The human paranasal sinuses are the major source of intrinsic nitric oxide (NO) production in the human airway. NO plays several roles in the maintenance of physiological homeostasis and the regulation of airway inflammation through the expression of three NO synthase (NOS) isoforms. Measuring NO levels can contribute to the diagnosis and assessment of allergic rhinitis (AR) and chronic rhinosinusitis (CRS). In symptomatic AR patients, pro-inflammatory cytokines upregulate the expression of inducible NOS (iNOS) in the inferior turbinate. Excessive amounts of NO cause oxidative damage to cellular components, leading to the deposition of cytotoxic substances. CRS phenotype and endotype classifications have provided insights into modern treatment strategies. Analyses of the production of sinus NO and its metabolites revealed pathobiological diversity that can be exploited for useful biomarkers. Measuring nasal NO based on different NOS activities is a potent tool for specific interventions targeting molecular pathways underlying CRS endotype-specific inflammation. We provide a comprehensive review of the functional diversity of NOS isoforms in the human sinonasal system in relation to these two major nasal disorders’ pathologies. The regulatory mechanisms of NOS expression associated with the substrate bioavailability indicate the involvement of both type 1 and type 2 immune responses. Nitric oxide (NO), a paramagnetic molecule with an odd number of electrons, is a radical with extreme reactivity that is responsible for many of its biological effects. Transmitted signals mediated by NO are important in the regulation of a variety of physiological and pathological functions, including functions in the nervous, vascular, and respiratory systems ,2,3,4. A2+. The rapid Ca2+ influx that is induced by various harmful triggers can thus activate cNOS with rapid responses so that cNOS can play a protective role. In contrast, the combination of iNOS and (CaM) does not require Ca2+ regulation ) on nasal NO levels in a specific area around the inferior turbinate in untreated AR patients : the nasChronic rhinosinusitis (CRS) is persistent inflammation of the nasal and sinus mucosa lasting ≥12 weeks, accompanied by two or more nose-related symptoms such as nasal blockage and nasal discharge ,101. As The establishment of a classification system for CRS endotypes has been attempted, involving histological features such as eosinophilia and specific molecular biomarkers. The combined analysis of the CRS phenotype and endotype could provide insights into treatment responses and pathobiology. Classification based on the level of sinonasal NO production and related enzymes has been a matter of debate, with continuing efforts. The measurement of nasal NO and NOS activities can provide a foundation for new and specific interventions targeting molecular pathways that underlie endotype-specific inflammation in CRS ,110,111.Patients with CRS usually show pathological features of extensive mucosal dysregulation induced by chronic inflammation. The mucosal damage combined with obstruction of the OMC in these patients contributes to decreased nasal NO levels derived from impaired ciliary activities ,112. HowMost of the existing research has consistently demonstrated a reduction in nasal NO levels in CRS patients, which suggests that nasal NO may be a potential clinical biomarker of sinus inflammation ,115,116 The pathology of nasal polyps is characterized by tissue remodeling, epithelial dysfunction, the activation of innate and adaptive inflammatory responses, and fibrin deposition ,70,105. Whether decreased levels of nasal NO in CRS are affected by the presence of comorbid AR is another matter of debate . The nasEosinophilic chronic rhinosinusitis (ECRS) is a refractory and intractable type of CRSwNP. It is histologically defined as >70 residual eosinophils/high-power field (HPF) in nasal polyp tissue . A cliniAnother study reported that preoperative high levels of FeNO with tissue eosinophilia in nasal polyps (≥70/HPF) were a useful biomarker for predicting the development of asthma symptoms after endoscopic sinus surgery (ESS) . We haveOn the other hand, it remains controversial whether a link exists between nasal NO levels and the severity of ECRS, due (probably) to the multifunctional roles of NO . A recenAlthough nasal NO has not been established as a useful clinical measure of sinonasal disease ,132, theC. albicans inhibited iNOS activities in macrophages and blocked NO production in a dose-dependent manner [One of the nonnegligible problems regarding the use of nasal NO as a potential biomarker for therapeutic assessment is how to identify the source of the nasal NO production responsible for the changes. The treatment of CRS may restore both the iNOS expression of the sinus ciliated cells and the ability of NO to pass through the paranasal sinus ostia. This is particularly important in cases with a unilateral or a limited area of sinus disease. The communicating air flow through the nasopharynx obscures the focused area in the sinonasal tracts. For example, changes in the nasal NO levels of patients with unilateral sinus disease (USD) during the peri-operative period failed to serve as a reliable assessment of disease severity and quality of life (QOL) status . Unlike t manner . It is cThe low nasal NO levels that are commonly observed in CRS patients are attributable mainly to the regulatory mechanisms of the expression and activities of the three NOS isoforms. However, there are other rate-limiting factors in cellular NO production, including the availability of intracellular arginine (which is the substrate for NOS) and the activities of arginino-succinate lyase (which converts citrulline back to arginine). This enzyme also plays important roles not only to help synthesize intracellular arginine but also to utilize extracellular arginine for NOS-dependent NO synthesis . In addiThe mechanisms regulating the expressions of ARG1 and ARG2 genes have been proposed to be involved in the induction of airway responsiveness by limiting substrate availability ,138. HowIn patients with perennial AR, increased expressions of both ARG1 and ARG2 were observed in the inferior turbinate mucosa, suggesting a possible role for the L-arginine–ornithine pathway in the upper airways through competition for the common substrate . One of This comprehensive review highlights that investigations of NO, a gaseous and multifunctional transmitter, remain a source of fruitful research regarding the human nasal system, including the paranasal sinuses. Multiple roles of NO from both physiological and inflammatory aspects are based on surrounding pro- or anti-inflammatory conditions, as well as the local concentrations of NO itself. The diverse backgrounds of the human nasal cavity and paranasal sinuses with anatomical complexity continue to manifest as unelucidated subtleties of the roles of nasal NO. The interpretation of the relationship between upper and lower airway functions based on NO levels is a topic that deserves further attention.There is consensus as to the diagnostic value of measuring the nasal NO in AR patients, and accordingly, such a measurement has become a popular tool for the objective assessments of the severity of AR and therapeutic efficacy. The classification of CRS phenotypes based on the level of the production of sinus NO and its metabolites has been a matter of debate, and efforts to establish such a classification are ongoing. The measurement of nasal NO and NOS activities can provide a foundation for new and specific biomarkers targeting molecular pathways that underlie endotype-specific inflammation. Focusing on these topics will confirm the significance of the regulatory processes of host signaling pathways for endogenous NO production. Additional or more extended studies can be performed to examine the effects of NOS modulators in treating intractable and refractory diseases in the sinonasal regions.


Archaeological excavations close to St Louis’ castle in Sidon, Lebanon have revealed two mass grave deposits containing partially articulated and disarticulated human skeletal remains. A minimum of 25 male individuals have been recovered, with no females or young children. Radiocarbon dating of the human remains, a crusader coin, and the design of Frankish belt buckles strongly indicate they belong to a single event in the mid-13th century CE. The skeletal remains demonstrate a high prevalence of unhealed sharp force, penetrating force and blunt force trauma consistent with medieval weaponry. Higher numbers of wounds on the back of individuals than the front suggests some were attacked from behind, possibly as they fled. The concentration of blade wounds to the back of the neck of others would be compatible with execution by decapitation following their capture. Taphonomic changes indicate the skeletal remains were left exposed for some weeks prior to being collected together and re-deposited in the defensive ditch by a fortified gateway within the town wall. Charring on some bones provides evidence of burning of the bodies. The findings imply the systematic clearance of partially decomposed corpses following an attack on the city, where adult and teenage males died as a result of weapon related trauma. The skeletons date from the second half of the Crusader period, when Christian-held Sidon came under direct assault from both the Mamluk Sultanate (1253 CE) and the Ilkhanate Mongols (1260 CE). It is likely that those in the mass graves died during one of these assaults. Following a call for military aid from Europe by the Byzantine emperor, Alexius I Comnenus, the first crusade from 1097–1099 resulted in the establishment of European rule over the coastal parts of what is now Syria, Lebanon, Israel, Palestine and Jordan. From the late 1291 CE sawKnowledge of the crusaders, settlers and their lives is mainly derived from historical texts. Life in the Latin East appears to have been one where the risk of injury was widespread, not simply as a result of open warfare but also from natural disasters such as earthquakes, accidents at construction projects, crime, assassination, internecine fighting, torture, and more mundane daily risks such as those associated with horse-riding , 4.Study of human remains from the crusader period cemeteries at the coastal city of Caesarea has demonstrated a range of skeletal trauma in the population there, but no evidence for weapon injuries . HoweverThe aim of this study is to improve our knowledge of warfare during the crusades through the detailed analysis of skeletal remains recovered from mass burials in the dry moat of the crusader castle at Sidon. We determine the date the event occurred, the demographic composition of the group of excavated individuals, their weapon injuries, and the manner in which survivors later dealt with the decomposing bodies.th century CE. During this period the city changed hands several times between Muslim and Frankish control [The port city of Sidon is situated on the eastern Mediterranean coast of south Lebanon, located south of Beirut and north of Tyre. The surrounding geographic landscape constitutes a coastal plain broadly defined by two rivers: the Nahr el-Līṭānī to the south and the Nahr el-Awalī to the north, with the plain bordered by the foothills of the Mount Lebanon range to the east . With it control , 16, and control –22.The main excavation area, known as College Site, lies to the north-northeast of the castle of St. Louis , running along part of the landward (eastern) edge of the old town district . The humin situ burning associated with this latter group.The composition of the assemblage, the taphonomic evidence, and the stratigraphy suggests an extended post-mortem interval prior to final deposition within the fortification ditch. The rectilinear grave cut contained comparatively more disarticulated human material by volume and/or smaller articulated portions of individuals, whilst the smaller assemblage which lay just outside the pit, included larger articulated sections. Two sacral fragments were matched between burials 101 and 110, indicating that the two deposits were highly likely to have been derived from the same event , 25. Tapterminus postquem of 1245 CE [Within the grave pit  a wide variety of artefacts were observed dispersed amongst the human and non-human bones, with no immediate patterning evident. Metal finds included copper alloy buckles and fittings, at least two different sizes of iron nails, other iron fittings, a silver coin, a silver finger-ring and a single copper alloy arrowhead . Other f 1245 CE .Determinations of biological sex were based on assessment of sexually dimorphic traits of the ossa coxae, crania and mandibulae of adult human bones or fragments thereof , 32. Est1⁴C programme was undertaken in order to investigate the chronological age of the human remains and to support efforts to identify whether the two deposits were contemporary or if they represented two separate periods of deposition  = 11.1; degrees of freedom = 7).A position . MandiblAttributions of perimortem trauma were made where features of damage to skeletal material were consistent with vital properties of bone fracture as reported by consensus in the literature –43. SuchThe remains from mass graves 101 and 110 represent a minimum of 25 individuals, based on the most frequently occurring identifiable bone element, the petrous part of the left temporal bone. This number is also broadly supported by the comparable numbers of postcranial remains including larger bone elements such as the femora and ulnae, and the smaller elements of the hands and feet . There iNone of the skeletal elements can be classified as female, while all the remains demonstrate either male morphology or indeterminate sex. In view of the incomplete and fragmentary nature of the material, we would argue that the whole bone sample is predominantly or exclusively male. Two of the individuals were teenagers and the rest were adults. Age at death was estimated to range from mid-teenage to elderly adult . There was no evidence of ash or in situ burning within the matrix around the bones.Perimortem trauma is present on a minimum of 100 bone elements, incorporating sharp force trauma (n = 62 lesions), penetrating force trauma (n = 5) and blunt force trauma (n = 35) . A minimWithin the assemblage, both light and heavy sharp force trauma is present, as characterised by linear incisions and nicks, scoop lesions indicating a glancing blow, and deeply penetrating cuts with associated blunt force characteristics . The majThe demographic characteristics of the human remains, coupled with the presence of widespread weapon-related perimortem trauma, is strong evidence that those interred in these two mass burial deposits were involved in an episode of armed conflict. There is no indication of the presence of any female individuals or children, and all the remains were of males of fighting age. In medieval Europe childhood ended around the age of 12, with progressive involvement in adult activities from that age .DNA analysis has recently been employed to determine the genetic ancestry of some of those found in these mass graves. Of those individuals studied, at least three had recent European ancestry, three were of local Near Eastern ancestry, and two individuals had mixed ancestry . Such fith century. There were two major attacks on Sidon during this time, and it is most plausible to suggest these mass graves resulted from one of these. The medieval chronicle ‘L’Estoire de Eracles’ records how in 1253 Mamluk forces from Damascus attacked Sidon while its walls were being rebuilt by King Louis IX of France. Hundreds of the population were killed when the Mamluks sacked the city, with others taken away as prisoners [The Templar of Tyre’ recounts how in August 1260 Sidon was again attacked, this time sacked by Mongol forces under the leadership of Kitbuqa, killing some and taking others captive [Dating of the mass graves using radiocarbon dating, the coin and other artefacts indicate the burials were deposited during the mid-13risoners . The chr captive . FollowiThe evidence for trauma most likely reflects injuries sustained in close combat, in which both pointed and bladed weapons were involved, in addition to crushing injuries from blunt force. The large sharp force injuries such as the ‘scoop’ lesion , where aThe distribution of lesions in The presence of multiple individuals with healed cranial trauma suggests at least part of the burial population had prior experience of violent conflict. Indeed, one cranial fragment exhibited healed and healing cranial trauma indicating multiple violent encounters in this individual’s life history. This makes an interesting comparison with the crusader period burials from Caesarea, where there were examples of healed trauma from accidents but no examples of weapon injuries at all . These hCanis lupus arabs) might have been able to access the remains if they were situated outside the city. Equally, any evidence of associated animal scavenging may have been eroded or lost as a result of subsequent taphonomic processes (e.g. the decay and loss of soft tissue evidence); the degree of fragmentation certainly made the full reconstruction of bones impossible in many cases. However, the generally good state of preservation without canid tooth marks argues against the complete taphonomic loss of the majority of any evidence for animal scavenging. Whilst larger mammalian scavengers have been noted to selectively remove body units, such as the upper or lower limbs, such actions do not occur in isolation, but rather as part of a wider pattern of sequential destruction that leaves recognisable signs on various regions of the skeleton. A hypothesis where scavengers only caused damage to bones that were removed, whilst ignoring the remainder, would be inconsistent with observed examples both from modern forensic cases and experiments with wild and captive animals [The general lack of evidence for animal scavenging is intriguing. It is possible the incomplete state of the human remains and their partial articulation may to some degree have resulted from the removal of extremities by larger animals. Such patterned disarticulation is typical of scavenging by canids –62. In s animals –62. It iThe relative scarcity of valuable contemporary artefacts (such as weapons or armour) associated with the remains is consistent with the post-battle stripping and looting of the corpses. The presence of disarticulated and articulated remains within a rectilinear pit demonstrates that the remains of the slain were deliberately collected together and buried , 64, andThese two mass graves at Sidon provide unequivocal evidence of intergroup violence during the period of the crusades. The minimum number of 25 individuals significantly exceeds the scale of the only other known mass burial context reported for the crusader period . As the The nature of the assemblage and taphonomic change on the remains indicates a relatively short period of post-mortem exposure prior to their final deposition at the base of the town fortification ditch. Based on modern forensic observations it can be estimated that an unburied body would take between 50 and 100 days (or 7 to 14 weeks) to skeletonize at the seasonal range of mean temperatures recorded in modern Lebanon between 1985 and 2015 . Asth century.The remains constitute clear evidence for the systematic clearance of bodies in the aftermath of urban conflict in the medieval period. The Sidon mass graves represent a unique find for the crusader period, and corroborate the contemporary account of John of Joinville, an eyewitness to the Seventh Crusade, and his description of how bodies were managed in the weeks following the sack of a city in the mid-13S1 FigExamples of metal artefacts recovered from burial 110: a-b) Base silver denaro of Frederick II, c.1245-1250 ; c) Silver ring with overlapping terminals; d) Cu alloy arrowhead; e) Kidney-shaped buckle with incised hands; f-g) Circular buckles .(TIF)Click here for additional data file.S2 Fig(TIF)Click here for additional data file.S1 Table(TIF)Click here for additional data file.


The Kenyan Ministry of Health envisages that family physicians should play an important role in the implementation of community orientated primary care (COPC) in collaboration with the community health team. The Kenyan Community Health Strategy forms a solid basis for the implementation of the COPC model. Residents and faculty of the Family Medicine department at the Aga Khan University Hospital Nairobi collaborated with the Kaloleni sub-county of Kilifi County government near Mombasa in a five-step COPC process to better understand and act against the high prevalence of HIV stigma in the coastal region. Firstly, a deeper understanding of human immunodeficiency virus (HIV) stigma was acquired through community visits and work in the comprehensive care clinic. Secondly, a collaborative implementation team was formed to design a targeted and feasible intervention. In a participatory approach, a two-step intervention was employed, firstly sensitising healthcare workers and community health volunteers (CHVs) on the high prevalence of HIV stigma in their community and educating them on HIV-related issues. Secondly, the information was disseminated to the community through home visits by CHVs, health talks and the set-up of an HIV support group at the facility. This short report illustrates the important contribution of family physicians to implementation of COPC and capacity building of the primary healthcare team. In this strategy, each sub-county is divided into administrative wards and within each ward there are several health facilities. A community health unit, linked to the first referral facility , consists of one or two community health extension workers (CHEWs) who oversee 20 community health volunteers (CHVs). Community health volunteers provide home-based services to 5000 people (500–1000 households) in the catchment area of the dispensary. The Community Health Unit is supported by a multidisciplinary team from the ward and sub-county and together they focus on local health challenges (2Community orientated primary care (COPC) has been promoted in family medicine academic circles as an essential method for providing high-quality primary care, especially in underserved and rural areas. Within this model, health providers of different cadres work together with community members to promote health, prevent disease and support treatment based on their assessed health needs in a defined geographical area.allenges .2Since its inception in 2012, the Family Medicine Department at the Aga Khan University in Nairobi has collaborated with the Ministry of Health in Kilifi County to strengthen local healthcare systems whilst enhancing future family physician’s skills in COPC. In their first and third years of training, family medicine residents work for 6 weeks in primary healthcare facilities in Kaloleni sub-county, a rural area inland from Mombasa. Under direct supervision of family physicians and guided by an online module, residents learn to enhance the capacity and skills of rural health facility staff in clinical care. They also collaborate within the community health unit to complete a five-step COPC project as follows: first year of training: (1) identifying and characterising the community, (2) involving the community, (3) identifying the community health problems, third year of training: (4) developing an intervention and (5) implementing and evaluating the impact of the intervention. The 2019 cohort of family medicine residents together with the Ministry of Health in Kilifi County, endeavoured to address HIV stigma in a rural Kenyan community in a COPC project.3 The project was undertaken in the Tsangatsini dispensary catchment area, a rural village in Kaloleni with an estimated population of 193 692 inhabitants.4 Tsangatsini dispensary is a level two health facility and offers services including maternity and child health services, laboratory services, pharmacy services and outpatient services including a comprehensive care clinic for people living with HIV. Family medicine residents undertook home visits and worked in the comprehensive care clinics to better understand the underlying reasons for HIV stigma and to enable a targeted intervention. It emerged that, apart from self-stigmatisation by patients living with HIV, there was insufficient knowledge of HIV amongst CHVs and healthcare workers (HCWs) who contributed to HIV stigma in the community. According to the HIV stigma index of 2014, Kilifi County had a stigma index of 48%, which is amongst the highest rates in the country. The stigma of having HIV negatively affects HIV care and follow up after diagnosis. It also impacts the quality of care given to HIV patients and isolates people in the community. Insufficient knowledge on HIV in Kilifi County can partially explain the relatively high HIV stigma index in comparison to other counties.6During the initial stages of the project, HIV-related stigma was identified as the focus for the COPC project through a prioritisation process.Family medicine residents worked together with the facility and community CHEWs and members of the multidisciplinary team, namely the sub-county public health officer, community health strategy focal person, HIV/STI-coordinator, a psychologist and reproductive health nurse, to discuss the approach to HIV stigma in the area. A two-phased strategy  was emplPhase 1 consisted of HIV-related sensitisation exercises, which were seen as the most impactful and resource efficient intervention for the area. A total of 10 HCWs, 2 CHEWs and all CHVs attached to Tsangatsini Dispensary were invited for 2 separate sensitisation meetings. The intervention was a one-day exercise facilitated by a trained psychologist, a certified HIV/STI trainer who was a member of both the Kaloleni community and the four family medicine residents. A public speaker with a HIV-positive status was invited to further raise awareness on stigmatisation. The content of the presentation was tailored to the needs of the respective groups.Phase 2 consisted of the development of an HIV knowledge dissemination plan in collaboration with the HCW in-charge of the Tsangatsini facility and the facility’s CHEWs. The following action plan was included:Weekly health education talks to patients in the facility on HIV and HIV stigma given by the trained facility CHEWFormation of two HIV support groups  at Tsangatsini facility led by the CHEWHuman immunodeficiency virus sensitisation activities by the CHVs during regular home visits. This involved discussing HIV-transmission with household members and informing them on the existence of HIV stigma and discrimination in the community.In the first month 32 CHVs conducted 226 sensitisation home visits and gave one health talk on HIV and HIV stigma. Monthly HIV support groups had not started because of low clinic attendance by HIV-positive patients. This might have been caused by a regional increase in coronavirus disease 2019 (COVID-19) cases at the start of the roll-out of the project that inhibited HIV-infected patients from coming to the clinics. The facility manager however expected to be able to start both support groups in the month to come. Continued health talks at the facility and discussion on HIV during home-visits by CHVs during further roll-out of the project are expected to have a positive effect on HIV-related stigma.Through the COPC rotation, family medicine residents learn about working with a multidisciplinary team and encouraging effective participation of the community. This provides them with a vital opportunity to practice integrating primary care practice and public health. They also develop their leadership skills by developing an intervention for a locally identified health problem. Moreover, they are involved in training and capacity building, with additional obvious benefits to the local health team.Human immunodeficiency virus stigma is an under-recognised health problem, which seriously hampers HIV care and increases the burden of the disease for those affected and their caregivers. More initiatives targeting HIV stigma in this area are therefore urgently needed. In addition, the impact of such projects should be monitored and evaluated. This is unfortunately not possible with the current format of the family medicine programme but ways of improving are currently explored.In conclusion, this report presents an example of how the community can be involved in designing an intervention for a locally identified health problem, through the process of COPC under the guidance of family physicians, whilst at the same time providing a valuable learning experience for medicine residents.


Primary malignant melanoma of the oral cavity is a rare tumor in clinical practice. Extensive malignant melanomas are still very rare in the literature. Patients with malignant melanoma of oral cavity are often diagnosed at the advanced stage of the disease due to their painless and nonspecific radiological findings. Histopathology is the gold standard for the final diagnosis and staging of the tumor. Surgery followed by radiotherapy is the standard treatment offered to patients with malignant melanoma. Here we present a rare case of extensive malignant melanoma of oral cavity which was successfully managed by surgical excision followed by adjuvant radiotherapy. The patient had a history of occasional paroral bleeding for the past three months and loosening of the upper last molar tooth for two months. He had consulted with a dentist for the same and was advised topical medication for two months. He was then referred to the Otorhinolaryngologist as the symptoms failed to respond to the treatment. Physical examination revealed a pigmented proliferative mass involving the gingival surface of the retromolar trigon, extending laterally to the buccal mucosa and gingivobuccal sulcus and superiorly to the alveolar process of the maxilla . No palpAll routine hematological and biochemical investigations were found to be normal. The incisional biopsy of the lesion indicated intact squamous epithelium and diffuse infiltration of the subepithelium by spindle-shaped tumor cells with prominent nucleoli. Immunohistochemistry showed strong positivity for Melanin A and S-100 in the tumor cells .The CECT scan of the whole abdomen and chest was found to be normal. Written informed consent of the patient were taken for surgical excision after the nature of the lesion, treatment options, prognosis of the disease, and the possibility of the need for adjuvant chemoradiation was explained to him and his family. Wide local excision along with left segmental mandibulectomy and infrastructural maxillectomy was performed . The tumThe patient was started on Ryle's tube feeding 24 hours after the surgery and was discharged seven days after the surgery. Histopathological section was suggestive of malignant melanoma with tumor-free resected margin with absence of lymphatic/ bony involvement. The patient was advised for postoperative radiotherapy, considering the grave prognosis of the disease. He has been on regular follow-up for the past 24 months and found asymptomatic without the recurrence of the disease .. More than 95% of the lesions are anti-S-100 antigen-positive, and more specific markers include HMB45, Melan-A, and anti-tyrosinase.in situ oral mucosal melanoma, invasive oral mucosal melanoma, and mixed in situ invasive lesions.,Primary malignant melanoma of oral mucosa is a rare tumor to encounter in clinical practice and accounts for about 0.2–8% of all melanomas.anyN0M0)Stage I: The presence of the primary tumor .anyN1M0)Stage II: Metastasis of tumor to regional lymph nodes (TanyNanyM1).Stage III: Metastasis of tumor to distant sites  as it invaded the mandibular bone. Although surgical excision is considered a curative option for early lesions of malignant melanoma, patients with extensive disease can be subjected to adjuvant chemoradiation/immunotherapy, despite poor radiosensitive tumor.Primary malignant melanoma of the oral cavity is a rare tumor in clinical practice. An extensive lesion with the involvement of retromolar trigon, superior and inferior alveolar mucosa, buccal mucosa, and palates is extremely rare and yet to be described in the literature. As these lesions are painless with nonspecific radiological features, patients are often diagnosed at advanced stage of the disease. Although the tumor possesses a poor prognosis, standard treatment with surgery and adjuvant radiotherapy can provide a favorable outcome with better survival of a patient.


Aging is a global trend and China is no exception. Older people in China mostly rely on their adult children for old-age support. This traditional provision pattern of old-age support, however, is challenged by hundreds of millions of internal migrant workers. They relocate from rural to urban regions for better employment and are no longer able to provide old-age support to their older parents in rural areas. The aim of this study was to determine the impacts of China’s public pension program expansion in rural areas on older people’s expectations for old-age support. Utilizing the natural experiment of program expansion, this study identified an instrumental variable as the county adoption of the pension program. In addition, the study analyzed a nationally representative longitudinal dataset CHARLS with fixed effects model. Results from the statistical model showed that given the participation in the pension program, older adults reported more reliance on pension for old-age support financially and less reliance on children. Heterogeneous effects were found for older adults living together with children and older adults living independently. These important findings suggest that the government partially assumes the responsibility for the old-age support of adult children in the traditional sense. The potential benefits of this study provide a policy implication for developing countries to alleviate old-age support problems and enable internal migration for economic development.


The present study investigates the layer-specific mechanical behavior of human skin. Motivated by skin’s histology, a biphasic model is proposed which differentiates between epidermis, papillary and reticular dermis, and hypodermis. Inverse analysis of ex vivo tensile and in vivo suction experiments yields mechanical parameters for each layer and predicts a stiff reticular dermis and successively softer papillary dermis, epidermis and hypodermis. Layer-specific analysis of simulations underlines the dominating role of the reticular dermis in tensile loading. Furthermore, it shows that the observed out-of-plane deflection in ex vivo tensile tests is a direct consequence of the layered structure of skin. In in vivo suction experiments, the softer upper layers strongly influence the mechanical response, whose dissipative part is determined by interstitial fluid redistribution within the tissue. Magnetic resonance imaging-based visualization of skin deformation in suction experiments confirms the deformation pattern predicted by the multilayer model, showing a consistent decrease in dermal thickness for large probe opening diameters.The online version supplementary material available at 10.1007/s10237-021-01424-w. Understanding and correctly predicting the mechanical properties of human skin are essential for medical applications. Planning of reconstructive surgery , papillary (PD) and reticular dermis (RD) as well as hypodermis (Hypo). Thickness values for the epidermis and the papillary dermis are chosen to be 100 N accounts for the number of fibers and All four layers are modeled as biphasic materials according to the theory of porous media Ehlers . Assuminn et al. . Thus, fp is the fluid hydrostatic pressure and The motion of the fluid depends on its chemical potential t et al.  and Strat et al. , we descFinally, fluid flow n et al.  and Ehlen et al. .The formulation of the constitutive model applied to different skin layers is based on the microstructure of the papillary and reticular dermis. For these layers, a clear correspondence between the fibrous components of the model and the collagen fibers as well as the matrix and the ground substance exists. A similar direct correlation does not exist for the other two layers, i.e., epidermis and adipose tissue. Yet, the histology of these layers and the results of mechanical tests . Measurements were performed on the volar forearm of a 29-year-old female volunteer. Experiments were performed after receiving written informed consent and according to the ethics and institutional guidelines EK 2018-N-45). A suction device . Human skin biopsies were accessed through the Dermatology department of the University Hospital Zurich with assistance of the SKINTEGRITY biobank. The donors provided signed informed consent that was approved by the local institutional review board (EK 647 and EK 800). The use of surplus skin for biomechanical experiments had been approved by the Ethical Committee of Canton Zurich (BASEC ID: 2017-00684). Skin biopsies were cut into specimens of Model parameters for each layer were determined based on an iterative procedure aiming at representing ex vivo uniaxial as well as in vivo suction observations. The corresponding parameter values are reported in Table The new model also well describes the experimental results for linear and instantaneous suction experiments for 2 mm and 8 mm probe opening diameters, as shown in Fig. The results of the parameter fit are reported in Table Hypodermis and muscle tissue are modeled using the same model formulation. Neither of the two layers has a significant influence on the mechanical response in the experiments considered. Thus, the simulations do not allow to evaluate corresponding model parameters for these tissues. Hence, an order of magnitude estimation of the parameters was performed using information available in the literature  for each layer during a uniaxial tension simulation. Figure The multilayer model predicts a heterogeneous distribution of osmotic pressure, fluid chemical potential and hydrostatic pressure during uniaxial experiments, as shown in Fig. The uniaxial experiments presented in Fig. The multilayer model allows to quantify layer-specific deformations in suction experiments, shown in Fig. The creep and relaxation of the skin observed in suction experiments depends on the motion of interstitial fluid. Gradients in the fluid chemical potential within the tissue are the driving force for fluid flux and influence the observed creep as well as relaxation behavior, as shown in Fig. T with t being the initial thickness of the sample. The reticular dermis, the stiffest layer, exhibits Linearized stiffness values for human skin in the literature vary significantly, from few kPa to several MPa depending on the chosen deformation state and the applied experimental method. For in vivo indentation, stiffness values range from 1 to 10 kPa  the reticular dermis is the stiffest layer in tension, bearing almost all load in uniaxial tensile tests; (b) the softer papillary dermis and epidermis ensure a more compliant response in suction experiments; (c) the differences in mechanical properties of the layers are responsible for out-of-plane curvature during ex vivo uniaxial tensile experiments; (d) the low permeability in epidermis and papillary dermis results in stronger hindrance for fluid flow which determines time-dependent phenomena in suction experiments. The model further predicts layer-specific deformations and changes in osmotic and hydrostatic pressures associated with each specific loading mode, and this information is important for the analysis of mechanotransduction in human skin. Several model assumptions and simplifications were identified for which future work is required, provided corresponding experimental information.Supplementary material 1 (pdf 638 KB)Below is the link to the electronic supplementary material.


Amongst medical undergraduates, the perception of educational environment (EE) has been associated with academic achievement and positive attitude toward the course. Nonetheless, there are sparse data on how it influences various learning processes and outcomes especially within psychiatry training. Consistent with situativity and self-determination learning theories, we hypothesized that a positive perception of the EE within psychiatry postings will be beneficial for the learning process, specifically pertaining to greater motivation to learn, better engagement, allowing them to feel more equipped, and greater appreciation of the subject. The DREEM (Dundee Ready Education Environment Measure) was administered to fourth-year medical undergraduate students from the Yong Loo Lin School of Medicine, Singapore, undergoing psychiatry rotations from 2015 to 2019. The students also completed five additional items evaluating the specific learning processes  and overall rating of the posting. We examined the relationship between DREEM domains and learning processes using correlation analysis. We explored learning processes as mediators of the relationship between total DREEM scores and overall rating of the posting. Altogether, 1343 (response rate 89.5%) medical undergraduates participated in the study. The overall DREEM score was 157.01 ± 15.86. Overall DREEM and subdomain scores were significantly correlated with several learning processes . Motivation and engagement were significant mediators of the relationship between total DREEM scores and overall rating of the psychiatry posting. Our results highlighted that a positive perception of EE was associated with the specific learning processes that mediated the overall rating of the posting. In the context of relevant learning theories and our study findings, improvement of the EE within undergraduate psychiatry training can potentially enhance overall learning experience through better motivation and engagement of our learners. The perception of the educational environment (EE) by learners reflects their learning experience , and a nSituated cognition and situated learning theories propose that thinking and learning, respectively, are situated in experience . LearninIn this cross-sectional study, we had two aims. First, we sought to evaluate the perception of the EE of undergraduate medical students following their completion of their psychiatry rotations at the Institute of Mental Health (IMH), the only tertiary psychiatric hospital in Singapore.Second, we sought to determine if perception of EE relates to the different learning processes, namely (i) motivation to learn about psychiatric disorders, (ii) engagement with the discipline of psychiatry, (iii) appreciation of relevant topics in psychiatry, and (iv) how equipped students feel about their understanding of psychiatric conditions.Based on extant data, we hypothesized that a positive perception of the EE would be associated with specific learning processes in our cohort of medical undergraduates undergoing their psychiatry rotations which mediated the overall rating of the posting.The study was conducted from 2015 to 2019. Batches of fourth-year undergraduate students from the Yong Loo Lin School of Medicine (YLLSOM) at the National University of Singapore undergo a psychiatry rotation lasting 6 weeks that comprises generally of a week of academic teaching at the University, 2 weeks attachment at a tertiary psychiatric hospital and 3 weeks attachment within a department of psychological medicine at a general hospital setting. Those undergraduate students who completed a two-week Psychiatry rotation at IMH were administered the DREEM questionnaire that surveyed their perception of various facets of the EE in relation to this particular rotation. The only demographic information collected was the gender of the student. All procedures performed in this study were in accordance with the Declaration of Helsinki. The study was approved as an exempt study by the Institutional Review Board of the National Healthcare Group, Singapore (NHG DSRB Ref: 2014/00422).The DREEM questionnaire consists of 50 items rated on a 5-point Likert scale ranging from 0 (strongly disagree) to 4 (strongly agree). Negatively worded items were reverse coded, and total scores could be obtained for five domains: i) Student Perception of Learning , ii) Student Perception of Teachers , iii) Student Perception of the Atmosphere of the Learning Environment , iv) Student Academic Self-Perceptions , and v) Student Social Self-Perceptions  ,31. ScorIn addition to the 50 standard DREEM items, our questionnaire included five items that served to measure various aspects of learning. The five items specifically explored (i) one’s motivation to learn about psychiatric disorders, (ii) level of engagement with the topic of psychiatry, (iii) one’s appreciation of the topic, (iv) how equipped one felt about managing psychiatric conditions, and (v) one’s overall rating of the rotation. The items above were rated on a five-point Likert scale ranging from Strongly Disagree to Strongly Agree. The item on Overall Rating of Session was rated on a five-point Likert scale corresponding to a continuum of Poor, Below Average, Average, Above average, and Excellent. The course instructors were not personally involved in the collection of the forms in order to reduce the risk of coercion. Instead, participants were instructed to leave their completed anonymous forms in a collection box prior to leaving the class.All analyses were conducted using IBM SPSS 23 . We first carried out descriptive analyses of DREEM overall and subdomain scores and examined DREEM score differences between genders using independent t-tests. Pearson correlations of the DREEM subdomains with the four learning processes and overall rating of posting were then performed. Statistical significance was set a priori at an alpha of 0.05 (two-tailed). Finally, we tested a mediation model using the PROCESS macro  to exploWe obtained data from 1343 students who participated in the study  out of 1500 students, with a response rate of 89.5%. Overall DREEM score was found to be in the highly positive range  Table 1Table 1. Our results also showed that there were statistically significant correlations of the cumulative DREEM score and all DREEM domains with items measuring impact on learning processes and overall rating of the posting see .Table 3.There was a significant difference between genders regarding SASP (t(1337) = 2.541, p = .011), with males having a better academic self-perception  than females . Males also gave higher scores than females on overall rating of the posting (t(1338) = 2.18, p = .030) .Fourteen participants who had missing data on one or more variables to be included in the mediation model were excluded from the analysis. There was a direct effect of total DREEM scores on overall rating of the posting. There was also an indirect effect of total DREEM score on overall rating of posting, with the learning processes of motivation and engagement being two significant mediators in the model. On the other hand, appreciation of the topic and feeling more equipped were not significant mediators. The results are presented in There were several main findings from this study. First, amid positive overall DREEM and subscale scores, there were significant gender differences  regarding academic self-perception and overall rating of the posting. Second, there were statistically significant correlations of the DREEM overall and subscale scores with specific learning processes and overall rating of the posting. Third, the learning processes of motivation and engagement were significant mediators of the relationship between total DREEM scores and overall rating of the posting.The overall DREEM scores in this study were higher compared with several earlier studies in Asia  but compWe found correlations between DREEM scores and learning processes highlighting inter-related and interactive features between these components. In addition, our mediation model sought to explore if the relationship between the EE and students’ overall rating of the posting was indeed mediated by the specific processes of learning. The components of motivation and engagement were the two significant mediators, while appreciation of the topic and feeling more equipped were not. The study findings outline several practical implications for training programs. First, it highlights the importance of knowing and continually improving the EE together with the efforts of the teacher and learner within the undergraduate learning journey in psychiatry. Second, the overall DREEM and specific subscale scores could serve as program feedback on the areas of EE that warrant further attention or continual efforts including areas of teaching, learning, encouragement of role autonomy, and garnering of social support for the learners. Third, there is high correlation between aspects of EE and specific learning processes. Understanding this encourages adequate and continual attention being paid to the development of a conducive EE for our undergraduate learners that can foster greater motivation and engagement. Consistent with adult learning theory ,48, bettThere are several limitations. First, the items were self-reported and may be affected by other factors apart from the EE such as personal life events and personality factors. Second, this study is cross-sectional in nature and is limited in its ability to provide deeper insights into the subjective mechanisms behind the findings reported. Future studies may want to capture additional qualitative comments to supplement the quantitative data to allow a richer appreciation of the details regarding specific domains in the EE. Longitudinal follow-up of the students and determination of how their appreciation of EE impacts on overall progress and assessment outcomes at the end of the year could be considered. Third, taking into consideration possible effects of respondent fatigue, the four learning processes and overall rating of the posting were assessed using single-item measures. This may not have adequately captured all facets of motivation, appreciation, engagement, and equipment of the subject matter. In addition, the items were all positively framed, which may increase the risk of response bias. Future studies may seek to expand on the items to further assess learning processes.In conclusion, we found that the perception of the EE had a significant impact on overall rating of posting which were mediated through learning processes such as motivation and engagement. In the context of relevant learning theories and our study findings, improvement of the EE within undergraduate psychiatry training can potentially enhance overall learning experience through better motivation and engagement of our learners.


Rabies lyssavirus (RABV) is enzootic in raccoons across the eastern United States. Intensive management of RABV by oral rabies vaccination (ORV) has prevented its spread westward and shown evidence of local elimination in raccoon populations of the northeastern US. The USDA, Wildlife Services, National Rabies Management Program (NRMP) collaborates with other agencies to implement broad-scale ORV and conducts extensive monitoring to measure the effectiveness of the management. Enhanced Rabies Surveillance (ERS) was initiated during 2005 and updated in 2016 to direct surveillance efforts toward higher-value specimens by assigning points to different methods of encountering specimens for collection . We used the 2016–2019 data to re-evaluate the point values using a dynamic occupancy model. Additionally, we used ERS data from 2012–2015 and 2016–2019 to examine the impact that the point system had on surveillance data. Implementation of a point system increased positivity rates among specimens by 64%, indicating a substantial increase in the efficiency of the ERS to detect wildlife rabies. Our re-evaluation found that most points accurately reflect the value of the surveillance specimens. The notable exception was that samples from animals found dead were considerably more valuable for rabies detection than originally considered . This work demonstrates how specimen prioritization strategies can be used to refine and improve ERS in support of wildlife rabies management. Effective surveillance is a fundamental component of wildlife disease management. Understanding the spatial and temporal extent of disease occurrence is critical to enact appropriate management actions aimed at the prevention of disease spread and elimination . SurveilProcyon lotor) constitute the largest proportion of rabid terrestrial wildlife and are most frequently infected with the raccoon variant of RABV [Vulpes vulpes) RABV in Western and Central Europe, canine RABV in coyotes (Canis latrans) in the United States, and raccoon RABV in Canada [A recognized wildlife zoonosis of global importance is rabies lyssavirus (RABV). Multiple variants of RABV independently and naturally circulate in carnivore and bat wildlife populations . In the  of RABV . The Wor of RABV . Oral ran Canada ,7,8. Then Canada .Surveillance is critical to know the spatial extent of the problem prior to management, the spread of disease to new areas or populations, and for assessments of disease elimination across heterogeneous landscapes . Public ERS can be comprised of multiple methods of surveillance including reports of strange acting animals , animals that were found dead upon encounter , animals found as roadkill from formal survey methods or opportunistic sampling , animals trapped specifically for RABV surveillance , animals that were nuisance-trapped or reported by the public as a nuisance but healthy , and animals for which the fate was not known or could not be described to any aforementioned categories . During 2004–2015, WS recognized that different surveillance specimens were more likely than others to detect RABV and began to develop a prioritization scheme for specimen collection to reflect these differences. In 2016, WS implemented a stratified point value system to give higher weights to specimen types that reflected the relative value of different surveillance methods  Table 1Table 1. The points associated with each surveillance method were developed based on an expert review of ERS data collected from Ohio during 2005–2007 . The objWe used ERS data from raccoon specimens collected by WS during 2016–2019 across all counties within two study areas of the eastern US . We usedThe WS ERS surveillance data included: date of specimen collection, species, location (latitude and longitude), surveillance method, and RABV status (positive or negative). RABV status testing was conducted by testing brainstem tissue samples collected from each animal using a direct rapid immunohistochemical test . We useIn this analysis, raccoon RABV occurrence was not of primary interest; instead, we needed to adequately account for the variations in RABV occurrence to ensure estimates of detection by the WS ERS method were appropriately assessed. Detection probabilities only varied by the WS ERS method within a study area, as the point-system used by managers is currently implemented uniformly across season and location. Once estimates of RABV detection were estimated in each study area, we used a weighted average to estimate the detection probability across the combined study areas. We used a weighted average because the number of specimens collected within study area 1 was roughly one-sixth of the collection from study area 2. To derive the estimated points from this analysis, we set the lowest probability of detection to one integer point and divided each detection probability by this lowest value to get relative point values. We estimated the upper and lower 95% credible intervals for these points by similarly adjusting the 95% credible intervals for their detection estimates.We also compared the number of specimens by WS ERS category collected during the four years prior to implementation of the point-system (2012–2015) against the four years of ERS points-system implementation (2016–2019). The WS ERS categories were not directly classified in the field prior to 2016. For the 2012–2015 data, we determined the surveillance categories post-hoc using the method of collection, the fate data, and the comments . We compDuring 2016–2019, there were 20,488 raccoons sampled across both study areas, with 2849 raccoons sampled in study area 1 and 17,639 raccoons sampled in study area 2 . There wAnimals reported to be strange-acting or found dead had the highest RABV detection probabilities between study areas . AnimalsThe number of specimens collected from study area 1 was one-sixth of that from study area 2 . The samp-value = 0.001 from a two-sample comparison of proportions). For comparison, the re-scaled points corresponded to fewer cumulative points pre-  compared to post-implementation .To examine the impact of the point system on the ERS data collection, we compared the composition of samples four years prior to and four years following implementation. The number of samples across the two study regions increased from 15,938 to 20,488—a 29% increase in the four years after the ERS points-system implementation . The cumThe WS Enhanced Rabies Surveillance (ERS) strategy was designed to increase the sampling intensity and to broaden the geographic scope for raccoon RABV detection . From itThe methods available to observe natural phenomena (the observation process) often obscures the underlying ecological process of interest and can result in biased estimates of the ecology process or incorrect inference regarding ecological and/or epizootiological dynamics. In particular, wildlife disease epizootiological processes often have several layers of observation obscuring the underlying disease pattern; there is the observation of the host species and separately the observation of the wildlife disease. This multi-layered complexity can make surveillance of wildlife diseases particularly difficult for inference across broad and heterogeneous landscapes. Approaches that can improve our detection of wildlife disease can improve our understanding of spatial and temporal epizootiology. A 0.5 percentage point increase in raw RABV positivity among specimens may not seem substantial, but when working with a multi-state, multi-agency program charged with eliminating a deadly zoonosis, that improvement in efficiency can facilitate resource allocation to other program areas such as ORV management or monitoring efforts, with a goal towards raccoon RABV elimination.It is important to note that the point values pre- and post-2016 are not directly comparable, as the field classifications were not directly assigned prior to 2016. Prior to 2016, classification of the specimen types was determined using a combination of data including specimen source, the fate of the animal, location of the animal, and the comments recorded upon collection . There wThe implementation of the ERS point-system has improved the overall probability of detecting raccoon RABV, which is critical to improving the efficiency of the program and informs the spatial and temporal distribution of raccoon RABV on the landscape . The rawThe results of this study show that the current point system generally does a good job at reflecting the relative values of the different surveillance methods . StrangePrior studies have described seasonal fluctuations in RABV incidence ,26. In aThe implementation of the ERS point system has demonstrated a marked improvement in the detection probability of raccoon RABV which in turn has facilitated a greater understanding of management effectiveness. Following the principles of science-based adaptive management, the point system has been reevaluated and updated based directly on surveillance data collected by managers. The advantages of an ERS point system are that it remains flexible and can be updated based on future data and epizootiological trends. The primary goal of the WS NRMP is to eliminate raccoon RABV in the eastern US. As the ORV management areas are shifted through time, it will be beneficial to continue to ensure the point-system values are reflective of data for efficiency in management operations.


The antimicrobial-resistance (AMR) in bacteria represents a major challenge for public health. The misuse and or overuse of antibiotics in livestock is known to have contributed to the emergence of AMR. To date, there is growing concern over the possibility of AMR transmission via the food chain . AMR fooThis Special Issue includes full research articles and one review focused on the emergence of AMR in food chain.Escherichia coli viability in lettuce with flow cytometry. The authors showed that this technique is a powerful tool for rapidly evaluating the effect of disinfection on Escherichia coli viability in lettuce. Additionally, the detection of VBNC cells is possible within a few minutes, which avoids their persistence, spread and, consequently, food-borne outbreaks [A critical problem is the existence of bacteria in a state of latency induced by stressful conditions called “viable but nonculturable (VBNC) cells”. The main aim of the study carried out by Texeira and co-workers was to conduct a thorough analysis of the efficacy of chemical disinfectants by assessing utbreaks .Staphylococcus aureus from milk was the focus of the contribution by Agbortabot Bissong and co-workers. The high frequency of AMR Staphylococcus aureus strains in milk intended for human consumption demonstrates the importance of this multi-drug resistant bacteria in terms of public health in the North West Province of South Africa [Salmonella serovars isolated from foods in Italy was investigated by Peruzy and co-workers. A high prevalence of AMR and multi-drug resistant Salmonella strains was found [Salmonella Rissen isolates from humans, animals, animal-derived products and the environment in China. A high incidence of AMR among Salmonella Rissen isolates recovered from various sources was observed [Salmonella Infantis antimicrobial susceptibility pattern and the prevalence of Salmonella Infantis Extended Spectrum β-Lattamase (ESBL) isolated from the broiler food chain and humans in Italy. The authors showed the great diffusion of ESBL multi-drug resistant Salmonella Infantis strains [Staphylococcus aureus from healthy pigs, diseased pigs and environment. The multidrug resistance observed among various isolates showed that pigs and pork may have an important role in AMR dissemination [Escherichia coli isolates form ready-to-eat meats in Ghana. They showed that the antibiotics used by farmers have a strong link with the resistance pattern of bacteria isolated from animals. With regard to this, ready to eat meats may be a source of AMR Escherichia coli isolates [The genotypic and phenotypic characteristics of biofilm producing and AMR in h Africa . The occas found . The conobserved . In thei strains . Zhou anmination . The stuisolates . The maiEnterobacteriaceae in the pork production chain. Overall, an increasing trend in the prevalence of presumptive ESBL producing Escherichia coli in pigs in the EU has been observed in the last decade. Although the prevalence of ESBL producing Escherichia coli is lower in pork meat than in pigs, pork meat can act as a transmission route for this group of critically important AMR bacteria [Anyway, further investigations focusing on the selective pressure applied by antimicrobial treatments on the expression of AMR genes in gut microbiota need to be carried out . Finallybacteria .This Special Issue collects multidisciplinary researches related to the possible emergence, spread and transfer of AMR in the food chain. The contributions here collected constitute a valuable knowledge reservoir for scientists working in the field of AMR.


The COVID-19 pandemic has impacted healthcare negatively across the globe. The practice of gastroenterology has been affected especially gastrointestinal (GI) endoscopy which is considered high risk for transmission of the virus. As a community of practitioners there is the need to share information and make evidence-based statements to guide GI practice in Ghana. This GASLIDD position statement based on the growing and rapidly evolving body of knowledge is to provide up to date information on the COVID-19 disease and guidance for the practice of gastroenterology in Ghana and beyond. It is to help the GI community of practice to maintain the highest level of health delivery and safety for our patients, staff, community and GI practitionersSelf-funded The pandemic caused by COVID-19 SARS-CoV-2) emanated from the pneumonia outbreak of unknown cause in Wuhan City, Hubei Province, China, in December 2019. An infected patient may show symptom severity ranging from a mild common cold-like illness, to a severe viral pneumonia leading to acute respiratory distress syndrome that is potentially fatal.  emanatedHowever, the situation surrounding the COVID-19 disease continues to evolve as new evidence emerge. There is new evidence suggesting the potential transmission through droplets and perhaps faecal sheddingThe Ghana Association for the Study of Liver and Digestive Diseases (GASLIDD) is a professional body made of the Physicians, Surgeons, Pathologists, Paediatricians, Radiologists, and Allied Health Professionals practicing in Ghana and abroad who are dedicated to the advancement of knowledge on the prevention, recognition, investigation and treatment of liver and digestive diseases. The association is also committed to the promotion of education and training in all fields of Gastroenterology and Hepatology and to the offering of professional/technical advice to the relevant authorities of the Ghana government and GI community of practice. As an expert group, GASLIDD provides the following information and recommendations to guide institutions and practices that provide endoscopy and gastrointestinal (GI) consultation services.Asymptomatic individuals can still shed the SARSCOV-2 virus although shedding is greatest when symptoms start. .Symptomatic COVID-19 adult patients commonly present with cough, fever, fatigue and sore throat.The elderly and individuals with co-morbidities such as heart disease, lung disease, Diabetes Mellitus, decompensated cirrhosis, HIV with low CD4 counts, and immunosuppression, (including liver and other solid organ transplant recipients) are at higher risk of developing more serious illness.GI symptoms such as nausea and/or diarrhea have been reported in COIVD 19 patients. There have been some reports of isolated diarrhea preceding cough and fever. Ageusia or dysgeusia are also early symptoms in the course of mild to moderate disease. Haematochezia has also been reported though rare. 15Molecular testing RT-PCR on respiratory specimens  is required to confirm the diagnosis.The viral RNA is detectable in some GI secretions and in stool. Gastrointestinal infection and potential fecaloral transmission must be considered.Abnormal liver enzymes are observed in 20–30% of persons with COVID-19 infection.There is usually a decrease in leukocyte count with elevated white blood cell count being a poor prognostic indicator.Seeking medical care early for symptoms such as fever, cough, and difficult breathing, and sharing previous travel and contact history with healthcare providers improve outcome of the disease.Practitioners must consider rescheduling elective endoscopic procedures. Priority can be given to procedures for cancer evaluation, prosthetic removals and evaluation of severe symptoms.There is an urgent need for pre-procedure screening for all patients. A special checklist (should have questions on symptoms and contacts) for screening must be administered to all patients before the decision to perform GI endoscopy or consultation is taken. Check the body temperature of patients as part of the screening process.Avoid bringing patients (or their escorts) who are over age 65 or have one of the recognized risks factors for severe COVID-19 disease into the medical facility.The GI community must acquire the requisite skills and knowledge for putting on and taking off PPEs appropriately.Appropriate personal protective equipment (PPE) must be worn by all members of the endoscopy team: gloves, mask, eye shield/goggles, face shields, and gown.Disinfection and reprocessing of endoscopes and accessories must continue along standard protocolsThere must be mandatory face mask wearing by all clients entering the premises of a health facility.Re-arrange seating at the clinics and procedure rooms to maintain the recommended social/physical distancing (at least 2 meters) by all patients.Only essential personnel should be present during procedures and at the clinics. Consider extended use or reuse of surgical masks and eye protection in accordance with hospital policies. Conservation of PPE is critical during this era.In the case of confirmed COVID-19 positive patients, or patients awaiting test results, isolation precautions should be taken, and re-evaluation done on the need for GI endoscopy. If considered non-urgent then procedure should be rescheduled but if considered urgent or emergency, then procedure should be performed in negative pressure room with appropriate PPEs.Institutions must have a dedicated phone line for follow-up for COVID-19 symptoms after consultation and procedures i.e., at day 7 and 14 post clinic visits.Virtual consultation systems must be encouraged to avoid overcrowding and assist with pre-hospital COVID-19 screening.Staff training and psychological support during this era is paramount for a safe work environment.Patients on immunosuppressive drugs for conditions like inflammatory bowel disease (IBD), autoimmune hepatitis, should be encouraged to continue taking their medications. The risk of disease flare outweighs the chance of contracting SARS-COV 2. These patients should also follow all the recommended guidelines for at-risk groups by avoiding crowds and limiting travel.Practitioners must also consider the gastrointestinal manifestations of medicines used in the treatment of COVID-19 .Requests for liver biopsy and abdominal ultrasound should be considered carefully just like GI endoscopy. These should only be performed if considered urgent or emergency.There is the need for a good collaboration with the local healthcare provider or primary care physicians to limit referrals and have phone or virtual consultations with gastroenterologists at the usual referral institutions in GhanaEnsure closure of toilet cover before flushing to avoid bio-aerosolsIf possible, avoid using toilet facilities immediately after usage by another personDo not withhold information from health professionals to create a safe environment and improve clinical outcomes.Given the dynamic nature of COVID-19 and the overflow of evidence or publication, we will encourage the GI community of practice to refer to other sources of information. We intend to update this information as new findings and recommendations emerge. The GASLIDD position statement is to provide up to date information on the COVID-19 disease and especially the impact of this disease on the practice of gastroenterology in Ghana and beyond. It is to help the GI community of practice to maintain the highest level of health delivery and safety for our patients, staff, community and ourselves as GI practitioners.


The collection also includes a series of Review articles on RAS biology and translational aspects of defining and treating RAS-driven diseases. In this Editorial, we summarize this collection and discuss the potential impact of the articles within this evolving area of research. We also identify areas of growth and possible future developments.Several cancers and rare genetic diseases are caused by dysregulation in the RAS signaling pathway. RAS proteins serve as molecular switches that regulate pathways involved in cellular growth, differentiation and survival. These pathways have been an intense area of investigation for four decades, since the initial identification of somatic RAS mutations linked to human cancers. In the past few years, inhibitors against several RAS effectors, as well as direct inhibitors of the K-RAS mutant G12C, have been developed. This Special Issue in DMM includes original Research articles on RAS-driven cancers and RASopathies. The articles provide insights into mechanisms and biomarkers, and evaluate therapeutic targets. Several articles also present new disease models, whereas others describe technologies or approaches to evaluate the function of RAS  Summary: This Editorial introduces DMM’s new Special Issue on the RAS pathway. The Guest Editors reflect on the impact of the featured articles on the landscape of the RAS field. The RAS superfamily of small GTPases includes over 150 members in humans . These p2022 marks the 40th anniversary of the initial discovery of RAS mutations in human cancers . Over thThe story of RAS from human genetics through to the first direct inhibitors represents a long and winding road of discovery, which has been greatly accelerated by a focused community of academic and industry scientists . HoweverDrosophila model for acute myeloid leukemia driven by K-RASG12V and identify several hypoxia pathway genes as possible drug targets. They also show the efficacy of the HIF-1α inhibitor echinomycin in these models (V600E-driven lung tumors by altering the immune microenvironment (Aberrant activation of the RAS pathway is the most common driver in human cancers. In the four decades since the discovery of RAS mutations in cancer, researchers have made significant advances in understanding their mechanistic underpinnings. For example, work previously published in DMM has shown that dysregulated RAS signaling affects phenotypic plasticity , an emere models . Similarironment . TogetheRMS. Lastly, Nilsson and colleagues report a new mouse model of sporadic thyroid carcinoma generated through inducible expression of BRAFV600E (in vivo RAS-driven cancer models in this issue provide new tools to evaluate therapeutics and to identify new targets for intervention.A challenge in the RAS field has been understanding the function of RAS in membranes. Marcel Schaaf and colleagues use single-molecule microscopy in a zebrafish model to study the dynamics and mobility of wild-type and mutant H-RAS. Based on their observations, the authors relate membrane dynamics to the activation state of RAS . Aside fRAFV600E . The in Germline mutations in genes encoding components of the RAS pathway cause a group of rare developmental disorders called the RASopathies. Improved understanding of the mechanisms of RAS dysregulation, coupled with expanded clinical sequencing means that the definition of RASopathy continues to evolve, as discussed in Katherine Rauen's Perspective . This arWhilst RASopathies are developmental disorders driven by mutations in components of the RAS pathway , the invIn this Special Issue, DMM editor Ross Cagan interviewed Kevan Shokat to discuss his success in ‘drugging the undruggable’ RAS and how blurring the boundaries between chemistry and biology can help develop novel cancer therapeutics . In her G12C was initially tractable due to the unique reactivity of the cysteine residue and the ability to find compounds that covalently target the mutant (G12D mutant is also amenable to direct inhibition (G12C inhibition (V600E inhibitors (These conversations with leaders in the RAS field show how knowledge has evolved quickly in recent years, most notably with the introduction of novel drugs to enable translational studies. K-RASe mutant . Extendihibition . In parahibition . Similarhibitors , this wohibitors  and EGFRhibitors , or downhibitors . Additiohibitors  are undeIn addition to the translational work, recent years have brought further insight into the basic biology of RAS. For example, researchers have made major advances in our understanding of the structural biology of complexes, drug-binding mechanisms, and the regulation of distinct target activation states . MoreoveThe articles in and beyond this Special Issue highlight significant advances in the field, from improved understanding of aberrant RAS signaling to therapy development. The increasing amount and validity of novel cell and animal models, even for some of the rarest RASopathies and RAS-driven cancers, will allow for further characterization of the disease pathology and can facilitate the development of novel therapeutic interventions. Recognizing the overlap between RASopathies, aging, neurological disorders and RAS-driven cancer shows how enhancing knowledge of each of these diseases can be mutually beneficial. It has also become clear that standardizing outcome measures and validating findings are of utmost importance for effective translation from model systems to patients. This rigor can propel the RAS field forward and result in better selection of candidate compounds and their most effective combination strategies to target multiple levels of the signaling pathway, eventually leading to a higher success rate in clinical trials for the broad range of diseases that are linked to RAS. We hope that you enjoy this Special Issue and the ongoing subject collection, which will continue to grow as new articles on the topic are published in DMM.


In the present work, a hybrid magnetic field assisted powder mixed electrical discharge machining had been carried out on the Aluminum-Silicon Carbide (Al-SiC) metal matrix composite. The aim of the study was to obtain higher surface finish, and enhanced material removal rate. The dielectric mediums employed were plain EDM oil, SiCp mixed and graphite powder mixed EDM oil for flushing through the tube electrode. The magnetic field intensity, discharge current, T-on/off duration and type of dielectric were the control variables used for present investigation. From the results, it was observed that the machining variables for instance, discharge current, T-on/off duration and type of dielectric conditions remarkably affected the material removal rate, micro-hardness and surface roughness of the machined composite material. The MRR augmented considerably with an increase in the magnetic field intensity along with peak current. Subsequently, the composite with lesser vol.% of SiC particulates witnessed sharp rise in MRR in maximum magnetic field environment (0.66T). In addition, quality of the machined surface improved significantly in graphite powder mixed dielectric flushing condition with intermediate external magnetic field environment. Besides, an enhancement of micro-hardness was quantified as compared to base material due to the transfer of the material (SiCp) during powder mixed ED machining. Metal Matrix Composites (MMCs) are the lightweight materials possessing enormous exceptional mechanical and physical properties such as high specific strength, stiffness and wear resistance ,2,3. SiCHowever, the reliability and safety of conventional ED machined components is being questioned repeatedly. The surface cracking of the machined components owing to the development of recast layer  and heat affected zone underneath it has been the prominent issue. The hybrid machining  has proved to be a key future technology to solve this issue. Owing to this, it’s never been an uphill task to achieve desired surface integrity as complex shapes and precision with the advent of hybrid EDM. The hybrid EDM is a mechanism to enhance the machining characteristics of a conventional EDM by combining various individual processes together to achieve desired surface integrity and stability of process and to overcome the limitations of the individual constituents ,11. FromA novel hybrid EDM methodology using the external magnetic field has showcases its process effectiveness by enhancing the effective debris expulsion from the melt pool. Some researchers and academicians have put forward the impact of magnetic field on MRR and Surface Roughness (SR)  experimeThis elaborative literature study encouraged the authors to dive deep into this magnetic and electric field interference to explore and uncover its process capabilities. The review of past work recognized the noteworthy effects of magnetic field on the EDM process parameters. Therefore, we aimed the present study towards the investigation of the effects of Magnetic field on the output parameters of Al-SiC composite when coupled with EDM. The quest for more efficient machining techniques necessitated the requirement of hybridization of state-of-the-art technologies with exceptional efficiency and stability. The main motive behind this study was to analyze the performance of magnetic field environment on powder mixed assisted EDM operation on machining characteristics for instance, MRR, MH, and SR of Al-SiC metal matrix composite. The prominent process parameters like peak current, duration of T-on/off, and magnetic field intensity were selected to analyze their effects on process performance.In this study, aluminum matrix-based composite  variantsThe electrolytic copper tube electrode  having 1To achieve accuracy in output responses, two replications were performed at random order to find out the mean. The Taguchi’s experimental design matrix  assistedOA) has must satisfy the inequality The selection of Taguchi’s orthogonal array depends on the number of factors  and interactions of interest  and the number of levels of process parameters  was used to measure workpiece weights before and after the machining. The investigation consisted of 27 distinct trials that helped to investigate the material removed, micro-hardness and surface quality of machined Al-SiC metal matrix composite using various input variables as tabulated in The experimental design matrix and results obtained, thereafter, are demonstrated in the Moreover, the maximum material removal was witnessed in Trial 24, wherein 118% increase in MRR was observed in graphite powder mixed dielectric flushing in extreme magnetic field intensity compared to similar parametric conditions in Trial 5. The probable reason for increase in MRR could be the effective molten debris flushing on the machined surface due to the generation of Lorentz forces by the interplay of magnetic as well as electrical fields which enhanced the plasma pressure. Apart from this, injecting the powder mixed dielectric through the hole in the tube electrode enhanced its pressure, augmented the debris flushing. The interaction between different variables was not evident to be significant while powder mixed magnetic field assisted EDM.The effect of various machining parameters and the surface conditions of the machined workpiece were analyzed by measurement of the indentation hardness. The micro-hardness measurements were carried out at the different locations of the machined surface as well as parent material, cross-sectionally. The machining parameters like magnetic field intensity, type of workpiece and pulse-on/off duration posed considerable effect on MH values, as shown in 0) with the generator setting of 40mA and 45 kV. The X-ray diffractograms of the machined surfaces  are shown in 2SiO5, SiO2, Si3W5 on the surface of machined MMCs, thus resulted in the enhanced hardness of machined surface [The machined surface was further analyzed using X-ray diffraction method on PANalytical’s X’PertPro MPD (Netherlands). The X-ray spectra of the workpiece was characterized using Cu-Kα radiations . It was observed that the interaction between magnetic field intensity (B) and T-on significantly affected the surface roughness. From The interaction between various process parameters was statistically analyzed at 95% confidence level  in the micro-hardness was witnessed due to the transfer of materials and formation of new phases while ED machining.The surface finish of machined MMCs was greatly affected by magnetic field intensity as well as type of dielectric. The surface finish improved steeply in graphite powder mixed dielectric flushing conditions at intermediate (0.33 T) magnetic field.Future Scope: The literature studies depicted that aluminum matrix composites have been the major choice in the field of EDM of MMCs, but no significant work is available for the composite with other matrix phase such cobalt, steel etc. In addition to this, the experimental research can be extended and analyzed using various other levels of magnetic field of permanent magnets as well as rotating electromagnets.


The diagnosis and management of juvenile ossifying fibroma (JOF) remains a highly debated topic with paucity of studies with long-term follow-up, hence the aim of this study was to report on the clinico-pathological features and management of these neoplasms. A retrospective analysis was performed on all histopathologically confirmed JOF presenting at two tertiary hospitals in Cape Town, South Africa over a period of 39 years. Clinical, demographic, histopathological and radiological features were analyzed. Surgical methods were documented and a minimum post-operative follow-up of 12 months was a prerequisite.P = 0.01). The majority of patients presented with marked swelling (88.2%). Interestingly, most neoplasms occurred in the mandible (76.5%) with all Psammomatoid JOF uncharacteristically occurring in the mandible. There was only one case of Trabecular JOF occurring in the sinonasal area. Most neoplasms appeared as unilocular (76.5%) and well-defined (82.4%) with mixed radio-density (70.6%) on radiographs and computed tomography. Curettage with peripheral ostectomy was shown to be the least invasive method with an accepTable recurrence rate (10%). Six lesions underwent resection without any recurrences however caused high morbidity to these young patients. Seventeen patients met the inclusion criteria and were included in this study. Overall, the ages of patients ranged from 3–31 years (mean= 13 years) with male to female ratio of 1.8:1. The ages of patients diagnosed with Trabecular JOF were significantly younger than patients with Psammomatoid JOF ( The high number of lesions occurring in the mandible for both variants of JOF demonstrates that site should not be a major determining factor in the diagnosis of JOF. Moreover, curettage with peripheral ostectomy should be used as the first line of management to minimize morbidity to the patient and that resection should be reserved for large and recurrent lesions. Key words:Juvenile ossifying fibroma, juvenile trabecular ossifying fibroma, juvenile psammomatoid ossifying fibroma, fibro-osseous lesions, maxillofacial region, multi-centre study. Juvenile ossifying fibroma (JOF) is a subtype of ossifying fibroma (OF) that usually occurs within the maxillofacial region of children and young adults . It is aThe management and prognosis of JOF is uncertain. In some cases, it may occur with minimal symptoms, while in other cases, especially in younger patients, it may present with local aggressive behaviour. Therefore, due to the aggressive nature of these tumours with the high recurrence rate, some authors advocate that these locally aggressive neoplasms be treated with surgical resection rather than conservative curettage ,5.The clinico-pathological features of JOF differ widely in the literature with few large studies available. Moreover, there are no management protocols based on long-term follow-up; hence the aim of this study was to report on the diagnostic features and management of these neoplasms.A retrospective analysis was performed on all histopathologically confirmed JOF presenting at two tertiary referral hospitals in Cape Town, South Africa from January 1980 to December 2019. This study followed the Declaration of Helsinki on medical protocol and ethics and the regional Ethical Review Board of the University of the Western Cape approved the study.The inclusion criteria included all records of patients diagnosed with JOF in the maxillofacial region including sinonasal areas with detailed demographic data, clinical features, radiographs and surgical treatment. Each patient’s record included at least one panoramic radiograph as well as any advanced imaging modalities such as computed tomography (CT) when available. CT was performed only in cases where the lesion was extensive and involved areas difficult to assess with conventional radiographs such as the paranasal sinuses. All lesions were histopathologically confirmed by an Oral Pathologist based on the final surgical specimen prior to inclusion in the study. Age and site were not included as part of the diagnostic criteria for diagnosis of JOF.Records were excluded from the study when the data were incomplete and the histopathological diagnosis was inconclusive. Records were also excluded when the surgical method used to manage the lesion was not described in detail or if the patient did not return for post-operative follow-up to detect any recurrences or complications. The minimum post-operative follow-up period was 12 months.Each patient’s age, gender and ethnicity were recorded. The clinical features of each neoplasm was recorded as well as the radiological features including site, demarcation, density, size, shape, locularity and its effect on adjacent anatomical structures. The histopathological characteristics were also noted. Surgical management and post-operative follow-up were analysed. All records and radiographs were assessed by one observer (author) and under the same conditions.The location of the lesion was categorized into different regions in the mandible and maxilla. The anterior region of the mandible extended from the mandibular left canine to right canine. The posterior region of the mandible extended from canine to the angle of the mandible. The anterior region of the maxilla extended from the left maxillary canine to right canine while the posterior region of the maxilla extended from canine to the maxillary tuberosity.The size of the lesion was measured in centimetres along the widest diameter of the lesion from one border to the opposite border. Radio-density was classified as either radio-lucent, radio-opaque and mixed (radio-lucent with areas of radio-opacity). Lesions were further classified as either unilocular in appearance whereby only one compartment is present or multilocular whereby the lesion appears to be formed of many adjacent compartments within the bone. External root resorption of secondary dentition was assessed on panoramic radiographs for flattening of the apical part of roots of teeth associated with the lesion.P < 0.05.Excel worksheet was used to collect the data. Data analysis was performed using Epi Info® 2000  by Fisher’s exact test or Mann-Whitney test to compare the findings and to correlate these findings with different parameters. Statistical significance was set at - Demographic featuresP = 0.01). Males were more commonly affected than females (M:F ratio = 1.8:1). The majority of patients were of mixed race  and African descent  while patients of Caucasian and Indian ethnicity were not affected in this sample. Detailed summary of demographic findings for each variant of JOF is shown in A total of 21 patients were diagnosed with JOF over a period of 39 years. Only 17 patients were included in the study as the other four patients did not meet the inclusion criteria. Overall, the ages of patients ranged from 3-31 years (mean= 13 years) while the ages of patients diagnosed with JTOF were significantly younger than patients with JPOF . No patient reported paraesthesia of branches of the trigeminal nerve.Rapid expansion of the affected facial bones is one of the main identifying features of JOF. The majority of patients presented with marked swelling and facial asymmetry (88.2%) while only two patients (11.8%) complained of pain. The period from initially noticing symptoms to presentation is relatively rapid (mean= 1.9 months) with no statistically significant difference between the two variants of JOF  with all JPOF uncharacteristically occurring in the mandible. There was only one case of JTOF occurring in the sinonasal area. The posterior regions of the jaws were more frequently affected.- Radiological featuresP > 0.05). There was marked expansion of the involved bones in nearly all neoplasms as expected  with few lesions presenting with ill-defined margins 17.6%). Most lesions appeared mixed in radio-density .In most instances, JOF caused displacement of the inferior alveolar canal or maxillary antrum. Displacement of teeth was a common feature while root resorption was less frequent (35.3%). The difference in size between JTOF and JPOF was however not statistically significant . Both were of the JTOF variant. One lesion recurred in the posterior mandible while the other in the maxilla.JOF is a rare aggressive neoplasm with variable evidence regarding its diagnosis and management. Due to the similarities in the histopathological features of fibro-osseous lesions of the jaws, clinical, radiological and pathological correlations are needed to arrive at an accurate diagnosis . Both vaAge is an important factor in the diagnostic criteria of JOF. In 2005, the World Health Organization (WHO) reported the age of onset of JOF to be 15 years and younger ,8; howevet al. (In terms of gender distribution, a previous study by Han et al.  reportedet al.  demonstrClinically, the majority of neoplasms caused rapid swelling in the maxillofacial region within a short period of time . This iset al. (Site is another important factor in these neoplasms due to their ability to cause severe deformity of the facial skeleton. Most studies in the literature report that JTOF usually occurs in the maxilla while JPOF has a predilection for the para-nasal sinuses . Both leet al.  also notRadiological features of JOF form an important part of the clinico-pathological correlation process to reach an accurate diagnosis . A distiMore than three-quarters of JOF in the literature are reported to be unilocular in appearance . In thisIn terms of histopathological findings, JOF and specifically JPOF shows somewhat distinct features which aids in making an accurate diagnosis. Histopathological examination still forms the main diagnostic method in achieving a diagnosis. Most of these features are widely accepted in the literature. A debated topic is the association of aneurysmal bone cysts with JOF. This cohort of neoplasms showed similar incidence of aneurysmal bone cysts as in the literature .et al. (et al. (Due to the aggressive nature of JOF and reported high recurrence rate, the best suited surgical method is widely debated. Han et al.  and Saro (et al.  advocate (et al.  in their (et al. . A manag (et al. .In conclusion, the high number of lesions occurring in the mandible for both variants of JOF demonstrates that site should not be a major determining factor in the diagnosis of JOF as previously reported. Moreover, curettage with peripheral ostectomy should be used as the first line of management to minimize morbidity to the patient and that resection should be reserved for very extensive and recurrent neoplasms.