Background: Autophagy, a highly conserved cellular catabolic process by which the eukaryotic cells deliver autophagosomes engulfing cellular proteins and organelles to lysosomes for degradation, is critical for maintaining cellular homeostasis in response to various signals and nutrient stresses. The dysregulation of autophagy has been noted in the pathogenesis of cancers. Our study aims to investigate the prognosis-predicting value of autophagy-related genes (ARG) in hepatocellular carcinoma (HCC).Results: The signature was constructed based on eight ARGs, which stratified HCC patients into high- and low-risk groups in terms of overall survival (OS) . The ARG signature is an independent prognostic indicator for HCC patients . The area under the receiver operating characteristic (ROC) curve (AUC) for 5-year survival is 0.765.Conclusion: This study provides a potential prognostic signature for predicting the prognosis of HCC patients and molecular insights into the significance of autophagy in HCC.Methods: Sixty-two differentially expressed ARGs and the clinical characteristics and basic information of the 369 enrolled HCC patients were retrieved from The Cancer Genome Atlas (TCGA) database. the Cox proportional hazard regression analysis was adopted to identify survival-related ARGs, based on which a prognosis predicting signature was constructed. Hepatocellular carcinoma (HCC), the fourth leading cause of all cancer-related deaths worldwide, accounts for 90% of all primary liver malignancies , the majCurrent antiviral drugs and surgical interventions, along with immunotherapeutic agents and targeted therapy, are improving HCC patients’ survival outcomes in an inspiring way, which, however, practically are often challenged by the tumor heterogeneity  and the Also, the lack of a robust model predicting the prognosis and the occurrence of resistance during courses of therapies contributes to poor survival outcomes.Recent advancements in the next-generation sequencing technology have characterized the genetic landscape of various types of cancer, including HCC, not only revealing the driver mutations in hotspot genes like TP53, CTNNB1, TERT promoter but identifying the dysregulated expression of genes related to diverse pathways in multiple biological processes such as the metabolic pathways, VHL/HIF oxygen-sensing pathway, the DDR pathway, and the autophagy.Autophagy, executed by autophagy-related genes (ARG), having roles in various cellular functions in cancer, both protecting against and contributing to the proliferation of cancer cells, is a highly conserved cellular catabolic process by which the eukaryotic cells deliver autophagosomes engulfing cellular proteins and organelles to lysosomes for degradation, which is critical for maintaining cellular homeostasis in response to various signals and cellular stresses. The dysregulation of autophagy has been noted in the pathogenesis of diverse diseases, including cancers.The conception of harnessing this pathway to improve clinical outcomes of cancer patients has been the attention of researchers seeking to redirect the upregulation of autophagy flux enabling tumor cell survival and growth since the terminological introduction of autophagy in 1963 by Christian de Duve > 1, we finally obtained 62 up-regulated ARGs , 1B. A bFunctional enrichment analysis of 62 differentially expressed ARGs provides a biological understanding of these genes. Top 30 of GO enrichment and top 30 of pathway enrichment are summarized in P < 0.001; To analyze ARGs’ involvement in HCC progression, we screened for ARGs that were significantly associated with prognosis. The univariate Cox regression analysis indicates that 32 ARGs that are correlated with the overall survival are all risk factors . A totalThis indicated that the prognostic index based on ARGs has a certain potential in survival prediction .The clinical significance of the signature was assessed by analyzing its correlation with the clinical parameters, which suggested significantly increased risk score in patients who were older than 65 , in GradDespite the numerousness of studies reporting that autophagy is not only involved in the initiation but the progression and drug resistance of HCC, the specific functions of ARGs and their clinical significance in HCC has not been exploited and clarified well yet , 19–22. The model we constructed consists of a group ARGs that are correlated with the survival outcomes of HCC patients confirmed by the univariate and then the multivariate cox regression analysis.Most of the genes incorporated for the construction of the signature were explored in previous studies as a progression promoter and a prognosis indicator for patients with HCC or other malignancies. The knockdown of RHEB, a key regulator in mTOR signaling pathway , was relLimitations of this study are:1) Data in our study were collected retrospectively, leaving some internal bias inevitable; 2) The prognostic signature established in our study needs further validation from more independent studies to make the signature more convincing; 3) Experimental explorations into the molecular mechanism underlying the functions of these genes.In summary, we first demonstrated the clinical significance of an ARG signature in predicting the overall survival of HCC patients. The ARGs were identified to be involved in HCC growth and progression through different pathways mentioned above. Adding to the reliability of the ARG signature is the consistency of our findings with previous studies showing that some of the ARGs are capable of forecasting the survival outcomes and monitoring tumor progression and treatment responses. Therefore, presumably the ARGs identified either in our study or elsewhere might hold promise as a novel biomarker for human HCC therapy, making the development and test of the effect of ARG inhibitors clinically desirable. It’s also of great interest to unravel the underlying molecular mechanism of these genes and their roles in other types of malignancies.In conclusion, our study demonstrates for the first time the potential prognostic role of an ARG signature in HCC, although more in-depth mechanisms and prognostic roles for this signature in HCC need to be confirmed in the future, our findings provide a preliminary basis to explore ARGs as a potential molecular target for the development of HCC therapies.To identify the ARGs that could predict the prognosis of HCC patients, we retrieved the mRNA expression data of 377 HCC patients from the Cancer Genome Atlas (TCGA) datasets. RNA-seq data of 221 ARGs and the clinical features of the patients were obtained for further analysis.Differentially expressed ARGs were identified from a list of total 632 ARGs in HCC from the TCGA datasets by using the EdgeR package in R statistical software. ARGs were only considered as differentially expressed ARGs when at least 2-fold change, evidenced by a p-value less than 0.05, in the expression level was observed. Gene functional enrichment analyses, using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), was conducted based on the differentially expressed ARGs to find the major functional and molecular attributes of these genes.The prognosis-predicting model based on ARGs was constructed using the multivariate cox regression analysis. A scoring formula for each HCC patient was established and weighted by its expected regression coefficients in a multivariate cox regression analysis after including the expression values for every single gene and was then employed to determine the use of the median risk score as the cut-off point characterize patients into a high-risk group and low-risk group. The Kaplan-Meier estimator and the multivariate cox regression analysis were adopted to assess the differences in survival in these two groups, and the role of risk scores in predicting survival outcomes for HCC patients, respectively. ROC curves were used to study the accuracy of the prediction model.https://www.r-project.org/). The univariate Cox regression analysis was used to evaluate the association between gene expression profiles and overall survival.Statistical analyses were performed mostly based on the R 3.5.1 curve and calculate the area under the ROC curve (AUC) for each dataset to measure the prognostic role of the model.All statistical tests were only considered significant when p <0.05 was achieved.


The use of time domain reflectometry (TDR) for real-time monitoring of bridge scour process has gone through several stages of development. The recently-proposed concept of bundled TDR sensing cable, in which two sets of insulated steel strands are twisted around and connected to a central coaxial cable to form a compact sensing cable, is a major change that has several advantages including the bottom-up sensing mechanism. Nevertheless, there is big room for improving its measurement sensitivity and signal to noise ratio (SNR). Changes in waveguide configuration also need to be made to avoid the adverse effect of insulation abrasion observed in field implementation. This study evaluated three new conductor and insulator configurations for constructing the sensing waveguide, including a balanced two-conductor waveguide (Type I), an unbalanced three-conductor waveguide with insulation coating on the middle conductor (Type II) and an unbalanced three-conductor with insulation coating on the two outer conductors (Type III). In all cases, the spacing between the two sets of steel strands  was especially enlarged by replacing some steel strands with non-conductor wires to increases measurement sensitivity and avoid shorted conditions due to insulation abrasion. Experimental results show that Type III has the best performance on all counts. A new improved TDR sensing cable was hence proposed based on Type III configuration. Its performance was further evaluated by a full-scale experiment to take into consideration the long range of measurement in most field conditions. Detailed discussions on improvements of measurement sensitivity and SNR, limitation of sensing range, and mitigating the adverse effect of insulation abrasion are presented.  Local scour is regarded as the top threat to bridge safety. More than half of bridge failures in the United States can be attributed to local scour ,2,3. In Aiming to monitor the scour process in harsh flow conditions, the TDR (time domain reflectometry) method especially draws our attention in recent years because it is a guided wave technique without electronic elements under water. Although it is still an intrusive method, it is considered to have great potential to better sustain severe flooding conditions and monitor the scour and deposition process. A TDR device sends out an electromagnetic pulse through a leading coaxial cable to a sensing waveguide and record reflections from the sensing section, which contains information regarding the changing interface (scour depth). The first attempt to use TDR technique for the purpose of scour monitoring can be found in the work of Dowding and Pierce , in whicThe idea of using a TDR-based sensor has been proposed for more than 20 years. However, the usefulness of such techniques and many others has been limited, especially in harsh flow conditions where scour is most critical. Existing TDR scour sensors are rod type, which is unfavorable in high-velocity flow and has a very small measurement range. The recent concept of bundled TDR sensing cable is a big step of change. However, the sensing performance was greatly sacrificed in pursuit of durability and workability. This study proposed a new TDR scour sensor through various waveguide considerations and thorough experimental evaluation, in order to improve the measurement sensitivity and confront the adverse effect of coating abrasion and the limitation of measurement range. Three new configurations of waveguide conductors and insulators were proposed and tested to compare their SNRs and measurement sensitivities. Two of the more promising designs were further examined for the effect of coating abrasion. Based on the experimental evaluation, an improved bundled TDR sensing cable was then recommended for future use. A full-scale sandbox experiment was conducted to reveal the measurement range of the new bundled TDR sensing cable with and without coating abrasion. The full-scale experimental data was also used to validate a new data reduction scheme to avoid the adverse effect of coating abrasion.ρ) as a function of time, which can be written as:v is the recorded voltage and iv is the magnitude of the incident step pulse. s/wt, w/at, and et, respectively. The time t0 marks the reflection from the connection between the coaxial cable and sensing waveguide. Time domain reflectometry is a versatile waveguide-based technique that has been adapted for various geotechnical measurements ,18,19,20t) in a medium section and knowing the medium section length (L), the pulse propagation velocity (V), which is related to the apparent dielectric constant (aK), can be determined by the following equation [V is the propagation velocity, c is the speed of light (2.998 × 108 m/s), aK represents the apparent dielectric constant , L is the length of a section and ∆t is the round-trip travel time in that section. To form a sensing waveguide and avoid conductive attenuation, part of the steel strands is insulated by PVC coating. The TDR sensing waveguide has a certain sampling range in the transverse direction. Within the sensing range of the TDR scour sensing cable, the dielectric media include the PVC coating and the surrounding media. The apparent dielectric constant (aK) in Equation (2) would be the effective average dielectric constant in each sensing section . Due to this insulation coating, the apparent dielectric constants in different media  become less distinct, resulting in weaker reflections at s/w and w/a interfaces comparing to the reflection at 0t. To facilitate waveform interpretation, Wang et al. [ρ). The new sediment/water interface (s/wt) due to scour can be easily identified as the first break in the differential waveform. With the measured s/wt and calibrated propagation velocity of sediment (sV), the crucial scour depth (in terms of length of sediment section sL) can be easily computed as:By measuring the round-trip travel time (∆equation : (2)V=cKg et al.  proposedIt is noted that the dielectric permittivity of water is slightly affected by temperature. Hence, vs. is theoretically also affected by temperature. However, the temperature effect is negligible for the sediment section due to small temperature variation under riverbed unless in the frozen state, in which dielectric constant drops significantly from the liquid state to the solid state.The bundled TDR sensing cable possesses good workability and enables the advantageous bottom-up sensing mechanism. However, the measurement sensitivity is greatly sacrificed due to the close proximity of insulated steel strands and opposing steel strands. Field implementation revealed an adverse effect of coating abrasion and a higher noise level than in a laboratory setting. The measurement sensitivity should be improved to enhance the signal to noise ratio to make the TDR method more robust. The first generation of bundled TDR sensing cable is a balanced type (two-conductor transmission line), which is prone to unwanted noise in the field . SymmetrTo avoid the abrasion problem and increase measurement sensitivity (or SNR), the conductors and insulators should be reconfigured. In addition to the original design, A is the amplitude of reflection signal from the sediment/water interface and σ is the standard deviation of the noise residing on the waveform. All sensing waveguides shown in The signal quality in terms of SNR for the original sensing cable and the three newly-proposed ones were experimentally evaluated by a laboratory sandbox experiment. The SNR for this study is first defined as: The schematic and a photo showing the sandbox experiment are shown in s/wt). Using the maximum sediment thickness (sL = 1.0 m) as the reference case, s/wt) can be clearly identified after taking the waveform difference with the reference waveform. After s/wt is determined, the apparent dielectric constant (aK) in the sediment section can be determined from the round-trip travel time  and sediment thickness by Equation (2). On the other hand, the standard deviation of noise residing on the waveform is determined as the standard deviation of the flat waveform in the coaxial cable before the reflection from the sensing section as marked as ① in As an example, t) and a higher aK value under the same amount of sediment thickness (sL). According to the results of travel time Δt and aK, all three new sensing waveguides have significantly better measurement sensitivity over the original TDR sensing cable. This can be attributed to the increase of spacing between two opposing conductors. The close proximity of the two sets of conductors in the original design makes the sensing area concentrated in the narrow space largely occupied by the PVC coating. The sensitivity weights much more near the middle conductor of an unbalanced waveguide (symmetric multi-conductor transmission line) in a way similar to that near the central conductor of a coaxial transmission line. This is probably why Type III (the waveguide with uncoated middle conductor) has further higher measurement sensitivity over Types I and II. Although Types I and II have similar measurement sensitivity, Type II has lower SNR because the balanced type is more prone to electrical noise. The noise level is smaller for both unbalanced waveguides (Types II and III). Because of its higher measurement sensitivity, Type III stands out as having the best SNR and measurement sensitivity. Both the unbalanced waveguides (Types II and III) were chosen to further examine the effect of coating abrasion before deciding the best design for the new TDR sensing cable. The two opposing conductors in the new TDR sensing waveguides are separated by PP wires. Conductor coating is now unnecessary to form a sensing waveguide, but it is used to avoid signal attenuation due to DC conductivity in saturated sediment and water. A previous field implementation has shown that the bedload and debris may abrade the insulation coating. In the new design where two conductors are separated by PP wires, the shorted condition due to coating abrasion can now be avoided. Nevertheless, how coating abrasion affects TDR measurements in the new waveguide design needs further investigation. A laboratory abrasion experiment was conducted to examine the abrasion effect on the two improved sensing cables . The testing setup is basically the same as the previous experiment in testing measurement sensitivity and SNR. The testing procedure is illustrated in The electric field energy of an unbalanced TDR probe is concentrated near the middle conductor . This meaK of the new TDR sensing cable are 41.2, 2.18 × 10−8 s, and 10.69, respectively. All indicators show that the new TDR sensing cable is superior to all waveguides shown in Based on the Type III configuration, a new improved TDR sensing cable was proposed for future field applications. It will have better measurement sensitivity, higher SNR, and insensitivity to the effect of coating abrasion. The diameter of steel strands is enlarged to increase the overall tensile strength of the bundled TDR sensing cable, but not too much to impede cable handling. Furthermore, the HDPE is used instead of PVC and PP to increase its resistance against abrasion. The prototype of the new TDR sensing cable is shown in Under a long range of measurement in most field conditions, cable resistance and dielectric loss will attenuate the electromagnetic signal and make the reflections smoother as sensing distance increases. A full-scale scour simulation experiment showed that the maximum measurement range of the original TDR scour sensing cable is about 6 m . The persL = 10 m as the reference waveform, the differential waveforms in sL) exceed 6 m. While the new scour sensing cable significantly improves the measurement sensitivity and SNR within the measurement range, the maximum measurement range remains similar. As sediment thickness increases, the reflection signal from the s/w interface gets weaker regardless of waveguide configuration. Although the DC electrical conduction path between two sets of conductors has been blocked by the insulation coating, signal attenuation with increasing sensing range may be attributed to frequency-dependent conduction effect and/or radiation loss. Hence, reconfiguration of sensing waveguide is unable to extend the sensing range of a single TDR sensing cable. A separate longer TDR sensing cable is needed to extend the measurement range in the field.The measured raw data of the full-scale scour simulation experiment for the intact TDR sensing cable are shown in s/wt) for determining the crucial scour depth [sL. sL and round-trip travel time (s/w − t0t) in sediments from the small-scale experiments (sL within 1 m) and full-scale experiments (sL within 6 m). The linear relationship of Equation (3) is quite stable regardless of the testing scale. The calibration results of vs. from small-scale experiments , the bottom-up scour sensing scheme requires only two parameters  as the reference, sL conditions. When the s/w interface under measurement is below the coating abrasion , the first break in the differential waveform is not affected by the coating abrasion. It represents a deeper scour depth below the coating abrasion. When the sediments are refilled above the coating abrasion, the differential waveform sees a slight drop (or more of a tilt) at the coating abrasion before the reflection drop at the refilled s/w interface. The effect of coating abrasion in the full-scale experiment is more pronounced than the results in The second phase of the full-scale experiment was to investigate the effect of coating abrasion under a long sensing range. A 50 cm coating abrasion was introduced between 3.25 and 3.75 m from the end of the sensing cable. This may occur during a large flooding event and the sediments above the coating abrasion represent refilled sediments after the flood recedes. Taking the same initial waveform  as the reference to get rid of intrinsic multiple reflections from the measurement system and facilitate identification of A bundled TDR sensing cable was recently proposed, significantly altering the idea of how a TDR scour sensing waveguide may be constructed for harsh flow conditions, in which none of the existing methods can work properly for monitoring the continuous scour dynamics. However, the sensing performance was greatly sacrificed in pursuit of durability and workability. This study proposed a new TDR scour sensor through various waveguide considerations and thorough experimental evaluation, in order to improve the measurement sensitivity and confront the adverse effect of coating abrasion and the limitation of measurement range. Three new conductor and insulator configurations for constructing the sensing waveguide were investigated, including a balanced two-conductor waveguide (Type I), an unbalanced three-conductor waveguide with insulation coating on the middle conductor (Type II), and an unbalanced three-conductor with insulation coating on the two outer conductors (Type III). In all cases, the spacing between the two sets of conductors was especially enlarged by replacing some steel strands with non-conductor wires. This enlarged separation of two opposing conductors increases measurement sensitivity and avoids shorted condition due to coating abrasion. The performance of the new designs, in terms of measurement sensitivity, SNR and ability to reduce the effect of coating abrasion, was experimentally evaluated and compared. The results show that Type III has the highest measurement sensitivity and SNR. It is also least affected by coating abrasion. A new improved TDR sensing cable was hence proposed based on Type III configuration. The performance of the improved TDR sensing cable was further evaluated by a full-scale experiment to take into consideration the long-range of measurement in most field conditions. Compared to the original design, the new TDR sensing cable significantly improves the measurement sensitivity and SNR, but the maximum scour measurement range remains similar. As sediment thickness increases, the reflection signal from the sediment/water interface gets weaker regardless of waveguide configuration. Although the DC electrical conduction path between two sets of conductors has been blocked by the insulation coating, signal attenuation with increasing sensing range persists and may be explained by frequency-dependent conduction effect and/or radiation loss. Therefore, a separate longer TDR sensing cable is needed to extend the measurement range in the field. Within the measurement range (about 6 m), the bed location associated with scouring can be accurately estimated within 5% error. The coating abrasion does not affect the monitoring of maximum scour depth, which is most critical to bridge safety. However, the measured waveforms after more extensive coating abrasion and sediment refilling become more complicated and the effect of coating abrasion is quite noticeable in the differential waveform. To better monitor the subsequent scouring in the refilled sediments and remove the effect of abrasion effect on future monitoring results, a new data reduction approach was proposed that involves updating the reference waveform and calibration of propagation velocity in refilled sediments. This new approach was successfully validated by the full-scale experiment. The much-improved measurement sensitivity and SNR of the new TDR sensing waveguide together with the new data reduction approach enable more robust automation of data interpretation. Field implementation will be carried out in the near future.


Viral outbreaks of varying frequencies and severities have caused panic and havoc across the globe throughout history. Influenza, small pox, measles, and yellow fever reverberated for centuries, causing huge burden for economies. The twenty-first century witnessed the most pathogenic and contagious virus outbreaks of zoonotic origin including severe acute respiratory syndrome coronavirus (SARS-CoV), Ebola virus, Middle East respiratory syndrome coronavirus (MERS-CoV) and Nipah virus. Nipah is considered one of the world’s deadliest viruses with the heaviest mortality rates in some instances. It is known to cause encephalitis, with cases of acute respiratory distress turning fatal. Various factors contribute to the onset and spread of the virus. All through the infected zone, various strategies to tackle and enhance the surveillance and awareness with greater emphasis on personal hygiene has been formulated. This review discusses the recent outbreaks of Nipah virus in Malaysia, Bangladesh and India, the routes of transmission, prevention and control measures employed along with possible reasons behind the outbreaks, and the precautionary measures to be ensured by private–public undertakings to contain and ensure a lower incidence in the future. Nipah virus (NiV), a bat borne pathogen, that causes lethal encephalitis in humans has recently been reported from Malaysia, Bangladesh, Singapore and India ,2,3. It Outbreaks of various zoonotic viruses occur as a result of the influence of several factors including human-to-human contact and animal interaction with severe environmental changes . EcologiNiV is an enveloped pleomorphic virus belonging to the genus Henipavirus of the family Paramyxoviridae . The genAttachment and entry into the host cell is controlled by the F and G proteins spanning across the envelope . The G pFruit bats of the genus Pteropus (flying foxes) are the natural reservoirs for NiV ,6. They In Malaysia, humans contracted the disease through NiV-infected pigs, the intermediate hosts of the virus . SpillovAbattoir workers are often in contact with excretions and secretions such as the urine, saliva, pharyngeal and respiratory secretions of infected pigs or raw pig meat and other products contaminated with NiV  Figure A. As pigInvestigations in Bangladesh report that a few infected patients had consumed raw palm sap about 30 days prior to the disease onset, suggesting the contamination of palm sap with secretions of NiV-infected bats . During Outbreaks in Bangladesh and India  share epidemiologic similarities concerning human-to-human transmission of NiV with no intermediate hosts . The outNiV outbreaks have so far been reported in three countries: Malaysia, Bangladesh and India. Although there are surveillance studies proving the presence of antibodies from other nations including Cambodia , ThailanIt was in September 1998 when the first case of outbreak began among the farmers in the pig farming industry near the city of Ipoh in the state of Perak, Malaysia. The second outbreak occurred in the state of Negri Sembilan at the end of December 1998. During this period, a similar and third outbreak was reported in the nearby areas of Bukit Pelandok ,34. In tMeanwhile NiV had spread to Singapore in late February 1999, following the importation of infected pigs from Malaysia, where 11 abattoir workers contracted the disease with one case of death . ImmediaThe first outbreak was recorded in the district of Meherpur, Bangladesh in April 2001 with 13 diagnosed cases . Down thThe first outbreak in India was reported between January and February 2001 in the district of Siliguri, a leading commercial city of West Bengal. Because Siliguri borders Bangladesh and because of a failure of initial laboratory investigations to discover the causative agent, patient samples were retroactively tested for the NiV virus . The serThe third, recent, and most intense NiV outbreak occurred in the state of Kerala during May 2018, where 23 NiV positive patients were identified with a case-fatality rate of 91% ,44. The In 2019, a recurring incidence of NiV was reported where one patient tested positive for NiV at the Ernakulam district of Kerala. A farsighted approach by the Kerala state government helped to tackle the 2019 outbreak. Approximately 300 contact persons, who had contact with the infected patient, were closely monitored for any possible Nipah-like symptoms. The index patient was moved to a strict isolation facility and keenly monitored, while the contact cases were advised to stay indoors and there was immediate reporting in case of any possible symptoms. As a precaution, monoclonal antibodies for the treatment of NiV were arranged from Australia in order to restrain any possible sporadic outbreak. Moreover, a fast and accurate diagnosis was facilitated by setting up test facilities within regional medical institutions. The recovery of the index case and containing the viral spread brought in huge accolades to the health sector and to government interventions in containing NiV during 2019.During the Malaysian outbreak, the incubation period ranged from 4 days to 2 months, whereas in Bangladesh it was 10 days ,46. The Genomic sequencing have identified two strains of NiV: NiV-B and NiV-M. Genetic characterization of the two strains demonstrated that NiV-B has a genome size of 18,252 nucleotides which is longer than NiV-M by six nucleotides . Even thThe two NiV strains are responsible for the outbreaks in various geographical areas. Bangladesh and Indian outbreaks have reported the source of the virus to be NiV-B while the Malaysian outbreaks were reported to be from NiV-M . ClinicaAlthough NiV-B has been reported to cause repeated outbreaks, surprisingly, all in vitro and in vivo therapeutic research have utilized the NiV-M strain rather than the more prevalent NiV-B strain. Animal models of hamsters, ferrets and African green monkeys have been used to study the infection dynamics and disease patterns caused by both strains ,53,54,55in vivo African green monkeys and clinical presentation of NiV in humans may be attributed to the close relation of monkeys to humans in comparison to ferrets and hamsters.NiV-M and NiV-B studies with African green monkeys demonstrated a 50% mortality on NiV-M infection while all experimental subjects infected with NiV-B succumbed to death . AdditioEarly diagnosis is very critical for NiV infection as serious case fatalities are a hallmark of the disease. Various samples are collected from infected individuals and animals for diagnostic purposes. Specimens collected from humans include nasal swab, throat swab, urine, blood and cerebrospinal fluid (CSF) whereas lung, spleen, and kidneys from dead animals are used to diagnose and isolate NiV . DiagnosThe most preferred and extremely sensitive diagnostic method is PCR. The conserved segments of viral genome, N, M and P are often targeted for the reverse-transcription PCR (RT-PCR) and nested PCR analysis. Though expensive, real-time RT-PCR, because of its extreme sensitivity, is employed extensively for NiV detection/diagnosis. Sensitivity of these techniques can be compromised if the viral genome undergoes rapid mutations ,59.Next generation sequencing is an alternative method aiding in effective identification of viral strain, however the method is not frequently used in diagnosis and when considering expenses. Another safe method for detecting NiV is immunohistochemistry since it uses formalin-fixed tissue samples ,59. ELISRapid spread via nosocomial and zoonotic modes with an asymptomatic incubation period contribute to the potency of NiV outbreaks. Symptoms of NiV infection develop with instances of recurring mild fever progressing to a severe case of acute respiratory distress syndrome, acute encephalitis, altered sensorium and disorientation . NiV infRibavirin and Acyclovir are two drugs used during the earlier outbreaks of NiV in Malaysia and Singapore ,62,63. AHendra virus subunit vaccine, an approved veterinary vaccine for equines in Australia, and a monoclonal antibody vaccine (m102.4) targeting the NiV recombinant viral envelope protein have proven their efficacy in various animal models; the latter has been administered on compassionate grounds to critical NiV patients . Non-humAwareness among public and health care professionals towards neglected and similar diseases and a preparedness to contain any future outbreak by the medical and government authorities in regions with previous outbreak history should be ensured periodically. Studies towards understanding the bat environment, its susceptibility to being a carrier of NiV and its precise prevalence could help prevent the risk involved by human intervention into their habitat. Sampling and sero-surveillance for the NiV antibody and NiV with ELISA and PCR method in humans as well as bats will help to keep a check on the possibility of an outbreak in the prevalent regions . Outbreaks similar to Kerala could be prevented by minimizing the patient-to-caretaker/attendant exposure via bodily fluids and close contact. Food materials, mats and sheets, dresses and patient aid materials of all sorts should only be handled when wearing masks and gloves. Proper incineration of the patient aids, the gloves and masks worn by the caretaker/attendant should be ensured. To reduce contracting the disease and its nosocomial spread, medical practitioners should wear proper personal protective equipment (PPE) while consulting encephalitic patients demonstrating NiV symptoms and should be moved to isolation from public on confirmation. Incineration of the corpse are the best practice, although burial of the corpse of the infected are not warranted, deep burial to a depth of 10ft along with proper PPE and disinfection of the handlers and burial land was followed in Kerala for particular cases on religious grounds. Contact with tissues or body fluids of the corpse may transmit NiV to healthy people . TherefoProcurement and consumption of raw fruits and products under unhygienic conditions in areas of NiV prevalence should be strictly prohibited. Bat-bitten fruits consumed raw are assumed to be one among the various reasons behind the recent outbreak in Kerala, very similar to the consumption of raw date palm sap contaminated with bat excreta leading to periodic outbreaks in Bangladesh . Proper Control at its best is the proper identification of the index case and further isolation containing the outbreak. A similar approach was made during the 2019 incidence of NiV in Kerala, India. A thorough study on the susceptibility (risk) and possible mode of spread in various regions could shed more light into the control measures to be observed. In Malaysia, on NiV identification, Japanese encephalitis-suspected pig farms known to harbor the NiV virus were isolated and classified as priority area 1; farmers and pig handlers were evacuated and culling of pigs in masses were done to reduce a further spillover of NiV . A regisPersistent and periodic outbreaks have been reported from villages in Bangladesh from 2001. On identification of an outbreak cluster, villagers were made aware of the cause and were advocated against the raw consumption of the date palm sap. Consumption after boiling the molasses or the sap was advised along with a proper covering of the vessels used for sap collection . TowardsThough outbreaks have been reported in India coinciding with the first Bangladesh outbreak, in Siliguri and Nadia of West Bengal state, specific pathogens leading to the outbreak could not be identified. Misconception due to the prevalence of Japanese encephalitis in the region led to identification as an NiV outbreak. Kerala being naïve to NiV infections had no previous records of an acute encephalitic, severe respiratory distress syndrome. Similar to earlier outbreaks, the index cases were assumed to be infected with Japanese encephalitis and had been rationally diagnosed to be an NiV infection. Proper health measures with well-instructed protocols and high vigilant government support helped in systematically containing a highly lethal and sporadic nosocomial outbreak with very few victims. Regional administration and the state government with the support of the national government announced the scenario to be a national emergency situation. Proper awareness and strict protocols formed by the national health authorities to be observed towards handling the condition were publicized widely through printed media, public broadcasts and social media. High alerts were made in affected areas and public meetings, gatherings and the conduct of mass events were revoked to contain further spread through close aids. Strict measures against misleading messages were ensured. Records of the ill residents from the affected area were mandated towards proper surveillance of the outbreak. Rigorous sampling and testing for any new NiV infection incidences along with individuals having visited the affected area were monitored. All control measures were withdrawn upon proper assertion of zero incidence cases with double the incubation period. Towards reducing the disease burden, governments approached international agencies for the urgent supply of antivirals and vaccines under trials. A very similar approach towards controlling and containing an annual successive outbreak succeeded with a single infection and no casualties. Proper observation of the preventive measures with proper awareness among the public lead to the successful containment.Human population is on the rise and is always dependent on factors such as availability of resources, climate, trade and development. The presence of NiV has been reported in some of the most densely populous regions of the world, the South East Asia region (SEAR) . The regEconomy, poverty and population are defining factors of a nation’s strengths. A majority of countries in the SEAR are underdeveloped or classified as developing nations. Pandemics, epidemics and natural calamities agonize the lives of citizens in these nations. Although pig farming has been a major source of income for farmers, the NiV outbreak in Malaysia roots from pigs and pig sties . MassiveDeforestation in the SEA region is considered to be happening at an alarming rate due to gracing and farmland development, industrialization and urbanization. Deforestation has been linked to human interactions with Ebola-infected bats and the outbreak of Ebola in Africa . SimilarDeforestation accounts for the major loss in bat habitats. Pteropus bats are frugivorous and nectarivorous and are known to reside in tropical forests across continents. They help disperse seeds of native and agro-economically important plants and crops. They are the sole pollinators in many oceanic islands apart from restoring the genetic diversity in intervened forest lands. Fruit collection, deforestation and tourism have contributed heavily to habitat loss. Human intervention in various modes reduce bat foraging, propensity and feeding habits and could impact on their physiology and immunology. Potentiating the hypothetical ideas on viral dynamics among the bat populations and their offspring, horizontal in contrast to vertical transmission has been identified as a major mode of NiV spread among the bat reservoir population .Chiroptera and Pteropodidae are bats known to be old world fruit bats and are critical for seed dispersal and pollination in tropical and paleotropic forests in Asia, Africa, Australia and many tropical regions around the globe. They help improve the plant diversity among various forest vegetation along with pollination and the spread of rare plant species native to the region. Habitat loss has forced many populations of bats to remain in urbanized parts of the world, constantly foraging in farms and orchards in close vicinity of human settlements ,77.Factors leading to virus shedding include physiological and environmental bat stress, weakened immunity, reduced maternal immunity, infection in new born and roost population and interaction, ultimately reducing food availability . HypotheTransient epidemic waves are short pulses of pathogens re-establishing in roosts or new pathogens colonizing due to resident pathogen clear off among metapopulations of bats. Viruses of low virulence could infect and spread in and out of populations suppressed by the bats immunity and could re-emerge on immunity reduction along with other stressing factors leading to a short pulse or waves of infection . Bats peNipah viral outbreaks documented in various parts of the world pose a substantial threat to the global community. Economies of the affected countries have been struck severely by these outbreaks, grounding to a high rate of morbidity and mortality and eventually declining their economic stability. Preparedness and proper awareness among populations could benefit in controlling and containing outbreaks of any dimension. Enumerating the factors influencing the outbreak, surveys and studies to better understand the virus dynamics among inter species populations with preventive measures could curtail future outbreaks to a greater extent. Authorities and governments should practice and follow preventive and containment measures towards controlling any possible sporadic outbreak of similar nature.


HBB has been shown to improve health worker skills and neonatal outcomes, but studies have documented problems with skills retention and little evidence of effectiveness at large scale in routine practice. This study examined the effect of complementing provider training with clinical mentorship and quality improvement as outlined in the second edition HBB materials. This “system-oriented” approach was implemented in all public health facilities  B pre and post training and during mentorship visits up to 1 year afterward. The study team extracted health outcome data across the entirety of intervention districts and conducted interviews to gather perspectives of providers and managers on the approach.n = 772) of health workers in maternity units directly received mentorship. Of the mentees who received two or more visits (n = 456), 60 % demonstrated competence (received > 80% score on OSCE B) on the first mentorship visit, and 100% by the sixth. In a subset of 220 health workers followed for an average of 5 months after demonstrating competence, 98% maintained or improved their score. Three of the tracked neonatal health outcomes improved across the ten districts and the fourth just missed statistical significance: neonatal admissions due to asphyxia (37% reduction); fresh stillbirths (27% reduction); neonatal deaths due to asphyxia (13% reduction); and death within 30 min of birth . Health workers expressed satisfaction with the clinical mentorship approach, noting improvements in confidence, patient flow within the maternity, and data use for decision-making.Nearly 40 % (Framing management of birth asphyxia within a larger quality improvement approach appears to contribute to success at scale. Clinical mentorship emerged as a critical element. The specific effect of individual components of the approach on provider skills and health outcomes requires further investigation. Globally, 24% of newborn deaths are due to birth asphyxia , which cRecognizing the potential of HBB to improve outcomes related to birth asphyxia, the Rwanda Ministry of Health (MOH) conducted a national scale-up of HBB training in 2011 by integrating it into the Essential Newborn Care (ENC) in-service training module and implementing a stand-alone one-time in-service cascade training of health providers attending births . HoweverOn-the-job training has been shown to be more effective for acquiring skills and improving performance compared to learning in traditional classroom settings . ClinicaAt the request of the MOH, the United States Agency for International Development (USAID)-funded Maternal and Child Survival Program (MCSP) co-designed a practice improvement approach and assisted the MOH to implement it in a phased manner across ten of the country’s 30 districts. The MOH chose these ten districts based on their lower than average maternal and newborn health indicators and lack of other partner support. All twelve public hospitals and 160 health centers in the ten districts were included in two phases of program implementation. In the first phase (January – December 2016), four districts received all components of the practice improvement approach while the other six received only the mentorship component. In the second phase (January 2017– June 2018) all ten districts received all components of the approach. In Rwanda, all health facilities provide vaginal delivery and assisted delivery services, with additional sick newborn care and cesarean section services available at the hospital level.The practice improvement approach involved initial in-service health worker training using a low dose high frequency (LDHF) method which is described elsewhere ; ongoingSeventy-three providers from the 12 district hospitals in the ten districts were selected as potential mentors, because they were already supervisors or they had scored well on an initial assessment of clinical skills for newborn care. They were given an initial three-day off-site orientation to the mentorship activity that included training in mentoring skills and refresher training in HBB. Ensuring the mentors were proficient clinically in training skills consisted of an additional five-day refresher training of comprehensive newborn skills to select the candidates that showed the most promise to be successful mentors. The focus of the 5-day refresher training was to both improve clinical skills and also to improve training/mentoring skills. There was hands- on training at an off-site non-clinical location. Sixty-eight of the participants qualified as mentors in the subsequent post-test.The selected mentors initially conducted LDHF in-service training with providers in four districts starting in January 2016  and expanded to six additional districts in January 2017 . Due to time and program resources, each public health facility selected two health providers (mentees) who attend births to receive the training. The mentors conducted LDHF in-service training over three sessions of 2 days each, spaced over a 3 week period, with one session per week. For each session, the first day was devoted to theory and the second focused on simulation with anatomical models. The same curriculum used to train mentors was employed. Participants completed pre- and post-tests on knowledge and skills.District-based mentors visited each health facility at least once a quarter. During each visit, the mentor focused on the two mentees who had or would receive LDHF using an observation checklist to assess progress in skills through observation of simulated resuscitation using a NeoNatalie anatomical model. The mentors also reviewed organization of services and observed other components of facility readiness. In cases where the mentees were not working or could not be located during the day of the mentorship visit, mentors would invite other additional mentees to participate in the mentorship visit. The mentees were also given materials and encouraged to conduct peer-to-peer mentorship activities in between visits from offsite mentors. Sixty-two (8%) of providers received clinical mentorship only without participating in LDHF trainings. Figure At the start of activities, all facilities were provided with newborn resuscitation equipment, both for clinical activities and for peer practice and mentorship. As part of LDHF training cascade, mentors and mentees were trained on the tenets of the quality improvement approach and given tools for its implementation. The materials were adapted from pre-existing Ministry of Health tools and aligned for the context of the program intervention. One of the main tools targeted the use of the birth audit asphyxia tools. During clinical mentorship visits, mentors then helped mentees identify gaps in facility and health provider readiness to provide quality newborn services. They discussed the trends in key indicators included in the routine information system with mentees, the facility in-charge, and the quality improvement (QI) committee. Existing QI committees at health centers and hospitals received ongoing coaching from MCSP staff on their regular review of data and formulation of quality improvement action plans. The action plan included quality improvement activities that were formulated to respond to the gaps identified. A report that included both action plans and actions that had been taken since the previous QI committee meeting was then shared with the facility in-charge.After 6 months of implementation, with the support of MCSP, the MOH convened semi-annual multi-district learning workshops. Participants included health providers, mentors, and hospital managers from across the districts included in the practice improvement activities, along with representatives from other donor and partner organizations. During this activity, participants shared the challenges they faced and the actions they had taken for practice improvement as well as lessons learned for making mentorship more effective and feasible. The meetings also provided an opportunity for mentors to improve their mentorship skills through hearing about the experiences of their associates.The study used a mixed methods before-after design to assess changes in selected outputs and outcomes, according to the theory of change. All health providers who received mentorship with MCSP support and all public facilities in the ten implementation districts were included in the assessment.Baseline October 2015) and final (May 2018) assessments were conducted for facility readiness to provide newborn services using a tool based on the Service Availability and Readiness Assessment (SARA)  and Serv015 and fInput indicators (numbers and percentages of providers trained and mentored) and activity indicators (pre and post training assessments of knowledge and skills) were collected by project staff, the latter using a standardized checklist for essential newborn care and newborn resuscitation. The MOH agreed on a mentorship checklist which was applied during mentorship visits. This checklist was adapted from the pre/post-test training assessment tool and was based on the standard HBB OSCE B materials . All menData on clinical practices and outcomes relevant to the theory of change were obtained from service statistics routinely reported in the Rwanda health management information system on a monthly basis. The indicators analyzed were the percent of newborns not breathing at birth who were successfully resuscitated, the number of asphyxia admissions to Neonatal Intensive Care for asphyxia, deaths due to asphyxia, deaths within 30 min of birth, and fresh stillbirths. These variables were included because they are outcomes that the study team expected to see improve with the implementation of a practice improvement intervention, as depicted in the theory of change Fig. . The indKey informant in-depth interviews with facility managers, mentors and mentees on the practice improvement approach were conducted at the end of the practice improvement activities at the end of the project. Transcripts of the interviews were imported into Atlas.ti for analysis. A list of codes was developed in advance of the interviews, and during analysis additional codes were developed. Participant quotes and general responses were linked to codes to summarize the main themes.The assessment protocol was reviewed and given a waiver by the Rwanda National Ethics Committee. The protocol was also determined to be non-human subjects research by Johns Hopkins University School of Public Health Institutional Review Board, as it was deemed a quality improvement activity. Ethical guidelines applicable to Human Subjects Research were nonetheless followed during data collection. Written informed consent was obtained from all qualitative participants.Table At baseline in 2015, 35% of health centers and 67% of hospitals had newborn resuscitation equipment (bag and mask) and at endline in 2018, 98% of health centers and 100% of hospitals had at least one bag and mask (newborn size) at the facility. During implementation of the practice improvement approach 993 (51%) of the estimated 1960 eligibleall providers, whether they had directly received offsite mentorship or not, as all providers at least received peer-to-peer mentorship.The average pre-test skills and knowledge score, conducted before the initial LDHF training session for providers, was 44% and the average post-test score was 88%. The clinical knowledge and skills assessment applied at the end of the project included 64 providers randomly selected from the 172 health facilities in the initiative. These providers scored an average of 85% on HBB skills and knowledge using the same assessment tool used during mentorship. It should be noted that the providers for the endline assessment were selected among Figure Figure p = 0.06).Three of the four relevant facility level newborn health outcomes tracked in the HMIS improved between 2015 and 2018, and the improvement in the fourth indicator just missed statistical significance  in the intervention districts. Moreover, nationwide in 2013, 39% of neonatal deaths were due to asphyxia, making it the leading cause of newborn death in Rwanda, whereas by 2018 the proportion of newborn deaths due to asphyxia decreased to 26% nationwide .Few other studies evaluating HBB have been done at as large a scale (33% of the population of Rwanda) and under as routine conditions , but we As posited by the recently published second edition of HBB materials, framing HBB in a larger quality improvement context appears to be critical to its success at scale. The previous scale up of HBB in 2011 in Rwanda was mainly focused on health provider training, but newborn deaths due to birth asphyxia remained high afterwards until initiatives started which included improvements in basic equipment, data use, and management/government mechanisms.Although the assessment was not designed to show the separate effects of each of the components of the practice improvement approach, there was some evidence that clinical mentorship was the critical component. There was no significant difference across districts related to the sequencing of mentorship with other components of the approach, and unexpectedly we found that the improvements in outcome indicators in the six Phase 2 districts started immediately in 2016 even when they had only received the mentorship component. Further, though 456 of the estimated 1960 providers in the maternity units received two or more mentorship visits, improvements in provider practice and newborn outcomes were seen across all maternity providers in the facilities. Although the mentors experienced difficulties because those originally trained were not always available for ongoing mentorship, their occasional absence in the facility allowed them to mentor other providers. While this happened as an adaptation of the initially planned rollout approach, it actually had the effect of benefitting a larger number of providers with mentorship and practice sessions. Peer to peer mentorship implemented between on-site mentorship visits may be another important factor in these successes. The improving percentage of mentees who scored 80% after each mentoring visit and the improvement or maintenance of skills among providers previously deemed competent also lends credence to the importance of mentoring for retention of skills among the entire group of health workers at a facility. In the interviews, facility staff identified mentorship as the component that they felt most helped them implement the practice improvements, including strengthening the functioning of their team, strengthening referral networks from health centers to hospitals, and motivating them to feel that achieving practice improvement was possible. This finding is consistent with the World Health Organization’s Quality of Care Framework guidance, which states that a positive attitude of a health worker can influence appropriate use of effective clinical and non-clinical interventions [Assuring the availability of the necessary equipment to perform resuscitation is critical to the success of improved provider skills and newborn outcomes. This was noted by MOH staff as an important element of continued advances in quality of care at the facility level.Activities that improved continuous learning above the level of the individual provider also appeared to be crucial. Mentorship efforts included review of data and quality improvement plans included efforts to improve data quality. This created a positive feedback loop, whereby the established facility quality committees and district managers began to trust and therefore use their data more. This was clear in the in-depth interviews with providers and managers. We feel that the semi-annual multi-district learning meetings were also critical, as it reinforced the mentorship and learning at the facility level. Mentors and their leaders noted that they thought the experience sharing at these meetings helped improve their practice and increase their motivation.This assessment had a number of limitations. First and foremost, as already stated, we were not able to compare results in the ten intervention districts to the other 20 non-intervened districts because of the differential intensity of data quality improvement efforts. Also, key informants may have been reluctant to give negative information about the program and its interventions. The project worked to overcome this issue by using external interviewers. While it took providers a variable number of mentorship visits to be deemed competent, the project was not able to investigate the underlying reasons for these variations. Future research could analyze these reasons to inform more effective scale up of the intervention. Finally, although the study team reviewed contextual information, the effects of other factors within the health system on observed improvements in provider skill and newborn outcomes could not be systematically controlled for.This assessment gives plausible evidence that a system-oriented practice improvement approach was associated with improved health worker knowledge and skills; improved clinical practices; and improvements in newborn health outcomes. However, the study cannot demonstrate the separate effects of each of the components of the approach. This gives one of the first demonstrations of how HBB might function effectively at scale under relatively routine conditions. In order for the approach to be institutionalized, the central and district levels will need to include the modest incremental costs of mentorship in their annual plans, especially to promote regular peer-to-peer mentorship.Additional file 1:Supplementary Material 1. Final mentorship data level 1. Mentorship scores of mentees over the course of mentorship visits, throughout project implementation.Additional file 2: Supplementary Material 2. Final level 2 and 3 data. Changes over time in the % of successfully resuscitated newborns. Changes over time in newborn health outcomes.


We study the Voronoi diagrams of a finite set of Cauchy distributions and their dual complexes from the viewpoint of information geometry by considering the Fisher-Rao distance, the Kullback-Leibler divergence, the chi square divergence, and a flat divergence derived from Tsallis entropy related to the conformal flattening of the Fisher-Rao geometry. We prove that the Voronoi diagrams of the Fisher-Rao distance, the chi square divergence, and the Kullback-Leibler divergences all coincide with a hyperbolic Voronoi diagram on the corresponding Cauchy location-scale parameters, and that the dual Cauchy hyperbolic Delaunay complexes are Fisher orthogonal to the Cauchy hyperbolic Voronoi diagrams. The dual Voronoi diagrams with respect to the dual flat divergences amount to dual Bregman Voronoi diagrams, and their dual complexes are regular triangulations. The primal Bregman Voronoi diagram is the Euclidean Voronoi diagram and the dual Bregman Voronoi diagram coincides with the Cauchy hyperbolic Voronoi diagram. In addition, we prove that the square root of the Kullback-Leibler divergence between Cauchy distributions yields a metric distance which is Hilbertian for the Cauchy scale families.


The pandemic of Coronavirus disease 19 is not abating since the outbreak began in December 2019. Africa is currently experiencing a surge after an initial low incidence and nosocomial infections could be contributing to this. A dominant factor responsible for this is a weak healthcare system because of many years of neglect due to abysmal budgetary allocation to the sector. The testing capacity for COVID-19 diagnosis in Africa is grossly inadequate coupled with a severe shortage of personal protective equipment and inadequate infectious diseases expert. These factors exposed the frontline health workers and patients to the hazard of nosocomial infection with the attendants´ morbidity and mortality. Deliberate efforts need to be made toward reducing nosocomial COVID-19 infection. The Coronavirus disease 19 (COVID-19) pandemic, caused by SARS-CoV-2 virus, shows no sign of abating since the outbreak was first reported in Wuhan City of China in December 2019. There are now about 13 million confirmed cases worldwide, which has resulted in 574,464 deaths as of July 15, 2020. On February 14, 2020, Africa recorded the first case in Egypt and currently has about 600,000 cases, with over 13,000 deaths [In May 2020, there was a report of nosocomial SARS-CoV-2 infections affecting 80 members of staff and 39 patients in a hospital in South Africa . SpecialFurthermore, the inadequate provision of personal protective equipment (PPE) is another factor that could influence nosocomial COVID-19, especially among the health workforce that is in the frontline. Africa is one of the worst-hit with the global shortage of PPE following the pandemic. Most countries in Africa depend on importation, including donations from international organizations and philanthropists to meet their PPE need. This has led to the rationing of the limited number of available PPE with consequent inadequate protection of frontline health workers resulting in the occurrence of high rates of infection among healthcare personnel. The appropriate and rational use of limited PPE by healthcare workers is also another challenge as many are not familiar with the process of donning and doffing of PPE which could be the source of nosocomial infection. This is further compounded by the possibility of infection being transmitted in the community when infected hospital personnel carry the pathogen to their family members, neighbor, and guests. Unchecked morbidity and mortality among healthcare personnel will result in increasing lost man-hours and a reduction in the healthcare workforce. For political reasons, it may be difficult to obtain accurate data on COVID-19 infection among healthcare workers which further impair the ability to appropriately manage the situation. There have been reports of declaration of industrial action by healthcare worker unions to protest insufficient PPE in hospitals and other factors that would have motivated the healthcare workers in the line of duties such as life insurance and other incentives.The inadequate number of infectious disease experts, including those that specialize in infection control in many parts of Africa, is a cause for concern as it relates to SARS-CoV-2 nosocomial transmission. Even though many infectious diseases including those with the potential to cause public health emergency of international concern (PHEIC) such as Lassa fever and Ebola viral disease with prior large-scale outbreaks, are prevalent in Africa. The investment and development of specialists in every aspect of infectious diseases have been grossly deficient. This includes experts in molecular biology and infectious disease immunology needed to conduct researches that address outstanding questions in infectious disease transmission and host response to infectious diseases including COVID-19 in the African setting. Hospital infection prevention and control experts, among others, are also desperately needed. Deliberate funding and investment within Africa will be required to address this . There i


Successful surgical treatment of patients with focal drug-resistant epilepsy remains challenging, especially in cases for which it is difficult to define the area of cortex from which seizures originate, the seizure onset zone (SOZ). Various diagnostic methods are needed to select surgical candidates and determine the extent of resection. Interictal magnetoencephalography (MEG) with source imaging has proven to be useful for presurgical evaluation, but the use of ictal MEG data remains limited. The purpose of the present study was to determine whether pre-ictal variations of spectral properties of neural activity from ictal MEG recordings are predictive of SOZ location.We performed a 4 h overnight MEG recording in an 8-year-old child with drug-resistant focal epilepsy of suspected right fronto-temporal origin and captured one ~45-s seizure. The patient underwent a right temporal resection from the anterior temporal neocortex and amygdala to the mid-posterior temporal neocortex, sparing the hippocampus proper. She remains seizure-free 21 months postoperatively. The histopathological assessment confirmed frank focal cortical dysplasia (FCD) type IIa in the MEG-defined SOZ, which was based on source imaging of averaged ictal spikes at seizure onset. We investigated temporal changes  together with spatial differences (SOZ vs. control regions) in spectral parameters of background brain activity, namely the aperiodic broadband offset and slope, and assessed how they confounded the interpretation of apparent variations of signal power in typical electrophysiological bands. Our data show that the SOZ was associated with a higher aperiodic offset and exponent during the seizure compared to control regions. Both parameters increased in all regions from 2 min before the seizure onwards. Regions anatomically closer to the SOZ also expressed higher values compared to contralateral regions, potentially indicating ictal spread. We also show that narrow-band power changes were caused by these fluctuations in the aperiodic component of ongoing brain activity. Our results indicate that the broadband aperiodic component of ongoing brain activity cannot be reduced to background noise of no physiological interest, and rather may be indicative of the neuropathophysiology of the SOZ. We believe these findings will inspire future studies of ictal MEG cases and confirm their significance. Epilepsy is one of the most common and debilitating neurological disorders in children  is now recognized as a valuable asset in the armamentarium of epileptologists and researchers. It allows for time-resolved source imaging of interictal spike waveforms and slow/fast oscillatory components of brain activity  estimates of electrophysiological brain signals typically reveal narrowband peaks that correspond to oscillatory signal components, superimposed on a broadband aperiodic profile traditionally discarded as background or brain “noise” . The profile of the aperiodic spectral component can be approximated from the parametric modeling of the PSD estimate derived from empirical signals. The two scalar parameters of the related parametric model are the spectral offset (yoffset) and the slope, represented by the exponent , seizures were suspected to localize to the right fronto-temporal cortex . At the MEG was acquired at the Montreal Neurological Institute  using a 275-channel whole-head MEG system . In addition to MEG and EEG, Electrooculography (EOG) and electrocardiography (ECG) were simultaneously recorded during acquisition for eye blink and cardiac artifact detection. We captured a single ~45-s seizure during the 4-h overnight MEG sleep recording. MEG seizure identification was done according to the current clinical standards.1 and nSOZ2), which contained rare dysmorphic neurons (but not frank FCD) and one ROI in the contralateral hemisphere (nSOZ3), with homologous location and size to the SOZ’s ROI, but presumably devoid of epileptogenic pathology . We performed data analysis with BrainstormWe derived the PSD using Welch’s method Welch,  as impleFor PSD analyses, we extracted the mean power in the delta (1–4 Hz), theta (5–7 Hz), alpha (8–12 Hz), beta (15–29 Hz), and low-gamma (30–59 Hz) frequency bands for both the raw power spectrum and the power spectrum after removal of the aperiodic fit. Z-scores of the resulting values were computed at every time point from the mean and standard deviation of all sources in the four ROIs for the same time windows as for the aperiodic spectral component parameters.Preprocessing of the data and removal of bad segments resulted in ~9 min of data before seizure onset, one 5-s epoch moments before seizure onset, one 5-s ictal epoch, and a post-ictal epoch shortly after seizure resolution. The interictal recording contained one interictal spike and the patient was in sleep stage N3 for most of the recording and sleep stage N2 from ~1 min before seizure onset. The data immediately following the ictal epoch was not analyzable due to movement artifact.t = 0). From ~100 s onwards, both values increased, reaching their peak during the seizure for all ROIs.1 and nSOZ3. Several minutes before seizure onset, both the offset and exponent were lower in the nSOZ1 compared to the SOZ. From ~100 s before seizure onset, these differences started to reduce. We observed the opposite phenomenon in the contralateral control ROI, with no clear differences with the SOZ long before the seizure and an increasing difference closer to seizure onset. We did not observe clear differences of both parameter values over the entire length of the recording between the SOZ and nSOZ2, both located in the resected brain region.To clearly identify relative differences between the ROIs, z-scores were also computed across all ROIs at each time point , which r3  increased, while they became smaller between the SOZ and nSOZ1. Further, there was no clear difference between SOZ and nSOZ2 over the entire recording. We observed similar patterns with the delta band power of the original PSD in right-lateralized ROIs . We interpret these observations as possibly being related to rapid ictal spread to contiguous regions surrounding the SOZ (nSOZ1 and nSOZ2), which would not have impacted the contralateral hemisphere ROI (nSOZ3). However, it must be kept in mind that the influence of lower frequency dynamics, which is represented in the aperiodic component is more widespread and can therefore influence contiguous areas.To our knowledge, no prior studies have examined temporal changes and spatial differences in the aperiodic power spectrum components of ictal MEG data. We found that both the offset and exponent parameters of the aperiodic fit increased shortly before the seizure and reached their highest values mid-seizure. This increase was observed in both the SOZ and control ROIs. However, values were relatively higher in the SOZ, especially as compared to the contralateral ROI , may reflect increased population spiking activity  and temporal changes that consisted of narrow-band components disappeared after 1/f compensation. The only difference that remained was between the SOZ and the contralateral ROI in the delta and theta frequency bands. Oscillatory signal power was higher in the SOZ in the theta frequency band and vice versa for the delta band, although less pronounced.These results show promise for SOZ delineation without the need for the definition of discrete events related to seizure onset and frequency bands of interest by an expert.Some limitations include the limited amount of peri-ictal recording that could be analyzed due to extensive head movement artifacts that occurred shortly following electrographic seizure onset. Inter-ictal and pre-ictal data segments were substantially longer, providing more data samples and potentially more robust outcomes. This case was meant to illustrate novel applications of methods to more precisely characterize the spectral components of ictal MEG recordings. These results will need to be reproduced and further investigated in larger case series and with longer ictal recordings to better define the range of observable dynamic changes that can occur in the course of seizures.In this study, we provide early evidence suggesting that the broadband aperiodic component of the PSD contains useful neurophysiological information rather than just “background brain noise” and could contribute to helping define the SOZ. Studies with longer ictal MEG recordings will be needed to confirm and expand on the present findings. Overall, our data suggest that this novel approach holds promise for aiding in localizing the SOZ in children with focal epilepsy.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Research Ethics Board of the Montreal University Health Centre. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin. Written informed consent was obtained from the minor(s)’ legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.SH conducted the analysis and interpretation of the data, drafted and revised the manuscript for intellectual content. JM and RD contributed to the design and conceptualization of the study, a major role in the acquisition of data, analysis, interpretation of the data, and revised the manuscript for intellectual content. ES-T helped with marking the seizure and interpreting the EEG. SA analyzed the pathology specimens used for confirmation of the seizure onset zone. SB contributed to the design and conceptualization of the study, analysis, interpretation of the data and revised the manuscript for intellectual content. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer GP declared a shared affiliation with the authors to the handling editor at time of review.


An 11-year-old girl presented with agenesis of the maxillary lateral incisors. Orthodontic treatment was performed to close the midline diastema and create adequate space between the central incisors and canines to replace the missing maxillary lateral incisors on both sides. Two-piece implants were placed, and shoulderless abutments were prepared following the “biologically oriented preparation technique” (BOPT) protocol. The soft tissues were allowed to heal directly on the prosthetic emergence profile of the interim crown restorations after implant exposure. Two months later, the gingival tissue adapted to the prosthetic components in a specular manner. No complications were noted at 24 months. The BOPT protocol, originally described for natural teeth, may be applied to dental implants with shoulderless abutments. Implant abutment morphology influences marginal bone loss and the biologic width of the peri-implant mucosa –5. SouzaAn 11-year-old girl was referred to the Department of Dentistry at the San Raffaele Hospital in Milan, Italy. The patient expressed dissatisfaction with smile, due to misaligned teeth and spaces between the anterior teeth. Radiographic examination revealed the agenesis of the maxillary lateral incisors . A multiAfter orthodontic treatment, the patient wore a removable retainer to maintain the space gained for replacement of the lateral incisors with implants . The maxImmediate loading was avoided, and the patient wore a removable retainer during osseointegration of the implant  . Four mThe impression copings  were connected to the implants, and an impression was made with vinyl polysiloxane material , using a perforated custom tray. Two implant analogs were connected to the copings inside the impression, and the cast was immediately poured using the type 4 dental stone. Two modifiable cylindrical shoulderless implant abutments  were connected to the analogs and adjusted (prepared without a finish line) directly on the cast to achieve the appropriate inclination for placement of the temporary crowns. The shoulderless abutments were prepared in the same manner as the natural abutment teeth in the BOPT protocol –14 Figu, and theAfter the interim restoration placement, the patient returned to the dental department periodically for 2 months during the healing process, which was documented using photographs. Four days after interim restoration placement, the keratinized tissue appeared inflamed and was in a more coronal position  than befAt the following clinical visit, the abutments and zirconia frameworks were evaluated, and new interocclusal wax in maximal intercuspation was made to check the occlusion again. The accuracy of the framework's fit was confirmed clinically with dual-cured paste . A framework transfer impression with polysiloxane material  was made, to capture the framework-soft tissue relationship. The impression was sent to the dental technician with a request that the final restorations be shaped in a manner that allowed the emergence profile to sustain the mature soft tissues. The final restorations were clinically checked and sent for the final glaze. At the final appointment, the finished crowns were cemented with temporary cement , and the patient expressed satisfaction with the esthetics.At the 24-month follow-up visit, no biological or technical complications were noted, and the gingiva appeared thick, pink, healthy, and completely adapted to the definitive restoration . The papThe healthy coexistence of dental restorations and the peri-implant structures is essential and is the primary goal of a prosthodontist. The peri-implant tissues should not bleed on probing, and a tight seal should exist between the peri-implant mucosa and the transmucosal component . The abuThe BOPT approach used for implant rehabilitation in this study demonstrated a good clinical outcome in the esthetic zone at the 24-month follow-up, with healthy peri-implant mucosa, pink and stippled gingiva, and interdental spaces completely filled by the interdental papillae. The interim crowns were not positioned according to the healed soft tissue, but the soft tissue was allowed to adapt itself against the prosthetic components during the healing stage. The position of the crown was predetermined and was based on the gingival tissue thickness and biologic width dimension. A limitation is apparent in cases in which the gingival thickness is not sufficient to ensure adequate space for the biologic width. Moreover, the technique is time consuming because the interim abutments must be adjusted by the dentist during the second stage surgery, which requires ample experience. The technique has not been backed by scientific literature, and long-term clinical studies are still required to understand the role of the abutment design in peri-implant mucosa formation and to better evaluate, both clinically and scientifically, the outcomes of shoulderless implant abutments.