A framework for implementing best laboratory practices for non-integrated point of care tests in low resource settings.

The method we respond to pandemics is still inadequate for dealing with the point of care testing (POCT) requirements of the next large epidemic. The proposed framework highlights the importance of having defined policies and procedures in place for non-integrated POCT to protect patient safety. In the absence of a pathology laboratory, this paradigm may help in the supply of diagnostic services to low-resource centers. A review of the literature was used to construct this POCT framework for non-integrated and/or unconnected devices. It also sought professional advice from the Chemical Pathology faculty, quality assurance laboratory experts and international POCT experts from the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). Our concept presents a comprehensive integrated and networked approach to POCT with direct and indirect clinical laboratory supervision, particularly for outpatient and inpatient care in low-resource health care settings.

Integrated vs non-integrated treatment outcomes in dual diagnosis disorders: A systematic review.

Background: The incidence of dual diagnosis (DD) (i.e. substance use disorders [SUD] and co-occurring mental disorders) is widespread; however, they vary widely in permutation and combination. As a result, establishing effective and empirically supported interventions for this clinical population remains challenging. Aim: This study aimed to examine current literature on the treatment outcomes for patients with DD. Method: A systematic review of randomised controlled trials (RCTs) published between 2009 and 2018 was conducted for two broad intervention categories identified by the literature: non-integrated and integrated treatment. Multiple electronic databases were searched using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA). Results: The search generated a total of 743 studies, of which 11 satisfied the inclusion criteria. These studies were thematically synthesised into two main analytical themes: 'treatment outcomes' and 'reported strengths and limitations of DD treatment'. Specifically, integrated treatment held an advantage over non-integrated treatment in significantly improving psychiatric symptomatology. However, no significant benefits were found between integrated and non-integrated treatment regarding substance misuse and treatment retention. Conclusion: Overall, the results provided insufficient evidence to support the enhanced efficacy of integrated or non-integrated treatment over the other in treating patients with DD. Contribution: The study's findings were used to provide recommendations to inform the clinical psychological service delivery of dual diagnosis treatment in South Africa and also to identify gaps in the literature and highlight areas for future research.

Climate-environment-water: integrated and non-integrated approaches to reservoir operation.

Integrated water planning and management face multiple challenges, among which are the competing interests of several water-using sectors and changing climatic trends. This paper presents integrated and non-integrated climate-environment-water approaches for reservoir operation, illustrated with Karkhe reservoir, Iran. Reservoir operation objectives are meeting municipal, environmental, and agricultural water demands. Results show the integrated approach, which relies on multi-objective optimization of municipal, environmental, and agricultural water supply, improves the municipal, environmental, and agricultural objectives by 70, 32, and 65% compared with the objectives' values achieved with the non-integrated approach, which implements a standard operating policy.

A Non-integrating Lentiviral Approach Overcomes Cas9-Induced Immune Rejection to Establish an Immunocompetent Metastatic Renal Cancer Model.

The CRISPR-based technology has revolutionized genome editing in recent years. This technique allows for gene knockout and evaluation of function in cell lines in a manner that is far easier and more accessible than anything previously available. Unfortunately, the ability to extend these studies to in vivo syngeneic murine cell line implantation is limited by an immune response against cells transduced to stably express Cas9. In this study, we demonstrate that a non-integrating lentiviral vector approach can overcome this immune rejection and allow for the growth of transduced cells in an immunocompetent host. This technique enables the establishment of a von Hippel-Lindau (VHL) gene knockout RENCA cell line in BALB/c mice, generating an improved model of immunocompetent, metastatic renal cell carcinoma (RCC).

Analysis of integrated clinical trial protocols in early phases of medicinal product development.

PURPOSE: While in the past, most clinical trial applications (CTAs) following non-integrated (standard) protocols were used to investigate one primary objective concerning a (new) drug, nowadays, the use of integrated protocols investigating multiple objectives within the same CTA becomes more and more popular. The aims of the present study were to investigate the usage and the impact of integrated protocols on regulatory activities and to find the motivation for their increasing use. METHODS: Two thousand nine hundred sixty-nine phase I and I/II CTAs submitted to the German Federal Institute for Drugs and Medical Devices (BfArM) during the time period from August 1, 2004, until August 31, 2014, were analysed with regard to protocol and sponsor status, duration until initial authorisation and the number of substantial amendments and their respective approval times. Additionally, applicants who submitted integrated protocols to BfArM were interviewed with respect to their opinion on integrated protocols in an online survey. RESULTS: The percentage of integrated protocols has constantly increased by approximately 10% within the last 10 years from 17.9% in 2004 to 28.2% in 2014. It could be shown that authorisation procedures with single integrated protocols take significantly longer until initial authorisation (58 vs. 53 days) requires more substantial amendments (1.9 vs. 1.2 amendments per CTA) and the approval of the entirety of amendments takes longer to process as compared to standard protocols (22 vs. 14 days). Nevertheless, applicants prefer the use of integrated protocols due to higher time and cost economy for the entire phase I development process. CONCLUSION: Although clinical trials (CTs) following integrated protocols are partly more time-consuming and costly, still, time and/or money may be saved during drug development due to the fact that overall, fewer CTs are needed than with standard protocols. Hence, the main reason for the increasing use of integrated protocols is improved time and cost efficiencies when conducting CTs.

A teoria das transformações e a postura do terapeuta: algumas considerações sobre mente primordial e fenômenos não integrados / The theory of transformations and the therapist’s stance: some considerations on primordial mind and non-integrated phenomena

O presente trabalho faz um apanhado da teoria das transformações proposta por W. Bion e dos desenvolvimentos de C. Korbivcher. O autor questiona a possibilidade de expansão das transformações autísticas para pacientes não neuróticos e traz duas situações clínicas que podem contribuir para a discussão. Recorre ao conceito de não integração e transformações não integradas (Korbivcher, 2013) para refletir sobre o fenômeno da contenção física. Entende que cada grupo de transformação (em alucinose, autística, não integrada) exige uma postura terapêutica diferente. Por fim, conjectura outro possível fator da função alfa: a delicadeza de emissão, uma ferramenta importante diante de situações de extrema turbulência emocional.

This paper provides an overview of the theory of transformations proposed by W. Bion and C. Korbivcher’s developments. The author questions the possibility of expansion of autistic transformations on non-neurotic patients and brings two medical conditions that can contribute to the discussion. He uses the concept of non-integration and non-integrated transformations (Korbivcher, 2013) to reflect on the phenomenon of physical restraint. He understands that each group of transformation (hallucinosis, autistic, non-integrated) requires a different therapeutic approach. Finally, he supposes another possible factor of the alpha function: the tenderness in the issue, an important tool in situations of extreme emotional turmoil.

El presente trabajo ofrece una visión general de la teoría de las transformaciones propuestas por W. Bion y los desarrollos de C. Korbivcher. El autor cuestiona la posibilidad de expansión de las transformaciones autistas para pacientes no neuróticos y trae dos situaciones clínicas que pueden contribuir a la discusión. Utiliza el concepto de no-integración y transformaciones no integradas (Korbivcher, 2013) para reflexionar sobre el fenómeno de restricción física. Entiende que cada grupo de transformación (en alucinosis, autista, no integrada) requiere un enfoque terapéutico diferente. Por último, supone otro posible factor de la función alfa: la delicadeza de la emisión, una herramienta importante en situaciones de agitación emocional extrema.

Insulin producing cells established using non-integrated lentiviral vector harboring PDX1 gene.

AIM: To investigate reprogramming of human adipose tissue derived stem cells into insulin producing cells using non-integrated lentivirus harboring PDX1 gene. METHODS: In this study, human adipose tissue derived stem cells (hADSCs) were obtained from abdominal adipose tissues by liposuction, selected by plastic adhesion, and characterized by flow cytometric analysis. Human ADSCs were differentiated into adipocytes and osteocytes using differentiating medium to confirm their multipotency. Non-integrated lentiviruses harboring PDX1 (Non-integrated LV-PDX1) were constructed using specific plasmids (pLV-HELP, pMD2G, LV-105-PDX1-1). Then, hADSCs were transduced with non-integrated LV-PDX1. After transduction, ADSCs(PDX1+) were cultured in high glucose DMEM medium supplement by B27, nicotinamide and ßFGF for 21 d. Expressions of PDX1 and insulin were detected at protein level by immunofluorescence analysis. Expressions of PDX1, neurogenin3 (Ngn3), glucagon, glucose transporter2 (Glut2) and somatostatin as specific marker genes were investigated at mRNA level by quantitative RT-PCR. Insulin secretion of hADSCs(PDX1+) in the high-glucose medium was detected by electrochemiluminescence test. Human ADSCs(PDX1+) were implanted into hyperglycemic rats. RESULTS: Human ADSCs exhibited their fibroblast-like morphology and made colonies after 7-10 d of culture. Determination of hADSCs identified by FACS analysis showed that hADSCs were positive for mesenchymal cell markers and negative for hematopoietic cell markers that guaranteed the lack of hematopoietic contamination. In vitro differentiation of hADSCs into osteocytes and adipocytes were detected by Alizarin red and Oil red O staining and confirmed their multilineage differentiation ability. Transduced hADSCs(+PDX1) became round and clusters in the differentiation medium. The appropriate expression of PDX1 and insulin proteins was confirmed using immunocytochemistry analysis. Significant expressions of PDX1, Ngn3, glucagon, Glut2 and somatostatin were detected by quantitative RT-PCR. hADSCs(PDX1+) revealed the glucose sensing ability by expressing Glut2 when they were cultured in the medium containing high glucose concentration. The insulin secretion of hADSCs(PDX1+) in the high glucose medium was 2.32 µU/mL. hADSCs(PDX1+) implantation into hyperglycemic rats cured it two days after injection by reducing blood glucose levels from 485 mg/dL to the normal level. CONCLUSION: Human ADSCs can differentiate into IPCs by non-integrated LV-PDX1 transduction and have the potential to be used as a resource in type 1 diabetes cell therapy.