West Africa is experiencing its first epidemic of Ebola virus disease (Ebola) . As of FOutbreaks in remote areas posed a significant challenge to CHTs to mount an effective investigation and rapid response because of limited resources, personnel, and means to reach remote areas. The RITE strategy provided a framework to coordinate assistance from the central MOHSW and other agencies under the leadership of the CHT and developed several tools to help plan, manage, and track a response effort. The objectives of the investigation and response teams were to 1) rapidly isolate and treat Ebola patients, either by establishing isolation and treatment facilities in the community or by safely transporting patients to existing Ebola treatment units (ETUs); 2) ensure proper collection and safe transportation of samples for Ebola laboratory confirmation; 3) ascertain the index case (the first person in the transmission chain who entered the community from another county in Liberia) in each outbreak to better understand importation and transmission patterns; 4) identify all generations of cases by improving case finding and contact tracing to ensure no cases were missed; 5) train teams in safe burial procedures; and 6) observe contacts for 21 days from the death or ETU admission of the last case to ensure interruption of transmission. Investigation and response teams included Liberian MOHSW national and county representatives, CDC, WHO, the United Nations Children’s Fund, and other multilateral and nongovernmental organizations.The RITE strategy clearly articulated the role of CHTs to coordinate efforts of partners involved in response activities to rapidly mobilize resources that could be tailored to the needs in each outbreak. After initiation of the RITE strategy in October, outbreak responses were supported with structured rapid response microplanning tools implemented by CHTs that delineated each intervention component  and the organizations responsible for implementation. Outbreaks and response activities were reviewed on a weekly basis at the national level at the county operations subcommittee of the national incident management system , allowinFor this report, Ebola outbreaks that occurred in remote areas, produced at least one generation of transmission in the community and had complete investigations were analyzed. An Ebola outbreak was defined as two or more epidemiologically linked Ebola cases. Cases were classified as suspected, probable, or confirmed using the Liberian case definitions .Initial alerts of possible Ebola outbreaks were received by CHTs as rumors, reports of clusters of ill persons or unexplained deaths, or reports of patients admitted to ETUs. Case investigation reports were gathered through interviews with ill persons or their proxies. Databases from ETUs were searched to supplement incomplete case investigation reports. Transmission-chain diagrams were constructed back to the first case to enter the county from another county in Liberia (the index case). The first generation of cases was defined as resulting from contact with the index patient, and the total number of generations was determined from the transmission-chain diagrams. To monitor the effectiveness of rapid response to outbreaks over time, the number of days between the symptom onset of the index patient and the date the CHT was first alerted to a potential outbreak, and the date the CHT first sent in a team to investigate were computed for each outbreak. Outbreak duration was calculated as the number of days between the symptom onset date of the index case and the last case in the outbreak, defined as the last case in a chain of transmission to occur before 21 days passed with no new cases. Demographic characteristics of patients and the proportion of patients isolated and treated in an ETU or similar facility were summarized by outbreak.Among 15 Ebola outbreaks in remote areas of nine counties with index case symptom onset dates during July 16–November 20, 2014, 12 investigations had complete data . InvestiThe median time between symptom onset in the index patient and an alert received by the CHT was 33 days (range = 0–58 days); the median time to alert was 40 days for the six outbreaks before October 1 (prior to initiation of the RITE strategy) and 25 days for the six outbreaks with onset after October 1 (after the RITE strategy) . The medInterventions in the 12 outbreaks included 1) engagement of traditional and community leaders in response activities; 2) community education about Ebola virus transmission and prevention; 3) active case finding, contact tracing and monitoring; 4) quarantine of asymptomatic high risk contacts at home or in designated quarantine facilities; 5) isolation and treatment of patients; and 6) safe burials. In each community, the appropriate level of intervention was determined by the community’s requests, the number and severity of cases, the remoteness and accessibility of the community, and the distance to Ebola treatment facilities. Resistance to assistance was encountered in several communities, and response was suspended until discussions with county and traditional officials or the increasing burden of cases and deaths encouraged community acceptance of intervention. In two outbreaks , the availability of nongovernmental partners to rapidly establish isolation and treatment facilities permitted on-site or nearby care of patients. In these and other outbreaks, some patients were able to reach ambulances at the closest road access point and were taken to established ETUs. In one outbreak , delays in the establishment of an isolation and treatment facility resulted in only one patient being cared for in the facility before the outbreak was over.Over time, the proportion of patients in each outbreak that were isolated and treated increased from a median of 28% in the early outbreaks to 81% in the later outbreaks . The proImplementing an effective rapid response is critical to limiting the magnitude and duration of Ebola outbreaks. The remoteness and complexity of the outbreaks described in this report have posed challenges to rapid response; movement of personnel and supplies was greatly hindered by distance, river crossings, poor or nonexistent roads , and limFour of the six outbreaks that occurred before development of the RITE strategy remained undetected until they were in at least the third generation of transmission, whereas five of the six later outbreaks were detected in the first or second generation. In addition to the RITE strategy, greater community awareness of Ebola helped alert authorities earlier to clusters of unexplained deaths or illness consistent with Ebola and also facilitated faster community acceptance of interventions. Availability of ETU beds for isolation and treatment of patients also improved significantly over the period covered by these outbreaks , and theWhat is already known on this topic?The epidemic in West Africa has resulted in the largest number of Ebola cases in history. Ebola is associated with a high case-fatality rate that can be reduced through supportive care. Ebola transmission can be interrupted through isolation of infected patients, infection control, monitoring of patients’ contacts, and safe burial of dead bodies. Remote rural areas pose challenges for rapid isolation and treatment of patients because of their distance, difficult access, and lack of communications infrastructure.What is added by this report?A national strategy in Liberia to coordinate rapid responses to remote outbreaks of Ebola reduced by nearly half the time between the first new case in remote areas and notification of health authorities. As coordination of the rapid response strategy improved over time, the median duration of outbreaks decreased from 53 to 25 days as the number of generations of cases decreased from a median of four to two. The proportion of patients isolated increased from 28% to 81%; survival improved from 13% to 50%.What are the implications for public health practice?Ebola outbreaks in remote rural areas require rapid responses, including the movement of patients to treatment facilities. Interventions can be as simple as arranging safe ambulance transport for patients who might have to walk out of remote areas, but might also require establishment of mobile isolation and treatment facilities if patients are too ill to move or delays in transport are anticipated. Comprehensive and innovative rapid response units can improve outcomes and shorten duration of Ebola outbreaks, and should be employed wherever possible.


Volar locking plate fixation of distal radius fractures is commonly performed because of its good clinical outcomes. The flexor carpi radialis (FCR) approach is one of the most popular approaches to dissecting the volar side of the distal radius because of its simplicity and safety. We describe an extremely rare case of an absent FCR identified during a volar approach for fixation of a distal radius fracture.A 59-year-old woman with distal radius fracture underwent surgery using the usual FCR approach and volar locking plate. We could not identify the absence of the FCR tendon preoperatively because of severe swelling of the distal forearm. At first, we wrongly identified the palmaris longus tendon as the FCR because it was the tendinous structure at the most radial location of the volar distal forearm. When we found the median nerve just radial to the palmaris longus tendon, we were then able to identify the anatomical abnormality in this case. To avoid iatrogenic neurovascular injuries, we changed the approach to the classic Henry’s approach.Although the FCR approach is commonly used for fixation of distal radius fractures because of its simplicity and safety, this is the first report of complete absence of the FCR during the commonly performed volar approach for fixation of a distal radius fracture, to our knowledge. Because the FCR is designated as a favorable landmark because of its superficially palpable location, strong and thick structure, and rare anatomical variations, there is the possibility of iatrogenic complications in cases of the absence of the FCR. We suggest that surgeons should have a detailed knowledge of the range of possible anomalies to complete the fixation of a distal radius fracture safely. Volar locking plate fixation of distal radius fractures is commonly performed because of its good clinical outcomes , 2. The Here, we describe an extremely rare case of the absence of the FCR, identified during the volar approach for fixation of a distal radius fracture.A 59-year-old right-handed female desk worker with no significant past medical history suffered a distal radius fracture (AO classification 23-A2 type) of the right hand Fig. , fracturFour months after the operation, the patient had no pain or neurologic problems and the X-rays showed complete bone union of the distal radius fracture Fig. . AlthougThe FCR originates from the medial epicondyle of the humerus and inserts into the trapezius, the second metacarpal, and the third metacarpal bones, and functionally contributes to the motion in flexion and the radial deviation of the wrist joint . AlthougBecause important neurovascular structures exist close together in the distal volar forearm, there have been many complications reported for volar plating of distal radius fractures, including injuries to the median nerve, the PCB of the median nerve, and the radial artery , 10. TheIn the present case, in addition to the absence of the FCR, we also identified an anomalous FCRB muscle. In general, the FCRB is considered to be an accessory muscle of the FCR that arises from the volar surface of the radius and inserts at various sites, including the base of the metacarpal bone, trapezium, and capitate . AlthougAlthough the FCR approach is commonly used for fixation of distal radius fractures because of its simplicity and safety, various types of anatomical variations and anomalies of the distal volar forearm structures including the median nerve, the PCB of the median nerve, and the flexor tendon have been reported. Because the FCR is designated as a favorable landmark because of its superficially palpable location, strong and thick structure, and rare anatomical variations, there is the possibility of iatrogenic complications in cases where the FCR is absent. We suggest that surgeons should have a detailed knowledge about the range of possible anomalies to complete the fixation of a distal radius fracture safely.


In the second and third sentences of the Results subsection of the Abstract, the sentence should read: AMACR by IHC was significantly associated with increased diagnosis of PCa . Subgroup-analysis showed that findings didn’t substantially change when only Caucasians or Asians  were considered.In the first sentence of the Meta-analysis Results subsection of the Evidence Synthesis, the sentence should read: he pooled result revealed that positive AMACR by IHC was significantly associated with increased diagnosis of PCa  and Subgroup-analysis showed that findings didn’t substantially change when only Caucasians .In the second sentence of the first paragraph of the Discussion, the sentence should read: AMACR expression by IHC was significantly associated with increased diagnosis of PCa . The overall analysis provided strong replication of the initial findings, confirming the AMACR for PCa.


Peroneal tendon dislocation in association with medial malleolus fracture is a very rare traumatic injury to the ankle. A 19-year old male patient was referred after injury sustained in a motorcycle accident with car, with concomitant traumatic peroneal tendon dislocation and medial malleolus fracture. The possible mechanism of this unusual injury could have been sudden external rotation force to the pronated foot in full dorsiflexed position of the ankle. Diagnosis of peroneal tendon subluxation or dislocation should be carefully evaluated in patients with single medial malleolus fracture. Although, it was first described in a ballet dancer, other sport activities like skiing, soccer and basketball could result in traumatic dislocation of the peroneal tendon. Usually peroneal tendon subluxation or dislocation is mistaken or undiagnosed because of similarity of the mechanism of injury to that of lateral ankle sprain and lack of apparent findings in plain radiographs3. We describe a case of minimally-displaced medial malleolus fracture in association with avulsion fracture of superior peroneal retinaculum to show the importance of small flake fractures around the ankle joint.Medial malleolus fracture usually occurs in association with fractures of lateral malleolus, posterior malleolus, proximal fibula, or with ligamentous injuries around the ankle joint. Concomitant traumatic peroneal tendon dislocation and medial malleolus fracture have been rarely reported in the literatureA 19-year old man was referred with pain in left ankle after motor-vehicle accident. On physical examination, swelling and ecchymosis around the ankle joint especially on medial side was obvious. Significant tenderness on medial malleolus and little tenderness on lateral malleolus were noted on palpation of the ankle joint. Neurovascular function of the foot and ankle was normal. Radiographs disclosed minimally-displaced fracture of the medial malleolus and a barely visible small avulsion fracture on the posterodistal part of the lateral malleolus . ComputeAfter obtaining consent from the patient and under general anaesthesia in the operating room, open reduction and internal fixation of the medial malleolus fracture was carried out using a malleolar screw and a Kirschner wire was shortened and buried beneath the skin. Examination during surgery revealed dislocation of peroneal tendons to the anterior aspect of the lateral malleolus with passive full dorsiflexion of the ankle joint, following which, through an incision on the posterior aspect of the distal lateral malleolus, the avulsed superior peroneal retinaculum (SPR) was exposed. The flake of bone and SPR were anchored to the lateral malleolus with two sutures. Stability of the peroneal tendons was fully achieved.Postoperatively, non-weight bearing short leg cast was applied for six weeks followed by a short leg walking slab to initiate range of motion of ankle for four more weeks. At follow-up one year after surgery, the patient was completely satisfied with the healed fracture and tendon injury  and had 4. In Grade I, peroneal tendons slip anteriorly on intact fibrocartilaginous ridge of retrofibular groove. A Grade II subluxation of peroneal tendons is characterized by anterior slipping of tendons under elevated fibrocartilaginous ridge of retrofibular groove. In Grade III, avulsion fracture of SPR (the “fleck sign”) from fibula is seen. In the case presented here, the little bone fragment on the posterodistal aspect of fibula showed Grade III peroneal tendon dislocation. Grade III has the lowest incidence (13%) among all grades described by Eckert and Davis.Diagnosis of flake fracture around the ankle joint is important because it usually shows avulsion of an essential ligament or an important retinaculum. Peroneal tendon subluxations have been classified by Eckert and Davis3, the medial malleolus fracture was Type B or Type C by the Herscovici et al classification5. These types of medial malleolus fractures occurred with external rotation forces on the pronated foot by the Lauge-Hansen classification. It meant that none of the medial malleolus fractures in the reported cases resulted from shearing force as seen in supination-adduction injuries of the ankle.In order to explore the possible mechanism of this injury, we reviewed the literature. In our case and other reported cases of concomitant medial malleolus fracture and traumatic avulsed SPRPossible mechanism would be sudden external rotation force applied to the pronated foot in full dorsiflexed position of the ankle. When the ankle is in full dorsiflexion with contraction of the peroneal tendons in the active pronated position of the foot, the tendons are in direct forceful contact to the anterior part of SPR which is attached to the fibula. Sudden external rotation force in this position of the foot and ankle could initially tear the anterior inferior tibiofibular ligament and open the syndesmosis from anterior, as described in the second stage of pronation external rotation injury of Lauge-Hansen classification. These changes could finally rotate the fibula externally. Sudden forceful external rotation of the fibula against powerful contraction of peroneal tendons in the fully dorsiflexed ankle could cause avulsion of SPR from fibula (Grade III) or dislocation of peroneal tendons without avulsion fracture (Grade I or II). This theory could explain the mechanism of injury of concomitant traumatic peroneal tendons dislocation and medial malleolus fracture. This is only a theory and it should be tested in research on cadavers.In conclusion, more attention should be paid to the lateral part of the ankle joint in patients with a solitary medial malleolus fracture of Type B or Type C by the Herscovici classification. When any small avulsed bone fragment from the posterior aspect of the lateral malleolus is revealed on radiography, instability of peroneal tendons must be looked for. After fixation of medial malleolus fracture under general anaesthesia, it is important to exclude any possible peroneal tendon subluxation even in the absence of evidence of bone fragment avulsion.The authors declare no conflicts of interest and no external funding was received in the preparation of this report.


In this study, the authors develop an exploratory synthesis of two major health concepts: Antonovsky's sense of coherence and Bandura's beliefs in one's own efficacy. Reinterpretation of each study in the light of the other can lead to greater conceptual development and expand existing knowledge. The mutual themes are presented with an explanation of their contribution to broader conceptual discussions. The existence of some similarities between the two concepts is suggested. Researchers can obtain valuable and additional arguments through cross-fertilization of ideas across presented studies united by shared assumptions. Further research is recommended among various age groups and social backgrounds in order to verify the possible benefits of such theoretical development. Theoretical and practical implications of such a synthesis are presented.


Contrast computed tomography and magnetic resonance imaging are widely used due to its image quality and ability to study pancreatic and peripancreatic morphology. The understanding of the various subtypes of the disease and identification of possible complications requires a familiarity with the terminology, which allows effective communication between the different members of the multidisciplinary team.  Demonstrate the terminology and parameters to identify the different classifications and findings of the disease based on the international consensus for acute pancreatitis ( Atlanta Classification 2012).  Search and analysis of articles in the "CAPES Portal de Periódicos with headings "acute pancreatitis" and "Atlanta Review".  Were selected 23 articles containing radiological descriptions, management or statistical data related to pathology. Additional statistical data were obtained from Datasus and Population Census 2010. The radiological diagnostic criterion adopted was the Radiology American College system. The "acute pancreatitis - 2012 Rating: Review Atlanta classification and definitions for international consensus" tries to eliminate inconsistency and divergence from the determination of uniformity to the radiological findings, especially the terminology related to fluid collections. More broadly as "pancreatic abscess" and "phlegmon" went into disuse and the evolution of the collection of patient fluids can be described as "acute peripancreatic collections", "acute necrotic collections", "pseudocyst" and "necrosis pancreatic walled or isolated". Computed tomography and magnetic resonance represent the best techniques with sequential images available for diagnosis. Standardization of the terminology is critical and should improve the management of patients with multiple professionals care, risk stratification and adequate treatment. Most important causes in children described by the availiable literature are (in order of frequency): biliary disease, medications, idiopathic, systemic diseases, trauma, metabolic disorders, hereditary and infectious causes,The severe form, regardless of the cause, can reach 25-45% of morbidity and mortality. About 5-10% of these individuals develop necrosis and affect their pancreatic parenchyma in 5% of cases, peripancreatic tissue 20% of the cases and both of them in 70%,,Imaging tests have fundamental importance in diagnosis, determination of severity, recognition of complications and the therapeutic choice. They have a direct impact on clinically suspected cases and differential diagnosisThe aim of this study was to demonstrate the terminology and the parameters for identifying the different classifications of the disease from the International Consensus for Acute Pancreatitis  or persistent (that persists for more than 48 h) and local (liquid or necrotic peripancreatic collections) or systemic complications (which may be related to pre-existing co-morbidities)The choice of imaging technique is dependent on the research reasons, clinical symptoms, duration of symptoms and laboratory findingsThus, its recommended perform the abdominal ultrasound for all patients with first presentation of acute pancreatitis, typical abdominal pain, increased pancreatic amylase and lipase, between 48-72 h of presentation and unknown cause,The analysis of pancreatic morphology by the computed tomography imaging allows the diagnosis, determine the extent and severity of the diseaseClinical presentations that consist of more than 72 h of evolution, critical patients, carriers of critical clinical "scores", high severity index, signs of rapid deterioration, systemic inflammatory response syndrome and leukocytosis are the determinants of the precedence of computed tomography with contrast above other techniques2,9,28,32. MRI is the technic of choice for cases that there are limitations or contraindications to the application of computed tomography, need of multiple tests for monitoring disease progress and negative CT results with acute pancreatitis presentations ,The Review of the Atlanta Classification, 2012, subdivides acute pancreatitis in two subtypes: edematous and necrotic. For both presentation the literature elucidates two stages that overlap and are closely related with two peaks of mortality: early and late. The initial phase usually ends at the end of the first week of symptoms onset, however it can reach the second phase with a resolution of pancreatic and peripancreatic ischemia, development of fluid collection or evolution for permanent necrosis and liquefactionIt is mild form of the disease that is usually resolved in the first week. Its main feature is the local or diffuse enlargement of the pancreas without the presence of necrosis. This increase is due to the intense inflammatory process causing interstitial or peripancreatic edema.,,,,Generally it is characterized as enlarged pancreas with normal relative enhancement and regular peripancreatic fat, thickened or ground-glass opacity due to the inflammatory process. The amount of pancreatic fat can be variable but without enhancement,,The intensity of the pancreas at this stage is similar to normal organ. The "phase in" generally has enlarged pancreas and attenuated fat. Images in "phase in" with fat suppression have the delineation of the pancreas and its enhanced edges. In the pre- contrast phase, the body shows high signal intensity increases monotonically in the post-contrast image (Gadolinium) representing normal pattern of capillarity. image sequences in " phase out " are sensitive to the presence of edema or fluid collections,Presentation with worse prognosis, characterized by inflammation with resultant necrosis of pancreatic or peripancreatic tissue. The damage to pancreatic perfusion and peripancreatic necrosis signs develop over several days, although the usage of early performed the contrasted CT may underestimate the severity of the disease,Both computed tomography and magnetic resonance imaging are essential to obtain suitable images of the arterial phase, since the maximum highlight the pancreas is obtained in the late arterial phase and the largest signal difference between viable and necrotic tissue is evident in that stageAfter contrast administration (Gadolinium) the findings include the highlight of parenchymal areas compromised. Changing the infusion and the formation of peripancreatic fluids collections can take several days to be evidenced by imaging.,,,,,Necrosis can be identified as areas of hypointensity on "phase in" and increased signal intensity areas on "phase out", both associated with well defined areas of not enhanced parenchyma in postcontrast enhanced sequences (Gadolinium)It is very important to differentiate fluid collections composed only of exudative fluid from those that have solid components from the necrosis process. The latest revision of Atlanta, 2012, uses the following terms for collections classification: "acute peripancreatic collections", "acute necrotic collections", "pseudocyst", "pancreatic necrosis walled or isolated" and "infected pancreatic necrosis.",,,,,,,Defined as a collection of fluid that develops during the initial phase of the disease, most cases after 48 h of onset of symptomsCharacterized as fluid collection, single or multiple, homogeneous and with low attenuation, without well-defined and confined in normal retroperitoneal fascial planes,Images following "phase out" sequence are very sensitive to peripancreatic fluids, which are evidenced by an increase in signal intensity. The sequence "phase in" shows hypointense signal on a background and hyperintense fat,,The term refers to fluid collections in peripancreatic region  that persist for more than four weeks, form visible wall that imprisons the content and have no solid componentMost pseudocysts resolve spontaneously; however, bleeding and infections may complicate the condition of the patient. Infected pseudocysts may have gas in computed tomography,,In case of suspicion and lack of characteristic clinical findings, it is necessary to perform a fine needle aspiration and morphological characterization of the contentThere are homogeneous collections of low attenuation with uniform capsular enhancement. The increase in intensity is typically observed during the interstitial phase in detriment of the presence of granulation tissue .,,,Sequential images in "phase in" show low signal intensity and in "phase out" usually have homogeneous increased signal intensity. The walls have minimal enhancement after contrast, due to the presence of fibrotic tissue,,,,,The term refers to collections containing liquid and necrotic tissue, which can be derived from the pancreatic parenchyma or adjacent tissue present in both intrapancreatic as peripancreatic region, and in most cases maintains communication with the pancreatic duct or its ramifications,,Magnetic resonance imaging has much higher sensitivity in the detection of necrotic tissue when compared to computed tomography,,,The main feature is the presence of heterogeneous attenuation, variable, higher than typical mitigations from only fluid collections. They may present as homogeneous attenuation without enhancement during the first week. The amount of solid content is variable and may be loculated,Necrotic debris are generally viewed as irregular regions of low intensity . Sequenc,,,Necrotic collections develop reactive and thick fibrotic wall that stores necrotic content inside after four weeks of evolution. The Atlanta Review uses the term "inflammatory wall" to describe this kind of collection. It has a higher incidence in the tail and body of the pancreas,,,It is presented as heterogeneous fluid and solid mitigations with different degrees of loculations with wall encapsulating well defined, which can extend to both pancreatic tissue as the extrapancreatic,,The sensitivity of magnetic resonance helps minimize diagnostic errors. Generally there are areas with heterogeneous intensity isolated by an intense accent wall in post-contrast, suggestive of isolation with solid and liquid content,,,,The development of secondary infection in pancreatic necrosis is associated with high morbidity and mortalityThe diagnosis of infection can be accomplished by gas visualization in both techniques. The extraluminal gas present in areas of necrosis might not form air-fluid levels depending on the stage of infection and the amount of necrotic tissue and fluid. In cases of doubt, confirmation can be obtained by fine-needle aspiration and microscopic analysis of the fluid or culture.Imaging tests are essential in the diagnosis and staging of acute pancreatitis. Computed tomography and magnetic resonance imaging are widely used, representing the best techniques with sequential cuts available for diagnosis. Tomography is the technique with greater acceptability and usage; however, MRI has the advantage in situations with CT contraindication and thorough soft tissue differentiation. The adequacy of terminology is critical and should facilitate the management of patients with multiple professionals, risk stratification and adequate treatment.


Six DVTs developed in the stocking group and 11 in the non-stocking group. The results suggest that the use of stockings reduces the incidence of DVT when added to herparin but the difference is not statistically significant. To obtain a predictive index for the development of DVT, discriminant analysis was applied to the control and stocking groups separately and combined. Five simple clinical variables gave a true positive prediction rate, for the combined group, of 94% and a false positive prediction rate of 26%.In a single-centre prospective trial 200 consecutive patients undergoing thoracic surgery were randomised to receive one of two prophylactic regimes against deep vein thrombosis (DVT). These were 5000 units of subcutaneous heparin twice a day, alone or combined with the wearing of graded compression stockings. The diagnosis of DVT was made clinically and with


The concept of tissue or compartmental immunity and its importance in the development of inflammatory or infectious diseases was introduced and gained strength following publication of the works of Engwerda and Kaye . From thAll these studies call attention to factors described recently and studied within the context of inflammatory skin diseases and their role in the evolution of these diseases. We believe that these works will give new insights into the complex dynamics of inflammatory and infectious cutaneous diseases. These concepts may serve as the basis for the development of new experimental models and may open possibilities for future investigations.Juarez A. S. QuaresmaMirian N. SottoAnna Balato


GHEs incorporate pipes with a circulating (carrier) fluid, exchanging heat between the ground and the building. The data show the average and inlet temperatures of the carrier fluid circulating in the pipes embedded in the GHEs (which directly relate to the performance of these systems). These temperatures were generated using detailed finite element modelling and comprise part of the daily output of various one-year simulations, accounting for numerous design parameters (including different pipe geometries) and ground conditions. An expanded explanation of the data as well as comprehensive analyses on how they were used can be found in the article titled  Specifications TableValue of the data•The data were generated using complex and computationally expensive numerical methods  and can be of use to researchers that are interested in modelling the heat transfer process in shallow geothermal systems.•The data allow researchers to further expand on the analyses presented in •The range of input parameters used to generate the data allow researchers to investigate different aspects of this technology and the importance of these parameters.•The dataset that incorporates randomness can lead to a more extensive statistical analysis of the impact of randomness on these systems.1The data describe the operation of vertical ground heat exchangers (GHE), used in shallow geothermal technologies to provide efficient and renewable heating and cooling to buildings. A modelled GHE consists of a borehole that has pipe loops embedded within it and transfers heat to and from the ground. The data of this article describe the daily average temperature of the circulating (carrier) fluid in the pipes (average of inlet and outlet) as well as the inlet temperature from which the outlet and the thermal load over time can be derived. These temperatures result from the simulated annual operation of various geothermal systems, each having different design parameters and/or ground conditions, ensuring a large number of annual datasets that satisfy a wide range of possible designs and/or locations. The data provide insights regarding the performance and efficiency of shallow geothermal systems.2The data were generated using a validated finite element numerical methodology, and applied through the software COMSOL Multiphysics, which was developed at the University of Melbourne λgrout) and For each simulation, different design parameters and conditions were used. Overall, the data are separated into three main categories, based on the geometry of the pipes within the GHE, describing the potential effect on the system performance when the placement of the pipes along the depth of the GHE is not as expected or varies. The first category describes the pipes being fixed in place along the depth of the GHE (labelled “Straight”), the second category describes the pipes moving in a sinusoidal pattern along the depth of the GHE (labelled “Variable”) and the third category describes the pipes moving randomly along the depth of the GHE (labelled “Random”).


BAD-responders showed a decline of the MMSE score together with a progressive impairment of executive functions. A voxel-based morphometry investigation (VBM), at the time of the second neuropsychological assessment, showed that the BAD-responders had larger grey and white matter atrophies involving the substantia innominata of Meynert bilaterally, the ventral part of caudate nuclei and the left uncinate fasciculus, brain areas belonging to the cholinergic pathways. A more widespread degeneration of the central cholinergic pathways may explain the lack of donepezil efficacy in those patients not responding to a treatment that operates on the grounds that some degree of endogeneous release of acetylcholine is still available.We explored the neuropsychological and neuromorphometrical differences between probable Alzheimer's disease patients showing a good or a bad response to nine months treatment with donepezil. Before treatment, the neuropsychological profile of the two patient groups was perfectly matched. By the ninth month after treatment, the


Sociodemographic factors, alcohol and drug intake, and maternal health are known to be associated with adverse outcomes in pregnancy for women with severe mental illness in addition to their use of psychotropic medication. In this study, we describe the demographic characteristics of women hospitalized for severe mental illness along with their use of medication and other drugs during the pregnancy period.A clinical case note review of women with psychosis who were hospitalized at the State Psychiatric Hospital in Western Australia during 1966–1996, gave birth between 1980 and 1992, and received psychiatric treatment during the pregnancy period. The mother’s clinical information was available from the case notes and the midwives record. The demographic characteristics of the mothers were described together with their hospitalization pattern and their medication and substance use during the pregnancy period.A total of 428 mothers with a history of severe mental illness were identified who gave birth during 1980–1992. Of these, 164 mothers received psychiatric care during the pregnancy period. One hundred thirty-two had taken psychotropic medication during this period. Mothers who were married, of aboriginal status or living in regional and remote areas appeared less likely to be hospitalized during the pregnancy period, while older mothers and those with a diagnosis of schizophrenia were more likely to be hospitalized. The number of mothers taking psychotropic medication in the first trimester of pregnancy was reduced compared to the previous 6 months. The decline in the number taking substances over the same period was not significant. In all, 16% of the women attempted suicide during the pregnancy period and 10% non-suicidal self-injury.The women demonstrate a pattern of decreased use of psychotropic medication use from the period before pregnancy to the first trimester of pregnancy. Our data highlight the importance of women with severe mental illness receiving regular ongoing monitoring and support from their psychiatrist during pregnancy regarding the level of medication required as well as counseling with regard to substance use, non-suicidal self-injury, and attempted suicide. Sociodemographic factors , alcoholvia linkage of the WA Midwives Notification System and the WA Mental Health Information System (MHIS). Further information was collected by clinical case note review for the women who were treated by psychiatric inpatient or outpatient services during the pregnancy period. The study focuses on this subgroup of women.Women with a diagnosis of schizophrenia, bipolar disorder, or unipolar major depression who were treated at the State Psychiatric Hospital of Western Australia between 1966 and 1996 and gave birth between 1980 and 1992 were identified The study had University of Western Australia Human Research Ethics Committee approval as well as specific approvals from the individual inpatient and outpatient mental health services at which the clinical records were held. The data were analyzed using SAS version 9.4 .The International Classification of Diseases, ninth Revision codes  were useNo further information was collected for the women who did not receive psychiatric inpatient or outpatient care during the study, but their demographic information was available for comparison with those who did receive psychiatric care.Demographic and clinical information was compared for all mothers included in the study, those receiving psychiatric care during their pregnancy period and those receiving psychiatric care and who took medication during the pregnancy period. For comparison of demographic characteristics, socioeconomic status was measured using the Australian Bureau of Statistics Socioeconomic Indices for Areas—index of relative disadvantage  and acceThe number of births where the mother was hospitalized voluntarily with a psychiatric diagnosis was calculated as was the average length of stay per birth in days for these admissions. This was repeated for involuntary admissions.t-test for paired samples.The number of mothers taking psychotropic medication and substances was calculated for the 6-month period before pregnancy and for each trimester. Whether or not there was a significant change in the proportion of women taking medication or substances prepregnancy and in the first trimester of pregnancy and then between the first and second trimester and the second and third trimester was tested using a The selection of the 428 mothers into the study is illustrated in Figure de facto relationship were in the group who were hospitalized compared to those who were single, divorced, or separated. The proportions of aboriginal mothers and those living in regional and remote areas were also lower in the hospitalized group. Mothers aged over 34 years appeared more likely to be hospitalized than their younger counterparts, as were those living in the city. Parity and low socioeconomic status appeared to have little effect on the risk of hospitalization during the pregnancy period. Table The demographic characteristics of the mother relating to each birth are shown in Table Table In this descriptive study, we have documented the sociodemographic circumstances and the use of psychotropic medication and substances during pregnancy for women with severe mental illness who received psychiatric inpatient or outpatient services during the pregnancy period.The majority of the women who were hospitalized took psychotropic medication (80%), which is indicative of the severity of the disease, with antipsychotics recorded as the dominant medication category (73%) followed by mood stabilizers (21%), anxiolytic/hypnotics (16%), antidepressants (12%), and benzodiazepines (9%). Our data show fewer women taking medication during pregnancy than in the period immediately before pregnancy. This may be because the women are concerned about the potential effect of their medication on the developing fetus , or on tA similar study in Germany  on a cohPsychotic illness is a known risk factor for substance use , 21. NinThe risk of suicide and non-suicidal self-injury are reduced during pregnancy in the general population , 24. As The demographic profile of the women shows little difference between those taking and not taking psychotropic medication. Differences between those receiving and not receiving treatment, however, may be associated with the location of the Statewide psychiatric hospital, which is in the metropolitan area and thus less accessible to those from regional and remote areas. As the majority of the aboriginal population live in rural and remote areas, this is likely to be why aboriginal mothers have a lower treatment rate. Higher treatment rates for single mothers are likely to be associated with a low level of support available at home . The higThere are a number of potential limitations to this study. The data are from the period 1980–1992 when the newer forms of antipsychotics and antidepressants were not widely available: atypical antipsychotics and SSRIs were introduced in the early nineties . Data weThis study on a cohort of 428 women of whom 164 received inpatient or outpatient psychiatric care for severe mental illness during the course of their pregnancy found that despite the severity of their illness, the women demonstrate a pattern of decreased use of psychotropic medication use from the period before pregnancy to the first trimester of pregnancy. Our study cannot provide data on the reason for this change, but we speculate that it may reflect motivation by the treating clinician, the mother, or both to maximize outcomes for the babies. However, of note, recently published clinical guidelines  for the The study had University of Western Australia Human Research Ethics Committee approval as well as specific approvals from the individual inpatient and outpatient mental health services at which the clinical records were held. Participant consent was not required for this study of medical records. Requirement for consent was waived on the basis of the study being low risk, the benefits from the research justified any risks of harm associated with not seeking consent and privacy and confidentiality were protected by meeting the required standards for data storage and security.KB analyzed the data and drafted the paper, AJ was responsible for conception and design of the study and coauthored the paper, VM was involved in the study design, supervised local data collection, performed overall data management, supervised the data analysis, and coauthored the paper. JD and JG conducted the case note review and coauthored the paper. All the authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


As a result, current treatments are often palliative and ignore the driving biological processes. In this context, the elucidation of the cause-and-effect relationships between cardiovascular biology and hemodynamics has the potential to advance the understanding of disease progression and to enable new diagnosis and treatments.Mechanical forces are powerful regulators of biology and disease. In the vasculature, the expression of particular cellular phenotypes appears to depend not only on a combination of intrinsic genetically programed biology but also on local hemodynamic environmental factors induced by blood flow  responsible for the pathological response and their normalization could potentially slow down the disease process and limit or completely block its development Figure D.via flow normalization have been recently developed and are currently being tested. One such effort consists of implanting a valve device at the anastomosis in order to isolate the arteriovenous shunt from the rest of the circulation  between hemodialysis sessions and to allow the passage of blood through the graft  during hemodialysis sessions  hemodynamic stress state and of the hemodynamic alterations triggering a pathological state. The characterization of blood flow is challenging due to its three-dimensionality, unsteadiness, turbulence, and strong coupling with the surrounding compliant vasculature  were able to generate only basic mechanical stimuli , current bioreactors are able to mimic more closely the complexity of the native hemodynamic environment. Examples of such devices are single and double cone-and-plate bioreactors to expose vascular tissue to single-sided or double-sided pulsatile WSS (Sucosky et al., While mechanobiological studies have already contributed immensely to the understanding of cardiovascular pathologies, only few have been translated into clinical solutions. Major challenges include the complexity of interpretation of biological data, the assessment of the isolated and synergistic roles of mechanosensitive molecules in the disease process, the identification of effective, but safe, molecular inhibitors aimed at blocking the mechanobiological cascade, and the design of effective procedures and devices to normalize blood flow. While those complex issues are still current, the recent realization of the potential use of mechanobiology as a discovery tool for novel treatments and diagnosis modalities has motivated some collaborative efforts between the clinical and engineering fields. Those synergies are necessary to complement the basic science of mechanobiology and to elevate it to effective clinical solutions.With the continuous progress in flow characterization techniques, bioreactor technologies and biological assessment methodologies, mechanobiology has emerged as a potential tool to deliver the next generation of therapies in cardiovascular disease. The characterization of mechanical cues promoting cardiovascular pathogenesis, the identification and modeling of key mechanosensitive molecules and molecular pathways involved in the early stage of disease, and the integration of this knowledge into patient-specific flow models could provide new therapeutic modalities and predictive capabilities that will transform clinical decision-making and personalized care in cardiovascular medicine.SA and AM wrote the paper and share first authorship. PS wrote the paper and conceived the work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The Addis Declaration  adopted EPI is a legacy of the successful campaign that led to the eradication of smallpox . In 1974EPI then went through a period of maturation that involved various levels of sophistication aimed at improving coverage, reaching previously unreached children, ensuring equitable access to vaccine and introducing new or underused vaccines. Some events have accelerated the transformation of EPI more than others; the creation of the Global Alliance for Vaccine and Immunization (Gavi) in 2000  marked uAlbeit large cross-national variations in national immunization coverage across the continent, EPI in it forth decade boasts commendable achievements in VPD control and elimination. The variable performance of the EPI program across Africa reflects most often a variety of countries implementation frameworks where factors such as insecurity/inaccessibility, structural health systems performance and overall governance environment play a key role.Reaching more people, with more vaccine, in an equitable way remains by far the biggest challenge of the EPI program in Africa as it enters adulthood: since the early eighties when EPI data were systematically compiled in the WHO/UNICEF Estimates for National Immunization Coverages (WUENIC) , the aveThe performance of the EPI program cannot be decoupled from the performance of the health system in which it emanates (operating environment); poor EPI performance often translates structural weaknesses in health systems. Sustained and predictable financing, peace and security, strategic partnerships and overall governance mind-set are important determinants of this operating environment. Health policy frameworks such as Agenda 2063: the Africa We Want  and otheThe advent of new vaccine technologies  have the potential to expand the reach of the program by freeing it from stringent cold chain and technical know-how requirements.The introduction of more new or underused vaccines: will extend the opportunity to protect more people against more diseases throughout the course of lifeThe adoption of information technology around supply chain management, population based registries, personalized vaccination records, reminder systems, etc… will push the EPI program into the digital age.EPI will be humbled by the imperative to find innovative ways to sustain community awareness on the benefits of vaccination, to increase demand and offer of services, to strengthen confidence in the program and to better communicate risk.The future health landscape of Africa in full of challenges: the prevalence of non-communicable diseases will continue to rise; the burden of cancer is expected to double between 2008 and 2020; injury and trauma will increasingly contribute to disease burden; challenges link to climate change, food insecurity, conflicts and water scarcity will increase. With this in mind, vaccines provided through EPI are the weapons at hands to remove VPD from the pool of health challenges the continent will grapple with in the future; this opportunity cannot be wasted.The author declares no competing interest.


The characteristics of each lineage and the proposed genetic cascades involved in their formation are reviewed. In addition, a list of the current markers used to identify these lineages


Vector-borne diseases (VBDs) represent a great proportion of the neglected tropical diseases (NTDs) in tropical regions of the world, where they disproportionately affect the poorest and most disadvantaged populations. That said, in recent years, the expansion of vectors from the tropics has placed many more people living in the temperate regions of the world at risk of contracting VBDs. The expansion of VBDs is occurring at a time when unprecedented discoveries are being made in vector biology in the areas of genetics, genomics, and physiology. With the goal of highlighting the significance of VBDs in the new century and emphasizing the role of basic vector research in the development of future disease control methods and for improving upon the existing approaches, we have advanced a call for papers that focused on vector research as part of our 10th anniversary celebration. It is our hope that these new discoveries in vector biology research will pave the way for translational methods to combat the old foes in the new climate.According to the World Health Organization (WHO), nearly half of the world’s population is infected with at least one type of vector-borne pathogen . Among tTrypanosoma brucei as the cause of cattle trypanosomiasis (cattle nagana) in 1895, and the British colonial surgeon Robert Michael Forde was the first to observe trypanosomes in the human blood in 1901. Both David Bruce and the German military surgeon Friedrich Karl Kleine provided conclusive evidence showing the cyclical transmission of T. brucei in tsetse flies at the beginning of 1900  response, and how the enzyme catalase protects mosquitoes from oxidative stress and helps dengue virus survival in the insect gut. We have also received a number of papers on triatomine-transmitted Chagas disease, which highlights the increasing significance of this disease burden in South America. These papers highlight the relevance of basic research on vector–pathogen interactions to find new venues to control transmission of VBDs. Many of the articles highlight the complexity of vector–pathogen–host interactions, which can serve as novel points of interference for control, including the role of pathogen-produced exosomes at the bite site, the role of vector saliva pre-exposure in disease, and viral modification of host gene expression.Wolbachia endosymbionts have gained attention because of the various host reproductive modifications they induce in order to enable their transmission (and that of the infected vector) through natural populations. Mosquitoes infected with a novel strain of Wolbachia have also been shown to resist transmission of dengue [Wolbachia endosymbiont–mediated pathogen interference, is currently being tested in trials against dengue in Southeast Asia and in implementation trials against Zika virus disease in Colombia and Brazil. Our collection highlights several papers that investigate Wolbachia effects on mosquito disease transmission traits and model the success of these applications.Research in vector microbiota continues to attract attention as commensal and symbiotic microbes harbored by insects can influence various disease transmission traits, including an effect on the gut barriers to prevent malaria infection in mosquitoes. In the last decade, the f dengue , chikungf dengue , and Zikf dengue . One traImproved knowledge of climate change effects and vector habitats, coupled with mathematical modeling efforts, can predict transmission dynamics and enhance the efficacy of ongoing or future control efforts in the field. The diversity of vectors and diseases presented in the Vector Biology collection emphasizes the growing significance of this area and these research investigations towards effective control. The ultimate goal is for the accumulating knowledge on vector–pathogen dynamics to inform and guide public health decisions for optimal outcomes. Several of the papers in this collection begin to make the link between basic science- and field-based discoveries and policy decisions. Additional papers, which are currently under review in our system, will be added to the collection.VBDs represent a great proportion of the NTDs. The high-quality vector biology research presented by various research groups from around the globe that includes basic research, field work, modeling, and translational research demonstrates the commitment to find new avenues towards the control of these NTDs. Importantly, this collection reinforces the commitment of our editorial board to continue publishing high-quality and impactful research in vector biology as they impact control of VBDs.


The heart has a limited ability to regenerate. It is important to identify therapeutic strategies that enhance cardiac regeneration in order to replace cardiomyocytes lost during the progression of heart failure. Cardiac progenitor cells are interesting targets for new regenerative therapies because they are self-renewing, multipotent cells located in the heart. Cardiac side population cells (cSPCs), the first cardiac progenitor cells identified in the adult heart, have the ability to differentiate into cardiomyocytes, endothelial cells, smooth muscle cells, and fibroblasts. They become activated in response to cardiac injury and transplantation of cSPCs into the injured heart improves cardiac function. In this review, we will discuss the current literature on the progenitor cell properties and therapeutic potential of cSPCs. This body of work demonstrates the great promise cSPCs hold as targets for new regenerative strategies. Heart failure remains a pressing healthcare problem because of its increasing prevalence and high rate of morbidity and mortality  were the first population of cardiac progenitor cells identified in the heart that possess the three key progenitor cell properties discussed above . Originally, P-glycoprotein and Abcg2 were identified as proteins that confer chemoresistance by extruding drugs out of the cytoplasm of cancer cells  were implanted to the time the LVADs were removed at the time of cardiac transplantation .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


IgA nephropathy (IgAN) is the most common glomerulopathy worldwide. After the development of Oxford classification of IgAN, it was established that pathological parameters can also be useful, independent of all clinical or laboratory parameters, in predicting the future course of the disease in individual patients. During the recent past, a novel fragment of the complement activation cascade became the focus of research as a biomarker of current or recent antibody action. This fragment is known as C4d and is now widely used in the investigation of solid organ graft pathology. The current enthusiasm surrounding the role of C4d in the diagnosis and prognosis of both primary and secondary glomerular diseases needs cautionary approach and further investigations are needed to define the exact implications of C4d in clinical practice.IgA nephropathy (IgAN) is the most common glomerulopathy worldwide . In the It is well known that the complement system of plasma proteins plays an important role in the pathogenesis and pathology of many renal diseases, especially glomerular diseases . A numbeRath et al in the current issue of this journal have investigated the role of C4d deposits in the glomeruli and peritubular capillaries of patients with IgAN . They inMM was the single author of the manuscript.Ethical issues  have been completely observed by author.The author declared no competing interests.None.


CCNO gene, encoding an atypical cyclin necessary for the generation of multiple motile cilia [CCNO or other genes required to generate MCCs such as MCIDAS [Primary Ciliary Dyskinesia-29  is an autosomal recessive disorder characterized by early onset, progressive and irreversible lung damage due to recurrent respiratory infections caused by the inability of the multiciliated cells (MCC) present in the respiratory epithelium to clear mucus and particles trapped in the upper airways. The airways of these patients show a nearly complete lack of cilia on the MCCs or have a few dysfunctional, motile cilia. The molecular cause of CILD29 is mutations in the coding region of the In addition to the respiratory airways, MCCs are present in the male and female reproductive epithelium and in the ependyma, the epithelium lining the brain ventricles, accomplishing different functions depending on their location. The mouse oviduct coils and the human Fallopian tube plicae are covered by a single layer of multiciliated columnar epithelium interspersed with non-ciliated, secretory cells. This structure allows the propulsion of gametes and embryos and supports fertilization and early embryogenesis. We recently described that the complete lack of CCNO in the mouse results in male and female infertility .-/-Ccno mice present few, abnormal cilia in the ependymal MCCs and develop hydrocephalus with higher penetrance than reported for the conditional knockout model or in the RGMC patients [Ccno-/- mice develop severe communicating hydrocephalus within the first month of postnatal life. Mice surviving this period can live for as long as their +/+Ccno or +/-Ccno siblings without overt neurological defects most likely due to compensation of the increasing intracranial pressure by thinning of the brain parenchyma.In the ependyma, the MCCs are responsible for recirculating the cerebrospinal fluid (CSF). CSF is produced from blood plasma in the choroid plexuses within the brain ventricles and it is reabsorbed in the arachnoid granulations through the superior sagittal sinus and into the venous circulation. Defective recircularization of the CSF leads to its accumulation and the dilatation of the brain ventricles, a condition called hydrocephalus. Hydrocephalus can arise during the embryonic development  or can be acquired postnatally. Most of these patients show increased intracranial pressure and often need urgent intervention to drain the CSF. The lack of cilia or the presence of immotile cilia in the ependymal MCCs is one of the causes of congenital hydrocephalus. Constitutive patients ,3–5. HenNormal Pressure Hydrocephalus (NPH) is a form of communicating hydrocephalus of unknown molecular cause that can progress over decades without severe neurological manifestations. The prevalence of idiopathic NPH in the elderly is estimated to be up to of 3% in patients greater than 65 years old. However, the insidious onset of symptoms and the lack of acute episodes lead to hydrocephalus often being mistaken for other chronic neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases. Because of the lack of consistent clinical symptoms, it is very likely that the number of diagnosed patients is greatly underestimated [-/-Ccno mice and the physiopathological findings in human NPH patients, it is tempting to speculate that CCNO haploinsufficiency could represent a molecular cause for idiopathic NPH. Interestingly,Because of the similarities between the CNS phenotype of constitutive +/-Ccno mice also develop hydrocephalus, albeit with lower penetrance [netrance . It is pCCNO mutation carriers could be important as they may be at risk of developing NPH, a disease which has an effective treatment but is often misdiagnosed as other incurable and devastating neurodegenerative disorders.Our results therefore suggest that the identification and follow up of heterozygous


In the current work, a human systems pharmacology model for gastrointestinal absorption and subsequent disposition of small molecules (monocarboxylic acids with molecular weight < 200 Da) was developed with an application to a ketone monoester. The systems model was developed by collating the information from the literature and knowledge gained from empirical population modelling of the clinical data. In silico knockout variants of this systems model were used to explore the mechanism of gastrointestinal absorption of ketones. The knockouts included active absorption across different regions in the gut and also a passive diffusion knockout, giving 10 gut knockouts in total. Exploration of knockout variants has suggested that there are at least three distinct regions in the gut that contribute to absorption of ketones. Passive diffusion predominates in the proximal gut and active processes contribute to the absorption of ketones in the distal gut. Low doses are predominantly absorbed from the proximal gut by passive diffusion whereas high doses are absorbed across all sites in the gut. This work has provided mechanistic insight into the absorption process of ketones, in the form of unique in silico knockouts that have potential for application with other therapeutics. Future studies on absorption process of ketones are suggested to substantiate findings in this study.Gastrointestinal absorption and disposition of ketones is complex. Recent work describing the pharmacokinetics (PK) of  Several modifications to these models are now available to study mechanistic aspects of drug transport. Of these, in vitro Caco-2 efflux transporter knockdown cell models, transfected models [in silico  mechanistic models for predicting oral drug absorption. There are proprietary models used for predictive purposes in drug development, including the ACAT model [™, the ADAM model [® and the GITA model [in silico systems pharmacology model that includes knockout variants as a means of investigating mechanisms of intestinal drug absorption. We use d-β-hydroxybutyrate (BHB) to demonstrate the approach.Gastrointestinal absorption of drugs is a complex process and involves various regions of the gut and transport mechanisms. Several experimental methods are available for quantification of drug transport across the gastrointestinal tract. The most commonly used  (PAMPA)  and cell (PAMPA) ; ex vivoechnique ; and in primates . While sd models  and knocd models , 7. Thesd models . AnotherAT model  implemenAM model  implemenTA model . In thisBHB, acetoacetate (AcAc) and acetone are endogenous metabolites of fatty acid metabolism, produced in the liver in response to starvation. BHB and AcAc are metabolically important. Typical concentrations of total endogenous ketones in blood, under normal conditions are less than 0.5 mM. Blood ketone concentrations equivalent to starvation-induced ketosis  may have therapeutic utility in a number of clinical conditions, specifically in treating neurological disorders [R)-3-hydroxybutyl (R)-3-hydroxybutyrate) that hydrolyses in vivo to produce BHB [isorders . Ketonesisorders , 14. A nduce BHB . A recenduce BHB . This woin silico structure of the biological component and incorporating a systems pharmacology approach to incorporate the therapeutic target will provide greater opportunity in exploring the contribution and influence of therapeutics on the biological systems. In this work, we demonstrate this by combining different modules of varying activity (for transport) across the gut to generate a simplified whole human system. This model is subsequently explored to study the influence of mechanistic processes, on absorption of ketones.Systems pharmacology provides an interface between systems biology and pharmacology . Applicain silico knockout variants.The objectives of this work were 1) to develop a systems pharmacology model that represents the gastrointestinal absorption of the ketone monoester and its systemic catabolism and 2) to explore mechanistic features of gastrointestinal absorption of ketones using A literature search was conducted using Medline, Embase and Cochrane libraries using defined keywords  to identify and collate information on the production, transport, and disposition of ketones (both endogenous and exogenous) and the factors governing these processes. The review focussed on identifying the metabolic processes and sites of metabolism, mechanisms involved in the transport of ketones across the gastrointestinal tract and consumption in the tissues for energy production. Information on pathway of endogenous production and associated feedback mechanisms were also identified.® . All reaction rates are defined as moles/time (mmol/h). Reactions and transport of ketones are defined either as first-order or saturable  processes. The general form of the equation used in this model, to represent the movement of a molecule from a given state isfi,a is the fractional millimoles of the ith state undertaking the ath process (e.g. a transport or metabolism process), Ai is the amount (mmol) of the ith state. Ji is the flux rate  or a rate constant of a saturable process ) that is dependent on amount (mmol) at tth time. All saturable transport processes and competitive inhibition for transport of substances was based on fractional receptor/transporter occupancy, which is similar to the Michaelis-Menten equation used to describe the saturable enzyme kinetics [The systems model is written as ordinary differential equations (ODEs) in MATLABkinetics . The genVimax, is the maximum velocity of the saturable process for ith state and kim, is the Michaelis-Menten constant that represents the amount (mmol) of the state where the velocity is half of the maximum. Note, all reactions/substrate transfers in the model are associated with a fraction to account for a complete molar balance. Competitive inhibitory processes for transport of ith state (competition exerted by jth state) are written in the form:Aj is the amount (mmol) of jth state and kjm, (in mmol) is the Michaelis-Menten constant for the jth state. Production of endogenous ketones is assumed to be constant with zero-order input. The negative feedback effect of circulating factors in the blood, on endogenous production is defined by a saturable process. The complete set of ODEs is provided in Here km) were either taken directly from the literature [Vmax) from in vitro and/or preclinical data [fmincon algorithm in MATLAB®  from the empirical data , volumes of tissues/organs were obtained from physiological parameters in the literature –24 and wterature –27 or sccal data , 28, 29.cal data . Remainidata see . A complThe model was calibrated by comparing the predictions (blood concentrations of BHB) of the systems model against empirical data at two dose levels (192 and 573 mg/kg of the ketone monoester). The data arose from a balanced design, where each individual at each dose level provided a pharmacokinetic blood sample at each time point. Since these data had several subjects per dose level the mean of the data was selected at each time point. These two doses were the extreme doses used in a clinical study . The modIn order to explore the influence and contribution of each subcomponent of the gut and role of specific absorption processes in the gut, knockout variants for absorption were created for regions and processes in the gut (see ‘Exploration of knockout variants’ in Results section). Knockouts were created by setting an indicator variable that governs a whole process to 0  or 1 . Separate knockouts of apical and basolateral transporters were created and a ‘passive absorption knockout’ was created by eliminating passive absorption from the model. A total of 10 knockout variants were identified across the length of the gut. These knockout variants were tested either alone or in various combinations (see ‘Exploration of knockout variants’ in Results section), in order to understand the contribution and influence of specific subcomponents and processes in the gut, on the gastrointestinal absorption of ketones. The influence of processes and regions of the gut on the absorption of ketones using knockouts were studied as 1) qualitative assessment and 2) quantitative assessment.All knockout variants were tested by studying simulated blood BHB concentration-time profiles. During exploration using knockout variants, model simulations were overlaid against the empirical data and compared for deviation in the profiles. Whenever the simulated profile deviated from the empirical profile in a knockout plot, the corresponding process/region was deemed to be influential. The greater the deviation of simulations from empirical data , the larger the contribution of the process/region to the absorption process.AUC (Area Under the Curve for BHB in blood) and shift in Tmax (time to maximum concentration of BHB in the blood). Fractional AUC was computed as:AUCknockout is the AUC of BHB in blood when the specific knockout was applied  was computed and values away from ‘0’ were deemed to be influential. These statistics were considered in a descriptive manner in this work.The influence of knockouts on the absorption process was studied quantitatively by computing the fractional contribution of d Tables  and AUCfNote, given exploratory nature of the current work, no statistical criterion was defined either for qualitative or for quantitative assessments that would confer significance of influence.A systems pharmacology model for catabolism of the ketone monoester and its metabolism products in humans was developed with a view to maintain the model structure to be as simple as possible but not simpler . The sysA brief description of each component in the model with an emphasis on its contribution to the kinetics of ketones is outlined below.+ coupled MCT1, belonging to SLC5A8 sub-family) are expressed along the gut wall. Of these, MCT1 and SMCT1 are expressed on the apical side and MCT4 is expressed on the basolateral side [2) is reported to increase from proximal to distal regions of the gut [max, down the gut regions in the model) of the transport of ketones. This forms the basis for four distinct subcomponents of the gut in this systems model. A diagrammatic representation of the transport proteins expression in the gut wall (enterocyte) is presented in The gut is divided into two subcomponents namely proximal gut and distal gut. Each of these subcomponents are further divided , providing a representation of spatial and temporal transport . These rral side , 34. Theral side . In addi the gut . This vaThe portal vein forms the link between gut and the liver. Ketones absorbed from across the gut wall are taken by the portal system and transported to the liver.The liver forms the major connecting link for absorption of ketones from the gut to the systemic circulation. The liver is represented as the site of metabolism and the site of endogenous ketone production . VariousThe systemic circulation is the site for transport of ketones in the body and also a site of metabolism of ketone ester to butanediol and BHB, butanediol to BHB and AcAc to acetone . All othAll other organs and tissues into which ketones are transported from the systemic circulation are presented together as one lumped component. This constitutes sites of metabolism such as heart, brain, kidney and skeletal muscle and sites of excretion such as lungs and kidneys. Transport of ketones (BHB and AcAc) in and out of the tissues from the systemic circulation is an active process and is facilitated by MCT1 and MCT2 transporters. MCT2 belongs to the SLC16A family of transporters and is a high affinity and low capacity transporter for both BHB and AcAc . All othGiven the objectives of the current work to explore mechanisms of gastrointestinal absorption of ketones, a fit-for-purpose approach was used in calibrating the systems model as opposed to routine model evaluation tests used for standard PKPD models , 44. Thein slico knockout variants. Assessment of influence using knockouts were studied both qualitatively and quantitatively.Influence and contribution of processes and regions of the gut on the absorption of ketones was studied using Knockout variants of the systems model see  were expKnockout of all absorption processes in successive subcomponents of the gut  are presented in Tmax), a negative AUCfraction was observed for knockout of passive diffusion  approach was used in developing the model. The design of subcomponents for the gut was driven by variability in expression of transport proteins along the gut , 34. ThoKeeping in view, the objectives of the current work, i.e., to explore mechanisms related to gastrointestinal absorption, using of ketones as an example, a fit-for-purpose approach was used in calibrating the model . This meInterpretation of results from application of knockout variants of the systems model have shown that there are at least three distinct regions in the gut that contribute to gastrointestinal absorption of ketones. Future clinical studies of absorption of ketones are recommended to test this hypothesis. We believe that the learnings from knock-outs in this model can be tested by delivery of test substance directly into duodenum, conducting clinical absorption studies in special population such as ileostomy and colectomy patients. Exploration of knockout variants have indicated that different mechanisms dominate the input process of ketones in different regions of the gut leading to dose-dependent nonlinear absorption processes. It was also observed that the low dose was predominantly absorbed from the proximal gut and that this was mainly driven by passive processes. In contrast to this, the high dose was absorbed across the length of the gut and this was predominantly driven by passive diffusion process in the proximal gut and active transport processes in the distal gut. This work highlights that while passive diffusion contributes to the initial input profiles of blood BHB, active transport processes contribute to later input processes. The findings from this work are in line with and support the findings from our previous work in which we developed an empirical population PK model for blood BHB concentration, where putative multiple absorption sites were suggested in the modelling process. The current work leads to the hypothesis that there are three distinct input sites for absorption of ketones in the gut. This hypothesis may be the subject of interest for testing in future studies with the ketone monoester, notably when particular targets for plasma profiles and exposure are defined.Though the current systems pharmacology model for ketones was able to serve the purpose of current objectives, it is by no means complete. Exploration and application of the systems model in the current work was limited to considering the influence of absorption of the ketone monoester on blood BHB concentrations only, exploration of other ketones in blood and ketones in other tissues was beyond the scope and objectives of the current work. The current set of parameter values of the model, though providing a good description of BHB profiles in the blood, are generally not identifiable and will need to be calibrated in future work when other ketones are tested in blood and/or other tissues. The immediate areas of expansion for the current model include exploration of BHB kinetics in tissues of metabolic interest such as skeletal muscle, kidney, brain and heart and sites of excretion such as kidneys and lungs. This can be achieved by differentiation of the tissue component of the model to yield organs of interest as separate components. This may be followed by extending the scope of this model to explore kinetics of other ketones and their precursors to understand the catabolism of the ketone monoester in a broader sense. These expansions will help to provide the capability to link pharmacodynamics of ketones with the pharmacokinetics, for future prospects with the ketone monoester that are intended for therapeutic applications.in silico knockout variants in exploring the mechanism of oral drug absorption. The initial part of this work relating to model development demonstrates how processes can be integrated to build a systems pharmacology model based on known mechanisms. The later part describes how some selective processes can then be differentiated from the whole (such as the use of knockout variants shown here) to explore mechanisms that are either difficult or impossible to perform experimentally . This work demonstrates the potential of systems models to complement or, in some circumstances, replace animal studies.This work demonstrates the utility of the systems pharmacology model approach in exploring the mechanisms of gastrointestinal absorption of therapeutic compounds. A unique feature of this work is the development of In conclusion, a systems pharmacology model for the absorption and catabolism of a ketone monoester is developed. This model is capable of describing blood BHB concentrations at two dose levels. Knockout variants of components of the systems model provided a notable and convincing mechanistic insight into the gastrointestinal absorption of ketones in terms of the influence of specific regions, processes of absorption and the dose-dependent nature of absorption. The current model provides an initial platform for continuous exploration of mechanisms of ketone disposition and its further expansion to provide insight into the mechanisms of pharmacological action of ketones in therapeutic applications. This approach can be extended to other therapeutic compounds with known complexities of drug actions.S1 Fig(DOCX)Click here for additional data file.S2 Fig(DOCX)Click here for additional data file.S1 Methods(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.


Background: This study evaluated and determined the proximity of an impacted third mandibular molar (TMM) to the inferior alveolar canal (IAC) by using CBCT and digital panoramic radiography.Materials and Methods: This descriptive-analytic research applied CBCT and panoramic radiographs for 60 subjects . Subjects selected showed a close proximity about the TMM to the inferior nerve canal on panoramic radiographs; these subjects then received CBCT radiographs. The CBCT findings for the proximity of the TMM to inferior nerve canal used the outcomes of surgical findings as the standard of comparison.Results: Eight cases showed positive surgical findings indicating vicinity of the third molar and the mandibular nerve canal. Only 13.3% of the cases in which panoramic views showed the proximity of the TMM and the IAC were confirmed during surgery. The result for CBCT radiographic diagnosis was 95%. Conclusion: It can be concluded that CBCT is preferred over panoramic radiography to determine the proximity of the impacted TMM to the IAC. Narrowing of the mandibular canal or root canal, disconnection of root borders in panoramic radiography, and the inferior-lingual proximity of the tooth to the root in CBCT strongly indicated the close nearness of the impacted TMM to the IAC.  Although panoramic imaging offers comprehensive coverage and easy access, identifying the exact proximity of the impacted TMM to the IAC in patients is not possible; hence, it is essential to augment diagnosis using cone-beam computed tomography (CBCT) .The extraction of an impacted TMM is a common minor operation in the maxillofacial region. Like other surgeries, this type can have the side effect of malfunction of the inferior alveolar nerve (IAN). It is necessary to precisely predict the vicinity of the third molar to the eIAN [5]. Such damage may cause paresthesia, hypoesthesia, and anesthesia of the lower lip. Its prevalence has been reported to be 4% to 8%; in less than 1% of cases, patients experience permanent numbness in that area [6-9]. This occurs because of the surgery in the area around the impacted molar root and the IAC results in exposure of or damage to the canal [10].One side effect of impacted third molar tooth surgery is the malfunction of the IAN . This is also the reason of one of the very frequent complaints against maxillofacial surgeons in the coroner’s court and increases belief by the public that surgical negligence has occurred during surgery [3]. An extensive survey of the proximity of the impacted third mandible molar to the IAN is necessary before surgery. Panoramic radiography is the most common equipment used for pre-surgery evaluation of impacted third molars .The proximity of the impacted third molar to IAN raises the risk of numbness up to 30% and may generate mental and social troubles for the patients [3-5]. This technique is gradually being replaced by CBCT, which allows 3D views of the anatomy with the least distortion at different angles [11]. The advantages of CBCT over CT include a decrease in the radiation surface, high-quality images, low scanning period, reduction in the radiation dosage to patient, and the decrease in metal artifacts in images [2].Although this technique has gained prominence in third molar surgeries because it involves a low dose of radiation, comprehensive coverage, and simplicity of analysis and access, it has drawbacks. These include low sensitivity, 2D views, inability to distinguish bone thickness, distortion of dimensions and magnification of both the vertical and horizontal dimensions and production of ghost images on the reverse side. Sensitivity values of 24% to 64% and specificity values of 74% to 98% have been recorded for panoramic radiography [3]. Studies show that nerve damage is the most frequent side effect of surgery for the extraction of the third molar (4.4% to 8.1%). Paresthesias recorded in 1.3% to 5.3% of the cases because of the vicinity of the impacted tooth to nerves [12]. Atsuko et al. surveyed the positions of the lower jaw molars and the mandible canal by using CBCT. They concluded that data on the distance between the canal and the tooth provided by CBCT are effective for the evaluation of possible damage to the IAN. The great resolution and less radiation dosage allow the use of these images for TMMs. CBCT images in specific and standard conditions and the rating of a sufficient number of samples are listed as the advantages in the study . The current study showed that panoramic radiography failed to correctly diagnose the relation between these two structures on its own. The influence of multiple observers for radiographic accuracy was eliminated by using only one observer and the reliability of the study increased. Several investigations have found that the factors used in panoramic radiography are better related to the proximity of the alveolar nerve to the impacted third molar of the lower jaw. Albert et al. compared panoramic radiography with conventional tomography to study the vicinity of the impacted third molar and the mandibular canal. They analyzed risk factors in the perception of close proximity of the tooth to the nerve and determined the topography of nerve to the mesial and distal roots. Their results determined that the darkening of the root was the most common factor isolated in panoramic radiography; in 13 out of 14 patients showing this sign, the third molar was in close vicinity to the nerve. In 4 out of 5 patients showing an island-shaped apex, the third molar was in close vicinity to the nerve. A dark bifid root apex and deflection of the root apex did not indicate a close proximity of the tooth root to the mandibular nerve. The performance of tomography versus panoramic radiography was not discussed [22]. Tantanapornkul et al. compared panoramic radiography and CBCT to evaluate the topographic proximity of an impacted third molar tooth to the mandibular canal. They considered 4 factors for the proximity of the nerve to the tooth: lack of continuity of mandibular canal; root darkening; mandibular canal deflection; and reduction of the root. The existence or nonexistence of a direct relationship between root and nerve were the criteria for CBCT. After the analysis of the radiographs, patients underwent surgery and the results determined during surgery were recorded. After surgery, patients were examined for the existence of paresthesia. The results revealed that every factor for panoramic radiography was related to the exposure of the nerve; hence, these factors effectively predicted the risk of harm to the nerve. The lack of continuity of the mandibular canal was introduced as the most important diagnostic factor. Specificity was 93% and sensitivity was 77% for CBCT, 70%, and 63% for panoramic radiography, respectively. This showed that CBCT outperformed panoramic radiography . Valmaseda-Castellón et al. showed that IAN injury might ensue after lower third molar operational extraction [24].When these factors were found in panoramic radiographs, the probability of the close vicinity of the impacted third molar tooth of the below jaw to the IAC increased significantly. There were no significant relationships found between radiographs of the disruption of the white cortical line of inferior alveolar, root deflection, and narrowing of the IAC. Studies have considered factors such as different numbers of observers, their specialties, the method of scoring of data, and results of surgery results in their research methods. The exposure during surgery and the surgeon assessment were considered the guidelines for evaluation. In other cases, paresthesia was considered for the vicinity of the two structures [21]. This was a restriction of the research. The present study employed observers, which had several advantages. Tantanapornkul et al. surveyed the results of CBCT and panoramic radiography to assess the closeness of the mandibular canal to an impacted third molar. Patients with impacted third molars of the lower jaw were scanned by panoramic radiography prior to surgery. The surgeons were asked to record all tooth extraction details and neurovascular exposure during tooth extraction. Patients for whom there was doubt about neurovascular exposure were dismissed from the research. Seven days after surgery, the side effects of third molar surgery of patients were recorded. Ten patients showed the side effects; patients with exposed neurovascular bundles showed notably higher side effects compared to other patients. The sensitivity of CBCT was 93%, which was notably greater than for those receiving only panoramic radiography. It was concluded that the CBCT was more effective in predicting neurovascular exposure after surgery for an impacted third molar than panoramic radiography. Moreover, its application under clinical conditions to evaluate impacted third molar pre-surgery had several advantages. Since identifying neurovascular exposure was done by the surgeon during surgery, the possibility exists that some areas were overlooked and these results showed the low specificity of images [18-22]; hence, they found that the diagnostic precision of panoramic radiography and CBCT were the same. The benefits of this study were the random viewing of panoramic radiographic images and CBCT, internal agreement of viewers for both techniques, and evaluation by one observer. The sensitivity and specificity of both CBCT and panoramic radiography have been reported differently in various studies; for example, a sensitivity of 96% and specificity of 27% have been announced in a similar study.Gaeminia et al. evaluated the proximity of impacted third molars to the mandibular canal by using CBCT and panoramic radiography. Their results revealed no significant relation between exposed IAN and nervous disorders after surgery by gender, place of surgery or third molar angle. They found no meaningful difference between these two techniques for the prediction of the risk of nerve exposure; however, the lingual location of the mandibular canal was notably correlated to IAN nerve damage. Three cases using panoramic radiography were significantly related to IAN nerve damage. CBCT sensitivity was 96% and specificity was 23% [In the current study, the sensitivity of CBCT was 100%, which indicates its effectiveness in diagnosing positive cases. Its specificity for diagnosing and identifying negative cases was 94%, which was lower than its sensitivity.This study confirmed that CBCT is the most accurate method of radiography for the determination of the proximity of impacted third molars of the lower jaw and the IAC. The results indicated that 3 of 7 factors used to evaluate panoramic radiography  notably matched with the operational results used as the standard. The CBCT diagnostic value was 95% in this study, indicating that, in 95% of cases, the results of operation were the same as the predictions from CBCT. The results of CBCT evaluation increased for simultaneous observation of the inferior-lingual relation to confirm the proximity of the impacted third molar of the lower jaw to the alveolar canal. Conflict of interestThe authors declare that they have no conflict of interest.


Congenital unilateral agenesis of the parotid gland is a rare condition with only few cases reported in the literature. A review of 21 cases in the available literature is presented in this article. We report on a further case of a 34-year-old woman with agenesis of the left parotid gland and lipoma of the right cheek. Clinicopathological characteristics of described cases in the literature were discussed.  The major salivary glands start to develop between the sixth and seventh week of gestation beginning with the parotid gland which arises from ectodermal lining of the stomatodeum . The subAgenesis of parotid glands may occur alone or in association with anomalies of the submandibular or lacrimal gland, first brachial arch developmental disturbances, or other congenital anomalies –7. The tWe present a case of unilateral agenesis of the parotid gland in combination with a lipoma of the cheek on the opposite site. The clinical and radiological findings in this patient are described. A review of the unilateral parotid gland agenesis in the literature is also presented considering a summary of the data regarding gender, age, defect site, and combined manifestations.A 34-year-old woman was referred to our department for evaluation of painless swelling of the right cheek over the last seven months. In addition, she often bit her right cheek. The swelling did not vary in size during eating and the patient had no other clinical symptoms and no history of recurrent parotitis. Xerostomia was not noted. There was no other relevant medical history and no family history of similar problems was reported. On clinical examination the oral mucosa was moistened by saliva. Bilateral hemifacial contour was normal, and there were no depressions in either preauricular region. Physical examination of the head and neck was without pathological findings, except for the absence of the left parotid gland papilla .Ultrasonographic examination of the head and neck area showed that the parotid gland on the left side was totally absent. The other major salivary glands were present without any pathology. A tumor in the right cheek ventral to parotid gland was observed with characteristic sonographic appearance of lipoma. For further evaluation of the tumor in the right cheek and assessment of the function of the other salivary glands magnetic resonance imaging (MRI) and scintigraphy with Technetium (Tc-99m) sodium pertechnetate were performed. MRI confirmed a lipoma of the cheek on the right side and a unilateral absence of the left parotid gland . Other pCongenital absence of the salivary glands is a rare condition which has been described to affect the parotid or submandibular glands . AgenesiThe true incidence of unilateral agenesis of the parotid gland is difficult to ascertain because it is often asymptomatic . Congenin = 12) or the presence of the parotid papilla was not documented (n = 9).In the available literature, only 22 cases of unilateral agenesis of the parotid gland have been described including the present case . Among tIn most reported cases the unilateral agenesis of the parotid gland was associated with a painless swelling of the contralateral parotid gland or facial asymmetry without any other significant clinical symptoms , 20, 25.The unilateral agenesis of the parotid gland may be clinically silent. Clinical suspicion should arise in cases of asymmetrical parotid areas and a painless unilateral swelling of the parotid gland. Clinical examination, especially the absence of the papilla of Stensen's duct, could be helpful for diagnosis. Mostly the unilateral agenesis of the parotid gland seems to be a coincident finding. We were able to confirm the diagnosis of parotid gland agenesis by using a combination of MRI and salivary gland scintigraphy.