Comparison of safety and efficacy between Nirmatrelvir-ritonavir and molnupiravir in the treatment of COVID-19 infection in patients with advanced kidney disease: a retrospective observational study.

Background: Nirmatrelvir-ritonavir is used in patients with coronavirus disease 2019 (COVID-19) with normal or mild renal impairment (eGFR ≥30 ml/min per 1.73 m2). There is limited data regarding its use in advanced kidney disease (eGFR <30 ml/min per 1.73 m2). We performed a retrospective territory-wide observational study evaluating the safety and efficacy of nirmatrelvir-ritonavir when compared with molnupiravir in the treatment of patients with COVID-19 with advanced kidney disease. Methods: We adopted target trial emulation using data from a territory-wide electronic health record database on eligible patients aged ≥18 years with advanced kidney disease (history of eGFR <30 ml/min per 1.73 m2) who were infected with COVID-19 and were prescribed with either molnupiravir or nirmatrelvir-ritonavir within five days of infection during the period from 16 March 2022 to 31 December 2022. A sequence trial approach and 1:4 propensity score matching was applied based on the baseline covariates including age, sex, number of COVID-19 vaccine doses received, Charlson comorbidity index (CCI), hospitalisation, eGFR, renal replacement therapy, comorbidities (cancer, respiratory disease, myocardial infarction, ischaemic stroke, diabetes, hypertension), and drug use (renin-angiotensin-system agents, beta blockers, calcium channel blockers, diuretics, nitrates, lipid lowering agents, insulins, oral antidiabetic drugs, antiplatelets, immuno-suppressants, corticosteroids, proton pump inhibitors, histamine H2 receptor antagonists, monoclonal antibody infusion) within past 90 days. Individuals were followed up from the index date until the earliest outcome occurrence, death, 90 days from index date or the end of data availability. Stratified Cox proportional hazards regression adjusted with baseline covariates was used to compare the risk of outcomes between nirmatrelvir-ritonavir recipients and molnupiravir recipients which include (i) all-cause mortality, (ii) intensive care unit (ICU) admission, (iii) ventilatory support, (iv) hospitalisation, (v) hepatic impairment, (vi) ischaemic stroke, and (vii) myocardial infarction. Subgroup analyses included age (<70; ≥70 years); sex, Charlson comorbidity index (≤5; >5), and number of COVID-19 vaccine doses received (0-1; ≥2 doses). Findings: A total of 4886 patients were included (nirmatrelvir-ritonavir: 1462; molnupiravir: 3424). There were 347 events of all-cause mortality (nirmatrelvir-ritonavir: 74, 5.06%; molnupiravir: 273, 7.97%), 10 events of ICU admission (nirmatrelvir-ritonavir: 4, 0.27%; molnupiravir: 6, 0.18%), 48 events of ventilatory support (nirmatrelvir-ritonavir: 13, 0.89%; molnupiravir: 35, 1.02%), 836 events of hospitalisation (nirmatrelvir-ritonavir: 218, 23.98%; molnupiravir: 618, 28.14%), 1 event of hepatic impairment (nirmatrelvir-ritonavir: 0, 0%; molnupiravir: 1, 0.03%), 8 events of ischaemic stroke (nirmatrelvir-ritonavir: 3, 0.22%; molnupiravir: 5, 0.16%) and 9 events of myocardial infarction (nirmatrelvir-ritonavir: 2, 0.15%; molnupiravir: 7, 0.22%). Nirmatrelvir-ritonavir users had lower rates of all-cause mortality (absolute risk reduction (ARR) at 90 days 2.91%, 95% CI: 1.47-4.36%) and hospitalisation (ARR at 90 days 4.16%, 95% CI: 0.81-7.51%) as compared with molnupiravir users. Similar rates of ICU admission (ARR at 90 days -0.09%, 95% CI: -0.4 to 0.2%), ventilatory support (ARR at 90 days 0.13%, 95% CI: -0.45 to 0.72%), hepatic impairment (ARR at 90 days 0.03%, 95% CI: -0.03 to 0.09%), ischaemic stroke (ARR at 90 days -0.06%, 95% CI: -0.35 to 0.22%), and myocardial infarction (ARR at 90 days 0.07%, 95% CI: -0.19 to 0.33%) were found between nirmatrelvir-ritonavir and molnupiravir users. Consistent results were observed in relative risk adjusted with baseline characteristics. Nirmatrelvir-ritonavir was associated with significantly reduced risk of all-cause mortality (HR: 0.624, 95% CI: 0.455-0.857) and hospitalisation (HR: 0.782, 95% CI: 0.64-0.954). Interpretation: Patients with COVID-19 with advanced kidney disease receiving nirmatrelvir-ritonavir had a lower rate of all-cause mortality and hospital admission when compared with molnupiravir. Other adverse clinical outcomes were similar in both treatment groups. Funding: Health and Medical Research Fund (COVID1903010), Health Bureau, The Government of the Hong Kong Special Administrative Region, China.

Diet induced obesity and type 2 diabetes drives exacerbated sex-associated disease profiles in K18-hACE2-mice challenged with SARS-CoV-2

SARS-CoV-2 infection results in wide-ranging disease manifestation from asymptomatic to potentially lethal. Infection poses an increased threat of severity to at-risk populations including those with hypertension, diabetes, and obesity. Type 2 Diabetes (T2DM), is characterized, in part, by insulin insensitivity and impaired glucose regulation. T2DM patients have increased disease severity and poorer outcomes with COVID-19. We utilized the diet-induced obesity (DIO) model of Type 2 Diabetes in SARS-CoV-2-susceptible K18-hACE2 transgenic mice to better understand the obesity co-morbidity. Female DIO, but not male DIO mice challenged with SARS-CoV-2 were observed to have shortened time to morbidity compared to normal diet mice. Increase in susceptibility to SARS-CoV2 in female DIO was associated with increased total viral RNA burden compared to male mice. RNAseq analysis was performed on the lungs of non-challenged, challenged, females, males, of either normal diet or DIO cohorts to determine the disease specific transcriptional profiles. DIO female mice had more total activated genes than normal diet mice after challenge; however, male mice experienced a decrease. GO term analysis revealed the DIO condition increased interferon response signatures and interferon gamma production following challenge. Male challenged mice had robust expression of antibody-related genes suggesting antibody producing cell localization in the lung. DIO reduced antibody gene expression in challenged males. Collectively this study establishes a preclinical T2DM/obesity co-morbidity model of COVID-19 in mice where we observed sex and diet specific responses that begin to explain the effects of obesity and diabetes on COVID-19 disease.

Real-World Clinical Performance of the Abbott Panbio with Nasopharyngeal, Throat and Saliva Swabs Among Symptomatic Individuals with COVID-19

BACKGROUNDPoint of Care Testing (POCT) SARS-CoV-2 antigen tests, such as the Abbott Panbio, have great potential to help combat the COVID-19 pandemic. The Panbio is Health Canada approved for the detection of SARS-CoV-2 in symptomatic individuals within the first 7 days of COVID-19 symptom onset(s). METHODSSymptomatic adults recently diagnosed with COVID-19 in the community were recruited into the study. Paired nasopharyngeal (NP), throat, and saliva swabs were collected, with one paired swab tested immediately with the Panbio, and the other transported in universal transport media and tested using reverse-transcriptase polymerase chain reaction (RT-PCR). Positive percent agreement (PPA) was calculated. Subsequently, individuals within 7 days of symptom onset who presented to community assessment centres for SARS-CoV-2 testing had Panbio testing completed and paired with RT-PCR results from parallel NP or throat swabs. RESULTS145 individuals were included in the study. Collection of throat and saliva was stopped early due to poor performance (throat PPA 57.7%, n=61, and saliva PPA 2.6%, n=41). NP swab PPA was 87.7% [n=145, 95% confidence interval 81.0% - 92.7%]. There were 1,641 symptomatic individuals tested by Panbio in community assessment centres, with 268/1641 (16.3%) positive for SARS-CoV-2. There were 37 false negatives, corresponding to a PPA of 86.2% [81.5% - 90.1%]. CONCLUSIONSThe Panbio test reliably detects most cases of SARS-CoV-2 from adults in the POCT community setting presenting within 7 days of symptom onset using nasopharyngeal swabs. Throat and saliva swabs are not reliable specimens for the Panbio.

Acceptable Performance of the Abbott ID NOW Among Symptomatic Individuals with Confirmed COVID-19

INTRODUCTIONPoint of care diagnostic tests for SARS-CoV-2, such as the ID NOW, have great potential to help combat the COVID-19 pandemic. The ID NOW is approved by the United States Food and Drug Administration (FDA) for the detection of SARS-CoV-2 in symptomatic individuals within the first 7 days of symptom onset for COVID-19 if tested within 1 hour of specimen collection. However, clinical data on the performance of the ID NOW is limited, with many studies deviating from the manufacturers instructions and/or having small sample size. METHODSAdults with COVID-19 in the community or hospital were recruited into the study. Paired throat swabs were collected, with one throat swab transported immediately in an empty sterile tube to the laboratory for ID NOW testing, and the other transported in universal transport media and tested by an in-house SARS-CoV-2 RT-PCR assay targeting the E-gene. Positive percent agreement (PPA) was calculated. RESULTS133 individuals were included in the study. 129 samples were positive on either the ID NOW and/or RT-PCR. Assuming any positive result on either assay represents a true positive, PPA of the ID NOW compared to RT-PCR with 95% confidence intervals was 89.1% [82.0% - 94.1%] and 91.6% [85.1% - 95.9%], respectively. When analyzing individuals with symptoms [≤] 7 days and who had the ID NOW performed within an hour, ID NOW PPA increased to 98.2%. DISCUSSIONIn this study, SARS-CoV-2 results from the ID NOW were reliable, especially when testing was adhered to manufacturers recommendations.

Transgenic mice over-expressing GABA(B)R1a receptors acquire an atypical absence epilepsy-like phenotype.

In this study, we tested whether over-expressing the GABA(B) receptor R1a subtype in transgenic mouse forebrain neurons would be sufficient to induce spontaneous absence seizures. As hypothesized, these transgenic mice develop spontaneous, recurrent, bilaterally synchronous, 3-6 Hz slow spike and wave discharges between 2 and 4 months of age. These discharges are blocked by ethosuximide and exacerbated by baclofen confirming their absence nature. The discharges occur coincident with absence-like behaviors such as staring, facial myoclonus, and whisker twitching. However, in contrast to typical absence epilepsy models, these mice move during the ictal event, display spike and wave discharges in both thalamocortical and limbic circuitry, exhibit impaired hippocampal synaptic plasticity, and display significantly impaired learning ability. Collectively, these features are more characteristic of the less common but more debilitating atypical form of absence epilepsy. Thus, these data support a role for the GABA(B)R1a receptor subtype in the etiology of atypical absence epilepsy.

Hormonal regulation of atypical absence seizures.

A time course study that examined the effects of the female estrous cycle on the chronic slow spike-and-wave discharges (SSWDs), gamma-aminobutyric B receptor (GABA(B)R) binding, and GABA(B)R protein expression was conducted in Long Evans hooded rats treated during development with a cholesterol synthesis inhibitor AY9944 (AY). In addition, a pharmacological study using the hormones progesterone, 17 beta-estradiol, mifepristone (intracellular progesterone receptor antagonist), tamoxifen (intracellular estrogen receptor antagonist), and allopregnanolone (progesterone metabolite) was performed to determine their effects on AY-induced seizures. The data indicate that there is a significant increase in both the duration of SSWD and GABA(B)R binding in the AY model, during the proestrus stage of the estrous cycle, the stage during which the levels of progesterone are at their highest. No changes in GABA(B)R1a or R2 protein levels were observed. In addition, the administration of both progesterone and allopregnanolone exacerbated seizures in the AY model, whereas 17 beta-estradiol attenuated the SSWD duration. Neither mifepristone nor tamoxifen blocked the effects of progesterone and 17 beta-estradiol, respectively, on SSWD duration in the AY model, suggesting that these two sex hormones are working in a manner independent of their intracellular receptors. These data suggest an important role for steroid hormones in the regulation and maintenance of AY-induced atypical absence seizures.