Plasmodium falciparum parasites that currently has a 20% fatality rate and disproportionately affects children under 5 years old. Despite Plasmodium parasites being blood restricted, the BBB becomes disrupted when the brain microvascular endothelial cells (BMECs) lining the microvasculature of the brain are activated in response to sequestration of Plasmodium-infected red blood cells (iRBCs), as shown by in vitro co-culture assays of BMECs and iRBCs[Breakdown of the blood brain barrier (BBB) is a feature of cerebral malaria (CM), a manifestation of infection with and iRBCs. As partFig 1) [The BBB keeps the central nervous system (CNS) separated from the circulatory system. This selective semipermeable barrier is formed by specialized BMECs that regulate bidirectional traffic of molecules into and out of the CNS via tight and adherens junctions. The endothelium is further enveloped by pericytes and astrocyte endfeet that are regulators of the the formation and maintenance of the barrier’s integrity , 3. ThesFig 1) . The NVUFig 2).Key features of the BBB include (1) tight and adherens junction proteins between adjacent endothelial cells, (2) interaction of endothelial cells with the extracellular matrix, a key layer composed of proteins that include collagens and laminins, and (3) modulation of junction proteins by endocytosis and endothelial-expressed matrix metalloproteinases (MMPs) to alter permeability of the membrane as required. However, these properties of the BBB are not intrinsic to BMECs themselves but are controlled by interactions of BMECs with adjacent cells such as pericytes and astrocytes  to modulate bulk fluid flow [Astrocytes are the most abundant glial cells in the brain, with a host of diverse functions that include regulation of the BBB . Specialuid flow . The powuid flow .Astrocytes have been shown to be directly involved in host defense , 11, as + T cells are attracted to the area. Although research in the P. berghei ANKA mouse model of CM (ECM) suggests that CD8+ T cells are critical in BBB disruption, apoptosis is not a prevalent feature of barrier disruption.Permeabilization of the BBB in CM has been demonstrated with increases in albumin, normally partitioned from the brain parenchyma by the BBB, in the cerebral spinal fluid of pediatric patients in Malawi . CurrentP. falciparum sequestration [Plasmodium-infected mice. Models of ECM have also correlated symptoms with reduced levels of astrocyte-produced proteins, such as BMEC-derived brain-derived neurotrophic factor (BDNF) , suggespatients  as well patients , but litFig 1). Using animals expressing Cre under the promoter for each of these markers, in vivo manipulation of molecules of interest can also be performed, although caution should be employed with regards to knowledge of other cells expressing these molecules in the vasculature of other tissues.Cerebral manifestations of malaria are most often studied using the mouse ECM model, in which vascular permeability and albumin entry into the brain parenchyma has been demonstrated using Evan’s blue. Decoupling the complex interactions between BMEC, pericytes, and astrocytes in vivo is required to understand BBB breakdown in CM. In vivo options for such research include the use of reporter mice to visualize the cells of the BBB by confocal or two-photon microscopy , 24. DebInteractions between the different cell types forming the NVU can also be studied using in vitro culture models. These are by their very nature reductionist, with limited functionality that does not replicate the vast in vivo characteristics of the BBB, particularly the effects of fluid shear stress from blood flow. However, BMECs are generally grown on the surface of permeable supports in a two-compartment transwell system. Addition of other astrocytes and pericytes along with variations of conditioned media can be used to investigate diffusible factors and cell interactions affecting BBB activation and integrity . AspectsP. falciparum infection is required to develop a more holistic model of CM pathogenesis.It is now appreciated that diffuse breakdown of the BBB in CM is due to a reduction in the paracellular BMEC junction proteins. However, junction proteins are ultimately controlled by adjacent pericytes and astrocytes; yet there is very little work done characterizing the response of these cell types in malaria. Determination of how astrocytes and pericytes regulate BMEC activation and the expression of junction proteins in the face of


Levees protect floodplain areas from frequent flooding, but they can paradoxically contribute to more severe flood losses. The construction or reinforcement of levees can attract more assets and people in flood-prone area, thereby increasing the potential flood damage when levees eventually fail. Moreover, structural protection measures can generate a sense of complacency, which can reduce preparedness, thereby increasing flood mortality rates. We explore these phenomena in the Jamuna River floodplain in Bangladesh. In this study area, different levels of flood protection have co-existed alongside each other since the 1960s, with a levee being constructed only on the right bank and its maintenance being assured only in certain places. Primary and secondary data on population density, human settlements, and flood fatalities were collected to carry out a comparative analysis of two urban areas and two rural areas with different flood protection levels. We found that the higher the level of flood protection, the higher the increase of population density over the past decades as well as the number of assets exposed to flooding. Our results also show that flood mortality rates associated with the 2017 flooding in Bangladesh were lower in the areas with lower protection level. This empirical analysis of the unintended consequences of structural flood protection is relevant for the making of sustainable policies of disaster risk reduction and adaptation to climate change in rapidly changing environments. In the year 1964, new levees were built to prevent flooding in the village of Char Jabbar, Bangladesh. The presence of this structural protection measure encouraged more human settlements and numerous people moved into this flood-protected area  feedbacks  of flood-prone areas behind the levee but also losses of ecological functions  of the country is under water  and fatalities  shows that the negative impacts of the 2017 flooding in Bangladesh were massive. Yet, when compared to the most recent events Fig. .Fig. 2FlTo better understand the interplay between structural protection levels and flood exposure/mortality, we explore the effects of structural flood protection in four different types of human settlements along the Jamuna River floodplain. They consist of two rural environments – the protected rural area in the Gaibandha district  and the unprotected rural area  in the Jamalpur district – and two urban environments, Gaibandha and Sirajganj, with different levels of structural flood protection . Also the increase rate in population density is higher in the protected area (22 persons/km2/year vs. 10 persons/km2/year).To corroborate these findings, we also compared changes in population density over the past 30 years in Shahjadpur Upazaila on the west bank of Jamuna river (protected) and in Nagarpur Upazila on the east bank of Jamuna river (unprotected). We found that population density is higher in the protected area , Government of Bangladesh). This difference cannot be explained by different levels of exposure since our spatial analysis, based on the 2017 flood extent map provided by the Dartmouth Flood Observatory (Brakenridge i) flood early warning systems are in place in all four test sites, while sex ratio, age, and the proportion of disabled people are relatively homogeneous.Secondary data for socio-economic factors are limited for our study area. We select few demographic and socio-economic factors that might influence the population density in our study area. Table Our findings show that the prevention of small flooding events via structural measures has not only been associated with more intense urbanization of flood-prone areas Figs.  and 4 buThe results of this case study support consolidated theories about the interplay between levels of structural flood protection, people and assets exposed to flooding, and social vulnerability to flooding. While similar outcomes have been broadly discussed in the flood risk literature with reference to US, European, and Australian cases studies  to soft (living with floods) approaches for flood risk management is a general trend in policy and scientific writing today  weights and values given by local people, experts, researchers, and governments to economic, environmental, and social benefits and costs. There are, in fact, multiple feasible (and desirable) trade-offs between hard and soft approaches and their identification calls for a transparent communication of positive (often intended) and negative (often unintended) effects of alternative measures in flood risk management.


Spondyloarthropathies (SpA) encompass a group of chronic inflammatory diseases sharing common genetic and clinical features, including the association with HLA-B27 antigen, the involvement of both the axial and the peripheral skeleton, the presence of dactylitis, enthesitis, and typical extra-articular manifestations such as psoriasis, inflammatory bowel disease, and acute anterior uveitis (AAU). The latter is commonly reported as a noninfectious acute inflammation of the anterior uveal tract and its adjacent structures. AAU may affect more than 20% of SpA patients representing the most common extra-articular manifestation of the disease. Considering the potential consequences of untreated AAU, early diagnosis and aggressive treatment are crucial to avoid complications of remittent or chronic eye inflammation, such as visual loss and blindness. The management of SpA has dramatically improved over the last decades due to the development of new treat-to-target strategies and to the introduction of biologic disease modifying antirheumatic drugs (bDMARDs), particularly tumor necrosis factor alpha inhibitors (TNFis), currently used for the treatment of nonresponder patients to conventional synthetic agents. Along with the improvement of musculoskeletal features of SpA, bDMARDs provided an additional effect also in the management of AAU in those patients who are failures to topical and systemic conventional therapies. Nowadays, five TNFis, one interleukin-17, and one interleukin 12/23 blocker are licensed for the treatment of SpA, with different proven efficacy in preventing and treating ocular involvement. The aim of this review is to summarize the current options and to analyze the future perspectives for the management of SpA-associated AAU. Spondyloarthropathies (SpA) embrace different chronic inflammatory diseases sharing common genetic (association with HLA-B27 antigen) and clinical features. The principal symptoms are inflammatory chronic back pain, peripheral arthritis , dactylitis, and enthesitis . The disIn this contest of very heterogeneous disease phenotype, the importance of personalised multidisciplinary management of the disease is mandatory. In the last decades, the development of new classification criteria allowing an earlier diagnosis and the availability of biologic and targeted synthetic therapies has vastly improved the management of SpA patients. Among biologic disease modifying antirheumatic drugs (bDMARDs), tumor necrosis factor alpha inhibitors (TNFis) are currently widely used for the treatment of SpA. To date, five TNFis  have been licensed for SpA by the European Medicines Agency and the US Food and Drug Administration. Recently, new potential treatment targets in SpA emerged enhancing the available treatment options with novel mechanisms of action. In particular, blockers of interleukin-17 , interleukin 12/23 , and phosphodiesterase-4  were included in the therapeutic armamentarium for SpA.Although the efficacy and safety profiles of the different available therapies have been clearly demonstrated for the management of musculoskeletal features of SpA, different performances in preventing and treating ocular involvement were proven.The aim of this review is to summarize the current options and to analyze the future perspectives for the management of SpA-associated AAU.Uveitis is one of the most common causes of blindness and represent a broad spectrum of disorders characterized by inflammation of the uveal tract  and its adjacent structures . According to the Standardization of Uveitis Nomenclature (SUN) criteria, uveitis can be classified according to the anatomic site of inflammation into anterior (characterized by the presence of intraocular inflammation in the anterior chamber), intermediate (inflammation of the pars plana), posterior (inflammation of the posterior segment), or panuveitis (involving anterior and posterior segment) . UveitisAnterior uveitis is the most common type of uveitis encountered in Western countries, while posterior and panuveitis are more frequently seen in developing countries due to the higher incidence of infectious uveitis involving the posterior segment of the eye. As mentioned before, the link between SpA and uveitis has been well described, since uveitis is the most common EAM in SpA and its main clinical presentation is with acute onset. However, about 50% of patients tend to have recurrent disease. . It has Definitive data about pathogenesis of AAU in SpA are still lacking, albeit some reports derived from experimental animal models have contributed to point out some evidences. Unlike other classical systemic inflammatory disorders, SpA are not characterized by defined serological markers to assist the diagnosis , with the exception of HLA-B27 . HLA-B27 is commonly linked to the whole group of diseases and in particular to AS  and has The most common ocular symptoms of AAU are acute eye pain, redness, and intense photophobia. Nonspecific visual changes such as floaters and different degrees of visual acuity loss may be present . AAU assAnterior uveitis associated with SpA is typically a nongranulomatous type of uveitis characterized by the presence of fine keratic precipitates visible at the slit lamp examination of the anterior segment. Intraocular pressure is usually low due to severe inflammation of the ciliary body. In severe forms of acute anterior uveitis, hypopyon and fibrin can be visualized as a white and dense clot in the anterior chamber.Posterior synechia, cataract, and secondary glaucoma are the most common ocular complications of uveitis. In about 15 to 20 % of patients the uveitis may have a more severe and chronic course and may involve the posterior segment with macular edema, retinal vasculitis, and papillitis leading to visual loss .Some authors speculate on the prognosis of HLA-B27 related AAU, reporting a higher frequency of recurrence and a worse outcome compared with HLA-B27 negative patients , 46.The use of bDMARDs could significantly affect the prognosis of AAU associated with SpA . In factThe management of uveitis reserves actually several clinical challenges. The therapeutic approach for uveitis requires careful consideration regarding etiology, involved anatomic site, chronicity, prior medication failure, and potential ophthalmic and systemic risks of proposed therapy: a definite diagnosis is crucial to establish an appropriate therapy. Treatment of noninfectious uveitis may be local, systemic, or a combination of the two. The therapeutic strategy evaluates the underlying diagnosis, severity of the disease, laterality, and presence of comorbidities. The treatment of SpA associated AAU should include the management of acute attack and the prevention of recurrences.The first-line symptomatic treatment of acute attack of AAU consists in a cycloplegic agent combined with corticosteroids, which may be administered systemically, topically, or by subconjunctival injection. Periocular prednisolone acetate and intraocular dexamethasone are the most commonly used local treatment in patients with HLA-B27 associated uveitis with posterior pole complications. In a minority of cases, subconjunctival corticosteroid injections may be needed, only when a marked anterior segment inflammation results in significant loss of vision . In the The key for the treatment of noninfectious uveitis relapsing or refractory to topic therapy is the control of systemic inflammation generated by the underlying autoimmune disease . SystemiIn conclusion, systemic immunosuppressive drugs have a potential in the management of AAU, even if their use showed no proven efficacy in the treatment of axial and enthesopathic involvement of SpA, limiting the opportunity to treat SpA-related AAU and the underlying disease with the same drug.To date SpA has fewer therapeutic options than rheumatoid arthritis and could exhibit heterogeneous therapeutic responses considering different site involvements. Given the complexity of SpA, a tailored management of the disease that includes targeted DMARDs  is mandatory.Biologic DMARDs are defined as manufactured therapies by recombinant DNA (deoxyribonucleic acid) technology and include bioengineered soluble receptors, monoclonal antibodies, Fab fragments, and cytokines that affect the expression of pro- and anti-inflammatory components of the immune system. To date the major class of bDMARDs employed in SpA care is the successful use of TNF blockade in persistently high disease activity despite conventional treatments . TNFis cTo date, bDMARDs have been used off-label to treat AAU because none of these therapies has been approved yet for adults, despite that their clinical efficacy has been reported in an amount of clinical cases and case series .TNF alpha is essential in the intraocular immune response and in the autoregulation of the physiologic apoptosis of ocular cells. Preclinical studies give several evidences that TNF blocking can be a possible therapeutic strategy in uveitis. In fact, TNFis switch the immune response towards a Th2 prevalent mechanism, decreasing also disease activity . ExperimRetrospective studies on TNFis have been focused on underlying systemic disease with associated uveitis and some prospective studies have been successfully completed . SeveralIn animal models infliximab has shown a good safety profile and efficacy in the treatment of uveitis and dry eye and in scarring healing on the eye's surface –89. It iRecently, these evidences had led to Food and Drug Administration and European Medicines Agency approval of adalimumab for the management of noninfectious intermediate uveitis, posterior uveitis, and panuveitis in adults. Adalimumab is licensed for the treatment of pediatric chronic noninfectious AAU in patients from 2 years of age, who have had an inadequate response to conventional therapies or in whom conventional therapy is inappropriate.Etanercept is a therapeutic option in SpA but its efficacy on uveitis is much debated , 103. BrGolimumab and certolizumab pegol efficacy in the treatment of uveitis has been reported only in few case reports and small case series of heterogeneous subgroups of patients, including patient nonresponders to prior TNFi , 105–110NCT02911116). Apremilast was not studied in AAU SpA-related. Ocular involvement is actually under assessment in a phase 3 randomized double-blind study designed to evaluate the efficacy and safety of apremilast in active Behcet's disease  [The ability of other mechanisms of action to manage uveitis in SpA is still under delineation. The involvement of IL-23-IL17 pathway and the consequent pivotal role of autoreactive T cells in the pathogenesis of noninfectious uveitis provide a rationale for treatment of AAU with IL-17 inhibitors . However2307513) .Although targeted therapies have provided a larger armamentarium to treat uveitis, challenges remain. Among small molecules, tofacitinib is an oral inhibitor of Janus kinase (JAK) 1 and 3 that is under investigation for the treatment of AS  and PsA The management of SpA and related AAU is extremely complex due to the pleomorphic characteristics of these diseases. Multidisciplinary approach is mandatory to achieve the target of an early diagnosis and aggressive treatment, in order to prevent disease progression and damage. The treatment armamentarium of SpA has been considerably improved over the last decades due to the development of new targeted drugs that provided an additional effect also in the management of AAU. The first line of treatment in AAU remains a combination of topical corticosteroids and mydriatic agents, reserving systemic corticosteroids for patients with refractory and severe involvement. The introduction of corticosteroid-sparing csDMARDs is a therapeutic option. Among csDMARDs, methotrexate and cyclosporine reported the most solid data in AAU treatment with an acceptable safety profile. TNFis are the most frequently used bDMARDs in the treatment of both SpA and AAU. In particular, monoclonal antibodies TNFis resulted more effective than etanercept in AAU potentially due to the paradoxical effect and a lower efficacy of the fusion protein. New mechanisms of action targeting the IL-23-IL17 pathway are still under delineation and further data are needed to make any statement.


Umbilical vein varix (UVV) is a very rare cord anomaly associated with intrauterine fetal death and fetal anomaly. We describe a case of extra-abdominal UVV with thrombosis. UVV was diagnosed at 23 weeks of gestation for the first time by ultrasonographic screening. Peak systolic velocity (PSV) near the UVV was partially increased up to about 100 cm/s, and blood flow was not detected in one of the umbilical arteries at 28 weeks of gestation. Therefore, the mother was hospitalized to monitor alterations of the PSV of the UVV frequently. Because the PSV of the UVV showed a sudden rapid increase up to about 150 cm/s at 32 weeks of gestation, she underwent emergent cesarean section on the same day to avoid sudden umbilical cord occlusion. The infant's birth weight was 1,744 g, and the Apgar scores were 8 and 9 at 1 and 5 minutes, respectively. The pathological examination showed UVV with thrombosis and an occlusion in one of the umbilical arteries. The neonatal laboratory data showed no coagulopathy. Based on our experience with this case, frequent ultrasonographic examination should be performed to detect the acute thrombosis in the case of extra-abdominal UVV, especially during the preterm period. Umbilical vein varix (UVV), variceal dilatation of the umbilical vein, is one of the rare umbilical anomalies associated with intrauterine fetal death and fetal malformations , 2. AlsoHere, we describe a case of extra-abdominal UVV with thrombosis that might have caused occlusion of one of the umbilical arteries. Because of immaturity of the baby, we carefully observed conservatively 9 more weeks until changes occurred. She underwent emergency cesarean section and a male baby was born without any complications.A 28-year-old woman  without relevant medical history became pregnant by artificial insemination with her husband's sperm and visited our hospital at 10 weeks of gestation. At 23 weeks of gestation, fetal screening ultrasonography showed two normal umbilical arteries and abnormal bean-like dilation of the umbilical vein , which wAt 32 weeks of gestation, edematous enlargement of the UVV and an increase of PSV of the UVV up to 149 cm/s were detected by ultrasonographic echocardiogram , and fetUVV or variceal dilatation of the umbilical vein is one of the umbilical anomalies that occur in either intra- or extra-abdominal portion of the umbilical cord . Some caIn our case, frequent ultrasound examinations could reveal increasing acute massive thrombosis in the varix and that in one umbilical artery before delivery. The pathological examination showed massive nonorganized thrombi and hematoma in and around the UVV and occlusion of one of the umbilical arteries by fibrin thrombi with focal calcification. These findings were compatible with those of the prenatal ultrasonography, and they suggest that the UVV and hematoma around it laterally compressed the umbilical artery, resulting in its occlusion and thrombus formation. In this regard, frequent ultrasonographic examinations were useful in deciding whether to perform emergent cesarean section before occurring umbilical cord complications including umbilical venous embolism . Our neo et al. recommends that serial ultrasonographic scans are required weekly from diagnosis to 28 weeks, and fetal cardiac monitoring along with the scans twice a week thereafter [It has been noted that fetal death tended to occur rapidly after an abnormal fetal nonstress test result . Some stereafter .This is the first reported case of an infant with extra-abdominal UVV associated with thrombosis who could be monitored in detail by ultrasonographic examinations for such a long period of time (nine weeks) in the preterm stage. Based on our experience, we suggest that frequent ultrasonographic examinations are useful for detecting acute increasing thrombosis in the case of extra-abdominal UVV.


Ever since Claude Bernards discovery in the mid 19th-century that a lesion in the floor of the third ventricle in dogs led to altered systemic glucose levels, a role of the CNS in whole-body glucose regulation has been acknowledged. However, this finding was later overshadowed by the isolation of pancreatic hormones in the 20th century. Since then, the understanding of glucose homeostasis and pathology has primarily evolved around peripheral mechanism. Due to scientific advances over these last few decades, however, increasing attention has been given to the possibility of the brain as a key player in glucose regulation and the pathogenesis of metabolic disorders such as type 2 diabetes. Studies of animals have enabled detailed neuroanatomical mapping of CNS structures involved in glucose regulation and key neuronal circuits and intracellular pathways have been identified. Furthermore, the development of neuroimaging techniques has provided methods to measure changes of activity in specific CNS regions upon diverse metabolic challenges in humans. In this narrative review, we discuss the available evidence on the topic. We conclude that there is much evidence in favor of active CNS involvement in glucose homeostasis but the relative importance of central vs. peripheral mechanisms remains to be elucidated. An increased understanding of this field may lead to new CNS-focusing pharmacologic strategies in the treatment of type 2 diabetes. The global prevalence of diabetes in adults – approximately 90% consisting of type 2 diabetes – was estimated to 6.4% in 2010 and is predicted to increase to 7.7% in 2030 . The macIn 1854, Claude Bernard reported that a lesion in the floor of the fourth ventricle in dogs altered glucose levels, thereby presenting the first evidence of the brain’s role in glucose regulation . In the The hypothalamus is located below the thalamus and above the pituitary gland and brain stem. It constitutes the floor of the third ventricle which contains cerebrospinal fluid (CSF). This anatomical position allows for access to nutrients and hormones. It consists of a network of interconnected nuclei among which the arcuate nucleus (ARC), ventromedial hypothalamus (VMH), dorsomedial nucleus (DMN), paraventricular nucleus (PVN), and the lateral hypothalamus (LH) are implicated in the regulation of glucose homeostasis. In the brainstem the nucleus of the solitary tract (NTS), area postrema (AP), dorsal motor nucleus of the vagus (DMNX) and the rostral ventrolateral medulla (RVLM) are key regions . GlucoseGlucose injected into the third ventricle of rodents leads to a reduction of systemic glucose levels, principally by suppression of hepatic glucose production (HGP) . The samNot only neurons but also surrounding glial cells are believed to have an active role in the sensing of nutrients. It has been hypothesized that astrocytes may metabolize glucose and proline into lactate for subsequent translocation in the so-called astrocyte-neuron-lactate-shuttle to neurons to signal glucose depletion . LikewisSimilarly, central administration of hormones or targeting of their intracellular pathways in neurons have demonstrated that insulin , leptin The transport of glucose across the blood–brain barrier (BBB) is primarily mediated by insulin-independent GLUT-1 and, particularly in conditions of CNS ischemia and glucose deprivation, by SGLT-1 . InteresATP-channels in the former and the signaling substance AMPK in the latter. In GE neurons, metabolism-independent sensing mechanisms involving SGLT1 and 3 and the sweet receptor T1R2/3 are also implicated  and this activates signaling pathways that differ for GE and GI neurons, involving activation of Kplicated . The recplicated , leptin plicated , glucagoplicated , GLP-1  – further divided into the sympathetic nervous system (SNS) and the parasympathetic nervous system (PASY) – and the hypothalamic-pituitary axis .The DMNX of the brainstem contains the soma of preganglionic parasympathetic nerve fibers and can thus transmit PASY signals to target organs like the liver  reducin increas, decreasEvidence of CNS involvement in glucose homeostasis also comes from a study in which mice that moved from a warm to a cold environment had a coordinated reduction in both insulin secretion and insulin sensitivity, despite the absence of hypoglycemia. This was reversed within 4 h of returning to room temperature and within 30 min of administration of the alpha-adrenergic blocker phentolamine. According to the authors, the results imply a key role of the brain in rapidly coordinating insulin secretion and insulin sensitivity via the SNS . The conThere is an intriguing epidemiological correlation between features of the metabolic syndrome and various diseases affecting the CNS of humans that gives indirect support to the brain’s involvement in peripheral glucose regulation. Depression is twice as common in patients with type 2 diabetes . A correAn increased prevalence of the metabolic syndrome has also been reported repeatedly in studies of patients with psychotic illness including schizophrenia . While tNaturally, epidemiological observations such as these do not prove causation, still leaving us with the question: does CNS diseases cause metabolic disorders or vice versa? In some cases, there is probably a bidirectional causality, e.g., for Alzheimer’s disease and type 2 diabetes . HoweverAs previously described, the ANS consists of the SNS and the PASY. It has a range of biologic effects including influencing glucose homeostasis in the periphery. Activation of the SNS raises circulating glucose levels by inhibiting insulin release from beta cells, stimulating release of glucagon from alpha cells, increasing release of epinephrine from the adrenal glands (augmenting and prolonging the effect of nervous activity) and increasing hepatic glucose production. In contrast, PASY activation lowers glucose levels by stimulating the secretion of insulin from beta cells and suppressing hepatic glucose production, while similarly increasing glucagon levels . While iStudies employing biochemical measurements of catecholamines as markers of SNS activity in subjects with insulin resistance, obesity and the metabolic syndrome have been inconsistent . Those uBy using microneurography, muscle sympathetic nerve activity (MSNA) can be measured as pulse synchronous nerve bursts in resting muscles and constitute a surrogate measure for sympathetic activity in the whole body . Some stHeart rate variability can be computed by analyzing long-term or short-term ECG monitoring and used as a marker of sympathetic and parasympathetic activity and to reflect the balance of the two. The PASY and the SNS activity influence the heart rate variability in partially differential frequency bands. PASY activity is affected by the respiratory cycle and is detectable up to 1 Hz while SNS activity is largely dependent on input from baroreceptors, mediating a slower response up to 0.15 Hz. Therefore, the high frequency (HF) band of 0,15–0,40 Hz corresponds well to PASY activity while the low frequency (LF) parameter of 0.04–0.15 Hz is influenced by both SNS and PASY activity . There aSeveral studies have shown a lower HRV in subjects with T2DM but whether HRV is a consequence of glycemic dysregulation or a causative mechanism behind the development of diabetes type 2 is not clear . One stuIt is generally accepted that increasing insulin resistance precedes the development of overt type 2 diabetes. First degree relatives to patients with type 2 diabetes have a markedly increased risk of developing type 2 diabetes and are more insulin resistant than subjects with no family history of type 2 diabetes . One stuMultiple studies have also found an association between obesity and impaired HRV. BMI in itself has been significantly related to HRV in some studies  but not In a systematic review from 2014 on the correlation between HRV and the metabolic syndrome, the authors concluded that heart rate variability was generally reduced in females with the metabolic syndrome compared to those without while results in men were inconsistent . Since tThere is some support of ANS disturbances in various CNS disorders. Low employment status and high psychosocial stress have been associated with low HRV . An impaThe well-documented propensity of beta-blockers to cause insulin resistance and impair glycemic control in patients with diabetes  and the An excess of glucocorticoids, such as seen in Cushing’s disease or pharmacological glucocorticoid treatment, typically leads to insulin resistance and obesity as well as other features of the metabolic syndrome . This raCirculating glucocorticoids act in several ways to disrupt normal glucose homeostasis. Glucocorticoids may cause beta cell dysfunction by influencing the uptake and metabolism of glucose in beta cells and may also attenuate the effects of GLP-1. In the periphery, glucocorticoids counteract insulin action by inducing insulin resistance through reduction of insulin downstream signaling substrates as well as indirectly by increasing lipolysis and proteolysis. Glucocorticoids also increase hepatic glucose production by activating enzymes involved in gluconeogenesis. Moreover, glucocorticoids also cause obesity and consequently insulin resistance by promoting differentiation and proliferation of adipocytes. Since glucocorticoid receptors are more abundant on visceral adipocytes, this favors visceral obesity . FinallyThere is a multitude of ways to assess activity in the HPA-axis. These include plasma levels of cortisol, salivary levels of cortisol, 24 h urinary excretion of cortisol (UFC) and hair cortisol concentration (HCC). Activity in the HPA axis is highly variable and influenced by a range of factors including circadian rhythmicity, exercise, stress, and food-intake. Therefore, not only absolute concentrations of but also the diurnal curve of levels and dynamic changes in cortisol levels, as measured by cortisol reactivity to stress and dexamethasone suppression test, are interesting markers.A few reviews on the topic have been published  and willIn summary, long-term elevations, disturbances in the diurnal pattern, abnormal reactivity to stress and impaired feedback regulation of cortisol may have a small but limited impact on the development of obesity and metabolic disorder. Finally, there is substantial evidence that the expression of 11βHSD1 is upregulated in the adipose tissue of obese humans and animals. Thus, local dysregulation of glucocorticoids just as HPA dysregulation may contribute to the development of obesity and the metabolic syndrome .BOX 1 | Neuroimaging techniques.Magnetoencephalography (MEG)This technique measures magnetic fields produced by electrical currents in the brain just as EEG measures electric fields. It is limited by the fact that cortical but not subcortical regions  can be evaluated and has been largely replaced by other techniques to study the impact of metabolic input on brain activity.Functional Magnetic Resonance Imaging (fMRI)Blood oxygen level dependent (BOLD) signal is based on the fact that deoxygenated hemoglobin is paramagnetic whereas oxygenated hemoglobin is not, resulting in a higher signal in T2 weighted MRIs in situations with increased blood flow. Cerebral blood flow can also be measured by arterial spin labeling (ASL) where the water of incoming blood in for instance carotid arteries are labeled magnetically which changes the T1 signaling of water in the region that is examined.The resolution in time and space is better than PET. Neuronal activity is not measured directly but via cerebral blood flow as a surrogate marker. By measuring spontaneous fluctuations in resting state brain activity, functional connectivity can be assessed and utilized to divide the brain into small functional units.Positron Emission Tomography (PET)This method measures gamma-rays that are emitted by unstable isotopes. Molecules that are labeled with positron-emitting isotopes are injected into the circulation. Fludeoxyglucose (18F) or FDG is widely used as a measure of glucose-uptake into tissues including the brain. To allow for neuroanatomic correlation of the signals, the method is combined with either CT or MRI and thus the space resolution does not differ from fMRI. However, the half-life of FDG is 110 min and it takes considerable time to generate a strong enough signal for the analysis. Hence, the time resolution is markedly limited compared to other methods.Single-Photon Emission Computed Tomography (SPECT)Similar to PET, this technique utilizes radioactive tracer material, but these emit gamma rays directly instead of positrons, limiting the spatial resolution as compared to PET.The methods employed in animal research previously discussed in this review are for obvious reasons not directly transferable to studies involving human subjects. The development and refinement of neuroimaging techniques has, however, offered an indirect way to explore changes in brain activity induced by and associated with metabolic changes. The neuroimaging techniques at hand  in healthy subjects . The effWhile the intracerebroventricular administration of nutrients and hormones performed in animal studies is not an option in studies of humans, intranasal treatment of insulin preferentially targets the CNS, and thus provides an alternative for studying CNS effects isolated from systemic effects . IntriguATP channel opener diazoxide induced a 30% reduction of HGP after 6 h in humans in the settings of a pancreatic clamp, excluding the influence of pancreatic hormones and suggesting extra-pancreatic effects  and proportion of patients reaching target HbA1c in a recent meta-analysis . The autRecently, the growth differentiating factor 15 (GDF15) has emerged as a satiety signal and potential target for treating obesity and metabolic disorders. It is secreted by adipocytes and many other cell types in response to cell injury and inflammation . GDF15 hPhysical exercise has been associated with altered brain fMRI responses to food-cues, favoring low-calorie foods over high calorie-foods . While oTaken together, evidence from animal and human studies demonstrates that the brain detects levels of circulating nutrients and hormones and consequently organizes an outward response that contributes to the regulation of whole-body glucose homeostasis. However, there are major knowledge gaps about the exact nature of this response and its relative importance compared to peripheral processes. As we have seen, animal studies have provided an anatomical map of CNS glucose regulation and have identified important neurons and neural circuits involved. Additionally, the CNS sensing of key nutrients and hormones has been characterized in detail and the intracellular signaling pathways have been outlined for most of them.Studies of humans entail inherent methodological challenges compared to animal studies that may explain the inconsistent findings in some areas. There are some intriguing epidemiological relationships between CNS and metabolic disorders and dysregulation of the ANS or HPA axis have both been proposed as the mediators of this connection. Attempts to demonstrate this have yielded somewhat discordant findings, however.The extra-pancreatic effects of diazoxide and GLP-1 may very well be extra-cerebral as well and the favorable effect of intranasal oxytocin on glucose metabolism is interesting but not necessarily secondary to actions in the CNS. The use of somatostatin and octreotide in some studies to inhibit pancreatic hormone secretion may possibly induce CNS effects on their own accord and may thereby affect the results. The use of intranasal preparations of insulin arguably has a preferential CNS effect but dose-dependent spillover into the systemic circulation has been demonstrated in some studies that would make interpretation of results precarious.Neuroimaging techniques have a large potential for further exploration of the interplay between CNS and systemic glucose regulation and have been used more extensively for investigation of appetite and feeding control with special regards to obesity. In these studies, resting-state or task-based neuroimaging is usually performed before and after some sort of metabolic intervention  and the imaging is then compared for differences before vs. after the intervention and in between different subjects . Arguably, studies aimed at investigating acute CNS effects on glucose regulation must adopt a more sophisticated study design. Ideally, neuroimaging would be performed before vs. after some sort of metabolic intervention with concomitant measurements of hormonal activity and nutrients. If a detectable change in the activity of a brain region were to occur after the metabolic intervention but before a change in hormonal activity and nutrient levels, a causative link between the two events could be argued, in congruency with the results from 18FDG uptake in PET may not correctly reflect changes in neuronal activity. The glucoCEST technique in MRI uses measurement of the proportion of phosphorylated and unphosphorylated 2-deoxy-D-glucose (2DG) and could thereby provide a better assessment of glucose metabolism than 18FDG-PET, while also embodying all the advantages with the fMRI modality. Likewise, MR spectroscopy provides a non-invasive method of measuring metabolite concentration in tissues and has for example been used to study hypothalamic glucose levels after hypoglycemic preconditioning (Other than in the work by itioning . NeverthIn one study by Since the brain is more or less dependent on glucose as a fuel substrate, its postulated ability to influence systemic glucose values or at least to correct hypoglycemia makes perfect sense from a teleological standpoint. As a consequence of the counter-regulatory response to hypoglycemia, systemic glucose levels are maintained at the expense of glucose uptake and utilization in insulin-sensitive organs such as muscles, adipose tissue and liver. Thus, the insulin-independent brain essentially prioritizes its own need for fuel over that of the rest of the body by mobilizing this counter-regulatory response. Expanding on this and on the “brain-centric” model, type 2 diabetes may be considered a condition in which the brain is “spoiled” by ever-increasing glucose levels and maintains those in a “selfish” fashion at the expense of the rest of the body.In an elegant study published recently by Overall, there is robust evidence in favor of brain involvement in the regulation of glucose metabolism. Further investigations are needed to characterize the neurocircuits involved and the cross-talk with peripheral tissues. The use of refined neuroimaging methods is a promising way to test hypotheses derived from animal studies on human subjects. Such research will deepen our understanding of the pathogenesis of type 2 diabetes and potentially open up avenues for novel pharmacological approaches.ML did most of the literature search. ML and JE conceived and wrote the manuscript. All authors contributed to literature search, reviewed and approved the final version.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.


Pterygium is a triangle-shaped fibrovascular hyperplasia of the bulbar conjunctiva on the cornea. The purpose of this study was to analyze Proteoglycans (PGs) by Immunohistochemistry (IHC) in pterygium tissues and to compare the results with normal conjunctiva. Twenty-four patients  undergoing primary pterygium excision and 17 healthy individuals , undergoing extracapsular cataract surgery, were included. Pterygium tissues and normal conjunctiva tissues were surgically removed. The tissue sections were fixed in 2% paraformaldehyde and incubated with monoclonal antibodies against PGs anti-mouse IgG. Immunohistochemical study showed stronger expression of keratan sulfate in the stroma of the pterygium compared to normal conjunctiva. An increased expression of heparan sulfate was observed in the epithelial layer and around the pterygium vessels. On the other hand, dermatan sulfate showed an increased expression and localization not only in the sub-epithelial area of the pterygium and normal conjunctiva, yet throughout the stroma of the pterygium. The differences in the expression and localization of the studied extracellular matrix proteoglycans in the pterygium tissue compared to normal conjunctiva may explain the tissue hyperplasia, structure, and the functional properties in pterygium. Pterygium is a triangle-shaped fibrovascular hyperplasia of the bulbar conjunctiva on the cornea. It is one of the most common external eye diseases, especially in tropical countries and in people, who spend a significant amount of time outdoors . AlthougAlthough it is known that the tissue of pterygium contains PGs, a thorough analysis of the important connective tissue components has not been conducted so far. The purpose of the current study was to evaluate the expression and tissue localization in three different GAGs, i.e. keratan sulfate, heparan sulfate, and dermatan sulfate, in the pterygium and normal conjunctiva.The study was conducted according to the tenets of the Declaration of Helsinki and received approval by the Institutional Review Board of the University Hospital of Patras. Exclusion criteria were any ophthalmic or systemic disease or use of topical or systemic medications. Informed consent was obtained from all eligible participants that participated in the study. oC overnight. They were then extensively washed in 50 millimole tris-buffered saline, pH 7.6, before the addition of a biotinylated goat anti-mouse secondary antibody. Immunoreactivity was performed by adding 3, 3’-diaminobenzidine tetrahydrochloride . Following immunostaining, the tissue sections were examined meticulously, using light microscopy. A negative control of the technique was accomplished without the primary antibody. The primary antibodies used to identify the distribution of pterygium and normal conjunctival PGs/GAGs were monoclonal antibodies against heparan sulfate (clone 10E4) diluted 1:20, -keratan sulfate (clone 5D4) diluted 1:200, and dermatan sulfate proteoglycan decorin (clone 6B6) diluted 1:1000 . Extracted data has been analysed subsequently.Pterygium tissues were surgically removed, while normal conjunctiva tissues were obtained from the perilimbal conjunctiva at the 12 o’clock position during extracapsular cataract extraction surgery. This area was chosen because it is protected from ultraviolet light by the upper lid. Specimens from pterygium and normal conjunctiva were obtained, formalin fixed, and paraffin embedded serial sections were immunostained using specific monoclonal antibodies against keratan sulfate, heparan sulfate, and dermatan sulfate. Tissue sections were incubated with mouse primary monoclonal antibodies at 4Twenty-four patients ) undergoing primary pterygium excision and 17 healthy individuals ) undergoing extracapsular cataract surgery were included in the study. There was an increase in the expression of keratan sulfate, heparan sulfate, and dermatan sulfate in pterygium tissue compared to normal conjunctiva. More specifically, the immunohistochemical study provided evidence of increased expression of keratan sulfate in the stroma of pterygium tissue in 75% of the specimens compared to the normal conjunctiva . An overOne of the major components of the ECM are PGs that upon interactions with several growth factors and other mediators, play pivotal biological roles and determine many cellular functions, such as the cellular adhesion, proliferation, migration, and cell differentiation and apoptosis . DiffereThe extracellular matrix seems to play a significant role in the pathogenesis and progression of pterygium. It has been revealed that there is no difference in the cellular proliferation pattern between pterygium and conjunctival tissues, proposing that the overexpression of ECM predominates over the cellular proliferation in the pterygium pathogenesis . FurtherThe current study had certain limitations. A larger number of specimens studied could give strength to the study. Although localization of the specific PGs is clearly demonstrated, calculation of color intensity of IHC stained specimens in the two groups could allow analysis of differences between the two groups in expression of the PGs/GAGs statistically and report its significance with more confidence.The current study clearly demonstrated differences in expression and localization of PGs/GAGs in pterygium and normal conjunctiva. Given the significant role of extracellular matrix in the pathogenesis and progression of various diseases it is therefore plausible to suggest that the overexpression and the different localization of the matrix PGs in the pterygium tissue, compared to normal conjunctiva, could contribute to tissue overgrowth, structural organization and junction of the pterygium tissue. Further studies are required in order to elucidate in detail whether certain PG populations are responsible for the pathogenicity of this disorder by evaluating the expression of mRNAs coding for the matrix and cell surface PG populations.


As South Africa embarks on the implementation of the community health care worker (CHW) 2018 policy, quantifying the resource requirements to effectively manage the programme across different geographical communities is essential. This study was conducted to quantify and compare costs associated with travel and service delivery demands on CHWs between area types in two districts.This economic analysis adopted a provider perspective to cost CHW services between January and November 2016. A total of 221 CHWs completed diaries for 10 days to document their activities. Quintile regression and the Kruskall Wallis test were used to test for differences in time and activities across urban and rural sites.While travel time across rural and urban settings within each district did differ it was not the most significant predictor of differences in time utilization. Time on activities showed more significant differences with overall median time by unit of activity being 15% longer in rural than urban areas in Sedibeng and 10% longer in uMzinyathi respectively. Most CHW time was spent conducting home visits . Median time per home visit in uMzinyathi was 50% longer in deep-rural areas than urban areas and 20% longer in rural than urban areas in Sedibeng. Referrals and number of home visits per capita  were low in both districts. Expenditure on the programme translated to under 4% of PHC expenditure per capita and remains under 5% if despite the new national minimum wage .Because home visits take longer and CHWs spend a lower share of time on visits, a higher number is required in rural and deep rural areas (33% and 66% respectively) than in urban areas. Effective budget planning will therefore need to recognize the different geographical needs. The South African health system is characterized by a large public sector and smaller private sector as well as Non-Governmental Organizations (NGOs). Although South Africa spends a relatively high percentage (8.6%) of its gross domestic product (GDP) on health, only 44% of total health expenditure 4.1% of GDP) takes place in the public sector, where most of the country’s population (86%) seeks care. This has resulted in sustained inequitable access to health care along socio-economic and geographical lines. In  In 17] IReasons for home visits varied across both across districts and within the different geographical communities of each district, partly because of the different services being delivered by CHWs in UmZinyathi and Sedibeng in addition to the different community needs as a result of the demographic profile of the sub-districts. Of concern were the low referral rates in both districts, 4% in Sedibeng, and only as high as 12% in UmZinyathi’s deep rural areas. These low referral rate raises concerns about the quality of screening conducted by the CHWs during the home visits and perhaps the quality of their training and supervision. The presence of dedicated supervisors who may provide on-site support would likely elicit higher case finding and higher rates of referral. Furthermore, dedicated supervisors may also improve the efficiency of CHWs and translate into a higher number of home visits per day, however this will need to be validated. A recently conducted study of focus group discussions of CHWs working in a sub-district in the Eastern Cape revealed similar challenges with infrequent on-site supervision  despite Since CHWs spend a longer time traveling to and within homes during visits in addition to spending a lower share of total time on home visits in rural areas, a higher number of CHWs will be required in rural/deep-rural areas than peri-urban areas to achieve the same level of coverage. The study found that a rural (farming) district would need 33% more CHWs than an peri-urban district in Sedibeng, while in uMzinyathi, a deep-rural district would require 62% more CHWs than an peri-urban district, assuming consistency in the current activities and levels of care. These numbers may change based on shifts in the kinds of services being delivered however. This demonstrates that there are geographical implications on the number of recipients CHWs can cater to daily and should be considered when developing policy and allocating resources towards the programme. According to this estimate and based on the current policy for an average of 250 households per CHW in peri-urban area, a CHW in a rural area would be expected to cover 169 households and 96 households in deep-rural areas. Although the cost per CHW is the same in rural and peri-urban areas, the increased number of CHWs required in rural and deep-rural areas means that budget allocations should be higher per capita in rural than peri-urban areas.Drawing on previous modelling work conducted by the South African Medical Research Council, the numSome limitations to the study need to be noted. Firstly, the basis of the geographical classification of sites from the DHIS is unclear and further work on clarifying Urban, peri-urban and rural classifications is needed for accurate comparisons. Secondly, the use of self-completed diaries enables a significant number of CHWs to fill diaries but raises the issue of reliability of the data. The alternative approach is applying a time and motion study which, due to its costs, would cover a significantly smaller number of observations and carries the limitation of the Hawthorne effect through Peri-urban, rural and deep-rural areas have different needs concerning community-based services, and such differences must be considered in resource allocation decisions. The study demonstrates that rural and deep-rural areas need more CHWs than peri-urban areas to provide effective coverage. Beyond the different geographical needs, overall, community-based services are extremely under-resourced; even when increasing CHW stipends to the national minimum wage, CBS services would represent under 5% of PHC expenditure per capita/ Increased resourcing towards supervision for CHWs is necessary to ensure the availability of dedicated supervisors with some level of clinical skills (ENs) who can support the work of the community health workers.S1 Dataset(XLSX)Click here for additional data file.


P < 0.001). Similar results for antimicrobial use (AMU) obtained at farm level were observed when calculated either by Swiss or European definitions. Nevertheless, marked differences could be observed in the assessment of the use of specific antimicrobial classes in the field based on DDDvet/DCDvet compared to DDDch/DCDch.Defined Daily Doses (DDD) and Defined Course Doses (DCD) have been established in both human and veterinary medicine in order to standardize the measurement of treatments in a population. In 2016 the European Medicines Agency published average defined daily dose (DDDvet) and defined course dose (DCDvet) values for antimicrobial agents used in livestock production. Similarly, national defined doses (DDDch and DCDch) for the pig sector in Switzerland have recently been determined. The aim of this study was to compare the outcome of calculating antimicrobial consumption based on either DDDvet/DCDvet or DDDch/DCDch. Data from 227 Swiss pig farms describing antimicrobial use in 2015 was collected. The numbers of treatment days and treatments were calculated using DDDvet/DCDvet and DDDch/DCDch respectively, for each farm in total and for different antimicrobial classes. Associations between calculated numbers of DDDvet/DCDvet and DDDch/DCDch on farm level were investigated. In addition, differences concerning antimicrobial use were investigated between different production types of farms . Using DDDch/DCDch values we calculated 1,805,494 treatment days and 433,678 treatments compared to 1,456,771 treatment days (19% ratio) and 303,913 treatments (30% ratio) based on DDDvet/DCDvet. Penicillins (21.4/26.6%), polypeptides (18.6/27.6%) and fluoroquinolones (9.5/8.8%) were the most frequently used classes of antimicrobials based on calculation using both DDDch and DDDvet. Similar findings were observed for complete treatments (DCDch/vet) . The number of treatment days or treatments per farm was higher for piglet-producers and farrow-to-finishing farms compared to finisher farms regardless of whether Swiss or European DDD or DCD values were used for the calculation (each  Antimicrobial use (AMU) is associated with the selection of resistant pathogens , 2 and tThe importance of antimicrobial resistance for public health is internationally acknowledged , 8 and AIn addition to monitoring systems measuring the amount of active ingredients, systems based on application equivalents have been established in several countries to monitor AMU in veterinary medicine –13. ThesIn 2016, following these principles, the European Medicines Agency (EMA) published average defined daily dose (DDDvet) and defined course dose (DCDvet) values for antimicrobial agents used in livestock production as a tool to facilitate standardized collection and presentation of AMU among European member states . These vThe aim of this study was to investigate the outcome of calculated antimicrobial consumption in the field based on either individual, Swiss values (DDDch/DCDch) or average, European values (DDDvet/DCDvet). The impact of using either DDD/DCDch or DDD/DCDvet values were tested for different age groups, administration routes and antimicrobial classes. Moreover, the impact of using either DDD/DCDch or DDD/DCDvet for evaluation of antimicrobial use on the study farms was considered, as well as differences in antimicrobial usage by farm type.The questions behind all these investigations were: Will an AMU monitoring system based on either Swiss or European definitions lead to comparable results in the field or not? And for which age groups, administration routes and antimicrobial classes can the most frequent AMU be observed in the pig sector of Switzerland?In cooperation with the Swiss Swine Health Service (SSHS), data from 227 Swiss pig farms concerning antimicrobial use in 2015 was collected, thus representing 3.3% of all pig farms in Switzerland in 2015 . All 227In order to quantify AMU, the amount of prescribed antimicrobial ingredient during the year 2015 of all participating farms was divided by the defined doses (DDD/DCDvet or DDD/DCDch) of the corresponding antimicrobial classes multiplied by the standard weights of the different age groups as defined by the European Surveillance of Veterinary Antimicrobial Consumption (ESVAC)   and for all antimicrobial classes. The term premix included all antimicrobial ingredients to be administered via the feed and/or water. By dividing the results using DDD/DCDvet by those based on DDD/DCDch, differences of Swiss or European definitions were investigated for the calculated AMU. The results of this calculations were termed ratio. A positive ratio with results > 0 indicated a higher number of estimated treatment days or treatments could be observed when using the European definitions DDD vet or DCDvet. In addition, the overall observed mean treatment durations given by the Swiss or European defined values were compared in the same way.For the evaluation of the AMU at the farm level and in order to compare the consumption on different farms, the number of kept (sows) or produced pigs (other age groups) in the year 2015 were taken into account. The amount of prescribed antimicrobial ingredients was divided by the different defined doses, the standard weights and the number of pigs for each age group. If necessary, the results of the different age groups were summarized together and the number of Defined Doses per farm was calculated.https://cran.r-project.org). Differences between the tested groups having a P ≤ 0.05 were considered statistically significant. The data for calculated AMU on farm level was tested for normality by the Shapiro-Wilk test. The association of Swiss and European dosages for a possible AMU monitoring system on the farms was evaluated using scatterplots and correlation analysis performed by Spearman's rho test. The differences between the various farm structures were investigated using the Kruskal-Wallis test for independent samples and post hoc pairwise analysis (Bonferroni correction).The preparation of all operating farm data and the calculation of the number of defined doses was carried out using Microsoft Excel 2011 . The statistical analysis and preparation of graphs to visualize the results was performed with R  and 303,913 DCDvet (−29.9% ratio) based on European defined doses . The meaThe amount of active ingredient and the calculated numbers of defined doses for different antimicrobial classes were summarized in A more detailed, combined consideration of age groups, administration routes, and antimicrobial class data shows that injection was the most frequent administration route for piglets independent of the method used for calculation, and that within this group penicillins and fluoroquinolones were the most frequently used antimicrobials . The useP < 0.001).Each dataset was tested for normality by Shapiro-Wilk test and for all datasets, independent of Swiss or European measuring method or type of farm, the null hypothesis was rejected  and defined course doses (DCD), analyzing the association between Swiss (ch) and European (vet) definitions, is given in P < 0.001) by Kruskal-Wallis-test and subsequent post hoc pairwise analysis  and piglets (DCDch) . These gFurthermore, when calculating the number of DDDs, relatively high use could be observed for premixes and in contrast, a relatively high total number of course doses could be observed for injections in this study. This can be explained by the comparison of treatment durations between injections and premixes, since the number of calculated course doses decreases with the increase in treatment duration of the premixes. Previous publications confirmed the high proportion of premixes used in the pig sector in Switzerland , 31. An A relatively high proportion of treatments with Highest Priority Critically Important Antimicrobials (HPCIAs) could be observed in this study . These findings are comparable to results recently published from the EFFORT consortium , but varThe results from the different farm types show again that the younger age groups are most frequently treated. Both, farrow-to-finishing farm as well as piglet-producing farms in contrast to the finishing farms keep the high consumption age groups of piglets and weaners. This could explain the significant difference. Due to the small number of calculated defined doses of finisher pigs, no significant difference between farrow-to-finishing and piglet-producing farms was observed.In order to gain a better understanding of the differences between these individual farms, further studies are needed to examine the role of the farmer  as well In summary, this study demonstrated a general association of the AMU systems at the farm level, nevertheless, differences were seen in detail according to whether the calculation was based on individual Swiss or average European values. The benefit of the European values for internationally comparative AMU monitoring is undisputed, but for a detailed evaluation, Swiss definitions could be more accurate as they are based on the specific approvals of the country. This must be considered in order to understand international AMU comparisons in the future. The study also highlighted the need to further evaluation for the use of HPCIAs.The datasets generated for this study are available on request to the corresponding author.Since this was only data that had no influence on the actual treatment of the animals, an animal welfare permit was not required. No manipulations or something similar were carried out on any animals.DK, XS, CM, and TE contributed conception and design of the study. TE organized the database and performed the statistical analysis. CM is responsible for the correctness of the pharmacological formulations and the part in the manuscript about measurement methodologies. TE wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.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 handling Editor declared a past co-authorship with one of the authors CM.


There are several local treatment methods for cervical intraepithelial neoplasia that remove or ablate a cone-shaped part of the uterine cervix. There is evidence to suggest that these increase the risk of preterm birth (PTB) and that this is higher for techniques that remove larger parts of the cervix, although the data are conflicting. We present a protocol for a systematic review and network meta-analysis (NMA) that will update the evidence and compare all treatments in terms of fertility and pregnancy complications.We will search electronic databases  from inception till October 2019, in order to identify randomised controlled trials (RCTs) and cohort studies comparing the fertility and pregnancy outcomes among different excisional and ablative treatment techniques and/or to untreated controls. The primary outcome will be PTB (<37 weeks). Secondary outcomes will include severe or extreme PTB, prelabour rupture of membranes, low birth weight (<2500 g), neonatal intensive care unit admission, perinatal mortality, total pregnancy rates, first and second trimester miscarriage. We will search for published and unpublished studies in electronic databases, trial registries and we will hand-search references of published papers. We will assess the risk of bias in RCTs and cohort studies using tools developed by the Cochrane collaboration. Two investigators will independently assess the eligibility, abstract the data and assess the risk of bias of the identified studies. For each outcome, we will perform a meta-analysis for each treatment comparison and an NMA once the transitivity assumption holds, using the OR for dichotomous data. We will use CINeMA  to assess the quality of the evidence for the primary outcome.Ethical approval is not required. Results will be disseminated to academic beneficiaries, medical practitioners, patients and the public.CRD42018115495 This will be the first network meta-analysis (NMA) to produce comprehensive summaries of the relative reproductive morbidity of treatment methods for cervical preinvasive and early invasive disease.We will use state-of-the-art methods for combining randomised and non-randomised studies in an NMA.Risk of bias will be evaluated at both study and outcome level.One possible limitation of this review is that we expect to find mainly retrospective cohort studies at high risk of recall, selection and publication bias.The introduction of systematic call and recall screening programmes in the UK has resulted in a profound decrease in the incidence and mortality from cervical cancer, as preinvasive precursors  can be detected by the screening programme and treated.Local conservative treatment for cervical preinvasive and early invasive disease removes or ablates a cone-shaped part of the cervix containing the precancerous cells. The choice of technique varies within the UK, across Europe and beyond. In some countries, knife excision  is still regularly performed; in others, laser ablation or laser conisation with the laser beam is common practice. In the UK, large loop excision of the transformation zone (LLETZ) is the preferred treatment, with some units offering alternative techniques more frequently than others. This preference is because LLETZ is quick, easy to do and of low cost.The mean age of women undergoing CIN treatment is similar to the age of women having their first child. Although, previously, complications from treatment were thought to be relatively mild and uncommon, an increasing body of retrospective observational studies and meta-analyses suggested that treatment, particularly excision, adversely affects future reproduction and the risk of prematurity.Although all treatment techniques are highly effective in preventing recurrent precancerous disease and future invasion,The quantification of the comparative reproductive morbidity of different treatment techniques and cone lengths has become a women’s health priority. This requires high-quality synthesis of the evidence in comprehensive summaries that will become available for effective patient counselling at colposcopy and antenatal clinics for patients, clinicians and policymakers. A clinical ranking of treatments with regards to the risk of PTB may allow the quantification of risk and the detection of women at high risk of PTB that would benefit from intensive surveillance antenatally, while minimising the unnecessary interventions for those at lower risk.The key methodological vehicle to synthesise evidence is systematic reviews and their quantitative component, meta-analysis. Network meta-analysis (NMA) is an extension of pairwise meta-analysis, which can be used to estimate the relative effectiveness of several competing treatments. An NMA has never been used before to assess the comparative efficacy and harms of the different treatment techniques in this field. For every treatment comparison NMA synthesises both direct evidence  and indirect evidence .The objective of this systematic review and NMA is to update the evidence and to compare the various local treatment methods to manage CIN in terms of fertility, early (<24 weeks of gestation) and late (>24 weeks) pregnancy complications. This is part of the CIRCLE project , which aims to generate a clinically useful raking of alternative options for treatment of CIN according to their efficacy (risk of preinvasive and invasive recurrence), morbidity and cost-effectiveness.This protocol complies with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols .29 Any c10.1136/bmjopen-2018-028009.supp1Supplementary dataWe will include women of all ages with a prior history of local surgical treatment for CIN or microinvasive early cervical cancer (stage IA1). Their status can be confirmed with histological or cytological diagnosis and irrespective of the grade of the treated lesion for both squamous and glandular intraepithelial neoplasia. Studies recruiting solely women at high risk of PTB (such as previous history of PTB) or studies including only patients treated during pregnancy will be excluded.We aim to compare nine different excisional or ablative techniques used for conservative treatment for CIN. The excisional techniques include CKC; laser conisation; needle excision of the transformation zone, also known as straight wire excision of the transformation zone; LLETZ, also known as loop electrosurgical excisional procedure; Fischer cone biopsy excision. The ablative techniques include radical point diathermy; cryotherapy; cold coagulation; LA. We will include studies comparing any of these treatments with each other or with no treatment. PTB, defined as <37 weeks of gestation.Spontaneous PTB, defined as <37 weeks of gestation.Severe PTB, defined as <32/34 weeks of gestation.Extreme PTB, defined as <28/30 weeks of gestation.Prelabour rupture of membranes defined as membrane rupture before the onset of labour.Low birth weight, defined as infant born weighing <2500 g .Neonatal intensive care unit admission.Perinatal mortality, defined as the number of stillbirths and neonatal deaths occurring within 28 days after birth.Total pregnancy rate, defined as any pregnancy occurring from CIN treatment till study completion irrespective of outcome .Rates of women requiring >12 months to conceive.First trimester miscarriage, defined as miscarriage at <12 weeks of gestation.Second trimester miscarriage, defined as miscarriage between 12 and 24 weeks of gestation.Outcomes and their classification into primary or secondary were decided after clinical experts’ opinion. Total pregnancy rate will be recorded for the whole study period and/or prespecified intervals, if data are available.We will include RCTs, quasi-RCTs and cohort studies comparing fertility and early (<24 weeks of gestation) or late (>24 weeks of gestation) pregnancy outcomes among surgical techniques and those that compare to no treatment. Studies that do not perform a comparison between treatments  will be excluded. Studies that compared a treatment with an untreated group will be included irrespective of the type of the untreated group . There will be no time or language restriction.www.controlled-trials.com/rct, www.clinicaltrials.gov and www.cancer.gov/clinicaltrials for ongoing studies. There will be no time or language restriction.An experienced librarian will search The Cochrane Gynaecological Cancer Specialised Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; and EMBASE for eligible studies from inception. The search algorithms for these databases are presented in 10.1136/bmjopen-2018-028009.supp2Supplementary datahttp://zetoc.mimas.ac.uk), and theses through WorldCat Dissertations. The selected conferences will include: British Society of Colposcopy and Cervical Pathology; International Federation of Cervical Pathology and Colposcopy; Annual Meeting of European Federation of Colposcopy; Annual Meeting of the American Society of Colposcopy and Cervical Pathology. We will contact experts in the field, including directors of UK cancer and colposcopy registries, to identify further reports of studies. We will include both published and unpublished studies.We will contact the corresponding author of any relevant ongoing trials for further information and unpublished data. In an attempt to identify any articles missed by the initial search, we will use the ‘related articles’ feature in MEDLINE. We will also hand search the references of the retrieved articles and meta-analyses. We will search conference proceedings and abstracts through ZETOC . At level 2, we will obtain the full text of all included articles and two reviewers will independently use the same inclusion criteria to determine eligibility. Disagreements at any level will be resolved via discussion with a third member of the review team.Two reviewers will extract data independently using a standardised data collection form in Excel. Disagreements will be resolved through discussion. Information extracted will include study characteristics , participants  and comparison group characteristics, setting, inclusion/exclusion criteria, intervention details, outcome measures and dropout rates. In RCTs, we will prefer arm-level data (number of events and sample size per intervention arm), but if these are missing, the study-level data will be used in the analysis, for example, reported ORs and a measure of their uncertainty . In observational studies, we will extract estimates of treatment effects that are adjusted for the lack of randomisation, that is, after taking into account the impact of potential confounders, or, if these are missing, the reported unadjusted estimates, as well as the corresponding uncertainty measure.Results of the meta-analyses will be interpreted in light of risk of bias assessment of the included studies. Two investigators will independently assess the methodological quality/risk of bias of the studies that fulfil the eligibility criteria and differences will be resolved by discussion with a third investigator.For RCTs, the risk of bias will be assessed using the toolFor non-randomised studies (NRS), we will use the ROBINS-I toolWe will generate descriptive statistics for eligible studies and study population characteristics, describing the types of comparisons and important clinical or methodological variables . We will present the evidence in a network diagram per outcome. The total number of patients will be reflected in the size of the nodes, while the weight of each edge will be proportional to the number of studies per treatment comparison.2 statistic along a 95% CI.metafor package.We will synthesise data to obtain summary ORs for dichotomous outcomes with a 95% CI in an inverse variance random-effects model assuming that the studies are estimating different but related treatment effects. In each meta-analysis, we will estimate the between-study variance with the restricted maximum likelihood estimatorWe will fit a random effects NMA model, taking into account the correlation induced by multiarm studies.et al,We expect that we will include several NRS in our dataset. In that case, we will employ the methods described by Efthimiou netmetarjagsFor each treatment comparison, we will report the estimated OR, the 95% CI and the 95% prediction intervals. We will also estimate the ranking probabilities for all treatments of being at each possible rank for each intervention. Thus, we will obtain a treatment hierarchy using the surface under the cumulative ranking curve (SUCRA) or P-scores and mean ranks.We will repeat our NMAs after grouping all excisional and all ablative techniques together; see groupings of treatments in NMA rests on the assumption of transitivity, that is, that effect modifiers have a similar distribution across treatment comparisons in a network.netmeta package.Checking the network for inconsistency offers an additional way of assessing the validity of the transitivity assumption. In order to evaluate the presence of inconsistency locally, we will separate the indirect from the direct evidence for each comparison and infer about their differences following the back-calculation method.et al.When a network includes both randomised and non-randomised evidence, we will also explore differences between the different types of evidence, as discussed in Efthimiou et al for dichotomous data.We will assess the extent of statistical heterogeneity by inspecting the 95% prediction intervals and by comparing the estimated value of the between-study variance with the empirical distribution derived by Turner In order to assess possible existence of small studies giving different effect estimates than larger studies, we will visually explore the funnel-plots for each treatment against the untreated group (using the relevant studies) when at least 10 studies inform the underling treatment comparison. We will also assess for small-study effects using the comparison adjusted funnel plothttp://cinema.ispm.ch/). Two team members will determine the degree of confidence in the estimated NMA results by assessing the six CINeMA domains: within-study bias , across-study bias , indirectness, imprecision, heterogeneity and incoherence .We will evaluate the credibility of the evidence contributing to the network estimates in the primary outcome using CINeMAWe have discussed the project with Jo’s Cervical Cancer Trust .Two patient representatives through Jo’s Trust with personal experience of cervical disease have assisted us in the design of the study and the development of research questions. We aim to recruit more patients through Jo’s Voice, who will help us understand the key priorities from patients’ perspective, produce lay summaries and disseminate the results to the wider public.This review does not require ethical approval. We identified four groups of potential stakeholders  and specific action items to effectively target them. We will publish papers in influential open access journals and we will present data at high-profile conferences. We will make the datasets available to the wider research community. We will organise a workshop with key stakeholders. We will develop information sheets and briefings, highlighting the key findings and circulate newsletters. We will engage the press with presentations and social media interviews and we will work closely with Jo’s Trust charity that plays an important role in educating patient communities.


Evaluating the impact of natural disasters on cancer patients is vital to the recovery of cancer treatment services and infrastructure. In September 2017, Hurricane Maria demolished the gynecologic cancer service in the United States territory of Puerto Rico and its outreach to the territory of the Virgin Islands of the United States. Patient access to brachytherapy for uterine cervix cancer patients can be difficult to measure in the aftermath of a hurricane. The United States National Cancer Institute (NCI) surveyed gynecologic radiation medicine providers on the island to generate an independent perspective on gynecologic brachytherapy service recovery after the hurricane. Providers were asked about patient displacement, infrastructure loss, and reestablishment of cancer treatment. Here, the NCI provides its perspective on recovery of these services as it relates to its pre-hurricane investment for staff in the NCI Community Oncology Research Program. The United States territory of Puerto Rico was devastated in September 2017 by the impact of two back-to-back hurricanes. While most of the island lost power after Hurricane Irma . Island-The NCI conducts trials in Puerto Rico supported by a Minority/Underserved NCI Community Oncology Research Program (PRNCORP) newly based at the Centro Comprensive de Cancer–Universidad de Puerto Rico (CCCUPR) Research Hospital, which opened in San Juan in June 2018 . The PRNHere, the NCI provides an independent perspective on its post-hurricane plans for a PRNCORP gynecologic research nurse. To provide context, the NCI collected infrastructure loss and care delivery data in Puerto Rico from the initial 12-month period after Hurricane Maria. It also queried its PRNCORP providers about hurricane-related patient displacement, infrastructure loss, and reestablishment of gynecologic brachytherapy services –8.Brachytherapy is a key element in the cure of advanced stage uterine cervix cancer and vitally improves survival , 10. TheIn the aftermath of Hurricane Maria, HDR brachytherapy services in Puerto Rico were suspended due to power outages and to patient transportation difficulties , 8. WithMedical images from computed tomography scanners, which draw upon electrical power, are used to judge adequacy of internal applicator placement, as brachytherapy treatment plan optimization cannot compensate for poor applicator positioning . Also, bSome aspects of brachytherapy such as pretreatment patient or plan verification, record-and-verify dose delivery, and quality assurance management can be done without electrical power. But others like remote video camera medical monitoring of a patient during real-time HDR brachytherapy treatment need power. These issues were encountered on the island after Hurricane Maria knocked out the power grid , 8.137Cesium radioactive sources  to accommodate the low rate of radiation emission in LDR brachytherapy. LDR 137Cesium radioactive sources were not available for brachytherapy pre-hurricane or post-hurricane on the island  state-of-the-art choices offer hope, (b) show women like themselves engage in such services for benefit, and (c) are explained in a clear, brief way with actionable steps for them to take . TargeteBrachytherapy after a natural disaster poses a unique treatment challenge within a single treatment course, care for women with advanced stage uterine cervix cancer within a total of eight uninterrupted weeks . Indeed,The NCI plans further Hurricane Maria uterine cervix cancer treatment outcome research over the next several years. Factors that influence treatment outcomes considered for study include assessment of patient trust, family support, health literacy, access to transportation, availability of child care, and the logistics of alternate language consent form and translation services .Several issues related to gynecologic brachytherapy should be considered here. First, this article considered uninterrupted brachytherapy, in a Spanish-language uterine cervix cancer population, on the territorial islands of Puerto Rico and the Virgin Islands of the United States together. This is because women with uterine cervix cancer from the Virgin Islands of the United States seek cancer care in San Juan-based cancer clinics or hospitals . OngoingWhile recovery of lifeline resources in the aftermath of natural disasters is beyond the scope of the NCI, the NCI can strategize with its stakeholders to develop generalizable cancer patient preparedness plans. For instance, the NCI, with CCCUPR and PRNCORP staff, might enable means to coordinate near-term stays in its affiliated research hospitals or a nearby American Cancer Society Hope Lodge. NCI also might collaborate with other Federal agencies for plans to ensure access to diesel fuel electricity generators or means to sterilize brachytherapy applicators. In addition, the NCI might furnish Spanish-language patient information that stresses the importance of uninterrupted cancer care, or, support a gynecologic research nurse as part of a team to reestablish accessible brachytherapy centers until post-hurricane lifelines recover.This article offers unique insights on how technical limitations and travel influences brachytherapy care delivery among women with advanced stage uterine cervix cancer in Puerto Rico in the aftermath of a hurricane. Respondents to NCI inquiries indicated that power outages blocked the immediate recovery and damaged roads delayed long-term reestablishment of brachytherapy services on the island. Post-hurricane, one of the strategies to restore brachytherapy service is to provide patient education resources that describe clearly the importance of brachytherapy as it relates to their survival from uterine cervix cancer. Staff charged with coordinating cancer treatments island-wide (like a dedicated gynecologic research nurse navigator) positively impacts the likelihood of service recovery and emphasizes a need for active engagement to ensure brachytherapy service quality in Puerto Rico.Further studies should be carried out in Puerto Rico to assess whether similar patterns are apparent for other cancer types. The same analysis could apply to other types of services for which travel time is a critical factor  to provide evidence of the impact of natural disasters on healthcare utilization across territories like Puerto Rico and the Virgin Islands of the United States.No datasets were generated or analyzed for this study.The research presented in this article involved the collection or study of existing data, documents, and records that were publicly available, or the information was recorded by NCI in such a manner that trial subjects cannot be identified directly or through identifiers linked to the subjects. The research is regarded exempt from Institutional Review Board oversight.CK and PI contributed to the collection and review of any data, analysis, and authentication, and the writing and approval of this manuscript. The views expressed are those of the authors and not those of the U.S. federal government. Links or discussions of specific treatments do not constitute endorsement.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.


Clostridium difficile infection. Meanwhile the efficacy of FMT for treating chronic diseases associated with microbial dysbiosis has so far been modest with a much higher variability in patient response. Notably, a number of studies suggest that FMT success is dependent on the microbial diversity and composition of the stool donor, leading to the proposition of the existence of FMT super-donors. The identification and subsequent characterization of super-donor gut microbiomes will inevitably advance our understanding of the microbial component of chronic diseases and allow for more targeted bacteriotherapy approaches in the future. Here, we review the evidence for super-donors in FMT and explore the concept of keystone species as predictors of FMT success. Possible effects of host-genetics and diet on FMT engraftment and maintenance are also considered. Finally, we discuss the potential long-term applicability of FMT for chronic disease and highlight how super-donors could provide the basis for dysbiosis-matched FMTs.Fecal microbiota transplantation (FMT) has become a highly effective bacteriotherapy for recurrent  For example, providing IBD patients with a targeted microbiota-based formulation containing only butyrate-producers would be a logical, safer, and potentially patient preferable alternative to whole fecal transplantation. Precision approaches have so far been trialed in CDI treatment but with mixed results (Petrof et al., Whilst much of the FMT literature has focused on bacteria being the therapeutically active agent, the successful resolution of CDI using sterile fecal filtrates has suggested non-bacterial elements might play a more significant role than previously appreciated (Ott et al., Despite being reported in the literature as far back as the fourth century, FMT research is still in its infancy, particularly with regards to its mechanism of effect. The lack of large randomized controlled clinical trials of FMT for the treatment of chronic diseases has meant that many observations, such as the existence of FMT super-donors, are not yet robustly supported by empirical evidence. The growing number of small-scale studies, whilst difficult to compare with each other, do however suggest the donor plays an influential role in FMT outcomes for indications outside of CDI. Considerable effort has since been spent in identifying the various factors which contribute to FMT success. In a broad sense, high diversity of the gut microbiota, particularly in the donor, appears to best predict a patient's response to FMT. More specifically, the efficacy of FMT likely depends on the ability of the donor to provide the necessary taxa capable of restoring metabolic deficits in recipients that are contributing toward disease. Further characterization of super-donors will likely result in the development of more refined FMT formulations to help standardize therapy and reduce variability in patient response. In parallel, continued optimization of FMT protocols, including a shift toward capsule-based approaches, will help combat the longevity issues associated with FMT and create a more patient-friendly alternative to current disease management schemes.BW wrote the manuscript. TV and WC commented on the manuscript. JOS directed and contributed to the writing of the 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.


The sacral canal is the continuation of the vertebral canal in the sacrum. The sacral canal contains spinal meninges, lumbar and sacral part of spinal nerves and filum terminale. So sacral canal has been used for the caudal epidural block. During routine osteology demonstration classes for undergraduate students, we observed a dry human sacrum with complete agenesis of the dorsal wall of the sacral canal. Knowledge of these variations is important to diagnose lower back pain, sciatica, caudal regression syndrome and to avoid complications related to caudal epidural block and other spinal surgeries like in placement of screw for spinal fusion. The sacral canal (SC) is the continuation of the vertebral canal in the sacrum. The SC is formed anteriorly by the fusion of sacral vertebral bodies and posteriorly is formed by the fusion of posterior elements namely the lamina, and spinous process . It contSpina bifida occulta (SBO) is one of the situations, representing an open neural arch due to insufficient fusion of the posterior elements of the spine. Despite the frequent appearance of SBO in clinical practice, controversy exists as to its importance. Kettler and Wilke categorized the SBO defects on a scale from 0 to III depending on the percentage of opening in the posterior neural arch. Beginning with a normal state, Grade 0 being the unaffected complete posterior arch to grade III “pan-sacral” was defined as the failure of closure from S1-S5 .We report a case of pan sacral agenesis of the dorsal sacral canal and discuss its clinical implications.During routine osteology illustration classes for undergraduate students of anatomy department at our institute, we observed a dry human sacrum with complete agenesis of the dorsal wall of the sacral canal. The bone probably belonged to a male cadaver as the sacral index and other features were suggestive. The laminae of sacral vertebrae were fused laterally but open in the midline. Other findings like an intermediate sacral crest, which represents the fused articular processes, and lateral sacral crest, which represent the fused transverse process, were present normally. The dorsal sacral foramen  were situated lateral to the intermediate crest Figure .The ventral and the lateral surface of the sacrum showed absolutely normal features without any anomaly Figure .Morphological variation of sacral hiatus like its shape, size, etc. has been reported several times in the literature. Among these variations, Hiatal agenesis and complete agenesis of the dorsal wall is a scarce finding. According to the literature, the incidence of pan sacral agenesis of SC ranges from 0.98% to 4.8% -4. This Several authors have reported this condition but its clinical significance remains contentious. At the one end of the spectrum lies complete asymptomatic variant and to the other end having a host of serious deficits including backache, lower limb and bladder/bowel affections . ResearcCEB has been extensively used both for diagnostic and therapeutic management of lumbosacral disorders. The CEB involves passing a spinal needle through the sacral hiatus to distribute medications into the sacral epidural space. In case of pan sacral agenesis of the dorsal wall of sacral canal, the CEB is possible but this procedure becomes risky to complications like an accidental puncture of dura mater. Similarly, the spine surgeons may face difficulty in the exposure of the sacrum for the surgical procedure including instrumentation using the transpedicular screw for spinal fusion. Dorsal agenesis of SC also places the sacral spinal nerves to risk to injury during such internal screw fixation .Complete agenesis of the dorsal wall of the sacral canal of these variations is important to diagnose lower back pain, sciatica, caudal regression syndrome and to avoid complications related to caudal epidural block and other spinal surgeries like in placement of screw for spinal fusion.