Protracted Delay Research Articles

Harnessing the host response for precision infectious disease diagnosis.

SUMMARYDetection of the presence of infection and its etiology must be accurate and timely to facilitate appropriate antimicrobial use. Diagnostic strategies that rely solely on pathogen detection often are insufficient due to poor test characteristics, inability to differentiate colonization from infection, or protracted delay to result. Understanding the human response across different pathogens on a clinical and molecular level can provide more accurate, timely, and useful answers, especially in critical illness and diagnostic uncertainty. Improvements in understanding the human immune response including genomics, protein analysis, gene expression, and cellular morphology have led to rapid innovation of new host response-based diagnostic tests. This review describes the limitations of pathogen-focused technology and the benefits of examining the breadth of immune response to diagnose infection. It then explores biomarkers that have been studied for this purpose and scrutinizes the performance of host-based multianalyte testing. Currently cleared diagnostics and those in late-stage development are described in depth, with a focus on the purpose of testing and its utility for clinicians. Finally, it concludes by examining opportunities for further host response-derived diagnostic innovation.

Design of Fatigue‐Resistant Hydrogels

AbstractHydrogels are made tough to resist crack propagation. However, for seamless integration into devices and machines, it necessitates robustness against cyclic loads. Central to this objective is enhancing fatigue resistance, an indispensable attribute facilitating the optimal performance of hydrogels within a multitude of biological contexts, spanning various plant and animal tissues, as well as diverse biomedical and engineering areas. In this review, recent research concerning the fatigue behavior of hydrogels, presenting a comprehensive consolidation of the inherent mechanisms that underpin diverse strategies aimed at fortifying fatigue resistance, is summarized. A critical facet in the architectural blueprint of fatigue‐resistant hydrogels is emphasized, involving the imposition of spatial constraints upon the main chains at the crack tips, thereby effectuating a protracted delay in their fracture initiation during prolonged cyclic loading. The integration of multiscale mechanisms encompassing networks, interactions, media, and structures stands as a pivotal factor in the design of fatigue‐resistant hydrogels. It is hoped that the review will considerably propel the pragmatic deployment of fatigue‐resistant hydrogels across a diverse array of applications, thus catalyzing advancements in multiple fields.

Impact Study of the Hetauda-Dhalkewar-Inaruwa Transmission Line on the Operation of Integrated Nepal Power System

Despite Nepal’s abundant hydroelectric resources, a substantial disparity exists between its electricity supply and demand. This discrepancy is exacerbated by the absence of high-voltage transmission lines, hindering efficient power evacuation from a handful of generating plants. This not only incurs financial losses for the utility but also compromises the reliability of the power supply. A prime example is the protracted delay in the construction of the 576 KM long Hetauda-Dhalkebar-Inaruwa 400kV double-circuit Transmission Line, primarily due to challenges posed by local residents unwilling to relinquish their land.The Integrated Nepal Power System (INPS) heavily relies on power generation concentrated in the central mid-hills region. The construction of the Hetauda-Dhalkebar-Inaruwa (HDITL) 400kV double-circuit Transmission Line is crucial for routing power to industrialize these areas, potentially bolstering the national GDP and generating employment opportunities. Furthermore, it is essential to connect the current hydropower output of around 2300 MW to the INPS system via a high-voltage transmission line to maximize its utilization. The HDITL project not only reduces line losses but also enhances grid stability. It facilitates energy export and direct transmission of high-generation power, such as the 456 MW from Upper Tamakoshi, thus saving approximately 400 MW of power and preventing losses for both the Government of Nepal (GoN) and the Nepal Electricity Authority. This research not only calculates the reduction in power and energy losses with the commissioning of HDITL but also assesses its monetary benefits. Utilizing INPS data and Digsilent Power Factory 15.1 for power flow analysis, the study estimates that HDITL can prevent a power loss of about 26.276 MW. Furthermore, it demonstrates that HDITL significantly improves the total generation power factor in INPS, from 0.88 to 0.99, and enhances the voltage profile, underscoring its critical role in Nepal’s energy infrastructure development.

Audit Committee Characteristics and Audit Efficiency: Evidence from Nigerian Listed Deposit Money Banks

The study examines the effect of audit committee characteristics on audit efficiency of Nigerian listed Deposit Money Banks. A sample size of 11 listed banks is selected using a census technique. The study covers a period from 2006 to 2020, resulting in 165 firm-year observations. The audit efficiency is proxy using audit fee and audit delay. The data obtained is analysed using the Ordinary Least Square Method (OLS). The result shows that audit committee is positively associated with audit fee, but negatively related to audit delay. The result indicates that audit committee members recommend a reputable independent accountants to the banks, who charge a premium audit price. However, the external auditors ensure financial reporting quality by reducing the protracted audit delay. Keywords: Audit delay, Audit committee members, Audit fees, Nigeria, Banks DOI: 10.7176/EJBM/14-16-05 Publication date: August 31 st 2022

Diet differences between wild and stocked age-0 to age-3 lake trout indicate influence of early rearing environments

Wild lake trout recently began to appear in abundance in Lake Champlain after over 40 years of stocking, providing an opportunity to compare the seasonal diet of wild and stocked juveniles. We sampled 2,349 age-0 to age-3 lake trout collected in bottom trawls from April to November 2015–2018, and examined the relationship between diet and spatial heterogeneity in abundance of wild and stocked juveniles. Stocked fish were, on average, the size of wild fish one year older. Wild juveniles had fewer empty stomachs and more items per stomach than stocked fish at each age. Mysis diluviana dominated the diet of age-0 and age-1 wild lake trout until they began to consume fish in fall at age-1. In contrast, the diet of newly-stocked fish (age-1) comprised rainbow smelt (Osmerus mordax), slimy sculpin (Cottus cognatus), alewife (Alosa pseudoharengus), with Mysis only abundant in summer and fall. Number and composition of diet items varied among geographic areas of the lake but did not explain differences in abundance of wild or stocked fish by area. Diet overlap was high between wild and stocked fish for each age class at each season, except in fall at age-0. Differences in the diet of wild and stocked juveniles likely reflect effects of early rearing experience. Recruitment of wild lake trout depends on availability and abundance of Mysis, but our diet data do not provide insight to explain why recruitment is finally occurring after a protracted delay.

Pachygyria in a Saudi preteen female: A case report and review of literature

Pachygyria is a component of a spectrum of malformation of cerebral neuronal migration. MRI is a fundamental neuroimaging tool for adequate description of cerebral structural pathology. As a component of lissencephaly-pachygyria spectrum, there are severe intertwined clinical and pathological manifestations, with/without other brain and systemic malformations. Clinical features include protracted seizures, delay or absence of developmental milestones, and varying degrees of mental retardation. This is a case of a preteen with previous infantile seizures and delay in developmental milestones. Her MRI showed uncommon but classic “leopord” and “tigroid” appearances of deep white matter changes, as well as the typical shallow and few cerebral cortical sulci, as well as cortical thickening of pachygyria. Despite several established genetic mutations documented in various disorders of cerebral neural migration, there was however no genetic assay yet for the patient at the time of this publication. Keywords: pachygyria; lissencephaly; neuronal-migration; heterotopia.

All Voices Must Be Heard and Respected

All Voices Must Be Heard and Respected

UNIFICATION OF FORMER FATA WITH KPK AND ITS IMPACT ON DOMESTIC SANCTUARY

FORMER FATA (Federally Administered Tribal Area), is the most praiseworthy part of Pakistan, always deemed to be the rudimentary part of Pakistani province known as KPK (Khyber Pakhtunkhwa). After countless efforts and protracted delay, it came into being on 31st, May 2018. However, after this historically important incident, many changes were observed in the overall economy as well as the sanctuary situation of the country. Very little research is available to highlight the positive as well as negative impacts on domestic sanctuary. Therefore, keeping in view the above-explained scenario present study is devised to highlight all these concerns as well as future perspectives to put Pakistan on the success staircase. In this study, various aspects of FORMER FATA are highlighted including the unification of cultural attributes of FORMER FATA and KPK, conversion of the Jirga method into legal management, transfiguration of educational set up from Madrassa to schools, colleges, and universities. The Domino effect of this study enlightens the unsatisfactory attitude of government authorities for bringing up the living standards of inhabitants of FORMER FATA along with dawdling development projects. Therefore, it is the utmost need of the hour for government authorities to understand the subject matter and reconsider the attributes of FORMER FATA by considering it vital part of KPK as well as of Pakistan.

Transition from care: Are we continuing to set care leavers up to fail in New Zealand?

The need for a supported transition for young people leaving care in New Zealand has been acknowledged with the implementation of new legislation and policy from 1 July 2019. One advantage of the protracted delay is the ability to draw on international research evaluating the impact of changes made in other jurisdictions. The article begins with an introduction to the New Zealand context. Current international research on the experience of care leavers is reviewed to identify key lessons and continuing challenges. Published research on the lived experience of young people leaving care and theoretical perspectives, developed to support a clearer understanding of their needs, provide the focus for this review. A summary of key lessons and challenges provides the framework for a critical analysis of New Zealand’s approach before concluding with a discussion of the implications going forward.

Coronavirus puts drug chemical industry on alert

Major drug companies have issued statements in recent days assuring the public that their inventories are adequate in the face of supply chain threats stemming from the novel coronavirus. Suppliers of active pharmaceutical ingredients (APIs) are also assuring customers that they are prepared for temporary interruption in the supply of key ingredients from firms in China, where the outbreak originated. API makers in Europe and the US warn, however, that supply disruptions could result from a protracted delay in restarting production at plants closed in recent weeks by the Chinese government or from prolonged transportation restrictions. James Bruno, president of the consulting firm Chemical and Pharmaceutical Solutions, says travel restrictions are already interrupting business with Chinese suppliers. “First of all, nobody is going to be able to get to China,” he says, “so all the audits are going to be canceled.” Bruno adds that the restrictions will prolong plant closures

Reduced abnormal integration of adult-generated granule cells does not attenuate spontaneous recurrent seizures in mice

Epileptic seizures lead to aberrant hippocampal neurogenesis, including increased proliferation of neural progenitors and abnormal integrations of newly generated granule cells – hilar ectopic granule cells (EGCs), mossy fiber sprouting (MFS), and hilar basal dendrites (HBDs). Previous results from ablating hippocampal neurogenesis after acute seizures have been controversial with regards to the development of spontaneous recurrent seizures (SRSs). While ablation of hippocampal newborn cells was effective, a sufficient decrease of subsequent abnormal integrations in chronically epileptic hippocampus was not well-established in these studies. Evaluations of the role of aberrant neurogenesis in epileptogenesis were therefore inconclusive. In this study, we ablated the hippocampal neurogenesis by methylazoxymethanol acetate (MAM) treatment both before and after pilocarpine induced status epilepticus (SE). We found that an overall ablation of newborn granule cells and a protracted delay after the cell ablation are required to eliminate subsequent abnormal integrations, including EGCs, MSF and HBDs. However, there were no alterations in frequency, duration and severity of chronic seizures were demonstrated following this regime. The current findings provide novel evidences that an overall decrease of abnormal integrations via cell ablation cannot exert significant effects on the development of SRSs at least in the model used in this study.

Civilian cerebral gunshot wounds: a South African experience.

Cerebral gunshot wounds represent one of the most lethal forms of traumatic brain injury, but there is a paucity of literature on the topic, especially from the developing world. We reviewed our experience and describe the spectrum and outcome of civilian cerebral gunshot wounds in a major metropolitan trauma centre in South Africa. This was a retrospective study of all patients with isolated cerebral gunshot wounds managed by the Pietermaritzburg Metropolitan Trauma Service over a 5-year period from 2010 to 2014. One hundred and two patients were included, 92% (94/102) were male and the mean age was 29 years. Fifty-four per cent (55/102) of all patients were from urban areas. The mean time from injury to arrival was 6 h (standard deviation: 5) for urban patients and 15 h (standard deviation: 5.2) for rural patients (P < 0.001). Ninety-four per cent (94/102) of all injuries were related to interpersonal violence and involved low velocity firearms. Twenty per cent of all patients (20/102) had a Glasgow Coma Scale 3-8, 20% (20/102) 9-12 and 61% (61/102) 12-15. All 102 patients underwent computed tomography scans. Thirty per cent (31/102) required neurosurgical interventions. The overall mortality rate was 22% (22/102). There was a significant difference in mortality between urban and rural patients (9% versus 36%, P < 0.001). Cerebral gunshot wounds are associated with significant mortality and protracted delay to definitive care is common in our setting. Those who survive the delayed transfer to definitive care generally do well and have reasonably good clinical outcomes.

Whither the TPP? Political Economy of Ratification and Effect on Trade Architecture in East Asia

In the race for establishing trading architecture consistent with new landscape of the global economy, the US is ahead of the game by concluding the Trans Pacific Partnership Agreement with 11 countries. To make it reality, the ratification is essential. In the battle for ratification in the US, declining globalism confronts rising protectionism. This paper models the ratification process as contest between globalism and protectionism, and analyzes the optimal timing for ratification. Based on this framework, various ratification scenarios are analyzed. The paper argues less likelihood for the lame-duck session passage and more likelihood for prolonged and protracted delay, due to changing political dynamics and declining intellectual support for globalism. Hence, the future of Trans Pacific Partnership Agreement may prove different, compared to the North American Free Trade Agreement and the Korea-US Free Trade Agreement, both of which were renegotiated and ratified eventually. Then, the US would lose the first move advantage. The paper also discusses strategic implications of delayed ratification on the evolution of trading architecture in East Asia.

Whither the TPP? Political Economy of Ratification and Effect on Trade Architecture in East Asia

In the race for establishing trading architecture consistent with new landscape of the global economy, the US is ahead of the game by concluding the Trans Pacific Partnership Agreement with 11 countries. To make it reality, the ratification is essential. In the battle for ratification in the US, declining globalism confronts rising protectionism. This paper models the ratification process as contest between globalism and protectionism, and analyzes the optimal timing for ratification. Based on this framework, various ratification scenarios are analyzed. The paper argues less likelihood for the lame-duck session passage and more likelihood for prolonged and protracted delay, due to changing political dynamics and declining intellectual support for globalism. Hence, the future of Trans Pacific Partnership Agreement may prove different, compared to the North American Free Trade Agreement and the Korea-US Free Trade Agreement, both of which were renegotiated and ratified eventually. Then, the US would lose the first move advantage. The paper also discusses strategic implications of delayed ratification on the evolution of trading architecture in East Asia.

Ano-genital Granulomatosis and Crohn's Disease: A Case Series of Males Presenting with Genital Lymphoedema.

Ano-genital granulomatosis is a rare chronic granulomatous condition of the skin that causes lymphoedema of the external genitalia. There is a reported association with Crohn's disease. Mechanisms of disease and optimal methods of treatment are poorly understood. A retrospective casenote review of 25 male patients with ano-genital granulomatosis presenting with genital lymphoedema was performed to determine the clinical and histopathological features of this condition and its relationship to intestinal Crohn's disease. A combination of penile and scrotal oedema was reported at presentation in 80% of patients; 40% of patients had associated intestinal Crohn's disease. The average time from symptom onset to diagnosis was 52.7 months. Half of cutaneous biopsies contained non-caseating granulomas and 14% contained intralymphatic granulomas. In all, 72% of patients responded to oral steroids initially but recurrence was common. Complete or partial response was achieved in 60% of patients treated with azathioprine. Three of six patients responded to anti-tumour necrosis factor [TNF] therapy. A small proportion of patients required circumcision or de-bulking surgery for more debilitating disease. Ano-genital granulomatosis is a rare condition that presents with genital lymphoedema, and there is frequently a protracted delay in diagnosis. There is a very strong association with intestinal Crohn's disease. Genital lymphoedema associated with gastrointestinal symptoms should prompt careful evaluation to exclude both ano-genital granulomatosis and Crohn's disease.

Challenges with participant reimbursement: experiences from a post-trial access study

Reimbursement of trial participants remains a frequently debated issue, with specific guidance lacking. Trials combining post-trial access and implementation science may necessitate new strategies and models. CAPRISA 008, a post-trial...

Renal Amyloidosis - Tempo of Proteinuria Resolution in Bortezomib Era

IntroductionAL amyloidosis is a systemic disease where the immunoglobin light chains produced by clonal plasma cells accumulate as insoluble fibrils causing end organ damage. In patients with AL amyloidosis, renal involvement is common, and proteinuria is frequently detected. Current treatment for AL amyloidosis aims at reducing production of these pathological immunoglobulin light chains by eliminating the clonal plasma cell population. Following treatment and normalisation of serum free light chains (SFLCs), improvement in end organ function, as demonstrated by reduction of proteinuria in patients with renal AL amyloidosis, occurs at a much slower rate. Although reduction in proteinuria has been linked to improved outcomes, the rate of this reduction has not been documented in detail in the literature. The purpose of this study is to analyse the tempo of proteinuria resolution in patients with renal AL amyloidosis following bortezomib based chemotherapy.MethodsCases were selected by retrospectively reviewing the hospital electronic database. All patients with biopsy confirmed renal AL amyloidosis were included. Induction chemotherapy was a combination of weekly bortezomib (1.6mg/m2), cyclophosphamide (300mg/m2) and dexamethasone (40mg) given in 4-weekly cycles. During the follow-up period, proteinuria was measured by urinary protein / creatinine ratio (PCR) from random urine samples. The results of the PCR over time were plotted on a scatter plot, and a best fit curve was fitted using IBM SPSS Statistics 20 software to determine the trend of PCR over time. Patients who did not complete bortezomib chemotherapy, or did not have follow-up urinary PCR were excluded.ResultsAfter applying the exclusion criteria, seven patients were analysed, and the baseline characteristics are listed in table 1. The median follow-up was 30.9 months (range: 13.2 – 44.1 months). The median age was 68.8 years (range: 52.5 – 80.5 years). Patients received a median of 6 cycles of chemotherapy (range: 2 – 9 cycles), and all patients received full doses of bortezomib based on their body surface area (average dose of 1.6mg/m2, range: 1.53 – 1.64mg/m2). Five of the 7 patients normalised their SFLCs after one cycle of chemotherapy, and the median time to normalisation was 26 days (range: 13 – 185 days).PCR was used to monitor the level of proteinuria following chemotherapy. One patient was excluded in this part of the analysis due to progressive diabetic and hypertensive nephropathy following an initial improvement in PCR after normalisation of SFLCs. Although there was marked fluctuation of PCR (figure 1), the PCRs followed an exponential decay pattern over time (R2 between 0.223 – 0.976). The median half-life of reduction was 6.2 months (range: 3.4 – 18.2 months).ConclusionsPCR from random urine samples is a useful and convenient way of assessing proteinuria in everyday outpatient setting. Although PCR fluctuates over time in patients with renal AL amyloidosis, there is a general downward trend following bortezomib based chemotherapy and normalisation of SFLCs. This downward trend appears to follow an exponential decay pattern, and most patients have a protracted delay between normalisation of SFLCs and improvement in proteinuria. In view of such delay, normalisation of SFLCs should be the goal of initial therapy, rather than reduction in proteinuria when treating patients with renal AL amyloidosis.Table 1Baseline patient characteristicsValue(range)Age (median)68.8 years(52.5 – 80.5 years)Male (%)55.6%Plasma cell burden (median)12.5%(6 – 25%)Kappa/Lambda light chain ratio (median)0.164(0.011 – 37.333)eGFR > 30ml/min (%)88.9%Protein / creatinine ratio at diagnosis (mean)698mg/L(243 – 1636mg/L) [Display omitted] DisclosuresSimpson:Onyx: Honoraria, Research Funding; Celgene: Honoraria; Janssen Cilag: Honoraria.

Memory consolidation in aging and MCI after 1 week.

To assess consolidation in amnestic mild cognitive impairment (aMCI), controlling for differences in initial learning and using a protracted delay period for recall. 15 individuals with aMCI were compared with 15 healthy older adult controls on a story learning task. Subjects were trained to criteria to equalize initial learning across subjects. Recall was tested at both the 30-min typically used delay and a 1-week delay used to target consolidation. Using repeated measures ANOVAs adjusted for age, we found group × time point interactions across the entire task between the final trial and 30-min delay, and again between the 30-min and 1-week delay periods, with aMCI having greater declines in recall as compared with controls. Significant group main effects were also found, with aMCI recalling less than controls. Consolidation was impaired in aMCI as compared with controls. Our findings indicate that aMCI-related performance typically measured at 30 min underestimates aMCI-associated memory deficits. This is the first study to isolate consolidation by controlling for initial learning differences and using a protracted delay period to target consolidation in an aMCI sample.

Mental state language and quality of conversational experience in deaf and hearing children

Deaf children of hearing parents show a protracted delay in performance on ‘theory of mind’ measures that suggests they encounter difficulties in acquiring knowledge of false beliefs and other mental states. Considerable evidence indicates that children's early experience of adults’ mental state talk predicts their later social-cognitive development. However, no previous study has analyzed very young deaf children's access to conversation about mental states. We compared the conversational turn-taking and input of hearing parents to deaf and hearing children aged 17–35 months in the UK and Sweden. Mothers of hearing children used far more cognitive mental state language with their infants and their conversations were characterized by more communicatively effective turn-taking than mothers of deaf children. Across two different cultures, these findings indicate that conversations differ significantly in these aspects of interaction thought to be crucial for later social-cognitive development.

Protracted delay in taste sensation recovery after surgical lingual nerve repair: a case report

IntroductionLingual nerve injury is sometimes caused by dental treatment. Many kinds of treatment have been reported, but many have exhibited poor recovery. Here the authors report changes in somatosensory and chemosensory impairments during a long-term observation after lingual nerve repair.Case presentationA 30-year-old Japanese woman claimed dysesthesia and difficulty eating. Quantitative sensory test results indicated complete loss of sensation in the right side of her tongue. She underwent a repair surgery involving complete resection of her lingual nerve using a polyglycolic acid tube containing collagen 9 months after the injury. A year after the operation, her mechanical touch threshold recovered, but no other sensations recovered. Long-term observation of her somatosensory and chemosensory function after the nerve repair suggested that recovery of taste sensation was greatly delayed compared with that of somatosensory function.ConclusionThis case shows characteristic changes in somatosensory and chemosensory recoveries during 7 postoperative years and suggests that taste and thermal sensations require a very long time to recover after repair surgery.