A REVIEW ON DECISION PROTOCOL AND FATWA IN MALAYSIA DISCUSSING ISSUE OF WITHHOLDING AND WITHDRAWAL OF LIFE-SUSTAINING TREATMENT IN INTENSIVE CARE UNIT

Withholding and withdrawal of life-sustaining treatments is one of the hot topics discussing in intensive care unit as most of the death occurs as a result of it. This point of transition from active intervention to the palliation process required a crucial decision-making process. The decision conveys information to families to be well prepared beforehand especially during the process of withdrawing life-sustaining treatment. Once the final decision to withdraw the treatment has been made, procedure of cessation of care, treatment withdrawal and nature of follow-up support will be informed to the family members. This article aims to explore the relationship between decision in withholding and withdrawal of life-sustaining treatment based on Malaysian intensive care unit protocol and the related fatwa in Malaysia. The methodology chosen for this study is content analysis of the relevant published literatures. This study reveals the decision for withholding and withdrawal life sustaining treatment in intensive care unit has correlation between the protocol and related fatwa in Malaysia.

A Real-World Study on Myopia Control 6 Months After Withdrawal of 1% Atropine Eye Gel

Purpose: This study aimed to observe the changes in spherical equivalent and ocular axial length 6 months after withdrawal of 1% atropine eye gel.Methods: Due to COVID-19, the follow-up of patients in our optometric clinic who were undergoing myopia control treatment with a dropwise 1% atropine “5+3” regimen was interrupted. No return visit was made after the 3 months of at-home treatment, and follow-ups resumed 6 months after treatment withdrawal. The contralateral eye was not treated over the 9-month period. A total of 16 patients aged 11.5 years (average) were enrolled from November 2019 to March 2021 during the COVID-19 pandemic. The treated eyes formed a treatment group (16 eyes) and the contralateral eyes formed a control group (16 eyes). The changes in spherical equivalent, ocular axial length, and intraocular pressure (IOP) were compared between groups. Results: After 9 months, the changes in spherical equivalent were significantly less in the treatment group (0.00 ± 0.20 [D]) compared to the control group (-0.67 ± 0.25 [D]) (P<0.05). The ocular axial length changes were significantly less in the treatment group (0.00 ± 0.06 mm) compared to the control group (0.25 ± 0.11 mm) (P<0.05). There was no significant difference between the two groups for changes in IOP. Conclusions: Despite treatment withdrawal after 3 months, treatment with 1% atropine eye gel successfully controlled myopia progression in the 6 months after withdrawal, as evidence by no rebound increase in myopic spherical equivalent after the withdrawal.

Reperfusion strategy and in-hospital outcomes for ST elevation myocardial infarction in secondary and tertiary hospitals in predominantly rural central China: a multicentre, prospective and observational study

ObjectivesTo assess differences in reperfusion treatment and outcomes between secondary and tertiary hospitals in predominantly rural central China.DesignMulticentre, prospective and observational study.SettingSixty-six (50 secondary and 16 tertiary) hospitals in Henan province, central China.ParticipantsPatients with ST elevation myocardial infarction (STEMI) within 30 days of symptom onset during 2016–2018.Primary outcome measuresIn-hospital mortality, and in-hospital death or treatment withdrawal.ResultsAmong 5063 patients of STEMI, 2553 were treated at secondary hospitals. Reperfusion (82.0% vs 73.0%, p<0.001) including fibrinolytic therapy (70.3% vs 4.4%, p<0.001) were more preformed, whereas primary percutaneous coronary intervention (11.7% vs 68.6%, p<0.001) were less frequent at secondary hospitals. In secondary hospitals, 53% received fibrinolytic therapy 3 hours after onset, and 5.8% underwent coronary angiography 2–24 hours after fibrinolysis. Secondary hospitals had a shorter onset-to-first-medical-contact time (176 min vs 270 min, p<0.001). Adjusted in-hospital mortality (adjusted OR 1.23, 95% CI 0.89 to 1.70, p=0.210) and in-hospital death or treatment withdrawal (adjusted OR 1.18, 95% CI 0.82 to 1.70, p=0.361) were similar between secondary and tertiary hospitals.ConclusionsWith fibrinolytic therapy as the main reperfusion strategy, the reperfusion rate was higher in secondary hospitals, whereas in-hospital outcomes were similar compared with tertiary hospitals. Public awareness, capacity of primary and secondary care institutes to treat STEMI, and establishment of deeper cooperation among different-level healthcare institutes need to further improve.Trial registration numberNCT02641262.

Advances in designing Adeno-associated viral vectors for development of anti-HBV gene therapeutics

Despite the five decades having passed since discovery of the hepatitis B virus (HBV), together with development of an effective anti-HBV vaccine, infection with the virus remains a serious public health problem and results in nearly 900,000 annual deaths worldwide. Current therapies do not eliminate the virus and viral replication typically reactivates after treatment withdrawal. Hence, current endeavours are aimed at developing novel therapies to achieve a functional cure. Nucleic acid-based therapeutic approaches are promising, with several candidates showing excellent potencies in preclinical and early stages of clinical development. However, this class of therapeutics is yet to become part of standard anti-HBV treatment regimens. Obstacles delaying development of gene-based therapies include lack of clinically relevant delivery methods and a paucity of good animal models for preclinical characterisation. Recent studies have demonstrated safety and efficiency of Adeno-associated viral vectors (AAVs) in gene therapy. However, AAVs do have flaws and this has prompted research aimed at improving design of novel and artificially synthesised AAVs. Main goals are to improve liver transduction efficiencies and avoiding immune clearance. Application of AAVs to model HBV replication in vivo is also useful for characterising anti-HBV gene therapeutics. This review summarises recent advances in AAV engineering and their contributions to progress with anti-HBV gene therapy development.

Stopping anti-TNF in CD remitters: pros and cons

Background: There is no cure for Crohn’s disease. Available treatments and treatment strategies, particularly anti-TNF, allow to heal intestinal lesions and maintain steroid-free remission in a subset of patients. Having in mind the remitting/relapsing nature of the disease, patients and health care providers often ask themselves whether the treatment could be withdrawn. Several studies have demonstrated a risk of relapse of CD after anti-TNF withdrawal, which varies from 20 to 50% at one year and from 50 to 80% beyond 5 years. These numbers clearly highlight that stopping therapy should not be a systematically proposed strategy in those remitting patients. Summary: Nobody would argue for anti-TNF withdrawal in patients with a high risk of short term relapse. Nevertheless, they also indicate that a minority of patients may not relapse over mid-term and that those who have relapsed may have benefited from a drug-free period before being again treated for a new cycle of treatment. The most relevant question is thus whether in those patients with a low to medium risk of disease relapse, treatment withdrawal could be contemplated. In this specific setting, there may be pros and cons for anti-TNF withdrawal. Amongst the pros are the potential side effects and toxicity of anti-TNF, the risk of loss of response over time, the patient preference allowing the patient to regain control of one’s health and investing in it, also improving adherence, the absence of negative impact on disease evolution of a transient anti-TNF withdrawal and finally the cost. Key messages: Although anti-TNF withdrawal in patients with sustained clinical remission is associated with a high risk of relapse, this risk seems to be much lower in a subgroup of patients, particularly in endoscopic and biologic remission. Stopping anti-TNF in this subgroup of patients may be associated with a favorable benefit/risk ratio.

Dermatological toxicity of EGFR inhibitors: pathogenetic rationale and an algorithm for acne-like rash correction

Therapy with epidermal growth factor receptor (EGFR) inhibitors is inevitably accompanied by the phenomena of dermatological toxicity. Being, on the one hand, a favorable prognostic factor for the effectiveness of anticancer therapy, these adverse events are one of the most frequent indications for treatment withdrawal. This article presents the clinical characteristics of a wide spectrum of dermatological adverse events, as well as the pathogenetic rationale for their correction. Algorithms for prescribing of external and systemic therapy based on the assessment of severity of skin lesions and skin appendages involvement are presented.

Case Report: Relevance of an Accurate Diagnosis and Monitoring of Infective Dermatitis Associated With Human T-Lymphotropic Virus Type 1 in Childhood

Human T-lymphotropic virus type 1 (HTLV-1) is a neglected retrovirus distributed worldwide and the ethiological agent of several pathologies, such as adult T-cell leukemia/lymphoma (ATLL), a chronic myelopathy known as HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) and infective dermatitis associated with HTLV-1 (IDH). HTLV-1 presents tropism for CD4+ T cells and induces deregulation of the cytokine profile. IDH is a severe, chronic superinfected eczema generally associated with Staphylococcus aureus and/or Streptococcus beta haemolyticus infection that responds partially to antibiotic therapy but prompt recurrence develops upon treatment withdrawal. IDH could be a risk factor for progression toward both HAM/TSP and ATLL and, similarly to other diseases associated with HTLV-1, it is sub-diagnosed particularly in non-endemic areas. Here, we present a case of IDH in a young boy living in Buenos Aires with symptoms since 2010, at the age of 5. HTLV-1 infection was suspected and confirmed in 2016. The patient exhibited chronic dermatosis with exudative eruption involving mainly the scalp, retroauricular regions, neck and abdomen. Clinical evaluations, routine laboratory tests, full blood count, and HTLV-1 diagnosis for this case are included.

CCR5 Blockade in Inflammatory PML and PML-IRIS Associated With Chronic Inflammatory Diseases' Treatments

Background and ObjectivesProgressive multifocal leukoencephalopathy (PML) is a disabling neurologic disorder resulting from the infection of the CNS by JC polyomavirus in immunocompromised individuals. For the last 2 decades, increasing use of immunotherapies leads to iatrogenic PML. Iatrogenic PML is often associated with signs of inflammation at onset (inflammatory PML) and/or after treatment withdrawal immune reconstitution inflammatory syndrome (PML-IRIS). Although immune reconstitution is a key element for viral clearance, it may also be harmful and induce clinical worsening. A C-C chemokine receptor type 5 (CCR5) antagonist (maraviroc) has been proposed to prevent and/or limit the deleterious immune responses underlying PML-IRIS. However, the data to support its use remain scarce and disputed.MethodsWe conducted a multicenter retrospective cohort study at 8 university hospitals in France and Switzerland by collecting clinical, biological, and radiologic data of patients who developed inflammatory PML (iPML) or PML-IRIS related to immunosuppressive therapies used for chronic inflammatory diseases between 2010 and 2020. We added to this cohort, a meta-analysis of individual case reports of patients with iPML/PML-IRIS treated with maraviroc published up to 2021.ResultsOverall, 27 cases were identified in the cohort and 9 from the literature. Among them, 27 met the inclusion criteria: 16 treated with maraviroc and 11 with standard of care (including corticosteroids use). Most cases were related to MS (92.6%) and natalizumab (88%). Inflammatory features (iPML) were present at onset in 12 patients (44.4%), and most patients (92.6%) received corticosteroids within the course of PML. Aggravation due to PML-IRIS was not prevented by maraviroc compared with patients who received only corticosteroids (adjusted odds ratio: 0.408, 95% CI: 0.06–2.63). Similarly, maraviroc did not influence time to clinical worsening due to PML-IRIS (adjusted hazard ratio = 0.529, 95% CI: 0.14–2.0) or disability at the last follow-up (adjusted odds ratio: 2, 95% CI: 0.23–17.3).DiscussionThe use of CCR5 blockade did not help to keep deleterious immune reconstitution in check even when associated with corticosteroids. Despite maraviroc's reassuring safety profile, this study does not support its use in iPML/PML-IRIS.Classification of EvidenceThis study provides Class IV evidence showing that adding maraviroc to the management of iatrogenic iPML/PML-IRIS does not improve the outcome.

Inhibition of the RacGEF VAV3 by the small molecule IODVA1 impedes RAC signaling and overcomes resistance to tyrosine kinase inhibition in acute lymphoblastic leukemia

Aberrant RHO guanine nucleotide exchange factor (RhoGEF) activation is chief mechanism driving abnormal activation of their GTPase targets in transformation and tumorigenesis. Consequently, a small-molecule inhibitor of RhoGEF can make an anti-cancer drug. We used cellular, mouse, and humanized models of RAC-dependent BCR-ABL1-driven and Ph-like acute lymphoblastic leukemia to identify VAV3, a tyrosine phosphorylation–dependent RacGEF, as the target of the small molecule IODVA1. We show that through binding to VAV3, IODVA1 inhibits RAC activation and signaling and increases pro-apoptotic activity in BCR-ABL1-transformed cells. Consistent with this mechanism of action, cellular and animal models of BCR-ABL1-induced leukemia in Vav3-null background do not respond to IODVA1. By durably decreasing in vivo RAC signaling, IODVA1 eradicates leukemic propagating activity of TKI-resistant BCR-ABL1(T315I) B-ALL cells after treatment withdrawal. Importantly, IODVA1 suppresses the leukemic burden in the treatment refractory pediatric Ph+ and TKI-resistant Ph+ B-ALL patient-derived xenograft models better than standard-of-care dasatinib or ponatinib and provides a more durable response after treatment withdrawal. Pediatric leukemia samples with diverse genetic lesions show high sensitivity to IODVA1 ex vivo and this sensitivity is VAV3 dependent. IODVA1 thus spearheads a novel class of drugs that inhibits a RacGEF and holds promise as an anti-tumor therapy.