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Lan-Lan Zhong,1,2,* Qian Zhou,3,* Cui-Yan Tan,3,* Adam P Roberts,4,5 Mohamed Abd El-Gawad El-Sayed Ahmed,1–2,6 Guanping Chen,1,2 Min Dai,7 Fan Yang,8 Yong Xia,9 Kang Liao,10 Yingjian Liang,3 Yongqiang Yang,1,11 Siyuan Feng,1,2 Xiaobin Zheng,3,* Guo-Bao Tian1,2,*1Program in Pathobiology, The Fifth Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangdong 519000, People’s Republic of China; 2Ministry of Education, Key Laboratory of Tropical Diseases Control, Sun Yat-sen University, Guangzhou 510080, People’s Republic of China; 3Department of Respiratory Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, People’s Republic of China; 4Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, L3 5QA, UK; 5Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK; 6Department of Microbiology and Immunology, Faculty of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology (MUST), Cairo, Egypt; 7School of Laboratory Medicine, Chengdu Medical College, Chengdu 610500, People’s Republic of China; 8Department of Microbiology, School of Basic Medical Science, Xinxiang Medical University, Xinxiang 453003, People’s Republic of China; 9Department of Clinical Laboratory Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, People’s Republic of China; 10Department of Clinical Laboratory, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, People’s Republic of China; 11School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou 510006, People’s Republic of China*These authors contributed equally to this workPurpose: The discovery of the plasmid-mediated colistin resistance genes, mcr, revealed a mechanism of transmission of colistin resistance, which is a major, global public health concern especially among individuals infected with carbapenem-resistant Gram-negative bacteria. To monitor the spread and epidemiology of mcr genes, a convenient and reliable method to detect mcr genes in clinical isolates is needed, especially in the primary care institutions. This study aimed to establish a restriction endonuclease-based multiplex loop-mediated isothermal amplification (multi-LAMP) assay to detect mcr genes (mcr-1 to mcr-5) harbored by colistin-resistant bacteria.Methods: A triple-LAMP assay for mcr-1, mcr-3, and mcr-4 and a double-LAMP assay for mcr-2 and mcr-5 were established. The sensitivity and specificity of the LAMP reactions were determined via electrophoresis and visual detection.Results: The sensitivity of the LAMP assay was 10-fold greater than that of PCR, with high specificity among the screened primers. Specific mcr genes were distinguished in accordance with band numbers and the fragment length of the digested LAMP amplification products. Furthermore, the LAMP assay was confirmed as a rapid and reliable diagnostic technique upon application for clinical samples, and the results were consistent with those of conventional PCR assay.Conclusion: The multi-LAMP assay is a potentially promising method to detect mcr genes and will, if implemented, help prevent infections by drug-resistant bacteria in primary-care hospitals due to rapid and reliable surveillance. To our knowledge, this is the first study to report the application of LAMP to detect mcr-2 to mcr-5 genes and the first time that multi-LAMP has been applied to detect mcr genes.Keywords: mcr genes, colistin resistance, multi-LAMP, rapid detection, enzyme digestion

Objectives: To identify the genes responsible for tetracycline resistance in a strain of Streptococcus australis isolated from pooled saliva from healthy volunteers in France. S. australis is a viridans Streptococcus, originally isolated from the oral cavity of children in Australia, and subsequently reported in the lungs of cystic fibrosis patients and as a cause of invasive disease in an elderly patient.Methods: Agar containing 2 mg/L tetracycline was used for the isolation of tetracycline-resistant organisms. A genomic library in Escherichia coli was used to isolate the tetracycline resistance determinant. In-frame deletions and chromosomal repair were used to confirm function. Antibiotic susceptibility was determined by agar dilution and disc diffusion assay.Results: The tetracycline resistance determinant from S. australis FRStet12 was isolated from a genomic library in E. coli and DNA sequencing showed two open reading frames predicted to encode proteins with similarity to multidrug resistance-type ABC transporters. Both genes were required for tetracycline resistance (to both the naturally occurring and semi-synthetic tetracyclines) and they were designated tetAB(46).Conclusions: This is the first report of a predicted ABC transporter conferring tetracycline resistance in a member of the oral microbiota. [ABSTRACT FROM AUTHOR]

Objectives: Tn916-like elements are one of the most common types of integrative and conjugative element (ICE). In this study we aimed to determine whether novel accessory genes, i.e. genes whose products are not involved in mobility or regulation, were present on a Tn916-like element (Tn6087) isolated from Streptococcus oralis from the human oral cavity.Methods: A minocycline-resistant isolate was analysed using restriction fragment length polymorphism (RFLP) analysis on amplicons derived from Tn916 and DNA sequencing to determine whether there were genetic differences in Tn6087 compared with Tn916. Mutational analysis was used to determine whether the novel accessory gene found was responsible for an observed extra phenotype.Results: A novel Tn916-like element, Tn6087, is described that encodes both antibiotic and antiseptic resistance. The antiseptic resistance protein is encoded by a novel small multidrug resistance gene, designated qrg, that was shown to encode resistance to cetyltrimethylammonium bromide (CTAB), also known as cetrimide bromide.Conclusions: This is the first Tn916-like element described that confers both antibiotic and antiseptic resistance, suggesting that selection of either antibiotic or antiseptic resistance will also select for the other and further highlights the need for prudent use of both types of compound. [ABSTRACT FROM AUTHOR]

Objective: Insulin degludec (IDeg) is a basal insulin that forms soluble multihexamers after subcutaneous injection, resulting in an ultra-long action profile. We assessed the efficacy and safety of IDeg formulations administered once daily in combination with mealtime insulin aspart in people with type 1 diabetes.Research Design and Methods: In this 16-week, randomized, open-label trial, participants (mean: 45.8 years old, A1C 8.4%, fasting plasma glucose [FPG] 9.9 mmol/L, BMI 26.9 kg/m(2)) received subcutaneous injections of IDeg(A) (600 μmol/L; n = 59), IDeg(B) (900 μmol/L; n = 60), or insulin glargine (IGlar; n = 59), all given once daily in the evening. Insulin aspart was administered at mealtimes. RESULTS At 16 weeks, mean A1C was comparable for IDeg(A) (7.8 ± 0.8%), IDeg(B) (8.0 ± 1.0%), and IGlar (7.6 ± 0.8%), as was FPG (8.3 ± 4.0, 8.3 ± 2.8, and 8.9 ± 3.5 mmol/L, respectively). Estimated mean rates of confirmed hypoglycemia were 28% lower for IDeg(A) compared with IGlar (rate ratio [RR]: 0.72 [95% CI 0.52-1.00]) and 10% lower for IDeg(B) compared with IGlar (RR: 0.90 [0.65-1.24]); rates of nocturnal hypoglycemia were 58% lower for IDeg(A) (RR: 0.42 [0.25-0.69]) and 29% lower for IDeg(B) (RR: 0.71 [0.44-1.16]). Mean total daily insulin dose was similar to baseline. The frequency and pattern of adverse events was similar between insulin treatments.Conclusions: In this clinical exploratory phase 2 trial in people with type 1 diabetes, IDeg is safe and well tolerated and provides comparable glycemic control to IGlar at similar doses, with reduced rates of hypoglycemia. [ABSTRACT FROM AUTHOR]

The production and implementation of clinical practice guidelines is currently a high political priority and a rapidly developing field within healthcare in the United Kingdom (UK). Their purpose is to provide clinicians with a synthesis of the best available external evidence and operationalize the implementation of evidence-based practice. Despite indications that clinical guidelines can make a difference to the quality of patient care, there is some evidence that practitioners struggle with their application. The aim of this paper is to report one element of a trial undertaken by three collaborating universities in the Northern and Yorkshire Region of the UK health service during 1997-1998. The objective was to understand what makes guidelines acceptable and usable, or otherwise, to health professionals. The findings reported in this paper describe the process of care in those general practices that elected to implement guidelines for the management of patients with venous leg ulcers. We conclude that planning for training, resource and quality improvement processes must be built into a team's guidelines implementation procedures. A preliminary needs analysis of the contextual 'hurdles and levers' within each primary healthcare team is also necessary to identify individual issues that must be addressed if the process is to succeed. These findings provide some lessons for successful implementation of clinical guidelines in general. Recommendations for nursing policy makers, managers, practitioners and researchers are included. [ABSTRACT FROM AUTHOR]

PURPOSE: To evaluate the predictive value of N-terminal pro B-type natiuretic peptide (NT-proBNP) reference cut-off values as diagnostic markers for left ventricular systolic dysfunction (LVSD). STUDY DESIGN: A retrospective study assessing the use of NT-proBNP in the diagnostic algorithm for the investigation of patients with suspected signs and symptoms of LVSD presenting to primary care. RESULTS: A generic NT-proBNP cut-off (150 ng/l) value has similar negative and positive predictive valves, specificity and sensitivity compared to age and sex specific cut-off values. CONCLUSION: When using NT-proBNP as a triage tool for screening patients with signs and symptoms suggestive of LVSD, a simple generic cut-off level is as effective as more complex age sex specific cut-off values. [ABSTRACT FROM AUTHOR]

Healthcare-associated infections (HAIs) are a significant burden to health systems, with antimicrobial resistance (AMR) further compounding the issue. The hospital environment plays a significant role in the development of HAIs, with microbial surveillance providing the foundation for interventions. We sampled 40 door handles at a newly built hospital prior to patients being admitted and then 6 and 12 months after this date. We utilized 16S rDNA sequencing to identify unique colonies, disc diffusion assays to assess the antibiotic resistance of Staphylococcus spp., and whole-genome sequenced (WGS) multidrug-resistant (MDR) isolates. Before patient admission, 43% of sites harbored Staphylococcus spp., increasing to 55% and 65% at six and 12 months, respectively, while Bacillus spp. saw a large increase from 3% to 68% and 85%, respectively. No ESKAPE pathogens were identified. Staphylococcus spp. showed relatively low resistance to all antibiotics except cefoxitin (56%) before patient admittance. Resistance was highest after 6 months of ward use, with an increase in isolates susceptible to all antibiotics after 12 months (11% and 54% susceptibility, respectively). However, MDR remained high. WGS revealed blaZ (25/26), and mecA (22/26) and aac6-aph2 (20/26) were the most abundant resistance genes. Two Staphylococcus hominis isolates identified at the first two time points, respectively, and three Staphylococcus epidermidis isolates identified at all three time points, respectively, were believed to be clonal. This study highlighted the prevalence of a resistant reservoir of bacteria recoverable on high-touch surfaces and the long-term persistence of Staphylococcus spp. first introduced prior to patient admission., Importance: Healthcare-associated infections (HAIs) are a significant burden to health systems, conferring increased morbidity, mortality, and financial costs to hospital admission. Antimicrobial resistance (AMR) further compounds the issue as viable treatment options are constrained. Previous studies have shown that environmental cleaning interventions reduced HAIs. To ensure the effectiveness of these, it is important to analyze the hospital environment at a microbial level, particularly high-touch surfaces which see frequent human interaction. In addition to identifying infectious microorganisms, it is also beneficial to assess typically non-infectious organisms, as traits including AMR can be transferred between the two. Our study identified that there were high levels of antibiotic resistance in typically non-infectious organisms found on high touch surfaces on a hospital ward. However, the organisms identified suggested that the cleaning protocols in place were sufficient, with their presence being due to repeated recolonization events through human interaction after cleaning had taken place.

Infections with Enterobacterales (E) are increasingly difficult to treat due to antimicrobial resistance. After ceftriaxone replaced chloramphenicol (CHL) as empiric therapy for suspected sepsis in Malawi in 2004, extended-spectrum beta-lactamase (ESBL)-E rapidly emerged. Concurrently, resistance to CHL in Escherichia coli and Klebsiella spp. decreased, raising the possibility of CHL re-introduction. However, many phenotypically susceptible isolates still carry CHL acetyltransferase (cat) genes. To understand the molecular mechanisms and stability of this re-emerging CHL susceptibility we use a combination of genomics, phenotypic susceptibility assays, experimental evolution, and functional assays for CAT activity. Here, we show that of 840 Malawian E. coli and Klebsiella spp. isolates, 31% have discordant CHL susceptibility genotype-phenotype, and we select a subset of 42 isolates for in-depth analysis. Stable degradation of cat genes by insertion sequences leads to re-emergence of CHL susceptibility. Our study suggests that CHL could be reintroduced as a reserve agent for critically ill patients with ESBL-E infections in Malawi and similar settings and highlights the ongoing challenges in inferring antimicrobial resistance from sequence data., (© 2024. The Author(s).)

Background: The burden of sepsis worsens due to the continuation of emerging pathogens such as multidrug-resistant Pantoea species., Methods: A multicenter study was conducted between October 2019 and September 2020 at four hospitals located in central, southern, and northern parts of Ethiopia. A total of 1416 sepsis patients were recruited and blood cultures were performed. At each study site, positive cultures were characterized by their colony characteristics, gram stain, and conventional biochemical tests. All Pantoea species were identified using Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI TOF) and subjected to whole genome sequencing (WGS) using Illumina HiSeq 2500. The phylogeny structure of Pantoea isolates was calculated using IQ-TREE v1.6.12 from single-nucleotide polymorphisms detected by Snippy v.4.6.0 and filtered by Gubbins v.2.3.4. Average nucleotide identity was estimated by using OrthoANI v.0.93.1 on Shovill v.1.1.0 assemblies. Antimicrobial resistance genes and plasmid replicons were detected using ARIBA v.2.14.6. Phylogenetic trees were visualized using iTOLv.6.5.2., Results: Multiple Pantoea species include: P. dispersa (n = 19), P. septica (n = 1), and a novel Pantoea spp. (n = 1), were identified among sepsis patients. All P. dispersa isolates and the novel Pantoea species were isolated at Dessie Referral Hospital and displayed phylogenetic clonality, including the ubiquity of an IncM1 plasmid and identical antimicrobial resistance (AMR) gene profiles, encoding bla CTX-M-15 , bla TEM-1D , bla SCO-1, and aac(3)-lla. The novel Pantoea spp. isolate harboured bla CTX-M-9 and bla TEM-1D and carried an IncN3 plasmid replicon. The P. septica was isolated at Tikur Anbessa Specialized Hospital in Addis Ababa and carried no detectable acquired AMR genes., Conclusion: The emerging Pantoea spp. carrying multiple AMR genes were identified from sepsis patients. Implementation of strong infection prevention strategies and building surveillance capacity with advanced bacteriology laboratories capable of identifying multidrug-resistant emerging pathogens is strongly recommended., (© 2024. The Author(s).)

Background and Objectives: Awake minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) generates minimal surrounding tissue damage and has been shown to be a safe, time-effective, and cost-reductive technique in single-level procedures. The purpose of this study was to advocate for the utilization of multilevel MIS-TLIF even in challenging cases as it has demonstrated positive outcomes., Methods: Chart review was conducted for consecutive patients undergoing awake multilevel MIS-TLIF from 2020 to 2023. Various demographic, preoperative, and postoperative variables were collected and descriptively analyzed., Results: Sixteen patients underwent multilevel awake MIS-TLIF at our institution during the specified period. Among them, 87.5% underwent a two-level procedure and 12.5% a three-level procedure. The median age ± IQR was 69.5 ± 11 years, with a slight male predominance (56.25%). Common comorbidities included hypertension (56.25%), obesity (37.5%), sleep apnea (25%), and type 2 diabetes (18.75%). The American Society of Anesthesiologists risk was 2 in 43.75% of patients and 3 in 56.25%. All patients presented pain, and 12.5% showed motor deficit. Intraoperative data showed a median of 196 minutes in the operating room where 156 ± 27.75 minutes corresponded to actual procedure time. The median estimated blood loss was 50 ± 70 cc. In the immediate postoperative period, 1 patient had nausea and emesis, and 1 reported fatigue. The median pain score during this period was 4.6 ± 2.03. Pain control medications were required for various patients, with methocarbamol (50%), hydromorphone (37.5%), and oxycodone (25%) being the most commonly prescribed in the postanesthesia care unit. No patient had new neurological deficits after the surgical intervention. The median length of stay was 2 days ±1.25. All patients were discharged with no complications., Conclusion: Multilevel awake MIS-TLIF emerges as a safe and effective technique for complex cases, enhancing patient quality of life with minimal blood loss and postoperative pain., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Extreme global warming can produce hydroclimate changes that remain poorly understood for sub-tropical latitudes. Late Palaeocene-early Eocene (LPEE; ~58-52 Ma) proto-Mediterranean zones of the western Tethys offer opportunities to assess hydroclimate responses to massive carbon cycle perturbations. Here, we reconstruct LPEE hydroclimate conditions of these regions and find that carbon cycle perturbations exerted controls on orbitally forced hydroclimate variability. Long-term (~6 Myr) carbon cycle changes induced a gradual precipitation/moisture reduction, which was exacerbated by some short-lived (<200 kyr) carbon cycle perturbations that caused rapid warming and exceptionally dry conditions in western Tethyan continental areas. Hydroclimate recovery following the greatest short-lived global warming events took ~24-27 kyr. These observations support the notion that anthropogenically driven warming can cause widespread aridification with impacts that may last tens of thousands of years., (© 2024. The Author(s).)

One Health surveillance involves the analysis of human, animal and environmental samples, recognising their interconnectedness in health systems. Such considerations are crucial to investigate the transmission of many pathogens, including drug-resistant bacteria and parasites. The highest rates of antimicrobial resistance (AMR)-associated deaths are observed in sub-Saharan Africa, where concurrently the waterborne parasitic disease schistosomiasis can be highly endemic in both humans and animals. Although there is growing acknowledgment of significant interactions between bacteria and parasites, knowledge of relationships between schistosomes, microbes and AMR remains inadequate. In addition, newly emergent research has revealed the previously underappreciated roles of animals and the environment in both AMR and schistosomiasis transmission. We consider shared environmental drivers and colonisation linkage in this narrative review, with a focus on extended-spectrum beta-lactamase-mediated resistance among bacteria from the Enterobacteriaceae family, which is exceedingly prevalent and responsible for a high burden of AMR-associated deaths. Then we examine novel findings from Malawi, where the landscapes of AMR and schistosomiasis are rapidly evolving, and make comparisons to other geographic areas with similar co-infection epidemiology. We identify several knowledge gaps that could be addressed in future research, including the need to characterise the impact of intestinal schistosomiasis and freshwater contact on intestinal AMR colonisation, before proposing a rationale for connecting AMR surveillance and schistosomiasis research within a One Health framework., (© The Author(s) 2024. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

East Asian winter monsoon (EAWM) activity has had profound effects on environmental change throughout East Asia and the western Pacific. Much attention has been paid to Quaternary EAWM evolution, while long-term EAWM fluctuation characteristics and drivers remain unclear, particularly during the late Miocene when marked global climate and Asian paleogeographic changes occurred. To clarify understanding of late Miocene EAWM evolution, we developed a high-precision 9-million-year-long stacked EAWM record from Northwest Pacific Ocean abyssal sediments based on environmental magnetism, sedimentology, and geochemistry, which reveals a strengthened late Miocene EAWM. Our paleoclimate simulations also indicate that atmospheric CO 2 decline played a vital role in this EAWM intensification over the Northwest Pacific Ocean compared to other factors, including central Asian orogenic belt and northeastern Tibetan Plateau uplift and Antarctic ice-sheet expansion. Our results expand understanding of EAWM evolution from inland areas to the open ocean and indicate the importance of atmospheric CO 2 fluctuations on past EAWM variability over large spatial scales.

Aim: Proof-of-concept study, highlighting the clinical diagnostic ability of FT-IR compared with MALDI-TOF MS, combined with WGS. Materials & methods: 104 pathogenic isolates of Neisseria meningitidis , Streptococcus pneumoniae , Streptococcus pyogenes and Staphylococcus aureus were analyzed. Results: Overall prediction accuracy was 99.6% in FT-IR and 95.8% in MALDI-TOF-MS. Analysis of N. meningitidis serogroups was superior in FT-IR compared with MALDI-TOF-MS. Phylogenetic relationship of S. pyogenes was similar by FT-IR and WGS, but not S. aureus or S. pneumoniae . Clinical severity was associated with the zinc ABC transporter and DNA repair genes in S. pneumoniae and cell wall proteins (biofilm formation, antibiotic and complement permeability) in S. aureus via WGS. Conclusion: FT-IR warrants further clinical evaluation as a promising diagnostic tool.

Intensification of northern hemisphere glaciation (iNHG), ~2.7 million years ago (Ma), led to establishment of the Pleistocene to present-day bipolar icehouse state. Here we document evolution of orbital- and millennial-scale Asian winter monsoon (AWM) variability across the iNHG using a palaeomagnetically dated centennial-resolution grain size record between 3.6 and 1.9 Ma from a previously undescribed loess-palaeosol/red clay section on the central Chinese Loess Plateau. We find that the late Pliocene-early Pleistocene AWM was characterized by combined 41-kyr and ~100-kyr cycles, in response to ice volume and atmospheric CO 2 forcing. Northern hemisphere ice sheet expansion, which was accompanied by an atmospheric CO 2 concentration decline, substantially increased glacial AWM intensity  and its orbitally oscillating amplitudes across the iNHG. Superposed on orbital variability, we find that millennial AWM intensity fluctuations persisted during both the warmer (higher-CO 2 ) late Pliocene and colder (lower-CO 2 ) early Pleistocene, in response to both external astronomical forcing and internal climate dynamics., (© 2024. The Author(s).)

Magnetotactic bacteria (MTB) have the remarkable capability of producing intracellularly membrane-enveloped magnetic nanocrystals (i.e. magnetosomes) and swimming along geomagnetic field lines. Despite more than 50 years of research, bacterial diversity and magnetosome biomineralization within MTB are relatively less known in the Gammaproteobacteria class than other groups. This is incompatible with the status of Gammaproteobacteria as the most diverse class of gram-negative bacteria with a number of ecologically important bacteria. Here, we identify a novel MTB strain YYHR-1 affiliated with the Gammaproteobacteria class of the Pseudomonadota phylum from a freshwater lake. In YYHR-1, most magnetosome crystals are organized into a long chain aligned along the cell long axis; unusually, a few small superparamagnetic crystals are located at the side of the chain, off the main chain axis. Micromagnetic simulations indicate that magnetostatic interactions among adjacent crystals within a chain reduce the Gibbs energy to enhance chain stability. Genomic analysis suggests that duplication of magnetosome gene clusters may result in off-chain magnetosomes formation. By integrating available genomic data from Gammaproteobacteria, the phylogenetic position of MTB in this class is reassigned here. Our new findings expand knowledge about MTB diversity and magnetosome biomineralization, and deepen understanding of the phylogenetics of the Gammaproteobacteria., (© The Author(s) 2023. Published by Oxford University Press on behalf of FEMS.)