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Introduction: The normative relationship between lumbar intervertebral disc space height (DSH) and neuroforaminal dimensions (NFD) has yet to be defined. Research question: The purpose of this study was to investigate the relationship between lumbar DSH and NFD using computed tomography (CT), accounting for influences of patient demographic and anthropometric characteristics. Materials and methods: We analyzed CT imaging of 350 female and 350 male patients. Anterior, middle, and posterior DSH were measured. NFD were defined as sagittal anterior-to-posterior (AP) width, axial AP width, foraminal height, and area. Statistical analyses were performed to assess associations among DSH, NFD, and patient height, weight, body mass index, sex, and ethnicity. Results: Irrespective of disc level, mean anterior, middle, and posterior DSH were 7.98 mm (n = 3500), 8.16 mm (n = 3500), and 4.09 mm (n = 3500). DSH measurements demonstrated increasing, linear trends moving caudally from L1-L2 to L5-S1, while NFD demonstrated a unimodal distribution pattern with largest NFD at L3-L4 and smallest NFD at L1-2 and L5-S1. Male patients demonstrated larger DSH compared to female patients from L1-S1. Asian patients demonstrated taller DSH across all levels L1-S1. Discussion and conclusion: This study describes 38,500 CT-based L1-S1 DSH and NFD in young patients without spinal pathology. DSH follows an increasing trend moving caudally from L1-S1, while NFD demonstrate a unimodal distribution clustered at L3-L4. NFD are not moderately or strongly associated with DSH. DSH is influenced by sex and ethnicity but is not moderately or strongly influenced by patient height, weight, and BMI.

Summary: Background: The standard malaria rapid diagnostic test (RDT) and newer ultra-sensitive RDT (uRDT) target Plasmodium falciparum histidine rich protein-2 (HRP2), which persists post-treatment. The duration of test positivity has not previously been studied in a low transmission setting. Methods: We conducted a longitudinal cohort study in a low transmission setting in Namibia. RDT-positive individuals identified through passive and active case detection were treated and followed weekly for testing by RDT and uRDT, HRP2 quantification, quantitative PCR (qPCR) of parasitemia, and quantitative reverse transcriptase PCR (RT-PCR) of gametocytemia, until RDT and uRDT were negative for two consecutive weeks. Determinants of persistent positivity were identified using Cox proportional hazards models. Findings: Among 137 participants with complete follow-up and no evidence of resurgence during follow-up, median duration of positivity was 42 days (range: 3−98 range) for RDT, compared to 67 days (range 12–105) for uRDT. In a sub-analysis of those with laboratory data before treatment (n = 60), drug resistance did not explain persistent positivity. Younger age (

Mucopolysaccharidosis type I (MPS I) is a rare metabolic disorder caused by deficiency of α-L-iduronidase (IDUA), resulting in glycosaminoglycan (GAG) accumulation and multisystemic disease. Current treatments include hematopoietic stem cell transplantation and enzyme replacement therapy, but these do not address all manifestations of the disease. We infused MPS I mice with an adeno-associated virus 9 (AAV9)-IDUA vector (RGX-111) at doses from 107 to 1010 vector genomes (vg) via intrathecal (IT), intravenous (IV), and intrathecal+intravenous (IT+IV) routes of administration. In mice administered doses ≤109 vg IT or ≤108 vg IV, there was no therapeutic benefit, while in mice administered 109 vg IV, there was a variable increase in IDUA activity with inconclusive neurocognitive and cardiac assessments. However, at the 1010 vg dose, we observed substantial metabolic correction, with restored IDUA levels and normalized tissue GAGs for all treatment groups. Aortic insufficiency was mostly normalized, neurologic deficit was prevented, and microcomputed tomography (micro-CT) analysis showed normalization of skeletal parameters. Histologic analysis showed minimal GAG storage and lysosomal pathology. We thus report a minimal effective dose of 1010 vg (5 × 1011 per kg) RGX-111 for IV and IT routes of administration in MPS I mice, which prevented neurocognitive deficit, cardiac insufficiency, and skeletal manifestations, as a model for genetic therapy of human MPS I.

Continuous challenges have been imposed on mental health science by Anxiety and Depression disorders as the most prevalent and debilitating psychiatric conditions worldwide. Pharmacologic and cognitive behavioral therapies, either alone or in combination, have been considered as the first-line therapies, however, resistant symptomatology is prevalent in comorbid conditions with symptoms remaining after interventions. The demand for new therapeutic solutions has given space to the development of non-invasive brain stimulation techniques (NIBS), and the transmagnetic direct current stimulation (tDCS) has been reported as a safe and well-tolerated technique for the treatment of several mental health conditions, including Anxiety and Depression disorders. Relying on quantitative electroencephalography(qEEG)- tDCS approach, the current study aims to inspect the effect of tDCS intervention on patients who suffer from anxiety-depression comorbidity, in particular, the impact of tDCS intervention on qEEG spectral power activity and resting-state connectivity organization during eyes closed and eyes open protocols. QEEG data were acquired from eight patients suffering from moderate to severe anxiety-depression comorbid symptoms along with poor coping skills to manage stress and negative affect. Twelve control subjects allocated in the control group exhibiting low to moderate symptoms in both anxiety and depression conditions went also through the qEEG data acquisition. In addition, a sham-controlled study was conducted, and the patient group went through resting-state qEEG-tDCS neuromodulation once a week for ten weeks. Various-stage qEEG recordings were performed to inspect the efficacy of tDCS treatment during the modulation of brain regions involved in the regulation of affective responses. Our results demonstrated that after tDCS neuromodulation, the patients' groups exhibited decreased absolute power abnormalities over the left anterior cingulate cortex and reduced abnormal activity in the alpha band over posterior regions; improved functional connectivity indexes; decreased anxiety and depressive scores while positive affect score was improved. Besides the promising improvements, our study did not find a significant tDCS effect on perceived stress and negative affect scores. Consistently, significant differences in absolute spectral power over the left anterior cingulate cortex were detected among the patient group, as compared to the controls, as expected. Therefore, our study offers preliminary data to understand the neuroplasticity changes that potentially result from the manipulation of cortical excitability during affective regulation protocols followed by the consequent decrease of comorbid anxiety and depressive symptomatology. The pilot study was followed by prospective registration with ChiCTR2200062142.

Precision agriculture, driven by advanced technologies and data-driven decision-making, has emerged as a transformative approach to address global food demand, resource constraints, and sustainability challenges. In this context, Model Predictive Control (MPC) has garnered significant attention as a powerful control strategy capable of optimizing farming processes through predictive and anticipatory control actions. This review comprehensively explores the fundamentals and applications of MPC in precision agriculture. The review begins with an overview of MPC's principles, formulation, and optimization techniques, emphasizing its predictive and adaptable nature. Subsequently, it delves into the diverse applications of MPC in precision agriculture, including crop growth and yield optimization, pest and disease management, and autonomous machinery and robotics. The integration of MPC with precision agriculture machinery and its role in autonomous farming systems are also explored. Success stories and case studies highlight real-world applications of MPC, showcasing its positive impact on crop yields, resource utilization, and economic viability. Additionally, demonstrated benefits such as water conservation, reduced chemical usage, and improved produce quality attest to the significance of MPC in sustainable farming practices. While MPC offers numerous advantages, the review also discusses challenges, such as computational complexity, model uncertainty, and sensor reliability. The review concludes by underscoring MPC's potential in driving precision agriculture towards a more sustainable, efficient, and technologically advanced future.

Background: The role of hypothermia in post-arrest neuroprotection is controversial. Animal studies suggest potential benefits with lower temperatures, but high-fidelity ECPR models evaluating temperatures below 30 °C are lacking. Objectives: To determine whether rapid cooling to 24 °C initiated upon reperfusion reduces brain injury compared to 34 °C in a swine model of ECPR. Methods: Twenty-four female pigs had electrically induced VF and mechanical CPR for 30 min. Animals were cannulated for VA-ECMO and cooled to either 34 °C for 4 h (n = 8), 24 °C for 1 h with rewarming to 34 °C over 3 h (n = 7), or 24 °C for 4 h without rewarming (n = 9). Cooling was initiated upon VA-ECMO reperfusion by circulating ice water through the oxygenator. Brain temperature and cerebral and systemic hemodynamics were continuously monitored. After four hours on VA-ECMO, brain tissue was obtained for examination. Results: Target brain temperature was achieved within 30 min of reperfusion (p = 0.74). Carotid blood flow was higher in the 24 °C without rewarming group throughout the VA-ECMO period compared to 34 °C and 24 °C with rewarming (p

The multipurpose properties of mixed metal oxides have garnered significant interest. This study’s ternary composite of MnO2/CuO/ZrO2 (MCZ) exhibited promising morphology, conductivity and electrochemical performance. The MCZ nanocomposite was synthesized via hydrothermal methods. The impact of electrolytes like Potassium hydroxide (KOH) on supercapacitor features was investigated. XRD analysis determined the crystalline structure, while FTIR confirmed the presence of Cu–O, O-Mn–O and Zr–O bonds. SEM revealed uniform aggregated particles, and EDAX determined the elemental composition. BET analysis measured pore radius and surface area. With a 1 M KOH electrolyte, electrochemical performance was evaluated using CV, GCD, and EIS. The supercapacitor electrode exhibited a specific capacitance of 869.76 F/g at a scan rate of 5 mV/s. The symmetric supercapacitor device showed an energy density of 213.09 Wh/kg and a power density of 3.83 kW/kg, maintaining cycling stability after 5000 cycles. The nanocomposite displayed high ionization in the solvent, facilitating efficient ion movement for charge transfer in supercapacitors. The MCZ nanocomposite’s areal-specific capacitance was 119.04 mF/cm2, with areal energy and power densities of 0.081 mWh/cm2 and 1.3885 mW/cm2, respectively. Increasing the specific surface area of electrode materials enhances capacitance and energy storage capacity. This study suggests that MCZ nanocomposite materials can improve supercapacitor performance.

ABSTRACT: Transfer of Salmonella to internal organs of broilers over a 35 d grow-out period was evaluated. A total of 360 one-day old chicks were placed in 18 floor pens of 3 groups with 6 replicate pens each. On d 0, broilers were orally challenged with a cocktail of Salmonella (equal population of marked serovars; nalidixic acid-resistant S. Typhimurium, rifampicin-resistant S. Infantis, and kanamycin-resistant S. Reading) to have 3 groups: L (low; ∼2 log CFU/bird); M (medium; ∼5 log CFU/bird); and H (High; ∼8 log CFU/bird). On d 2, 7 and 35, 4 birds/pen were euthanized and ceca, liver, and spleen samples were collected aseptically. Gizzard samples (4/pen) were collected on d 35. The concentration of Salmonella in liver and spleen were transformed to binary outcomes (positive and negative) and fitted in glm function of R using cecal Salmonella concentrations (log CFU/g) and inoculation doses (L, M, and H) as inputs. On d 2, H group showed greater (P ≤ 0.05) cecal colonization of all 3 serovars compared to L and M groups. However, M group showed greater (P ≤ 0.05) colonization of all 3 serovars in the liver and spleen compared to L group. Salmonella colonization increased linearly in the ceca and quadratically in the liver and spleen with increasing challenge dose (P ≤ 0.05). On d 35, L group had greater (P ≤ 0.05) S. Infantis colonization in the ceca and liver compared to M and H groups (P ≤ 0.05). Moreover, within each group on d 35, the concentration of S. Reading was greater than those of S. Typhimurium and S. Infantis for all 3 doses in the ceca and high dose in the liver and gizzard (P ≤ 0.05). Salmonella colonization diminished in the ceca, liver, and spleen during grow-out from d 0 to d 35 (P ≤ 0.05). On d 35, birds challenged with different doses of Salmonella cocktail showed a similar total Salmonella spp. population in the ceca (ca. 3.14 log CFU/g), liver (ca. 0.54 log CFU/g), spleen (ca. 0.31 log CFU/g), and gizzard (ca. 0.42 log CFU/g). Estimates from the fitted logistic model showed that one log CFU/g increase in cecal Salmonella concentration will result in an increase in relative risk of liver and spleen being Salmonella-positive by 4.02 and 3.40 times (P ≤ 0.01), respectively. Broilers from H or M group had a lower risk (28 and 23%) of being Salmonella-positive in the liver compared to the L group when the cecal Salmonella concentration is the same (P ≤ 0.05). Oral challenge of broilers with Salmonella spp. with various doses resulted in linear or quadratic increases in Salmonella colonization in the internal organs during early age and these populations decreased during grow-out (d 35). This research can provide guidance on practices to effectively mitigate the risk of Salmonella from chicken parts and enhance public health.

As additive manufacturing (AM) production volumes grow to the industrial scale, quality systems must also scale to verify that every part satisfies requirements. Quality systems are particularly challenging for personalized medical devices, where every patient requires a unique design. This research studies the repeatability of an additively manufactured guide for knee surgery that is personalized to the size and shape of a patient and explores concepts for predicting geometric accuracy. We created 258 unique surgical guide designs with different sizes of the critical features to simulate practical conditions, and manufactured 2100 parts using multi-jet fusion AM. An automated measurement technique collected 8400 individual feature dimensions. Across four critical features, the standard deviation of feature size was 0.076 to 0.173 mm, however the accuracy was consistently different than the target dimensions by -0.308 to 0.017 mm. We show how machine learning (ML) models can predict these geometry distortions and explore the number of parts required to effectively train these models. The accuracy of these models are 0.033 to 0.075 mm, such that the part shape distortion can be accurately predicted to within one standard deviation across a wide range of part sizes.

Mucopolysaccharidosis type II (MPS II) is an X-linked recessive lysosomal disease caused by iduronate-2-sulfatase (IDS) deficiency, leading to accumulation of glycosaminoglycans (GAGs) and the emergence of progressive disease. Enzyme replacement therapy is the only currently approved treatment, but it leaves neurological disease unaddressed. Cerebrospinal fluid (CSF)-directed administration of AAV9.CB7.hIDS (RGX-121) is an alternative treatment strategy, but it is unknown if this approach will affect both neurologic and systemic manifestations. We compared the effectiveness of intrathecal (i.t.) and intravenous (i.v.) routes of administration (ROAs) at a range of vector doses in a mouse model of MPS II. While lower doses were completely ineffective, a total dose of 1 × 109 gc resulted in appreciable IDS activity levels in plasma but not tissues. Total doses of 1 × 1010 and 1 × 1011 gc by either ROA resulted in supraphysiological plasma IDS activity, substantial IDS activity levels and GAG reduction in nearly all tissues, and normalized zygomatic arch diameter. In the brain, a dose of 1 × 1011 gc i.t. achieved the highest IDS activity levels and the greatest reduction in GAG content, and it prevented neurocognitive deficiency. We conclude that a dose of 1 × 1010 gc normalized metabolic and skeletal outcomes, while neurologic improvement required a dose of 1 × 1011 gc, thereby suggesting the prospect of a similar direct benefit in humans.

The study examined organic vegetable attributes, consumer decisions and consumption patterns of consumers in Ghana. A sample of 399 consumers was selected using a simple random sampling technique and data was collected through structured questionnaires. The study analyzed the important attributes of organic vegetables using Kendall's coefficient of concordance. The factors influencing consumers' decision to consume organic vegetables and the proportion of their total expenditure allocated to organic vegetables was analyzed using Cragg's double hurdle model. Finally, ordered logit regression was employed to analyse the factors influencing the consumption patterns of organic vegetables consumers. The results revealed that consumers prioritize health concerns and sensory attributes when purchasing organic vegetables as these were identified as the most important attributes. Also, socioeconomic factors, viz. age group, educational level and income level, as well as institutional factors, viz. market type, availability of organic vegetables and accreditation, significantly influenced the decision and expenditure on organic vegetables. In addition, consumers exhibited irregular consumption patterns, and a significant proportion of consumers acquired information about organic vegetables through family and friends. Furthermore, the ordered logit regression analysis revealed several factors that significantly influenced the consumption patterns of organic vegetables. These include age category, educational level, household head, household size, income level, type of market, time to market, and accreditation. The study recommends that government and other stakeholders should consider consumers' consumption patterns, attributes of organic vegetables they consider prior to purchasing as well as factors influencing their decision-making when developing marketing strategies and policies for organic vegetable farmers. This approach can help meet consumer demands and help improve the development and promotion of organic vegetables in the market.

This case serves as a reminder of the infrequent, yet consequential occurrence of cerebellar degeneration linked to phenytoin usage. Whilst emphasizes the importance of monitoring patients on long-term phenytoin therapy, and it further suggests considering employing bedside imaging tools such as Ultrasound fusion imaging for follow-up of patients at risk of this type of disorder. We present a case study involving a 23-year-old woman who experienced significant neurological impairment resulting in severe cerebellar atrophy while undergoing phenytoin treatment. On cessation of phenytoin, the patient exhibited improvement with enhanced cerebellar function.

Summary: Background: The protection of fourth dose mRNA vaccination against SARS-CoV-2 is relevant to current global policy decisions regarding ongoing booster roll-out. We aimed to estimate the effect of fourth dose vaccination, prior infection, and duration of PCR positivity in a highly-vaccinated and largely prior-COVID-19 infected cohort of UK healthcare workers. Methods: Participants underwent fortnightly PCR and regular antibody testing for SARS-CoV-2 and completed symptoms questionnaires. A multi-state model was used to estimate vaccine effectiveness (VE) against infection from a fourth dose compared to a waned third dose, with protection from prior infection and duration of PCR positivity jointly estimated. Findings: 1298 infections were detected among 9560 individuals under active follow-up between September 2022 and March 2023. Compared to a waned third dose, fourth dose VE was 13.1% (95% CI 0.9 to 23.8) overall; 24.0% (95% CI 8.5 to 36.8) in the first 2 months post-vaccination, reducing to 10.3% (95% CI −11.4 to 27.8) and 1.7% (95% CI −17.0 to 17.4) at 2–4 and 4–6 months, respectively. Relative to an infection >2 years ago and controlling for vaccination, 63.6% (95% CI 46.9 to 75.0) and 29.1% (95% CI 3.8 to 43.1) greater protection against infection was estimated for an infection within the past 0–6, and 6–12 months, respectively. A fourth dose was associated with greater protection against asymptomatic infection than symptomatic infection, whilst prior infection independently provided more protection against symptomatic infection, particularly if the infection had occurred within the previous 6 months. Duration of PCR positivity was significantly lower for asymptomatic compared to symptomatic infection. Interpretation: Despite rapid waning of protection, vaccine boosters remain an important tool in responding to the dynamic COVID-19 landscape; boosting population immunity in advance of periods of anticipated pressure, such as surging infection rates or emerging variants of concern. Funding: UK Health Security Agency, Medical Research Council, NIHR HPRU Oxford, Bristol, and others.

Introduction: Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare and underdiagnosed condition, often presenting with variable symptoms, making it challenging to identify. This case report highlights the clinical relevance of CTEPH, emphasizing its misdiagnosis as asthma and the need for increased awareness in recognizing its atypical presentations. Objective: To present a case of CTEPH misdiagnosed as asthma, showcasing the importance of early identification and raising awareness about the underrepresentation of this disease. Case report: A 39-year-old male with a history of misdiagnosed asthma presented with progressive dyspnea. Despite treatment with inhalers, symptoms persisted. Further investigations revealed dilated pulmonary arteries, right ventricular dysfunction, and elevated pulmonary pressures. Subsequent examinations confirmed CTEPH, leading to referral for surgical thromboembolectomy. Postoperative assessments demonstrated significant improvements in hemodynamic parameters. Discussionconclusion: This case underscores the challenges in diagnosing CTEPH, especially when presenting as asthma. Heightened awareness among healthcare professionals is crucial for timely recognition, considering the potential for favorable outcomes with appropriate intervention. Recognition of CTEPH as a differential diagnosis for dyspnea, particularly in those with a history of pulmonary embolism, is essential for providing accurate diagnosis and timely intervention.

The chimney endovascular aortic repair technique has become an increasingly used option for the treatment of juxtarenal aortic aneurysms; however, type IA and gutter endoleaks complicate this approach in up to 5.9% of cases. Successful treatment of these leaks is challenging. We report a case of a patient who underwent two-vessel chimney endovascular aortic repair in the treatment of a 5.9-cm juxtarenal aortic aneurysm and developed a type IA endoleak. The endoleak was successfully treated with Heli-FX EndoAnchor placement. Resolution of the endoleak was noted at continued follow-up through 54 months.

This study aimed to assess the influence of the physical-chemical factors (particle size, shake flask speed, starting pH, and pulp density) in bioleaching of Zambian chalcopyrite using a novel native isolated Acidithiobacillus ferrooxidans strain DJN1 2021 from samples collected within mining area at Copper Nkana slag dump also known as the Black Mountain in Kitwe, Copperbelt Province in Zambia. The bacterium isolation was done using the modified 9 K selective media and was identified as A. ferrooxidans by using conventional procedures and 16S rRNA gene sequencing. The resulting sequences were analyzed by trimming and generating consensus sequences using Bio-edit software. Blasting results produced a significant alignment of 99.6% similarity with the corresponding sequences of A. ferrooxidans in GenBank. The phylogenetic analysis entails that the isolated strain was identified as A. ferrooxidans and named A. ferrooxidans strain DJN1 2021 with accession number MZ713091. Bioleaching of chalcopyrite (CuFeS2) by A. ferrooxidans (DJN1 2021) was conducted in shake flasks (100 ml) with a 9 K medium. The experiments were tested to optimize the initial pH, particle size, pulp density, and shake flask speed in the recovery of copper from its ore. The results revealed that all of the factors significantly influence the bioleaching process. When the initial pH was 1.8, copper was extracted at the rate of 30.6% within 30 bioleaching days. This was the maximum dissolution observed. The effect of revolution speed in the three different shake flask speeds (i.e. 50 rpm, 90 rpm, and 150 rpm) showed a significant difference in the rate of copper dissolution. A marked difference was observed between shake flask speeds of 50 rpm and 90 rpm with dissolutions of 29.4% and 30.0% respectively. In experiments to look into the effect of particle size, two size fractions were subjected to bioleaching on a shake flask, i.e. (

Summary: Rhabdomyosarcoma accounts for roughly 1% of adult sarcomas, with pleomorphic rhabdomyosarcoma (PRMS) as the most common subtype. Survival outcomes remain poor for patients with PRMS, and little is known about the molecular drivers of this disease. To better characterize PRMS, we performed a broad array of genomic and immunostaining analyses on 25 patient samples. In terms of gene expression and methylation, PRMS clustered more closely with other complex karyotype sarcomas than with pediatric alveolar and embryonal rhabdomyosarcoma. Immune infiltrate levels in PRMS were among the highest observed in multiple sarcoma types and contrasted with low levels in other rhabdomyosarcoma subtypes. Lower immune infiltrate was associated with complete loss of both TP53 and RB1. This comprehensive characterization of the genetic, epigenetic, and immune landscape of PRMS provides a roadmap for improved prognostications and therapeutic exploration.

In resource-limited settings, patients are often first presented to clinical settings when seriously ill and access to proper clinical microbial diagnostics is often very limited or non-existing. On February 16th, 2022 we were on a field trip to test a completely field-deployable metagenomics sequencing set-up, that includes DNA purification, sequencing, and bioinformatics analyses using bioinformatics tools installed on a laptop for water samples, just outside Moshi, Tanzania. On our way to the test site, we were contacted by the nearby Machame hospital regarding a child seriously ill with diarrhea and not responding to treatment. Within the same day, we conducted an onsite metagenomics examination of a fecal sample from the child, and Campylobacter jejuni was identified as the causative agent. The treatment was subsequently changed, with almost immediate improvement, and the child was discharged on February 21st.

Background: Considerable interest has been expressed in the use of bisphosphonates to treat periprosthetic osteoporosis with the clinical goals of reducing periprosthetic fractures and prolonging implant survival. Methods: A systematic review was performed with the goal of identifying both basic science and clinical studies related to the risks and benefits of bisphosphonate use in total joint arthroplasty. Results: Studies have shown that bisphosphonates may increase early bony ingrowth, decrease the postoperative loss of bone mineral density, and increase the longevity of implants by reducing the need for revisions secondary to aseptic loosening. Continuing bisphosphonates for 1 year postoperatively seems to provide the greatest benefit, with only marginal benefit being shown by continuing therapy for up to 2 years. Current data present some concerns for an increased risk of periprosthetic fractures especially in younger patients, and prolonged therapy is not recommended due to the potential risk of atypical femur fractures. Patients should be counseled regarding the risk of side effects of bisphosphonates, including the risk of osteonecrosis of the jaw, which is a rare but serious side effect. They should also be counseled on the risk of atypical femur fractures and gastrointestinal intolerance. Conclusions: Orthopedic surgeons could consider bisphosphonates for up to 1 year postoperatively regardless of the patient’s prior bone mineral density, after discussion regarding the risks and benefits with the patient.

Recent work has established associations between elevated p21, the accumulation of senescent cells, and skeletal muscle dysfunction in mice and humans. Using a mouse model of p21 overexpression (p21OE), we examined if p21 mechanistically contributes to cellular senescence and pathological features in skeletal muscle. We show that p21 induces several core properties of cellular senescence in skeletal muscle, including an altered transcriptome, DNA damage, mitochondrial dysfunction, and the senescence-associated secretory phenotype (SASP). Furthermore, p21OE mice exhibit manifestations of skeletal muscle pathology, such as atrophy, fibrosis, and impaired physical function when compared to age-matched controls. These findings suggest p21 alone is sufficient to drive a cellular senescence program and reveal a novel source of skeletal muscle loss and dysfunction.

Hippocampal sclerosis of aging (HS-A) is a common degenerative neuropathology in older individuals and is associated with dementia. HS-A is characterized by disproportionate hippocampal atrophy at autopsy but cannot be diagnosed during life. Therefore, little is known about the onset and progression of hippocampal atrophy in individuals with HS-A. To better understand the onset and progression of hippocampal atrophy in HS-A, we examined longitudinal hippocampal atrophy using serial MRI in participants with HS-A at autopsy (HS-A+, n = 8) compared to participants with limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) without HS-A (n = 13), Alzheimer’s disease neuropathologic change (ADNC) without HS-A or LATE-NC (n = 16), and those without these pathologies (n = 7). We found that participants with HS-A had lower hippocampal volumes compared to the other groups, and this atrophy preceded the onset of dementia. There was also some evidence that rates of hippocampal volume loss were slightly slower in those with HS-A. Together, these results suggest that the disproportionate hippocampal atrophy seen in HS-A may begin early prior to dementia.

The distribution of the high concentrations of arsenic (As) and fluoride (F-) in groundwater on a Pan-European scale could be explained by the geological European context (lithology and structural faults). To test this hypothesis, seventeen countries and eighteen geological survey organizations (GSOs) have participated in the dataset. The methodology has used the HydroGeoToxicity (HGT) and the Baseline Concentration (BLC) index. The results prove that most of the waters considered in this study are in good conditions for drinking water consumption, in terms of As and/or F- content. A low proportion of the analysed samples present HGT≥ 1 levels (4% and 7% for As and F-, respectively). The spatial distribution of the highest As and/or F- concentrations (via BLC values) has been analysed using GIS tools. The highest values are identified associated with fissured hard rock outcrops (crystalline rocks) or Cenozoic sedimentary zones, where basement fractures seems to have an obvious control on the distribution of maximum concentrations of these elements in groundwaters.

Decarbonising economies and improving environment can be enhanced through circular economy, energy, and environmental systems integrating electricity, water, and gas utilities. Hydrogen production can facilitate intermittent renewable electricity through reduced curtailment of electricity in periods of over production. Positioning an electrolyser at a wastewater treatment plant with existing sludge digesters offers significant advantages over stand-alone facilities. This paper proposes co-locating electrolysis and biological methanation technologies at a wastewater treatment plant. Electrolysis can produce oxygen for use in pure or enhanced oxygen aeration, offering a 40% reduction in emissions and power demand at the treatment facility. The hydrogen may be used in a novel biological methanation system, upgrading carbon dioxide (CO2) in biogas from sludge digestion, yielding a 54% increase in biomethane production. A 10 MW electrolyser operating at 80% capacity would be capable of supplying the oxygen demand for a 426,400 population equivalent wastewater treatment plant, producing 8,500 tonnes dry solids per annum (tDS/a) of sludge. Digesting the sludge could generate 1,409,000 m3CH4/a and 776,000 m3CO2/a. Upgrading the CO2 to methane would consume 22.2% of the electrolyser generated hydrogen and capture 1.534 ktCO2e/a. Hydrogen and methane are viable advanced transport fuels that can be utilised in decarbonising heavy transport. In the proposed circular economy, energy, and environment system, sufficient fuel would be generated annually for 94 compressed biomethane gas (CBG) heavy goods vehicles (HGV) and 296 compressed hydrogen gas fuel cell (CHG) HGVs. Replacement of the equivalent number of diesel HGVs would offset approximately 16.1 ktCO2e/a.

Purpose: Clinical OCT angiography (OCTA) of the retinal microvasculature offers a quantitative correlate to systemic disease burden and treatment efficacy in sickle cell disease (SCD). The purpose of this study was to use the higher resolution of adaptive optics scanning light ophthalmoscopy (AOSLO) to elucidate OCTA features of parafoveal microvascular compromise identified in SCD patients. Design: Case series of 11 SCD patients and 1 unaffected control. Participants: A total of 11 eyes of 11 SCD patients (mean age, 33 years; range, 23–44; 8 female, 3 male) and 1 eye of a 34-year-old unaffected control. Methods: Ten sequential 3 × 3 mm parafoveal OCTA full vascular slab scans were obtained per eye using a commercial spectral domain OCT system (Avanti RTVue-XR; Optovue). These were used to identify areas of compromised perfusion near the foveal avascular zone (FAZ), designated as regions of interest (ROIs). Immediately thereafter, AOSLO imaging was performed on these ROIs to examine the cellular details of abnormal perfusion. Each participant was imaged at a single cross-sectional time point. Additionally, 2 of the SCD patients were imaged prospectively 2 months after initial imaging to study compromised capillary segments across time and with treatment. Main Outcome Measures: Detection and characterization of parafoveal perfusion abnormalities identified using OCTA and resolved using AOSLO imaging. Results: We found evidence of abnormal blood flow on OCTA and AOSLO imaging among all 11 SCD patients with diverse systemic and ocular histories. Adaptive optics scanning light ophthalmoscopy imaging revealed a spectrum of phenomena, including capillaries with intermittent blood flow, blood cell stasis, and sites of thrombus formation. Adaptive optics scanning light ophthalmoscopy imaging was able to resolve single sickled red blood cells, rouleaux formations, and blood cell–vessel wall interactions. OCT angiography and AOSLO imaging were sensitive enough to document improved retinal perfusion in an SCD patient 2 months after initiation of oral hydroxyurea therapy. Conclusions: Adaptive optics scanning light ophthalmoscopy imaging was able to reveal the cellular details of perfusion abnormalities detected using clinical OCTA. The synergy between these clinical and laboratory imaging modalities presents a promising avenue in the management of SCD through the development of noninvasive ocular biomarkers to prognosticate progression and measure the response to systemic treatment.

ABSTRACT: For many, digital transformation is the new normal. However, in particular, pipeline businesses in traditional industries, such as standard-setting organizations (SSOs), are reluctant to radically rethink their business models, as they have often successfully prevailed for decades. The literature shows that there is a great deal of theory to be found on digital transformation, but a practical and, at the same time, scientific approach is yet missing. Following the design science framework, this paper introduces a two-step approach to transform a pipeline business model into a digital standardization platform. This is achieved by mapping the incumbent pipeline business mode146l and its ecosystem with the Platform Business Model Canvas introduced by Eisape. The representation of the current ecosystem is then digitally transformed according to the three key transformation points introduced by Alstyne et al., shifting the current ecosystem into the digital realm. The illustrative case study on DIN e.V. (the German SSOs) demonstrates the new methodology and its suitability for real applications. The result is a platform business model for a digital standardization platform, which, compared via an index to the traditional business model, has the potential to disrupt the entire standardization industry.

Namibia is ethnically diverse and rich in indigenous knowledge on the medicinal uses of plants. However, this knowledge in treating gastrointestinal conditions is not well documented despite its contributions to the healthcare system in Namibia. This study aimed at documenting the ethnomedicinal uses of plants used to treat gastrointestinal conditions in the Iikokola village and validating their use through phytochemical analysis. A survey was conducted using semi-structured questionnaires with consenting knowledge holders. Voucher specimens were collected and deposited with the National Herbarium of Namibia for botanical nomenclature. Among the 26 knowledge holders approached 23 participated in the study, of which 16 were females and 7 were males. A total of 19 plant species belonging to 10 plant families were reported to treat at least one gastrointestinal condition and 14 other ailments. Most species belong to Fabaceae and Combretaceae families (FIV=100). The gastrointestinal use of 32% of the plants documented in this study has not been reported elsewhere. Diarrhea, vomiting, and stomach pain are frequently managed using medicinal plants. Decoctions from roots of Grewia tenax, Terminalia sericea, Corchorus tridens, Albizia anthelmintica, and Lantana camara, were mostly used for gastrointestinal ailments. Oral administration was the only route used in the administration of gastrointestinal remedies, among all age groups. Phytochemical compounds such as coumarins, flavonoids, saponins, and tannins which have been linked to the antidiarrheal activity of plants, were detected in organic and aqueous extracts. Organic extracts of T. sericea and G. tenax showed higher total phenolic and flavonoid contents ≤ 169.46 and ≤ 74.03 mg QE/g respectively. These phytochemical properties add value to their ethnomedicinal use is rational although antimicrobial properties and safety profile should be determined. The traditional uses of medicinal plants reported in this study will help safeguard and guide future research aiming at developing plant-based treatments for gastrointestinal conditions.

We report a case of reinfection by SARS-CoV-2 with the second virus harboring amino acid changes in the Spike protein (141-143del, D215A, ins215AGY, L452R, D614G), orf1a, helicase, orf3a, and Nucleocapside. The virus associated with the reinfection, from an endemic lineage containing the S:L452R immune escape mutation, was circulating in Panama at the time.

Introduction: Although Graves' disease (GD) is the most common cause of hyperthyroidism in adolescents, it is very rare for it to result from the production of thyroid-stimulating hormone (TSH) receptor autoantibodies due to Graves' immune reconstitution inflammatory syndrome (IRIS). Especially for paediatric patients, very little is known about the aetiology and complete pathogenesis of Graves’ IRIS. Furthermore, details of a valid treatment plan are severely lacking. The case report presented here is only the third for paediatric patients worldwide. Case presentation: We report on a Caucasian female adolescent who initially presented with non-specific complaints about discomfort and tightness in the anterior part of the neck and thyroid enlargement. Based on clinical, laboratory and thyroid ultrasound findings, she was diagnosed with GD. However, after several months of outpatient treatment, the patient's GD could still not be fully managed with conservative therapy alone. Only when the patient was hospitalized for the third time was it discovered that she had previously been diagnosed with human immunodeficiency virus infection and had received highly active antiretroviral therapy (HAART) for the previous 29 months. Consequently, the production of autoantibodies to TSH receptors and abnormal changes in thyroid hormones had led to the development of GD and her final diagnosis was established as Graves' IRIS. Ultimately, a total thyroidectomy was performed. Discussion/conclusion: This case report demonstrates how fundamentally important it is to have full access to a patient's complete anamnesis and results of all previous investigations. Clinicians should be made aware of the potential existence of thyroid dysfunction and other autoimmune or infectious processes in paediatric patients initiating or reinitiating HAART. Further research is needed to optimize the treatment for such paediatric patients.

A glasshouse experiment was conducted to understand the influence of rhizobia, Bradyrhizobium liaoningense and an arbuscular mycorrhizal fungus, Ambispora leptoticha on growth and yield performance of soybean cultivars, MAUS 2 and MAUS 212 (drought susceptible) and DSR 12 (drought tolerant) under different levels of moisture stress conditions. Three different water levels [100%, 75% and 50% FC] with three microbial inocula (B. liaoningense, A. leptoticha and B. liaoningense + A. leptoticha) served as main treatments and the water level treatments were imposed 31–45 days after sowing. Various growth, physiological and microbial parameters were recorded besides analysing the samples for nutrients. The results showed that the plant growth parameters like biovolume index, total dry biomass, root volume and seed yield were significantly higher in dual inoculated plants in all the cultivars at all the moisture levels. There was an increase in mean seed weight by 88% and dry biomass by 58% in dual inoculated plants compared to uninoculated plants. Further physiological parameters and nutrients level improved significantly with dual inoculation under stress condition. However significant difference in recorded parameters was not observed in plants grown at 100% and 75% FC suggesting dual inoculation of B. liaoningense + A. leptoticha is beneficial when stress is severe in all the 3 cultivars. The microbial and nutrient parameters followed the same trend. Further of the two drought susceptible cultivars, MAUS 2 performed better compared to MAUS 212 in all the studied parameters under stress with dual inoculation. The results therefore signify the importance of rhizobia and mycorrhizal inoculation for imparting stress tolerance in soybean.

Methicillin-resistant Staphylococcus aureus (MRSA) is resistant to beta-lactam antibiotics, while some strains are multi-drug resistant and may produce disease-causing toxins. Drug resistant strains are often responsible for chronic, persistent and recurrent infections, which pose a challenge for healthcare practitioners. Our study aimed to determine the prevalence of nasal MRSA and methicillin-resistant coagulase-negative staphylococci (MRCoNS) among school children in the Mariental community, southern Namibia. This was a cross-sectional study in the Mariental District. Nasal specimens (swabs) were collected from 272 randomly selected learners aged 6–14 years attending school in the area during the months of March, September and October 2016. Isolation and identification of staphylococci were performed using standard microbiological methods. Methicillin-resistant isolates were identified by their resistance towards cefoxitin (30 µg) using the Kirby-Bauer disk diffusion assay. Enterotoxin production among multi-drug resistant MRSA isolates was detected with a SET-RPLA toxin detection kit. Methicillin-resistant S. aureus was isolated from 48 (17.6%) learners and MRCoNS from only seven (2.6%). Methicillin-resistant S. aureus colonization was significantly higher (P = 0.003) in the age group 11–14 years than in the group 6–10 years. Among the 433 staphylococcal isolates screened for cefoxitin resistance, 51 (11.8%) were MRSA and seven (1.6%) were MRCoNS. From the 51 MRSA isolates, 22 (43.1%) were multi-drug resistant of which six were enterotoxigenic. This is the first report on MRSA and MRCoNS among school children in Namibia. The presence of multi-drug resistant and potentially virulent staphylococci among school children in Mariental, Namibia, is of concern. Self-infection by these bacteria poses various health risks for the children. It is recommended that school health programmes improve current hygiene practices. Frequent handwashing can prevent staphylococcal disease and spread of resistant strains among learners and the wider community.

Purpose: To report the impact of intravitreal anti–vascular endothelial growth factor (VEGF) therapy on a retinal capillary hemangioma (RCH) using clinical OCT angiography (OCT-A) in addition to standard imaging modalities. Observations: A 25-year-old male patient with Von Hippel-Lindau (VHL) disease presented with a history of bilateral RCH. No view was present in the right eye. Examination of the left eye revealed six peripheral RCH, the smallest of which was temporal to the macula with active exudation. This RCH was thought to be the source of cystoid macular edema (CME) involving the fovea, and therefore, the source of vision decline. 11 injections of 1.25mg of Bevacizumab EA across 14-month was given. Comparison of the pre- and post-treatment OCT-A at the temporal RCH showed a reduction of CME and regression of RCH. Conclusion: Anti-VEGF therapy appeared to stabilize the visual acuity and produce partial regression of RCH. It offers a safe option when visual acuity is threatened. OCT and OCT-A have the ability to document the impact of antiangiogenic therapy on RCH. 3D renderings of OCT-A offer enhanced sensitivity to recognition of structural and functional changes of RCH which may prove useful for monitoring treatment response.

Summary: Background: Due to challenges in measuring changes in malaria at low transmission, serology is increasingly being used to complement clinical and parasitological surveillance. Longitudinal studies have shown that serological markers, such as Etramp5.Ag1, can reflect spatio-temporal differences in malaria transmission. However, these markers have yet to be used as endpoints in intervention trials. Methods: Based on data from a 2017 cluster randomised trial conducted in Zambezi Region, Namibia, evaluating the effectiveness of reactive focal mass drug administration (rfMDA) and reactive vector control (RAVC), this study conducted a secondary analysis comparing antibody responses between intervention arms as trial endpoints. Antibody responses were measured on a multiplex immunoassay, using a panel of eight serological markers of Plasmodium falciparum infection - Etramp5.Ag1, GEXP18, HSP40.Ag1, Rh2.2030, EBA175, PfMSP119, PfAMA1, and PfGLURP.R2. Findings: Reductions in sero-prevalence to antigens Etramp.Ag1, PfMSP119, Rh2.2030, and PfAMA1 were observed in study arms combining rfMDA and RAVC, but only effects for Etramp5.Ag1 were statistically significant. Etramp5.Ag1 sero-prevalence was significantly lower in all intervention arms. Compared to the reference arms, adjusted prevalence ratio (aPR) for Etramp5.Ag1 was 0.78 (95%CI 0.65 – 0.91, p = 0.0007) in the rfMDA arms and 0.79 (95%CI 0.67 – 0.92, p = 0.001) in the RAVC arms. For the combined rfMDA plus RAVC intervention, aPR was 0.59 (95%CI 0.46 – 0.76, p < 0.0001). Significant reductions were also observed based on continuous antibody responses. Sero-prevalence as an endpoint was found to achieve higher study power (99.9% power to detect a 50% reduction in prevalence) compared to quantitative polymerase chain reaction (qPCR) prevalence (72.9% power to detect a 50% reduction in prevalence). Interpretation: While the observed relative reduction in qPCR prevalence in the study was greater than serology, the use of serological endpoints to evaluate trial outcomes measured effect size with improved precision and study power. Serology has clear application in cluster randomised trials, particularly in settings where measuring clinical incidence or infection is less reliable due to seasonal fluctuations, limitations in health care seeking, or incomplete testing and reporting. Funding: This study was supported by Novartis Foundation (A122666), the Bill & Melinda Gates Foundation (OPP1160129), and the Horchow Family Fund (5,300,375,400).

The geophysical investigation of dambo groundwater reserves using electrical resistivity methods was conducted in Linthipe 4B sub basin in Central region of Malawi. With the increasing over-utilization of shallow wells in dambos for smallholder irrigation, this study was carried out to investigate whether dambo groundwater reserves could serve as sustainable irrigation water sources and to examine the aquifer characteristics in Linthipe sub basin. Vertical Electrical Sounding (VES) points were established in the basin using the Schlumberger configuration array. Data was analysed using IPI2win and Surfer software applications. Contrary to other commercial software applications which are costly for government departments when analysing geophysical data, partial curve matching and one dimensional (1-D) computer iteration techniques were used to interpret the VES curves and the pseudo-cross section resistivity profiles due to their simplicity and cost-effectiveness. The study has revealed that the aquifer properties in the basin are exceptionally variable in terms of state of weathering, depth, thickness, lithology, aquifer recharge configuration, geologic material and hydraulic gradients. These variations showed that the shallow wells in the basin have significant fractures suggesting high water potential for climate smart irrigation usage in the study area. The potential groundwater zones for climate smart irrigated farming were detected at VES 1, 2, 3, 4, 5 and 6 noted by low aquifer resistivity with high values of aquifer thickness. However, VES points, 7, 8 and 9 were likely to be zones of low water bearing potential because they had high values of aquifer resistivity with low aquifer thickness. The findings also validated the effectiveness, timeliness, and efficiency of using vertical electrical resistivity technique in exploring groundwater for irrigation. The results from this study have highlighted that feasible shallow well depth for a sustainable irrigation system is a function of geologic resistance and aquifer thickness when the geologic material has low resistance and broader thickness. This study noted that knowledge of aquifer recharge rates in dambos is required in order to effectively control abstraction rates for sustainable irrigation in basins. There is a need to promote the usage of geophysical studies, reforestation, river basin management trainings and aquifer recharge technologies in exploring sites for shallow well development for irrigation. The study further recommends the usage of geographical information systems (GIS) and Artificial Intelligence (AI) in improving the results of groundwater monitoring studies in Malawi.

Fibrin- associated diffuse large B cell lymphoma (FA-DLBCL) is a rare entity, often incidental finding, categorized under “diffuse large B cell lymphoma associated with chronic inflammation (DLBCL-CI)“ in 2017 World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues. Here we report a 48-year-old male with FA-DLBCL who experienced recurrence within one year from initial presentation. The patient had a history of an abdominal aortic aneurism and underwent an endovascular aneurysm repair (EVAR) in 2013. Later in 2019, he was found by CT aortogram to have endoleak of the aneurysm repair. He underwent an open abdominal aortic aneurysm repair with explant of the endovascular stent. The explanted graft was sent to pathology and was found on gross examination to have ample adherent tissue. On microscopic examination this tissue was composed of abundant fibrinous material with several foci of large pleomorphic lymphocytes with enlarged round to polyhedral nuclei, prominent nucleoli, open chromatin, and scanty cytoplasm. Necrosis was also seen in a largest focus of tumor infiltrate. By immunohistochemistry, the atypical, large lymphocytes expressed CD20 and MUM-1; and positive for EBV, by Epstein-Barr virus (EBV) in situ hybridization (EBER-ISH). Together, the diagnosis for FA-DLBCL was made. Further work up by PET scan showed no active disease. The patient re-presented 10 months later with right lower extremity ischemia due to the vascular graft thrombosis. The thrombectomy specimen showed identical findings of his initial FA- DLBCL. Here we discuss the clinicopathologic findings of this entity and the importance of clinical follow up.

Background/purpose: Intraoral and perioral burning sensations may be sequelae of burning mouth syndrome (BMSD) or burning mouth symptoms (BMSP), which present a diagnostic challenge. The aims of the study were to evaluate the efficacy of a topical anesthetic as a diagnostic test to differentiate BMSD from BMSP and to assess the comorbidities and responses to various pharmacologic treatments in BMSD and BMSP patients. Materials and methods: A total of forty-four charts of patients with burning mouth that visited the Rutgers School of Dental Medicine Orofacial Pain Clinic between January 1st, 2000 and November 1st, 2014 were retrospectively reviewed. Twenty patients were diagnosed with BMSD, and 24 patients were diagnosed with BMSP attributed to local and systemic causes. The diagnosis was determined per the guidelines of the International Association for the Study of Pain and American Academy of Orofacial Pain. The main goal of this study was to evaluate the effect of topical anesthetic medication applied to the burning site. Results: The percentage of change in pain reduction following topical anesthetic application in the BMSP group was significantly higher than that of the BMSD group (p

Summary: Skeletal muscle is composed of post-mitotic myofibers that form a syncytium containing hundreds of myonuclei. Using a progressive exercise training model in the mouse and single nucleus RNA-sequencing (snRNA-seq) for high-resolution characterization of myonuclear transcription, we show myonuclear functional specialization in muscle. After 4 weeks of exercise training, snRNA-seq reveals that resident muscle stem cells, or satellite cells, are activated with acute exercise but demonstrate limited lineage progression while contributing to muscle adaptation. In the absence of satellite cells, a portion of nuclei demonstrates divergent transcriptional dynamics associated with mixed-fate identities compared with satellite cell replete muscles. These data provide a compendium of information about how satellite cells influence myonuclear transcription in response to exercise.

Purpose: Fundus albipunctatus is an inherited cause of congenital stationary night blindness. The objective of this report is to describe structural changes occurring in a macular phenotype of a novel RDH5 mutation producing fundus albipunctatus using high-resolution in vivo imaging. A 62-year-old male with longstanding night blindness underwent imaging and genetic evaluation. High-resolution images of the photoreceptor mosaic were compared to those of a healthy subject. Results of a comprehensive ophthalmic evaluation and genetic testing with imaging including fundus photography, spectral-domain optical coherence tomography (OCT), fluorescein angiography (FA), OCT angiography (OCT-A), and adaptive optics scanning light ophthalmoscopy (AOSLO) are described. Observations: The patient presented with visual acuity of 20/25 in both eyes and longstanding poor dark adaptation. Anterior segment examination was unremarkable. Fundoscopy revealed well circumscribed bilateral perifoveal mottling and atrophy in both eyes. Discrete white-yellow flecks were present beyond the vascular arcades extending to the far periphery. Genetic testing revealed a novel compound heterozygous RDH5 mutation (c.388C > T, p.Gln130*; c.665T > C, p.Leu222Pro). OCT demonstrated perifoveal photoreceptor and outer retinal irregularities, which corresponded to a window defect with late staining on FA. OCT-A demonstrated normal retinal vasculature with patchy areas of non-perfusion in the choriocapillaris. Macular abnormalities in both eyes were imaged using AOSLO to assess cone and rod photoreceptor architecture. While clinical features are consistent with a primary rod disorder, confocal AOSLO showed a paucity of normal cones with a small spared central island in both eyes. Rods appeared larger and more irregular throughout the macula. Non-confocal split detection AOSLO imaging revealed the presence of cone inner segments in dark regions of confocal imaging, indicating some degree of photoreceptor preservation. Conclusions and Importance: The AOSLO imaging of this particular macular phenotype of fundus albipunctatus demonstrates some of the structural photoreceptor abnormalities that occur in this condition, adding insight to the variable presentation of RDH5 retinopathy. The presence of preserved inner segment architecture suggests the possibility that gene therapy could play a future role in treating this condition.

Biconformal gravity, based on gauging of the conformal group to 2n dimensions, reproduces n-dim scale-covariant general relativity on the co-tangent bundle in any dimension. We generalize this result to include Yang-Mills matter sources formulated as SU(N) gauge theories with a twisted action on the full 2n-dimensional biconformal space. We show that the coupling of the sources to gravity does not stop the reduction of effective dimension 2n→n of the gravity theory, and instead forces the Yang-Mills source to reduce to ordinary n-dimensional Yang-Mills theory on the gravitating cotangent bundle, with the usual Yang-Mills energy tensor as gravitational source. The results apply as well to gravity with sources on Kähler manifolds and in double field theories.

Background: Cognitive behavioural therapy (CBT), incorporating exposure and response prevention (ERP) is widely recognised as the psychological treatment of choice for obsessive-compulsive disorder (OCD). Uncertainty remains however about the magnitude of the effect of CBT with ERP and the impact of moderating factors in patients with OCD. Method: This systematic review and meta-analysis assessed randomised-controlled trials of CBT with ERP in patients of all ages with OCD. The study was preregistered in PROSPERO (CRD42019122311). The primary outcome was end-of-trial OCD symptom scores. The moderating effects of patient-related and study-related factors including type of control intervention and risk of bias were examined. Additional exploratory analyses assessed the effects of treatment fidelity and impact of researcher allegiance. Results: Thirty-six studies were included, involving 2020 patients (537 children/adolescents and 1483 adults) with 1005 assigned to CBT with ERP and 1015 to control conditions. When compared against all control conditions, a large pooled effect size (ES) emerged in favour of CBT with ERP (g = 0.74: 95% CI = 0.51 to 0.97 k = 36), which appeared to diminish with increasing age. While CBT with ERP was more effective than psychological placebo (g = 1.13 95% CI 0.71 to 1.55, k = 10), it was no more effective than other active forms of psychological therapy (g = −0.05: 95% CI -0.27 to 0.16, k = 8). Similarly, whereas CBT with ERP was significantly superior when compared to all forms of pharmacological treatment (g = 0.36: 95% CI 0.7 to 0.64, k = 7), the effect became marginal when compared with adequate dosages of pharmacotherapy for OCD (g = 0.32: 95% CI -0.00 to 0.64, k = 6).A minority of studies (k = 8) were deemed to be at low risk of bias. Moreover, three quarters of studies (k = 28) demonstrated suspected researcher allegiance and these studies reported a large ES (g = 0.95: 95% CI 0.69 to 1.2), while those without suspected researcher allegiance (k = 8) indicated that CBT with ERP was not efficacious (g = 0.02: 95% CI -0.29 to 0.33). Conclusions: A large effect size was found for CBT with ERP in reducing the symptoms of OCD, but depends upon the choice of comparator control. This meta-analysis also highlights concerns about the methodological rigor and reporting of published studies of CBT with ERP in OCD. In particular, efficacy was strongly linked to researcher allegiance and this requires further future investigation.

The role of immunotherapy in bladder urothelial cancers is rapidly expanding. Since the initial second-line therapy approval for patients who fail prior platinum-based chemotherapy, the use of immunotherapy with checkpoint inhibitors has been rapidly evolving. There are approved indications for first-line metastatic disease in the platinum-ineligible patients or the cisplatin-ineligible PD-L1 positive patients, and there is a label for high-risk non-muscle-invasive bladder cancer who are BCG-refractory. In addition, a trial on maintenance immunotherapy with avelumab showed positive findings with improvement in overall survival that has also changed standard of care for these patients. There are ongoing clinical trials evaluating its use in the neoadjuvant and adjuvant perioperative muscle-invasive bladder cancer setting. The pivotal trials that led to these FDA approvals and promising and ongoing trials are discussed herein.

Summary: Histone methyltransferase KMT2D harbors frequent loss-of-function somatic point mutations in several tumor types, including melanoma. Here, we identify KMT2D as a potent tumor suppressor in melanoma through an in vivo epigenome-focused pooled RNAi screen and confirm the finding by using a genetically engineered mouse model (GEMM) based on conditional and melanocyte-specific deletion of KMT2D. KMT2D-deficient tumors show substantial reprogramming of key metabolic pathways, including glycolysis. KMT2D deficiency aberrantly upregulates glycolysis enzymes, intermediate metabolites, and glucose consumption rates. Mechanistically, KMT2D loss causes genome-wide reduction of H3K4me1-marked active enhancer chromatin states. Enhancer loss and subsequent repression of IGFBP5 activates IGF1R-AKT to increase glycolysis in KMT2D-deficient cells. Pharmacological inhibition of glycolysis and insulin growth factor (IGF) signaling reduce proliferation and tumorigenesis preferentially in KMT2D-deficient cells. We conclude that KMT2D loss promotes tumorigenesis by facilitating an increased use of the glycolysis pathway for enhanced biomass needs via enhancer reprogramming, thus presenting an opportunity for therapeutic intervention through glycolysis or IGF pathway inhibitors.

Summary: Background: Sick newborns admitted to neonatal units in low-resource settings are at an increased risk of developing hospital-acquired infections due to poor clinical care practices. Clusters of infection, due to the same species, with a consistent antibiotic resistance profile, and in the same ward over a short period of time might be indicative of an outbreak. We used whole-genome sequencing (WGS) to define the transmission pathways and characterise two distinct outbreaks of neonatal bacteraemia in a west African neonatal unit. Methods: We studied two outbreaks of Burkholderia cepacia and multidrug-resistant extended spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae in a neonatal unit that provides non-intensive care on the neonatal ward in the Edward Francis Small Teaching Hospital, Banjul, The Gambia. We used WGS to validate and expand findings from the outbreak investigation. We retrospectively sequenced all clinical isolates associated with each outbreak, including isolates obtained from swabs of ward surfaces, environmental fluid cultures, intravenous fluids, and antibiotics administered to newborns. We also sequenced historical B cepacia isolates associated with neonatal sepsis in the same ward. Results: Between March 1 and Dec 31, 2016, 321 blood cultures were done, of which 178 (55%) were positive with a clinically significant isolate. 49 episodes of neonatal B cepacia bacteraemia and 45 episodes of bacteraemia due to ESBL-producing K pneumoniae were reported. WGS revealed the suspected K pneumoniae outbreak to be contemporaneous outbreaks of K pneumoniae (ST39) and previously unreported Klebsiella quasipneumoniae subspecies similipneumoniae (ST1535). Genomic analysis showed near-identical strain clusters for each of the three outbreak pathogens, consistent with transmission within the neonatal ward from extrinsically contaminated in-use intravenous fluids and antibiotics. Time-dated phylogeny, including retrospective analysis of archived bacterial strains, suggest B cepacia has been endemic in the neonatal ward over several years, with the Klebsiella species a more recent introduction. Interpretation: Our study highlights the emerging threat of previously unreported strains of multidrug-resistant Klebsiella species in this neonatal unit. Genome-based surveillance studies can improve identification of circulating pathogen strains, characterisation of antimicrobial resistance, and help understand probable infection acquisition routes during outbreaks in newborn units in low-resource settings. Our data provide evidence for the need to regularly monitor endemic transmission of bacteria within the hospital setting, identify the introduction of resistant strains from the community, and improve clinical practices to reduce or prevent the spread of infection and resistance. Funding: Medical Research Council Unit The Gambia at the London School of Hygiene & Tropical Medicine, Fajara, The Gambia.

Summary: Cell cycle progression and cell fate decisions are closely linked in human pluripotent stem cells (hPSCs). However, the study of these interplays at the molecular level remains challenging due to the lack of efficient methods allowing cell cycle synchronization of large quantities of cells. Here, we screened inhibitors of cell cycle progression and identified nocodazole as the most efficient small molecule to synchronize hPSCs in the G2/M phase. Following nocodazole treatment, hPSCs remain pluripotent, retain a normal karyotype and can successfully differentiate into the three germ layers and functional cell types. Moreover, genome-wide transcriptomic analyses on single cells synchronized for their cell cycle and differentiated toward the endoderm lineage validated our findings and showed that nocodazole treatment has no effect on gene expression during the differentiation process. Thus, our synchronization method provides a robust approach to study cell cycle mechanisms in hPSCs. : In this study, Vallier and colleagues show that small molecule cell cycle inhibitors can be used to successfully synchronize and enrich hPSCs in different cell cycle phases. Particularly, the G2/M inhibitor nocodazole successfully enriched cells in G2/M, G1, and S phases of the cell cycle, without affecting pluripotency and differentiation capacity as shown by molecular and genome-wide single-cell RNA-seq analyses. Keywords: hPSCs, cell cycle, nocodazole, cell cycle synchronization, single-cell RNA-seq, mesoderm, endoderm, ectoderm

Summary: Background: An estimated 5·1 million stillbirths and neonatal deaths occur annually. Household surveys, most notably the Demographic and Health Survey (DHS), run in more than 90 countries and are the main data source from the highest burden regions, but data-quality concerns remain. We aimed to compare two questionnaires: a full birth history module with additional questions on pregnancy losses (FBH+; the current DHS standard) and a full pregnancy history module (FPH), which collects information on all livebirths, stillbirths, miscarriages, and neonatal deaths. Methods: Women residing in five Health and Demographic Surveillance System sites within the INDEPTH Network (Bandim in Guinea-Bissau, Dabat in Ethiopia, IgangaMayuge in Uganda, Matlab in Bangladesh, and Kintampo in Ghana) were randomly assigned (individually) to be interviewed using either FBH+ or FPH between July 28, 2017, and Aug 13, 2018. The primary outcomes were stillbirths and neonatal deaths in the 5 years before the survey interview (measured by stillbirth rate [SBR] and neonatal mortality rate [NMR]) and mean time taken to complete the maternity history section of the questionnaire. We also assessed between-site heterogeneity. This study is registered with the Research Registry, 4720. Findings: 69 176 women were allocated to be interviewed by either FBH+ (n=34 805) or FPH (n=34 371). The mean time taken to complete FPH (10·5 min) was longer than for FBH+ (9·1 min; p

The present study, deal about the antibiosis activity of soil bacteria, isolated from 10 different locations of rhizosphere and diverse cultivation at Kochi, Kerala, India. The bacteria were isolated by standard serial dilution plate techniques. Morphological characterization of the isolate was done by Gram’s staining and found that all of them gram positive. Isolated bacteria were tested against 6 human pathogens viz., Escherichia coli, Enterococcus sp., Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus aureus and Acinetobacter sp. Primary screening was carried out by perpendicular streaking and seed overlay method. Based on the result of primary screening most potential isolates of S1A1 and S7A3 were selected for secondary screening. Both the isolates showed positive results against Enterococcus sp. and S.aureus. The maximum antagonistic activity of 20.98 and 27.08 mm zone of inhibition was recorded at S1A1 against Enterococcus sp. and S. aureus respectively, at 180 µl concentration. Molecular identification was carried out by 16S rRNA sequence. The 16S rRNA was amplified from the DNA samples by using PCR. The amplified 16S rRNA PCR products were purified and sequenced. The sequences were subjected to NCBI BLAST. The isolates S1A1 and S7A3 BLAST results showed 99% and 95% respectively, similarity with the available database sequence of Bacillus amyloliquefaciens. The sequences were deposited in GenBank and the accession numbers KY864390 (S1A1) and KY880975 (S7A3) were obtained. Keywords: Soil bacteria, Isolates, 16S rRNA, PCR