Age-Friendly Health Systems 4Ms: Implementing Medication Management in Hamad Medical Corporation, Qatar.

PURPOSE: To implement the Age-Friendly Health Systems (AFHS) 4Ms framework, focusing on Medication and its impact on Mobility, Mentation, and What Matters, within Hamad Medical Corporation in Qatar. METHOD: A quality improvement approach was used to implement, extend, and sustain the AFHS 4Ms framework at Hamad Medical Corporation. The Medication "M" was described as the use case to illustrate the impact of high-risk medications on Mobility, Mentation, and What Matters, using an evidence-based, interdisciplinary approach. RESULTS: Implementation of the AFHS 4Ms framework revealed success in aligning multidisciplinary teams to prioritize patient-centered care and caregiver engagement. Through this collaboration, a process map, modified medication screening tool, documentation templates, and educational efforts were developed. CONCLUSION: Applying the AFHS 4Ms framework into health care settings is crucial to improve the care of older adults. Medication management is a cornerstone, involving interdisciplinary team input during screening and act phases to ensure proper medication prescribing and use in older adults. [Journal of Gerontological Nursing, 50(6), 6-9.].

Antidepressant-like activity of a brain penetrant HCN channel inhibitor in mice.

Changes in Hyperpolarization-Activated Cyclic Nucleotide-Gated (HCN) channel function have been linked to depressive-like traits, making them potential drug targets. However, there is currently no peer-reviewed data supporting the use of a small molecule modulator of HCN channels in depression treatment. Org 34167, a benzisoxazole derivative, has been patented for the treatment of depression and progressed to Phase I trials. In the current study, we analysed the biophysical effects of Org 34167 on HCN channels in stably transfected human embryonic kidney 293 (HEK293) cells and mouse layer V neurons using patch-clamp electrophysiology, and we utilised three high-throughput screens for depressive-like behaviour to assess the activity of Org 34167 in mice. The impact of Org 34167 on locomotion and coordination were measured by performing rotarod and ledged beam tests. Org 34167 is a broad-spectrum inhibitor of HCN channels, slowing activation and causing a hyperpolarising shift in voltage-dependence of activation. It also reduced I h-mediated sag in mouse neurons. Org 34167 (0.5 mg/kg) reduced marble burying and increased the time spent mobile in the Porsolt swim and tail suspension tests in both male and female BALB/c mice, suggesting reduced depressive-like behaviour. Although no adverse effects were seen at 0.5 mg/kg, an increase in dose to 1 mg/kg resulted in visible tremors and impaired locomotion and coordination. These data support the premise that HCN channels are valid targets for anti-depressive drugs albeit with a narrow therapeutic index. Drugs with higher HCN subtype selectivity are needed to establish if a wider therapeutic window can be obtained.

Analysis of the impact of a pandemic on the control of the process safety risk in major hazards industries using a Fault Tree Analysis approach.

The control of the risks associated with major hazard events is critical to the safe and continuous operation of the process industry. Over the last decades, the process industry has been successful at establishing and implementing robust Process Safety Management (PSM) systems to prevent and mitigate the consequences of such major hazard events. While there exist some industry guidelines developed relatively recently for events initiated by natural disasters and security-related threats, for initiating events like outbreaks of pathogens and pandemics, there is currently a clear lack of understanding of the impact of the restrictions and disruption caused by a pandemic on the ability of companies operating major hazard facilities to keep controlling the risks associated to their hazardous operations. Moreover, there is no industry guideline on how to account for such an impact in PSM systems for process safety hazards. The recent COVID-19 outbreak caused serious disruptions to normal operations that have challenged industry in their ability to control risks. The objective of this paper is to perform an analysis of the impact of a pandemic situation on the implementation of selected elements of PSM systems related to the identification and evaluation of the risks of a major hazard and their control. The approach chosen involves the analysis of the root causes of the failure of the selected PSM elements using a Fault Tree Analysis method. The findings provide the first steps in the establishment of recommendations for the upgrade of PSM systems to face events such as pandemics.

COVID-19 in a liver transplant recipient: Could iatrogenic immunosuppression have prevented severe pneumonia? A case report.

BACKGROUND: Coronavirus disease (COVID) is a new and highly contagious infectious disease caused by the coronavirus (COVID-19 or severe acute respiratory syndrome coronavirus 2). There is limited data regarding the incidence and management of COVID-19 in immunocompromised patients' post-transplantation. In the pre-COVID-19 era, these patients were already at an increased risk of developing opportunistic infections. These often manifested with atypical symptoms. CASE SUMMARY: We report another case of uneventful COVID-19 pneumonia in a 58-year old male who was 18 mo' post liver transplantation. He received tacrolimus monotherapy since July 2019. The clinical manifestations included only epigastric pain radiating to the right hypochondrium, nausea and vomiting. He had no fevers, cough, shortness of breath, anosmia or dysgeusia even if the chest computed tomography scan revealed an extension of the multiple patchy ground-glass density shadows to the upper lobe of the left lung too. He was hospitalised and received a course of oral chloroquine (200 mg × 3 per day) for a period of 10 d. Interestingly, the COVID 19 infection was uneventful though there were no modifications to his tacrolimus dosing. He was successfully discharged. We performed subsequent follow-up via telemedicine. CONCLUSION: In light of the current pandemic, it is even more important to identify how the liver recipient's patients present and are managed, especially for immunosuppression treatment.

Rehabilitation of a maxillary partial edentulous patient using an implant-supported overdenture retained with two bilateral milled bars.

The use of implants has enabled more treatment options for prosthetic rehabilitation of partially and completely edentulous patients. This clinical report describes a treatment approach for an 80-year-old patient taking advantage of the remaining natural teeth for prosthetic rehabilitation. The final treatment plan included natural tooth-supported and implant-supported crowns combined with a milled bar partial overdenture retained by tilted dental implants. The overdentures supported by the milled bar implants provide the advantages of both fixed and removable restorations. In addition to patient satisfaction, the overdentures also minimise alveolar bone resorption, increase longevity and stability and improve masticatory efficiency.

The effects of insecticides on two splice variants of the glutamate-gated chloride channel receptor of the major malaria vector, Anopheles gambiae.

BACKGROUND AND PURPOSE: Between half to 1 million people die annually from malaria. Anopheles gambiae mosquitoes are major malaria vectors. Unfortunately, resistance has emerged to the agents currently used to control A. gambiae, creating a demand for novel control measures. The pentameric glutamate-gated chloride channel (GluCl) expressed in the muscle and nerve cells of these organisms are a potentially important biological target for malaria control. The pharmacological properties of Anophiline GluCl receptors are, however, largely unknown. Accordingly, we compared the efficacy of four insecticides (lindane, fipronil, picrotoxin, and ivermectin) on two A. gambiae GluCl receptor splice variants with the aim of providing a molecular basis for designing novel anti-malaria treatments. EXPERIMENTAL APPROACH: The A. gambiae GluCl receptor b1 and c splice variants were expressed homomerically in Xenopus laevis oocytes and studied with electrophysiological techniques, using two-electrode voltage-clamp. KEY RESULTS: The b1 and c GluCl receptors were activated with similar potencies by glutamate and ivermectin. Fipronil was more potent than picrotoxin and lindane at inhibiting glutamate- and ivermectin-gated currents. Importantly, b1 GluCl receptors exhibited reduced sensitivity to picrotoxin and lindane. They also recovered from these effects to a greater extent than c GluCl receptors CONCLUSIONS AND IMPLICATIONS: The two splice variant subunits exhibited differential sensitivities to multiple, structurally divergent insecticides, without accompanying changes in the sensitivity to the endogenous neurotransmitter, glutamate, implying that drug resistance may be caused by alterations in relative subunit expression levels, without affecting physiological function. Our results strongly suggest that it should be feasible to develop novel subunit-specific pharmacological agents.

GluClR-mediated inhibitory postsynaptic currents reveal targets for ivermectin and potential mechanisms of ivermectin resistance.

Glutamate-gated chloride channel receptors (GluClRs) mediate inhibitory neurotransmission at invertebrate synapses and are primary targets of parasites that impact drastically on agriculture and human health. Ivermectin (IVM) is a broad-spectrum pesticide that binds and potentiates GluClR activity. Resistance to IVM is a major economic and health concern, but the molecular and synaptic mechanisms of resistance are ill-defined. Here we focus on GluClRs of the agricultural endoparasite, Haemonchus contortus. We demonstrate that IVM potentiates inhibitory input by inducing a tonic current that plateaus over 15 minutes and by enhancing post-synaptic current peak amplitude and decay times. We further demonstrate that IVM greatly enhances the active durations of single receptors. These effects are greatly attenuated when endogenous IVM-insensitive subunits are incorporated into GluClRs, suggesting a mechanism of IVM resistance that does not affect glutamate sensitivity. We discovered functional groups of IVM that contribute to tuning its potency at different isoforms and show that the dominant mode of access of IVM is via the cell membrane to the receptor.

Effects of glutamate and ivermectin on single glutamate-gated chloride channels of the parasitic nematode H. contortus.

Ivermectin (IVM) is a widely-used anthelmintic that works by binding to and activating glutamate-gated chloride channel receptors (GluClRs) in nematodes. The resulting chloride flux inhibits the pharyngeal muscle cells and motor neurons of nematodes, causing death by paralysis or starvation. IVM resistance is an emerging problem in many pest species, necessitating the development of novel drugs. However, drug optimisation requires a quantitative understanding of GluClR activation and modulation mechanisms. Here we investigated the biophysical properties of homomeric α (avr-14b) GluClRs from the parasitic nematode, H. contortus, in the presence of glutamate and IVM. The receptor proved to be highly responsive to low nanomolar concentrations of both compounds. Analysis of single receptor activations demonstrated that the GluClR oscillates between multiple functional states upon the binding of either ligand. The G36'A mutation in the third transmembrane domain, which was previously thought to hinder access of IVM to its binding site, was found to decrease the duration of active periods and increase receptor desensitisation. On an ensemble macropatch level the mutation gave rise to enhanced current decay and desensitisation rates. Because these responses were common to both glutamate and IVM, and were observed under conditions where agonist binding sites were likely saturated, we infer that G36'A affects the intrinsic properties of the receptor with no specific effect on IVM binding mechanisms. These unexpected results provide new insights into the activation and modulatory mechanisms of the H. contortus GluClRs and provide a mechanistic framework upon which the actions of drugs can be reliably interpreted.