Mutations in nucleotide metabolism genes bypass proteasome defects in png-1/NGLY1-deficient Caenorhabditis elegans.

The conserved SKN-1A/Nrf1 transcription factor regulates the expression of proteasome subunit genes and is essential for maintenance of adequate proteasome function in animal development, aging, and stress responses. Unusual among transcription factors, SKN-1A/Nrf1 is a glycoprotein synthesized in the endoplasmic reticulum (ER). N-glycosylated SKN-1A/Nrf1 exits the ER and is deglycosylated in the cytosol by the PNG-1/NGLY1 peptide:N-glycanase. Deglycosylation edits the protein sequence of SKN-1A/Nrf1 by converting N-glycosylated asparagine residues to aspartate, which is necessary for SKN-1A/Nrf1 transcriptional activation of proteasome subunit genes. Homozygous loss-of-function mutations in the peptide:N-glycanase (NGLY1) gene cause NGLY1 deficiency, a congenital disorder of deglycosylation. There are no effective treatments for NGLY1 deficiency. Since SKN-1A/Nrf1 is a major client of NGLY1, the resulting proteasome deficit contributes to NGLY1 disease. We sought to identify targets for mitigation of proteasome dysfunction in NGLY1 deficiency that might indicate new avenues for treatment. We isolated mutations that suppress the sensitivity to proteasome inhibitors caused by inactivation of the NGLY1 ortholog PNG-1 in Caenorhabditis elegans. We identified multiple suppressor mutations affecting 3 conserved genes: rsks-1, tald-1, and ent-4. We show that the suppressors act through a SKN-1/Nrf-independent mechanism and confer proteostasis benefits consistent with amelioration of proteasome dysfunction. ent-4 encodes an intestinal nucleoside/nucleotide transporter, and we show that restriction of nucleotide availability is beneficial, whereas a nucleotide-rich diet exacerbates proteasome dysfunction in PNG-1/NGLY1-deficient C. elegans. Our findings suggest that dietary or pharmacological interventions altering nucleotide availability have the potential to mitigate proteasome insufficiency in NGLY1 deficiency and other diseases associated with proteasome dysfunction.

Nasopalatine Duct Cyst Treated by Transnasal Endoscopic Marsupialization: A Case Report.

Introduction: Nasopalatine duct cyst (NDC) is the most prevalent non-odontogenic cyst emerging from the epithelial remnants in the maxillary incisive canal. A sublabial or transpalatal approach is performed to enucleate NDC completely. More recently, transnasal endoscopic marsupialization has been used gradually. Case Presentation: A 24-year-old male patient with a large nasopalatine duct cyst with a diameter of 51 mm was managed by transnasal endoscopic marsupialization under general anesthesia. The presentation involves painless swelling around the left side of the anterior maxilla and bulging of the hard palate. No postoperative complications were observed after a 3-month follow-up. Transnasal endoscopic marsupialization is a minimally invasive surgery for large NDC. Clinical discussion: Approximately 1% of the population has a nasopalatine duct cyst. Surgical treatment was carried out under general anesthesia; the cyst was dissected and removed using a typically transnasal endoscopic marsupialization technique. Conclusion: The cause of the NDC is unclear. Simple surgical resection and clinical and radiological control are recommended to ensure the case is resolved correctly.

Rare case in Somalia: Fahr's syndrome.

Introduction and importance: Fahr's syndrome is primarily familial, autosomal dominant, and genetically diverse. Basal ganglia calcification that is bilaterally symmetrical is a hallmark of this illness. Although the specific origins of this illness are unknown, it may be brought on by problems with calcium metabolism, infections, toxins, hereditary factors, hypoparathyroidism, and pseudohypoparathyroidism. The prevalence of this syndrome is less than 0.5%. Case presentation: An 11-year-old female comes to the Emergency Department with her parents complaining of high-grade fever and convulsions for 1 week. Convulsion, which is a generalized tonic-clonic seizure, duration was ~5 min and associated with urinary incontinence and biting tongue. On examination, the patient was confused and irritable. Vital signs were normal; there is weakness in the right arm and right leg, associated with irregular movement. There was alternation in her level of consciousness, slurring of speech, and psychiatric symptoms. Another aspect of the neurological examination and systems was normal, and there was no meningeal irritation. Clinical discussion: The pathogenesis of Fahr's syndrome is not completely known. The calcification is caused by flaws in the transport of radioactive particles and tissue damage caused by free radicals. Bilateral calcification found on a computed tomography (CT) scan of the brain, autosomal dominant inheritance, the absence of any infection, drugs, or toxins, the absence of mitochondrial dysfunction, and the presence of progressive neurological dysfunction is the clinical criteria for diagnosing Fahr's syndrome. Conclusion: Basal ganglia calcification that is bilaterally symmetrical is a hallmark of Fahr's syndrome. CT scans are the gold standard for conclusively diagnosing Fahr's syndrome.

Reliability-based analysis of horizontal curve design by evaluating the impact of vehicle automation on roadway departure crashes and safety performance.

Roadway departure (RwD) crashes are significant safety concerns, especially at horizontal curves. The design of these curves plays a crucial role in mitigating RwD crashes. Thus, a thorough understanding of the interaction between driver behavior, vehicle automation, and geometric design is vital. Substantive safety, which emphasizes the inherent safety in a road's design and function, serves as the foundation of our approach. Building on this, the study employs a safe system approach to investigate the performance of horizontal curves under both non-automated and partially automated conditions, using a reliability-based analysis focusing on Stopping Sight Distance as the primary driver demand. Factors including Perception-Brake Time and Take-Over Time for automated vehicles are examined. The analysis covers horizontal curves, characterized by their geometric design and crash data. Our findings highlight a shift in the performance of horizontal curves under automation, emphasizing the need to consider automation in roadway design within the safe system approach. This study demonstrates how a reliability-based analysis can guide designers in making informed decisions regarding the geometric design of horizontal curves to reduce RwD crashes. To enhance transportation safety in the era of increasing automation, ongoing exploration of the relationships between driver behavior, automation, and road design is indispensable.

Practical Guidelines for Standardised Resolution of Important Protocol Deviations in Clinical Trials Conducted in Sub-Saharan Africa.

A clinical trial is any research on human subjects that involves an investigational medicinal product or device. Investigational medicinal products include unlicensed drugs or drugs used outside the product license (e.g. for a new indication) (ICH-GCP). As per the internationally accepted ICH-GCP guidelines, clinical trials should be conducted strictly per the approved protocol. However, during the lifecycle of a trial, protocol deviations may occur. Under ICH efficacy guidelines, protocol deviations are divided into non-important (minor) or important (major), and the latter can jeopardise the participant's rights, safety or the quality of data generated by the study. Existing guidelines on protocol deviation management do not detail or standardise actions to be taken for participants, investigational products, data or samples as part of a holistic management of important protocol deviations. Herein, we propose guidelines to address the current literature gap and promote the standardisation of actions to address important protocol deviations in clinical trials. The advised actions should complement the existing local institutional review board and national regulatory authority requirements.

Malaria in adults after the start of Covid-19 pandemic: an analysis of admission trends, demographics, and outcomes in a tertiary hospital in the Gambia.

BACKGROUND: Malaria remains a major public health concern in The Gambia. The study assessed the trend of malaria admissions and outcome of adult patients admitted after the start of the COVID-19 pandemic in a tertiary hospital in The Gambia. METHODS: This was a retrospective hospital-based study and data was collected from the 18th October 2020 to 28th February 2023. Demographic data, clinical features, investigations, treatment, and outcomes were recorded. RESULTS: A total of 499 malaria cases were admitted to the hospital over the 29 months of the study period. Data from 320 (67.2% of the total cases) adult patients admitted into the internal medicine department were analysed. The median age was 22 years, range (15-90) and 189 (59.1%) cases were youth with a youth (15-24 years) to older adult (> 24 years) ratio of 1.4:1. The majority of the patients were male 199 (62.2) with a male to female ratio of 1.6:1. The total number of malaria cases admitted into the internal medicine department increased from 103 cases in 2021 to 182 cases in 2022and admission peaked in November in both years. The total number of admitted malaria cases during the peak of the malaria season also increased from 92 patients between September 2021 and December 2021 to 132 patients from September 2022 to December 2022.There was also an increase in both severe and uncomplicated malaria during the same period. The total mortality was 31 (9.7%) and the rate was similar in 2021 9 (8.7%) and 2022 15 (8.4%). Patients with impaired consciousness were more likely to die when compared to those without impaired consciousness [19 (23.6%) vs 12 (5%), p ≤ 0.001]. Patients with acute kidney injury were also more likely to die when compared with those without acute kidney injury [10 (20.4%) vs 15 (7.7%), p = 0.009]. CONCLUSION: The findings show an emerging and consistent trend of malaria admissions and the outcome in the youth and older adult population after the start of the COVID-19 pandemic in The Gambia. This, therefore, suggests the need for the implementation of targeted malaria prevention interventions in this population to further prevent the spread of the disease to the more vulnerable population.

Clinical manifestation, staging and prognosis of hepatocellular carcinoma in Gambian patients.

BACKGROUND: As a result of the lack of screening programs and the difficulty in making a proper diagnosis, the majority of hepatocellular carcinoma (HHC) patients present late in low-resource countries. The study therefore assesses the clinical features, stage and prognostic variables of patients with HCC in The Gambia. METHODS: From December 2015 to January 2019, patients with a confirmed diagnosis of HCC were enrolled. All patients' medical history, ultrasound scan, FibroScan and laboratory details were collected. RESULTS: Two hundred and sixty (260) patients were enrolled. The mean age of HCC patients was 40 years, and 210 (80.7%) of them were male. The most common gastrointestinal symptoms were early satiety 229 (88.1%) and abdominal pain 288 (87.7%), while the most common constitutional symptoms were weight loss 237 (91.2%) and easy fatiguability 237 (91.2%). Hepatomegaly 205 (78.8%) was the most common sign. On ultrasound scan, lesions were mostly multifocal 175 (67.3%), and the median FibroScan score was 75 kPa. The median fibrosis 4 and aspartate transferase platelet ratio index were 4.6 and 2.2, respectively. Hepatitis B surface antigen (HBsAg) was positive in 170 (65.4%) patients, and the median AFP level was 3263 ng/ml. HCC patients with positive HBsAg were more likely to be male 145 (85.3%) vs 62 (72.1%) (p = 0.011), much younger 39.9 vs 51.4 yrs (p = < 0.0001), more likely to have abdominal pain 156 (91.8%) vs 68 (79.1%) (p = 0.002), jaundice 78 (45.9%) vs 29 (33.7%) (p = 0.042), dark urine 117 (68.8%) vs 46 (53.5%) (p = 0.018), raised transaminases (Aspartate transaminases 224.5 (32-7886) vs 153 (18-610), p = < 0.01, Alanine transferases 71 (5-937) vs 47 (8-271), p = < 0.001) and decreased platelet count 207 (33-941) vs 252 (52- 641) (p = 0.021) compared to patients with HCC who were HBsAg-negative. CONCLUSIONS: The prognosis of patients with HCC is poor in developing countries such as The Gambia, where screening programs and treatment modalities are scarce. Young males are disproportionately affected, and HBV is a major cause of HCC in The Gambia.

Penile amputation after neonatal circumcision: a case report.

In children, one of the most common surgical procedures worldwide is circumcision, which has strong religious implications and is frequently performed for nontherapeutic reasons. Circumcision is typically associated with old customs. Complete penile amputation is extremely uncommon, and the prognosis is little understood. Case Presentation: A 7-day-old male term baby was circumcised with a cauter by an unexperienced practitioner, and the patient was admitted to the department of pediatric surgery. Both the glans and the body had become discolored and necrotic. The patient was taken into the theater and given general anesthesia. The authors removed the debridement and inserted a catheter into the urethra to prevent urethral stenosis. Discussion: The procedure of circumcision has several medical benefits and is widely performed for religious, cultural, and medical reasons. It is generally agreed that circumcision prevents against sexually transmitted diseases, penile and cervical cancer in adults, as well as urinary tract infections in children.Partial or complete penile amputation injuries are rare and frequently the result of psychotic self-harm. Operators must correctly conduct the circumcision in order to prevent the potential complications that can happen when the procedure is performed out by untrained hands.The most common cause of penile amputation injuries, whether partial or total, is psychotic self-harm. Operators must carry out the procedure carefully to prevent the potential complications that can happen when circumcision is performed by untrained hands. Conclusion: The authors present here a case of a 7-day-old boy who had ritual circumcision with a cauter complicated by an entire penile amputation, which was treated with the insertion of a catheter to prevent the closure of the urethra. The patient reported his penis was circumcised with cautery one day later the glans and the entire penis became discolored and necrosis, unfortunately, the entire penis was lost with the overlying skin.

Use of an adapted participatory learning and action cycle to increase knowledge and uptake of child vaccination in internally displaced persons camps (IVACS): A cluster-randomised controlled trial.

BACKGROUND: Vaccination is a key public health intervention that can reduce excess mortality in humanitarian contexts. Vaccine hesitancy is thought to be a significant problem requiring demand side interventions. Participatory Learning and Action (PLA) approaches have proven effective in reducing perinatal mortality in low income settings and we aimed to apply an adapted approach in Somalia. METHODS: A randomised cluster trial was implemented in camps for internally displaced people near Mogadishu, from June to October 2021. An adapted PLA approach (hPLA) was used in partnership with indigenous 'Abaay-Abaay' women's social groups. Trained facilitators ran 6 meeting cycles that addressed topics of child health and vaccination, analysed challenges, and planned and implemented potential solutions. Solutions included a stakeholder exchange meeting involving Abaay-Abaay group members and services providers from humanitarian organisations. Data was collected at baseline and after completion of the 3 month intervention cycle. RESULTS: Overall, 64.6% of mothers were group members at baseline and this increased in both arms during the intervention (p = 0.016). Maternal preference for getting young children vaccinated was >95% at baseline and did not change. The hPLA intervention improved the adjusted maternal/caregiver knowledge score by 7.9 points (maximum possible score 21) compared to the control (95% CI 6.93, 8.85; p < 0.0001). Coverage of both measles vaccination (MCV1) (aOR 2.43 95% CI 1.96, 3.01; p < 0.001) and completion of the pentavalent vaccination series (aOR 2.45 95% CI 1.27, 4.74; p = 0.008) also improved. However, adherence to timely vaccination did not (aOR 1.12 95% CI 0.39, 3.26; p = 0.828). Possession of a home-based, child health record card increased in the intervention arm from 18 to 35% (aOR 2.86 95% CI 1.35, 6.06; p = 0.006). CONCLUSION: A hPLA approach, run in partnership with indigenous social groups, can achieve important changes in public health knowledge and practice in a humanitarian context. Further work to scale up the approach and address other vaccines and population groups is warranted.

Genomic epidemiology of SARS-CoV-2 infections in The Gambia: an analysis of routinely collected surveillance data between March, 2020, and January, 2022.

BACKGROUND: COVID-19, caused by SARS-CoV-2, is one of the deadliest pandemics of the past 100 years. Genomic sequencing has an important role in monitoring of the evolution of the virus, including the detection of new viral variants. We aimed to describe the genomic epidemiology of SARS-CoV-2 infections in The Gambia. METHODS: Nasopharyngeal or oropharyngeal swabs collected from people with suspected cases of COVID-19 and international travellers were tested for SARS-CoV-2 with standard RT-PCR methods. SARS-CoV-2-positive samples were sequenced according to standard library preparation and sequencing protocols. Bioinformatic analysis was done using ARTIC pipelines and Pangolin was used to assign lineages. To construct phylogenetic trees, sequences were first stratified into different COVID-19 waves (waves 1-4) and aligned. Clustering analysis was done and phylogenetic trees constructed. FINDINGS: Between March, 2020, and January, 2022, 11 911 confirmed cases of COVID-19 were recorded in The Gambia, and 1638 SARS-CoV-2 genomes were sequenced. Cases were broadly distributed into four waves, with more cases during the waves that coincided with the rainy season (July-October). Each wave occurred after the introduction of new viral variants or lineages, or both, generally those already established in Europe or in other African countries. Local transmission was higher during the first and third waves (ie, those that corresponded with the rainy season), in which the B.1.416 lineage and delta (AY.34.1) were dominant, respectively. The second wave was driven by the alpha and eta variants and the B.1.1.420 lineage. The fourth wave was driven by the omicron variant and was predominantly associated with the BA.1.1 lineage. INTERPRETATION: More cases of SARS-CoV-2 infection were recorded in The Gambia during peaks of the pandemic that coincided with the rainy season, in line with transmission patterns for other respiratory viruses. The introduction of new lineages or variants preceded epidemic waves, highlighting the importance of implementing well structured genomic surveillance at a national level to detect and monitor emerging and circulating variants. FUNDING: Medical Research Unit The Gambia at London School of Hygiene & Tropical Medicine, UK Research and Innovation, WHO.

Retrospective Evaluation of Nosocomial Bacterial Infections and Their Antimicrobial Resistance Patterns Among Hospitalized Patients in Mogadishu, Somalia.

Background: Nosocomial infection constitutes a significant public health challenge globally, with resource-limited countries bearing the greatest burden. Sadly, the emergence of drug-resistant strains of these pathogens have worsened the already precarious situation. Methods: This study aimed to determine the incidence of nosocomial infections, the causative agents, and their antimicrobial susceptibilities among patients admitted to a tertiary hospital in Mogadishu, Somalia. The study included patients who had positive cultures 48 hours after admission. Abstracted data include the patient's demographic, infection outcome, the agents involved, and the site of infection. Results: A total of 330 patients were found to have acquired nosocomial infection, comprising 100 (30%) patients from the ICU department. The median age for the patients in this study was 36 years. Patients who died of all-cause mortality were older than those discharged. Most of the bacteria were collected from sepsis/bloodstream infections (34%) dominated by Staphylococcus aureus (42.1%), Acinetobacter baumannii (14.0%), Escherichia coli (14.0%), and Klebsiella spp. (7.0%). Urinary tract infections were mainly associated with Escherichia coli (37.5%), Staphylococcus aureus (18.8%), and Klebsiella spp. 50% of all microorganisms were multidrug-resistant. Conclusion: The findings of this study suggested that hospital infection control and prevention strategies need to be strengthened to improve the quality of care among hospitalized patients.

A presentation of iatrogenic hypospadias after traditional circumcision: A case report.

Introduction and Importance: Traditional circumcisions may cause complications such as hemorrhage, infection, amputations of the penis, meatal stenosis, and urethro-cutaneous fistula. In addition to all these complications, iatrogenic hypospadias, as in our case, is a rare condition. In general, complications are mild and preventable, especially in children, but when the procedure is carried out by unskilled providers, in unsterile conditions, or with inadequate equipment and supplies, severe complications are more likely to occur. Several degrees of urethral erosion, including iatrogenic hypospadias, might result from further injury. Particularly in intensive care facilities, the ventral male urethra can undergo this kind of trauma. Case presentation: A 4-year-old child was circumcised at the age of 3 years, and after that, he bled profusely. His parents brought him to the hospital after 4 months. On physical examination of the patient, the glans was normal but there was an opening near the glans in the distal urethra at the subcoronal level. After the pre-operative check-up, the patient was prepared for elective surgery. An incision and dissection were performed to reveal the fistula tract all around by placing marker sutures from the edges of the fistula. The fistula opening was repaired with 6/0 PDS (polydioxanone) and a second layer was created over the urethral fistula repair, and then the skin was closed with 4/0 Vicryl (polyglactin). Clinical discussion: Around the world, circumcision continues to be the most common procedure done on children. Injuries to the penis may actually happen with a 1% complication incidence. A poorly placed suture at the frenulum in an effort to achieve hemostasis is the most frequent cause of the fistula. This causes strangulation and necrosis of a portion of the urethral wall, which leads to the creation of a sub glandular fistula. It is important to properly identify and treat any life-threatening injuries to the urethra as soon as possible. Conclusion: Considered a medical procedure that necessitates great care, circumcision should only be carried out by qualified surgeons under sterile hospital circumstances. Most circumcision-related injuries result from clamp circumcisions (such as Mogen or Gomco), and they can range from minor loss of penile skin to more serious glans, distal urethral, and penile shaft injuries.

Knowledge and attitude of hepatitis B infection among patients with the infection in the main liver clinic in The Gambia.

Introduction: adequate knowledge on hepatitis B virus (HBV) infection is important among patients with the infection as this impacts their health-seeking behavior. This study therefore assessed the knowledge and attitude among patients infected with HBV in The Gambia. Methods: this cross-sectional study was conducted at the main liver clinic, Medical Research Council Gambia at London School of Hygiene and Tropical Medicine (MRCG@LSHTM). A questionnaire was administered on a one-on-one basis to assess the level of knowledge and attitude of people with chronic HBV. Results: a total of 152 HBV patients were recruited into the study. Majority of the participants were male 136 (89.5%), within the 30-39 years age group. Sixty-four (42.1%) of the patients attained secondary education and 72 (47.4%) were working as civil servants. The mean knowledge score was 11.09/20 (standard deviation = 4.89). HBV patients having tertiary level education (p-value =0.001) or HBV diagnosis greater than 1 year (p-value =0.031) were more likely to have adequate knowledge of HBV infection. No significant associations were found between the socio-demographic and clinical characteristic variables and attitude. However, majority of the participants (56.6%) reported been worried about having HBV infection ever since being diagnosed. Conclusion: this study has highlighted the need for more patient health education especially for those with lower levels of education and newly diagnosed patients. It also further confirms the need for cultural and appropriate language consideration in providing education and information for HBV patients in The Gambia at the point of diagnosis.

Clinical manifestations and outcomes of severe malaria in adult patients admitted to a tertiary hospital in the Gambia.

BACKGROUND: Malaria is a major public health concern in The Gambia. There is limited data on the clinical manifestation and outcome of severe malaria in adult patients in The Gambia. The study therefore assessed the clinical manifestations and outcome of severe malaria in adult patients admitted at the Edward Francis Small Teaching Hospital. METHODS: The study retrospectively reviewed the records of all malaria patients admitted from 18th October 2020 to 2nd February 2022. Demographic data, clinical features, investigations, treatment, and outcomes were recorded. RESULTS: A total of 131 confirmed malaria patients were recruited into the study. The median age was 21 yrs, range (15-90) and most of them were within the youth age group (15-24yrs) 85 (64.9%). The majority of the patients were also male 88 (67.2%) with a male to female ratio of 2:1. The most common symptom at presentation was fever 119 (90.8%) and the most common sign was pallor 48 (36.6%). Seventy-six patients (58.1%) and 55 (41.9%) patients met the criteria for severe malaria and uncomplicated malaria diagnosis, respectively. The most common clinical feature amongst patients with severe malaria were impaired consciousness 34 (44.7%), severe anaemia 26 (34.2%) and acute kidney injury 20 (26.3%). Patients with severe malaria were younger with mean age of 22.9 vs. 29 yrs (p = 0.004), more likely to be referred from a lower-level health facility 62 (81.6%) vs. 34 (61.8%) (p = 0.012), to have a longer duration of admission (p = 0.024) and to die 13 (17.1%) vs. 0 (0%) (p = 0.001) as compared to patients with uncomplicated malaria. The total mortality was 13 (9.9%) and all the patients who died had severe malaria. Mortality was higher in patients with impaired consciousness 9 (26.5%) and there was a significant relationship between death and impaired consciousness 9 (69.3%) vs. 25 (21.4%) p = 0.001. CONCLUSION: Severe malaria still affects young adults in an endemic area with significant mortality. This suggests the need for targeted malaria prevention, surveillance, case management and control strategies in this population group in The Gambia to help reduce morbidity and mortality of malaria.

Genomic epidemiology of SARS-CoV-2 infections in The Gambia, March 2020 to Jan 2022

BackgroundCOVID-19, caused by SARS-CoV-2, is one of the deadliest pandemics over the last 100 years. Sequencing is playing an important role in monitoring the evolution of the virus, including the detection of new viral variants. This study describes the genomic epidemiology of SARS-CoV-2 infections in The Gambia. MethodsNasopharyngeal and/or oropharyngeal swabs collected from suspected cases and travellers were tested for SARS-CoV-2 using standard RT-PCR methods. SARS-CoV-2 positive samples were sequenced following standard library preparation and sequencing protocols. Bioinformatic analysis was done using ARTIC pipelines and lineages assigned using Pangolin. FindingsBetween March 2020 to January 2022, there were almost 12,000 SARS-CoV-2 confirmed cases distributed into four waves, each of them lasting between 4 weeks and 4 months, with more cases during the rainy seasons (July-October). As shown by the 1643 sequenced samples, each wave occurred after new viral variants and/or lineages were introduced in The Gambia, generally those already established in Europe and/or in other African countries. Local transmission was higher during the first and third wave, with mostly B.1.416/Senegal/Gambian lineage and AY.34.1/Delta subtype, respectively. The second wave was driven by two variants, namely Alpha and Eta and B.1.1.420 lineage. The Omicron/fourth wave was the shortest. InterpretationEfficient surveillance, including strengthening entry points and screening asymptomatic individuals especially during the rainy seasons would be important to promptly detect and control future waves in The Gambia and the subregion. FundingMedical Research Unit The Gambia at LSHTM, UK Research and Innovation funding (grant reference MC_PC_19084), MRC/UKRI MC_PC_19084 and World Health Organisation.

Antimicrobial Resistance and Predisposing Factors Associated with Catheter-Associated UTI Caused by Uropathogens Exhibiting Multidrug-Resistant Patterns: A 3-Year Retrospective Study at a Tertiary Hospital in Mogadishu, Somalia.

Background: Widespread and rapidly emerging multidrug-resistant uropathogens, particularly carbapenem-resistant pathogens, are a public health concern that impairs the determination of empirical therapy. This study aims to evaluate the antimicrobial susceptibility profile and factors associated with catheter-associated urinary tract infection (CA-UTI). Method: This retrospective study was carried out on a total of 779 urine cultures over a 3-year period. Antimicrobial sensitivity tests were performed using the standard Kirby−Bauer disk diffusion method. Results: The prevalence of CA-UTI in our study was 12.7%; a total of 47% of cultures had multi-drug-resistant (MDR) uropathogens, and 13% of the cultures showed extended-spectrum beta-lactamase (ESBL)-producing pathogens. Elderly patients, intensive care unit admissions, and associated comorbidities were correlated with higher rates of CA-UTI caused by multidrug-resistant uropathogens (p < 0.021, 95% CI: 0.893−2.010), (p < 0.008, 95% CI: 1.124−5.600), (p < 0.006, 95% CI: 0.953−2.617). Latex catheters and prolonged catheterization time were associated with increased risk of CA-UTI (p < 0.0001, 95% CI: 0.743−1.929, p = 0.012, 95% CI: 0.644−4.195). Patients with MDR uropathogens had prolonged hospital stays, i.e., 49% in more than 2 weeks (p < 0.04, 95% CI: 0.117−3.084). E. coli was the most common pathogen (26.3%), followed by Acinetobacter baumannii (24.3%). Acinetobacter baumannii showed the highest MDR pattern (88.5%), followed by Pseudomonas aeruginosa (68%). Acinetobacter baumannii and Klebsiella pneumoniae were associated with prolonged hospital stays (>2 w at 73.1 and 69%, respectively). Higher antimicrobial resistance against ceftriaxone (85.7%), meropenem (54.3%), ertapenem (50%), ciprofloxacin (58.5%), amikacin (27%), tigecycline (7.6%), and colistin (4.6%), was revealed in the study. Conclusion: Aside from the higher antimicrobial resistance against cephalosporins and fluoroquinolones, the findings of this study revealed that carbapenems are facing increased rates of antimicrobial resistance and are associated with substantial morbidity, prolonged hospitalization times, and increased healthcare expenses.

Effect of Zinc Dialkyl Dithiophosphate Replenishment on Tribological Performance of Heavy-Duty Diesel Engine Oil.

Soot is the main contamination that affects oil performance and increases the frequency of oil changes in heavy-duty engine oil. Several studies discussed that additive concentration in engine oil can be influenced due to additive depletion over time and additive adsorption on soot particles. To extend oil drain intervals and improve oil performance, filter manufactures explore removing the soot to a certain level and replenishing the consumed additives. Zinc dialkyl dithiophosphate (ZDDP) is one of the most favored antiwear additives that react very rapidly with rubbing surfaces to form tribofilm that reduces wear. In this study, the experimental work aims to investigate the effect of ZDDP replenishment on tribological performance in the existence of soot and after removing soot from heavy-duty used oil. The study reveals that reclaiming the used oil can be achieved by removing the soot to a certain level. The results demonstrate that the reclaimed oil after removing soot is still not as good as the fresh oil. This study proves that additive depletion, additive adsorption on soot, and the decomposition of antiwear additive adversely influence the reclaimed oil performance. However, replenishing the consumed additive by adding a small amount of ZDDP helps to improve the reclaimed oil performance compared to a large amount of ZDDP which is required to re-gain the oil performance in the existence of soot.

Beyond the myocardium? SGLT2 inhibitors target peripheral components of reduced oxygen flux in the diabetic patient with heart failure with preserved ejection fraction.

Recent cardiovascular outcome trials have highlighted the propensity of the antidiabetic agents, SGLT2 inhibitors (SGLT2is or -flozin drugs), to exert positive clinical outcomes in patients with cardiovascular disease at risk for major adverse cardiovascular events (MACEs). Of interest in cardiac diabetology is the physiological status of the patient with T2DM and heart failure with preserved ejection fraction (HFpEF), a well-examined association. Underlying this pathologic tandem are the effects that long-standing hyperglycemia has on the ability of the HFpEF heart to adequately deliver oxygen. It is believed that shortcomings in oxygen diffusion or utilization and the resulting hypoxia thereafter may play a role in underlying the clinical sequelae of patients with T2DM and HFpEF, with implications in the long-term decline of extra-cardiac tissue. Oxygen consumption is one of the most critical factors in indexing heart failure disease burden, warranting a probe into the role of SGLT2i on oxygen utility in HFpEF and T2DM. We investigated the role of oxygen flux in the patient with T2DM and HFpEF extending beyond the heart with focuses on cellular metabolism, perivascular fibrosis with endothelial dysfunction, hematologic changes, and renal effects with neurohormonal considerations in the patient with HFpEF and T2DM. Moreover, we give a commentary on potential therapeutic targets of these components with SGLT2i to gain insight into disease burden amelioration in patients with HFpEF and T2DM.

Pharmacology and toxicology of eteplirsen and SRP-5051 for DMD exon 51 skipping: an update.

Duchenne muscular dystrophy (DMD) afflicts 1 in 5000 newborn males, leading to progressive muscle weakening and the loss of ambulation between the ages of 8 and 12. Typically, DMD patients pass away from heart failure or respiratory failure. Currently, there is no cure, though exon-skipping therapy including eteplirsen (brand name Exondys 51), a synthetic antisense oligonucleotide designed to skip exon 51 of the dystrophin gene, is considered especially promising. Applicable to approximately 14% of DMD patients, a phosphorodiamidate morpholino oligomer (PMO) antisense oligonucleotide eteplirsen received accelerated approval by the US Food and Drug Administration (FDA) in 2016. Throughout clinical trials, eteplirsen has been well tolerated by patients with no serious drug-related adverse events. The most common events observed are balance disorder, vomiting, and skin rash. Despite its safety and promise of functional benefits, eteplirsen remains controversial due to its low production of dystrophin. In addition, unmodified PMOs have limited efficacy in the heart. To address these concerns of efficacy, eteplirsen has been conjugated to a proprietary cell-penetrating peptide; the conjugate is called SRP-5051. Compared to eteplirsen, SRP-5051 aims to better prompt exon-skipping and dystrophin production but may have greater toxicity concerns. This paper reviews and discusses the available information on the efficacy, safety, and tolerability data of eteplirsen and SRP-5051 from preclinical and clinical trials. Issues faced by eteplirsen and SRP-5051, including efficacy and safety, are identified. Lastly, the current state of eteplirsen and exon-skipping therapy in general as a strategy for the treatment of DMD are discussed.