differentiation. Dcx knockout (KO) mice show disorganized hippocampal pyramidal neurons. The CA2/CA3 pyramidal cell layer is present as two abnormal layers and disorganized CA3 KO pyramidal neurons are also more excitable than wild-type (WT) cells. To further identify abnormalities, we characterized Dcx KO hippocampal neurons at subcellular, molecular and ultrastructural levels. Severe defects were observed in mitochondria, affecting number and distribution. Also, the Golgi apparatus was visibly abnormal, increased in volume and abnormally organized. Transcriptome analyses from laser microdissected hippocampal tissue at postnatal day 60 (P60) highlighted organelle abnormalities. Ultrastructural studies of CA3 cells performed in P60 (young adult) and > 9 months (mature) tissue showed that organelle defects are persistent throughout life. Locomotor activity and fear memory of young and mature adults were also abnormal: Dcx KO mice consistently performed less well than WT littermates, with defects becoming more severe with age. Thus, we show that disruption of a neurodevelopmentally-regulated gene can lead to permanent organelle anomalies contributing to abnormal adult behavior.

The Effects of a Perindopril-Based Regimen in Relation to Statin Use on the Outcomes of Patients with Vascular Disease: a Combined Analysis of the ADVANCE, EUROPA, and PROGRESS Trials.

PURPOSE: To study the effects of a perindopril-based regimen on cardiovascular (CV) outcomes in patients with vascular disease in relation to background statin therapy. METHODS: A pooled analysis of the randomized ADVANCE, EUROPA, and PROGRESS trials was performed to evaluate CV outcomes in 29,463 patients with vascular disease treated with perindopril-based regimens versus placebo. The primary endpoint was a composite of CV mortality, nonfatal myocardial infarction, and stroke. Multivariable Cox regression analyses were performed to assess the effects of a perindopril-based regimen versus placebo in relation to statin use. RESULTS: At randomization, 39.5% of the overall combined study population used statins. After a mean follow-up of 4.0 years (SD 1.0), the cumulative event-free survival was highest in the statin/perindopril group and lowest in the no statin/placebo group (91.2% vs. 85.6%, respectively, log-rank p < 0.001). In statin users (adjusted hazard ratio [aHR] 0.87, 95% confidence interval [CI] 0.77-0.98) and non-statin users (aHR 0.80, 95% CI 0.74-0.87), a perindopril-based regimen was associated with a significantly lower risk of the primary endpoint when compared to placebo. The additional treatment effect appeared numerically greater in non-statin users, but the observed difference was statistically nonsignificant. CONCLUSION: Our data suggest that the treatment benefits of a perindopril-based regimen in patients with vascular disease are independent of statin use.

On the Mortality of Companies.

Using data from both the US and UK we examine the survival and mortality of companies in both the early stage or start-up and mature phases. The shape of the mortality curve is broadly similar to that of humans. Even small single cellular organisms such as rotifers have a similar shape. The mortality falls in the early stages in a hyperbolic manner until around 20-30 years when it begins to rise broadly according to the Gompertz exponential law. To explain in simple terms these features we adapt the MinMax model introduced by the authors elsewhere to explain the shape of the human mortality curve.

[The contribution of teleconsultation and isolation of symptomatic cases in control of the COVID-19 outbreak a military base]. / Apport de la téléconsultation et de l'isolement des cas symptomatiques dans la maîtrise de l'épidémie COVID-19 au sein d'une base militaire.

BACKGROUND: The first wave of COVID-19 swept over France during the first quarter of 2020, leading to saturation of the health care system. We wished to study, in a French military medical unit assisting one of the country's largest armed forces populations, the impact of teleconsultation and the systematic isolation of all possible, probable and confirmed cases of COVID-19. METHODS: This is a retrospective study carried out from March 9 to May 31, 2020 on the basis of our activity register. The variables collected included type of medical consultation procedure, occupational status, classification of cases and date of onset of first symptoms. We have paralleled our activity with that of SOS Médecins and the emergency departments of the Île-de-France region. RESULTS/DISCUSSION: During this period, 1719 episodes of care (teleconsultations or physical consultations) were recorded, of which 91% (n=1561) were linked to COVID-19. We identified 598 "suspected" (possible and probable) and confirmed cases. "Isolated" teleconsultations (not followed by a face-to-face medical consultation, sample taking or necessitating the dispatch of prompt assistance) represented 86% of episodes of care (n=1482). Comparison of our activity and the number of new cases with the databases of SOS Médecins and the Île-de-France emergency services suggests that our isolation strategy was timely and effective. CONCLUSION: The contribution of teleconsultation was substantial and reassuring. Teleconsultation makes it possible to absorb a large volume of patients, is easy to implement, and entails no nosocomial risk. Isolation of infected patients should be a priority during an outbreak. Once it has become a priority to rapidly bring an epidemic under control, this attitude must be extended to all symptomatic patients.

A joint explanation of infant and old age mortality.

Infant deaths and old age deaths are very different. The former are mostly due to severe congenital malformations of one or a small number of specific organs. On the contrary, old age deaths are largely the outcome of a long process of deterioration which starts in the 20s and affects almost all organs. In terms of age-specific death rates, there is also a clear distinction: the infant death rate falls off with age, whereas the adult and old age death rate increases exponentially with age in conformity with Gompertz's law. An additional difference is that whereas aging and old age death have been extensively studied, infant death received much less attention. To our knowledge, the two effects have never been inter-connected. Clearly, it would be satisfactory to explain the two phenomena as being two variants within the same explanatory framework. In other words, a mechanism providing a combined explanation for the two forms of mortality would be welcome. This is the purpose of the present paper. We show here that the same biological effects can account for the two cases provided there is a difference in their severity: death triggered by isolated lethal anomalies in one case and widespread wear-out anomalies in the second. We show that quite generally this mechanism leads indeed, respectively, to a declining and an upgoing death rate. Moreover, this theoretical framework leads to the conjecture that the severity of the death effects, whether in infancy or old age, is higher for organisms which comprised a larger number of organs. Finally, let us observe that the main focus of the paper is the drastic difference of the age-specific death rates (i.e., decreasing versus increasing) because this difference is found in many species, whereas the question of the best fit (e.g., Gompertz versus Weibull) is rather specific to human mortality.

Direct visualization of the arterial wall water permeability barrier using CARS microscopy.

The artery wall is equipped with a water permeation barrier that allows blood to flow at high pressure without significant water leak. The precise location of this barrier is unknown despite its importance in vascular function and its contribution to many vascular complications when it is compromised. Herein we map the water permeability in intact arteries, using coherent anti-Stokes Raman scattering (CARS) microscopy and isotopic perfusion experiments. Generation of the CARS signal is optimized for water imaging with broadband excitation. We identify the water permeation barrier as the endothelial basolateral membrane and show that the apical membrane is highly permeable. This is confirmed by the distribution of the AQP1 water channel within endothelial membranes. These results indicate that arterial pressure equilibrates within the endothelium and is transmitted to the supporting basement membrane and internal elastic lamina macromolecules with minimal deformation of the sensitive endothelial cell. Disruption of this pressure transmission could contribute to endothelial cell dysfunction in various pathologies.

Magnitude and significance of the peak of early embryonic mortality.

Embryonic development is of great importance because it determines congenital anomalies and influences their severity. However, little is known about the actual probabilities of success or failure and about the nature of early embryonic defects. Here, we propose that the analysis of embryonic mortality as a function of post-fertilization time provides a simple way to identify major defects. By reviewing the literature, we show that even small initial defects, e.g., spatial cellular asymmetries or irregularities in the timing of development, carry with them lethal effects in subsequent stages of embryogenesis. Although initially motivated by human study, in this contribution, we review the few embryonic mortality data available for farm animals and highlight zebrafish as a particularly suited organism for such a kind of study because embryogenesis can be followed from its very beginning and observed easily thanks to eggshell transparency. In line with the few other farm animals for which data are available, we provide empirical evidence that embryonic mortality in zebrafish has a prominent peak shortly after fertilization. Indeed, we show how subsequent mortality rates decay according to a power law, supporting the role of the early embryonic mortality peak as a screening process rapidly removing defective embryos.

Physical models of infant mortality: implications for defects in biological systems.

Reliability engineering concerned with failure of technical inanimate systems usually uses the vocabulary and notions of human mortality, e.g., infant mortality vs. senescence mortality. Yet, few data are available to support such a parallel description. Here, we focus on early-stage (infant) mortality for two inanimate systems, incandescent light bulbs and soap films, and show the parallel description is clearly valid. Theoretical considerations of the thermo-electrical properties of electrical conductors allow us to link bulb failure to inherent mechanical defects. We then demonstrate the converse, that is, knowing the failure rate for an ensemble of light bulbs, it is possible to deduce the distribution of defects in wire thickness in the ensemble. Using measurements of lifetimes for soap films, we show how this methodology links failure rate to geometry of the system; in the case presented, this is the length of the tube containing the films. In a similar manner, for a third example, the time-dependent death rate due to congenital aortic valve stenosis is related to the distribution of degrees of severity of this condition, as a function of time. The results not only validate clearly the parallel description noted above, but also point firmly to application of the methodology to humans, with the consequent ability to gain more insight into the role of abnormalities in infant mortality.

MRI-based score to predict surgical difficulty in patients with rectal cancer.

BACKGROUND: Rectal cancer surgery is technically challenging and depends on many factors. This study evaluated the ability of clinical and anatomical factors to predict surgical difficulty in total mesorectal excision. METHODS: Consecutive patients who underwent total mesorectal excision for locally advanced rectal cancer in a laparoscopic, robotic or open procedure after neoadjuvant treatment, between 2005 and 2014, were included in this retrospective study. Preoperative clinical and MRI data were studied to develop a surgical difficulty grade. RESULTS: In total, 164 patients with a median age of 61 (range 26-86) years were considered to be at low risk (143, 87·2 per cent) or high risk (21, 12·8 per cent) of surgical difficulty. In multivariable analysis, BMI at least 30 kg/m2 (P = 0·021), coloanal anastomosis (versus colorectal) (P = 0·034), intertuberous distance less than 10·1 cm (P = 0·041) and mesorectal fat area exceeding 20·7 cm2 (P = 0·051) were associated with greater surgical difficulty. A four-item score (ranging from 0 to 4), with each item (BMI, type of surgery, intertuberous distance and mesorectal fat area) scored 0 (absence) or 1 (presence), is proposed. Patients can be considered at high risk of a difficult or challenging operation if they have a score of 3 or more. CONCLUSION: This simple morphometric score may assist surgical decision-making and comparative study by defining operative difficulty before surgery.

Coupling between death spikes and birth troughs. Part 1: Evidence.

In the wake of the influenza pandemic of 1889-1890 Jacques Bertillon, a pioneer of medical statistics, noticed that after the massive death spike there was a dip in birth numbers around 9 months later which was significantly larger than that which could be explained by the population change as a result of excess deaths. In addition it can be noticed that this dip was followed by a birth rebound a few months later. However having made this observation, Bertillon did not explore it further. Since that time the phenomenon was not revisited in spite of the fact that in the meanwhile there have been several new cases of massive death spikes. The aim here is to analyze these new cases to get a better understanding of this death-birth coupling phenomenon. The largest death spikes occurred in the wake of more recent influenza pandemics in 1918 and 1920, others were triggered by the 1923 earthquakes in Tokyo and the Twin Tower attack on September 11, 2001. We shall see that the first of these events indeed produced an extra dip in births whereas the 9/11 event did not. This disparity highlights the pivotal role of collateral sufferers. In the last section it is shown how the present coupling leads to predictions; it can explain in a unified way effects which so far have been studied separately, as for instance the impact on birth rates of heat waves. Thus, it appears that behind the apparent randomness of birth rate fluctuations there are in fact hidden explanatory factors.

Three-dimensional computer-assisted dissection of pancreatic lymphatic anatomy on human fetuses: a step toward automatic image alignment.

PURPOSE: Pancreatic cancer is the fourth cause of death by cancer worldwide. Lymph node (LN) involvement is known to be the main prognostic factor. However, lymphatic anatomy is complex and only partially characterized. The aim of the study was to study the pancreatic lymphatic system using computer-assisted anatomic dissection (CAAD) technique and also to update CAAD technique by automatizing slice alignment. METHODS: We dissected three human fetuses aged from 18 to 34 WA. 5-µm serial sections of duodeno-pancreas and spleen blocks were stained (hematoxylin-eosin, hematoxylin of Mayer and Masson trichrome), scanned, aligned and modeled in three dimensions. RESULTS: We observed a rich, diffuse but not systematized lymphatic network in the peri-pancreatic region. There was an equal distribution of LNs between the cephalic and body-tail portions. The lymphatic vascularization appeared in continuity from the celiac trunk to the distal ends of its hepatic and splenic arterial branches parallel to the nerve ramifications of the celiac plexus. We also observed a continuity between the drainage of the pancreatic head and the para-aortic region posteriorly. CONCLUSION: In view of the wealth of peri-pancreatic LNs, the number of LNs to harvest could be increased to improve nodal staging and prognostic evaluation. Pancreatic anatomy as described does not seem to be compatible with the sentinel LN procedure in pancreatic surgery. Finally, we are now able to offer an alternative to manual alignment with a semi-automated alignment.

[Involuntary psychiatric care for inmates in France: Only for "dangerous" patients?] / Les soins psychiatriques sans consentement en milieu pénitentiaire sont-ils réservés aux patients « dangereux ¼ ?

The unités hospitalières spécialement aménagées (UHSA) are full-time inpatient psychiatric units for inmates in France. Their creation has been associated with several advances in access to psychiatric care for inmates in recent years. However, there is still only one means of involuntary hospitalization for prisoners in France: care by decision of a representative of the state (les soins sur décision d'un représentant de l'état [SDRE]). Interestingly, for SDRE to be recognized as legal by the French judge, the patient must be "a danger to himself or to the others". Thus, there is a major difference with involuntary hospitalization outside the prison, and there are specific criteria for involuntary psychiatric hospitalization for inmates in France. This situation questions the general framework of involuntary psychiatric care and is very inconsistent with French law. Indeed, the goal of the loi no 94-43 du 18 janvier 1994 relating to public health and social protection is to ensure equivalent care for all patients, incarcerated or not.

[Diagnosis and treatment of scabies by general practitioners: A survey of practices in France]. / Description des pratiques des médecins généralistes dans le diagnostic et la prise en charge de la gale commune.

BACKGROUND: Although there is evidence suggesting an epidemiologic increase of scabies in France, few studies have assessed medical practice in terms of diagnosis and treatment. OBJECTIVES: To describe the management of scabies by general practitioners (GPs). PATIENTS AND METHODS: A questionnaire was addressed to the 524 GPs of the Doubs department in France regarding the management of cases of scabies diagnosed between January and June 2015. RESULTS: The response rate was 57 % (n=299). At least one case of scabies was observed by 89 % of GPs in the previous six months and more than three cases were diagnosed by 59 % of GPs. The main clinical criterion for diagnosis was the specific localization of pruritus (82 %). No diagnostic test was used by 94 % of GPs other than except direct parasitological examination, which was used by 6 %. A systematic examination by a dermatologist was prescribed by 3 % of GPs, by 78 % of them in the case of diagnostic doubt, and not at all by 19 %, even though 66 % of GPs' offices were located under 10 kilometers from a dermatologist's office. Ivermectin (IVM) alone was prescribed by 38 % of GPs, either as a single dose (22 %) or as two repeated doses (16 %). Topical treatment alone was prescribed by 2 % of GPs and the association of IVM and topical treatment was used by 26 %, either as a single dose (19 %) or as two repeated doses (7 %). All household members and any sexual contacts were systematically treated by 77 % of GPs, but 9 % did not prescribe any treatment. Decontamination advice was given by 100 % of GPs. Recurrence of scabies was observed by 25 % of GPs despite systematic treatment (93 %) of patients' close contacts. DISCUSSION: Our study confirms the frequency of scabies in general medicine and the interest of GPs in this evaluation of practice. Our data also demonstrate the heterogeneity of management by GPs and the limitations of/poor compliance with national recommendations on scabies proposed by the Haut conseil de santé publique (Public Health Council) in 2012. CONCLUSION: Our study emphasizes the critical role of GPs in the management of scabies and the need for specific recommendations concerning their practices.

The Treatment Effect of an ACE-Inhibitor Based Regimen with Perindopril in Relation to Beta-Blocker use in 29,463 Patients with Vascular Disease: a Combined Analysis of Individual Data of ADVANCE, EUROPA and PROGRESS Trials.

INTRODUCTION: In everyday practice, angiotensin converting enzyme inhibitors and beta-blockers are cornerstone treatments in patients with (cardio-)vascular disease. Clear data that evaluate the effects of the combination of these agents on morbidity and mortality are lacking. METHODS: In this retrospective pooled analysis of three large perindopril outcome trials (ADVANCE, EUROPA, PROGRESS), clinical outcomes were evaluated in 29,463 patients with vascular disease. Multivariate Cox regression analyses were performed in patients randomized to a perindopril-based regimen or placebo (treatment effect), and data were stratified according to background beta-blocker treatment. The primary endpoint was a composite of cardiovascular mortality, non-fatal myocardial infarction, and stroke. RESULTS: The cumulative incidence of the primary endpoint over mean follow-up of 4.0 years (Sd 1.0) was significantly lower in the beta-blocker/perindopril group (9.6%; 545/5700 patients) as compared to beta-blocker/placebo (11.8%; 676/5718 patients) (p < 0.01). Adding perindopril to existing beta-blocker treatment reduced the relative risk of the primary endpoint by 20% (hazard ratio (HR) 0.80; 95% confidence interval (CI) 0.71-0.90), non-fatal myocardial infarction by 23% (HR 0.77; 95% CI 0.65-0.91), and all-cause mortality by 22% (HR 0.78; 95% CI 0.68-0.88) as compared to placebo. Significant treatment benefit was not observed for stroke (HR 0.93; 95% CI 0.75-1.15). Significance was maintained for the primary endpoint and cardiovascular endpoints when data were further stratified by baseline hypertension. However, the mortality benefit was only observed in patients with hypertension with background beta-blocker use. CONCLUSIONS: These data suggest that the beneficial cardioprotective effects of perindopril treatment are additive to the background beta-blockers use.

Three-dimensional stereophotogrammetric analysis of 50 smiles: A study of dento-facial proportions.

OBJECTIVES: The purpose of this study was to analyze 50 smiles using 3D stereophotogrammetry (3D-spg)-based facial reconstruction, to calculate ratios involving measurements of the distances between dental and facial landmarks and to compare these ratios with the golden ratio φ (1.618). MATERIALS AND METHODS: Fifty subjects with no obvious malocclusion participated in this study. For each subject, 4 photographs were acquired using the LifeViz Mini™, an absolute calibration 3D-spg system. Facial and dental landmarks (based on Farkas' definitions) were fixed, and 8 distances were measured. Four ratios were then calculated and compared with the value of 1.618. RESULTS: The ratio "incisal edge of the maxillary central incisor-lower border of the chin/subnasal point-incisal edge of the maxillary central incisor" (IE-Me/SN-IE) was 1.693 ± 0.190, the ratio "right endocanthion-left endocanthion/right exocanthion-right endocanthion" was 1.582 ± 0.173, the ratio "incisal edge of the maxillary central incisor-distal edge of the right canine/distal edge of the right canine-right labial commissure" was 1.670 ± 0.355, and the ratio "right labial commissure-left labial commissure/distal edge of the right canine-distal edge of the left canine" was 1.602 ± 0.136. In contrast, the vertical ratio IE-Me/SN-IE significantly differed from the golden ratio (1 sample t test, P = .009). CONCLUSION: This study revealed that the observed ratios were surprisingly close to the golden ratio. Only the vertical ratio differed from the golden ratio, whereas the horizontal ratios appear to be adequately approximated by φ. CLINICAL SIGNIFICANCE: If the distances from reference points of the face to teeth within a harmonious smile exhibited recurring esthetic proportions, knowledge of such ratios would provide an additional tool for the elaboration of esthetic treatment plans. In addition, this knowledge could provide guidance when planning tooth positions and dental proportions by encouraging consideration of the global nature of the oro-facial sphere.