Exploring drivers and challenges influencing antibiotic prescribing in outpatient settings and possible mitigation strategies in the United Arab Emirates: a qualitative study.

Objectives: Healthcare institutions implement antimicrobial stewardship (AMS) programmes to optimize the use of antibiotics. The focus is often on inpatient rather than outpatient settings. We aimed to explore perceptions of AMS stakeholders on effective interventions for appropriate antibiotic use in outpatient settings, and the role of clinical pharmacists in the AMS multidisciplinary team. Methods: A qualitative semi-structured interview study using thematic analysis by two researchers independently. Participants that practice AMS programmes were recruited from healthcare facilities in the United Arab Emirates (UAE). Interviews were conducted face to face or online and transcribed verbatim. Results: Four themes emerged: (i) Perceived factors leading to unnecessary or inappropriate antibiotic prescribing and their impact on patients and the community; (ii) current outpatient AMS activities and perceived barriers and facilitators for their sustainability; (iii) suggested outpatient AMS strategies to be implemented in outpatient settings; and (iv) perceived future AMS implementation barriers and suggested mitigation strategies. Conclusions: Several AMS interventions, together with the presence of a clinical pharmacist, may be effective in improving antibiotic use in UAE outpatient settings. Future research should investigate the most appropriate AMS strategy considering barriers and possible mitigation strategies to ensure sustainability.

Conditional deletion of KCC2 impairs synaptic plasticity and both spatial and nonspatial memory.

The postsynaptic inhibition through GABAA receptors (GABAAR) relies on two mechanisms, a shunting effect due to an increase in the postsynaptic membrane conductance and, in mature neurons, a hyperpolarization effect due to an entry of chloride into postsynaptic neurons. The second effect requires the action of the K+-Cl- cotransporter KCC2 which extrudes Cl- from the cell and maintains its cytosolic concentration very low. Neuronal chloride equilibrium seems to be dysregulated in several neurological and psychiatric conditions such as epilepsy, anxiety, schizophrenia, Down syndrome, or Alzheimer's disease. In the present study, we used the KCC2 Cre-lox knockdown system to investigate the role of KCC2 in synaptic plasticity and memory formation in adult mice. Tamoxifen-induced conditional deletion of KCC2 in glutamatergic neurons of the forebrain was performed at 3 months of age and resulted in spatial and nonspatial learning impairment. On brain slices, the stimulation of Schaffer collaterals by a theta burst induced long-term potentiation (LTP). The lack of KCC2 did not affect potentiation of field excitatory postsynaptic potentials (fEPSP) measured in the stratum radiatum (dendrites) but increased population spike (PS) amplitudes measured in the CA1 somatic layer, suggesting a reinforcement of the EPSP-PS potentiation, i.e., an increased ability of EPSPs to generate action potentials. At the cellular level, KCC2 deletion induced a positive shift in the reversal potential of GABAAR-driven Cl- currents (EGABA), suggesting an intracellular accumulation of chloride subsequent to the downregulation of KCC2. After treatment with bumetanide, an antagonist of the Na+-K+-Cl- cotransporter NKCC1, spatial memory impairment, chloride accumulation, and EPSP-PS potentiation were rescued in mice lacking KCC2. The presented results emphasize the importance of chloride equilibrium and GABA-inhibiting ability in synaptic plasticity and memory formation.

Cholera amid COVID-19: Call from three nations; India, Bangladesh, and Nepal.

Covid-19 was a major pandemic of the 21st century that flinched away every individual worldwide. The extensive impact of this rapidly spreading deadly virus doomed the health care systems with the unexpected wave wreaked havoc leading to a global health crisis. It has been a high burden on the functioning existing medical system, overloads health professionals, disruption of the medical supply chain. The economy of the nations has been at losses with a significant slowing down in revenue growth over the past 2 years. After taking its toll, drawing away other diseases including cholera. The three developing nations; India, Bangladesh and Nepal, are now at the verge of facing an outbreak of Cholera. It is not surprising to hear cholera in this nation but the fact that its negligence due to Covid-19 pandemic and monkeypox along with a crumbled health system due to the pandemic has made these nations vulnerable for health crisis. Along with this three nations, cholera has made its way to different parts of this globe and it is high time that attention must be drawn towards it as mismanagement could even cause life.

Hippocampal injury and learning deficits following non-convulsive status epilepticus in periadolescent rats.

The effects of non-convulsive status epilepticus (NCSE) on the developing brain remain largely elusive. Here we investigated potential hippocampal injury and learning deficits following one or two episodes of NCSE in periadolescent rats. Non-convulsive status epilepticus was induced with subconvulsive doses of intrahippocampal kainic acid (KA) under continuous EEG monitoring in postnatal day 43 (P43) rats. The RKA group (repeated KA) received intrahippocampal KA at P43 and P44, the SKA group (single KA injection) received KA at P43 and an intrahippocampal saline injection at P44. Controls were sham-treated with saline. The modified two-way active avoidance (MAAV) test was conducted between P45 and P52 to assess learning of context-cued and tone-signaled electrical foot-shock avoidance. Histological analyses were performed at P52 to assess hippocampal neuronal densities, as well as potential reactive astrocytosis and synaptic dysfunction with GFAP (glial fibrillary acidic protein) and synaptophysin (Syp) staining, respectively. Kainic acid injections resulted in electroclinical seizures characterized by behavioral arrest, oromotor automatisms and salivation, without tonic-clonic activity. Compared to controls, both the SKA and RKA groups had lower rates of tone-signaled shock avoidance (p < 0.05). In contextual testing, SKA rats were comparable to controls (p > 0.05), but the RKA group had learning deficits (p < 0.05). Hippocampal neuronal densities were comparable in all groups. Compared to controls, both the SKA and RKA groups had higher hippocampal GFAP levels (p < 0.05). The RKA group also had lower hippocampal Syp levels compared to the SKA and control groups (p < 0.05), which were comparable (p > 0.05). We show that hippocampal NCSE in periadolescent rats results in a seizure burden-dependent hippocampal injury accompanied by cognitive deficits. Our data suggest that the diagnosis and treatment of NCSE should be prompt.

Overexpression of wild-type human amyloid precursor protein alters GABAergic transmission.

The function of the amyloid precursor protein (APP) is not fully understood, but its cleavage product amyloid beta (Aß) together with neurofibrillary tangles constitute the hallmarks of Alzheimer's disease (AD). Yet, imbalance of excitatory and inhibitory neurotransmission accompanied by loss of synaptic functions, has been reported much earlier and independent of any detectable pathological markers. Recently, soluble APP fragments have been shown to bind to presynaptic GABAB receptors (GABABRs), subsequently decreasing the probability of neurotransmitter release. In this body of work, we were able to show that overexpression of wild-type human APP in mice (hAPPwt) causes early cognitive impairment, neuronal loss, and electrophysiological abnormalities in the absence of amyloid plaques and at very low levels of Aß. hAPPwt mice exhibited neuronal overexcitation that was evident in EEG and increased long-term potentiation (LTP). Overexpression of hAPPwt did not alter GABAergic/glutamatergic receptor components or GABA production ability. Nonetheless, we detected a decrease of GABA but not glutamate that could be linked to soluble APP fragments, acting on presynaptic GABABRs and subsequently reducing GABA release. By using a specific presynaptic GABABR antagonist, we were able to rescue hyperexcitation in hAPPwt animals. Our results provide evidence that APP plays a crucial role in regulating inhibitory neurotransmission.

The relation of structural valve deterioration to adverse remodelling and outcome in patients with biological heart valve prostheses.

AIMS: Native valve aortic stenosis is associated with adverse remodelling of the left ventricle and remodelling is stopped or even reversed with aortic valve replacement (AVR). However, the degeneration of bioprostheses and development of structural valve deterioration (SVD) may affect this. METHODS AND RESULTS: To assess the association with SVD, remodelling and outcome 451 patients from a single surgical centre who had undergone AVR with a Mitroflow pericardial bioprosthesis were studied. All patients were assessed in 2014 and a subgroup of patients (N = 327) were re-exanimated again after at least 18 months [median time of 27 (interquartile range, IQR 26-33) months] including echocardiography, measurements of N-terminal pro-brain natriuretic peptide, and assessment of functional status. SVD was based on echocardiography. Moderate SVD was present in 63 patients (14%) and severe SVD in 19 (4%), in the subgroup with follow-up echocardiography 48 patients (15%) patients had moderate to severe SVD at first examination. Patients with SVD had significantly greater increase in left ventricular (LV) mass index [21.6 g/m2 (IQR 5.7-48.3 g/m2) vs. 9.1 g/m2 (-8.6 to 27.3 g/m2), P = 0.01]. Further, patients with SVD had lower LV ejection fraction [55% (IQR 51-62%) vs. 60% (IQR 54-63%), P = 0.01] at follow-up. During follow-up, 94 patients (21%) met the composite endpoint of death or reoperation due to SVD and 41 patient readmitted for heart failure. In multivariable Cox regression analysis, severe SVD [hazard ratio (HR) 2.64 (1.37-5.07), P = 0.004] was associated with composite endpoint, and readmission for heart failure [HR 3.82 (1.53-9.51), P = 0.004]. CONCLUSION: SVD in aortic bioprostheses is associated with adverse LV remodelling and adverse outcome.

Structural valve deterioration in the Mitroflow biological heart valve prosthesis.

OBJECTIVES: Concern has been raised regarding the long-term durability of the Mitroflow biological heart valve prosthesis. Our aim was to assess the incidence of structural valve degeneration (SVD) for the Mitroflow bioprosthesis in a nationwide study in Denmark including all patients alive in Denmark who had received a Mitroflow aortic bioprosthesis since 2000. METHODS: Patients alive in Denmark with a Mitroflow bioprosthesis implanted since January 2000 were invited to participate in a nationwide cross-sectional study with a predefined definition of SVD. Of 1552 patients, 861 patients had died and 47 patients had been reoperated with 40 reoperations due to SVD. The remaining 644 patients were invited for evaluation; 574 patients accepted and were evaluated for SVD. The incidence of SVD was calculated using competing risk regression analysis with death as the competing event. RESULTS: A total of 173 patients were diagnosed with SVD by echocardiography. Of these, 64 (11%) patients had severe SVD and 109 (19%) patients moderate SVD. Severe SVD was associated with the age of the prosthesis and small prosthesis size [Size 21: hazard ratio (95% confidence interval, CI) 2.72 (0.97-8.56), P = 0.06; Size 19: 6.26 (1.63-24.06), P = 0.008]. The cumulative incidences of reoperation or severe SVD at Year 9 were 12.5% for Size 19, 7.6% for Size 21 and 3.1 (1.2-6.4)% for Size 23. Median survival in patients with prosthesis Sizes 23-29 was 6.4 (95% CI 5.7-7.0) years, with Size 21 it was 6.5 (95% CI 5.9-7.1) years and with Size 19 it was 6.9 (95% CI 5.7-8.2) years (P = 0.78). CONCLUSIONS: The incidence of undetected severe SVD was as high as the incidence of operated SVD. The overall risk for SVD is high for the Mitroflow bioprosthesis, especially if the prosthesis is small and older than 5 years.