ABSTRACT
Background: The unprecedented scale of the COVID-19 pandemic and rapid evolution of SARS-CoV-2 variants underscores the need for broadly active inhibitors with a high barrier to resistance. The coronavirus main protease (Mpro) is an essential viral enzyme required for viral polyprotein processing and is highly conserved across human coronaviruses. Pomotrelvir (PBI-0451) is a novel Mpro inhibitor currently completing phase 2 clinical trial. Here we describe the mechanism of action, broad activity against SARS-CoV-2 clinical isolates, combination studies with other SARS-CoV-2 inhibitors and favorable resistance profile of pomotrelvir. Method(s): The kinetic parameters of pomotrelvir Mpro inhibition and its interaction with nirmaltrevir were determined in a kinetic protease assay. The IC50s of pomotrelvir on mutant Mpro proteins were measured in an endpoint Mpro assay. Combination studies of pomotrelvir with remdesivir and molnupiravir were carried out in A549-hACE2 cells infected with SARS-CoV-2 NLuc virus. Activity against SARS-CoV-2 clinical variants was assessed by infection of A549-ACE2-TMPRSS2 cells followed by immunostaining of the viral nucleocapsid protein. Result(s): Pomotrelvir is a potent competitive inhibitor of SARS-CoV-2 Mpro (Ki =2.7 nM). Binding of pomotrelvir and the Mpro inhibitor nirmatrelvir to the active site is mutually exclusive. In the SARS-CoV-2 NLuc assay, pomotrelvir is additive when combined with remdesivir or molnupiravir, two nucleoside analogs targeting viral RNA synthesis. When the effect of Mpro substitutions previously selected in a resistance study of pomotrelvir were analyzed in an enzyme assay, only Mpro-N133H showed a significant increase in IC50 (45-fold). The catalytic efficiency of Mpro-N133H is reduced by 10-fold and the recombinant virus SARSCoV-2 (WA1) -N133H is not viable, suggesting that N133H has lower replicative fitness. Lastly, pomotrelvir exhibits broad activity against all SARS-CoV-2 clinical isolates tested to date, including five omicron variants. Conclusion(s): PBI-0451 is a potent competitive inhibitor of SARS-CoV-2 Mpro and is broadly active against SARS-CoV-2 clinical isolates including omicron variants. Results from inhibitor interaction studies support the potential combination of pomotrelvir with remdesivir and molnupiravir but not nirmatrelvir. Enzymatic characterization of in vitro selected pomotrelvir resistant variants indicates they either confer no resistance or have reduced fitness.
ABSTRACT
Background Evidence about how population mental health has evolved from before and over the COVID-19 pandemic remains mixed, with impacts on mental health inequalities being unclear. We investigated changes in mental health and sociodemographic inequalities from before and across the first year of the pandemic. Methods Data from 11 UK longitudinal population-based studies with pre-pandemic measures of psychological distress were analysed, estimates pooled, and stratified by age, sex, ethnicity, country and lone household status. Trends in the prevalence of poor mental health were assessed before the pandemic (TP0) and across the pandemic at three time periods (initial lockdown (TP1), easing of restrictions (TP2), and a subsequent lockdown (TP3)). Results In total, 49,993 adult participants were analysed across the 11 cohort studies. There was an overall worsening in mental health from pre-pandemic scores across all three pandemic timepoints, (TP1 Standardised Mean Difference: 0.15 (95% CI: 0.06 - 0.25);TP2 SMD: 0.18 (0.09 - 0.27);TP3 SMD: 0.21 (0.10 - 0.32)) with no evidence of improvement during the period of eased lockdown restrictions in summer 2020. Changes from pre-pandemic psychological distress were higher in females during the pandemic (TP3 SMD: 0.23 (0.11 - 0.35)), amongst those with degree-level education (TP3 SMD: 0.26 (0.14 - 0.38)), and adults aged 25-44 years. We did not find evidence of changes in distress differing by ethnicity, lone household status or UK nation. Conclusions The substantial deterioration in mental health seen in the UK during the first lockdown did not reverse when lockdown lifted and a sustained worsening was observed across the pandemic. Mental health declines have been unequal across the population and these results have implications for policy, including the need for specific investment for support for those most affected to mitigate the effects of the pandemic and measures to reduce inequalities within these specific groups. Key messages • A sustained deterioration in mental health was observed from before the start of the COVID-19 pandemic, and did not recover when social restrictions were eased. • Deterioration in mental health varied by sociodemographic factors, namely age, sex, and education, and highlights a need for improved mental health care provision to minimise widening inequalities.
ABSTRACT
Aim: Numerous international organizations have provided guidelines for clinical follow-up after breast cancer treatment during the first 5 years, ranging from 3 to 6 months with reduced frequency or visits after this. In most guidelines, annual mammography is also recommended. In the face of a global pandemic rise of telemedicine, COVID-19 has forced us to re-examine the efficacy of existing guidelines for in-person follow-up practices. Method(s): Between 2010 to 2020, 3264 patients with early and advanced stage breast cancer treated by breast conserving surgery (BCS) or mastectomy with recorded relapses by December 2021 was analyzed. Mode of detection of the relapse was noted. Result(s): A total of 100 relapses was identified. Twenty-eight of these patients relapsed concurrently with metastatic disease. Locoregional relapse rate in this series was 2.2%. Forty-nine relapses occurred in the ipsilateral breast or chest wall. Fifteen were in the ipsilateral axilla and eight relapses occurred in the both the ipsilateral breast and axilla. Forty-three relapses (43%) were symptomatic, twenty (20%) were detected clinically, thirty (30%) were detected by surveillance mammography, one patient (1%) presented with elevated tumor markers and six (6%) others presented on scheduled CT or PETCT scans. The average time interval between relapse and last mammogram was 16.7 months. Conclusion(s): Routine scheduled in-person assessment still has an important role in the detection of relapses of breast cancer. However, the importance of self-awareness and self-examination should be emphasized and ideally, with a system for early return to the clinic if abnormality is suspected.
ABSTRACT
This year was marked by the COVID-19 pandemic, which altered transplant program activity and affected waitlist and transplant outcomes. Still, 8906 liver transplants were performed, an all-time high, across 142 centers in the United States, and pretransplant as well as graft and patient survival metrics, continued to improve. Living donation activity decreased after several years of growth. As of June 30, 2020, 98989 liver transplant recipients were alive with a functioning graft, and in the context of increasing liver transplant volume, the size of both the adult and pediatric liver transplant waitlists have decreased. On February 4, 2020, shortly before the pandemic began, a new liver distribution policy based on acuity circles was implemented, replacing donor service area- and region-based boundaries. A policy change to direct pediatric livers to pediatric recipients led to an increase in deceased donor transplant rates and a decrease in pretransplant mortality rate among children, although the absolute number of pediatric transplants did not increase in 2020. Among adults, alcohol-associated liver disease became the predominant indication for liver transplant in 2020. After implementation of the National Liver Review Board and lower waitlist priority for most exception cases in 2019, fewer liver transplants were being performed via exception points, and the transplant rate between those with and without hepatocellular carcinoma has equalized. Women continue to experience higher pretransplant mortality and lower rates of liver transplant than men.
Subject(s)
COVID-19 , Tissue and Organ Procurement , Adult , COVID-19/epidemiology , Child , Female , Graft Survival , Humans , Liver , Male , Pandemics , SARS-CoV-2 , Tissue Donors , United States/epidemiology , Waiting ListsABSTRACT
Disruptions related to the COVID-19 pandemic and its associated virus suppression measures have affected many worldwide but those already suffering from psychological distress may have been especially vulnerable. We investigated associations between pre-pandemic psychological distress and disruptions to healthcare, economic activity, housing, and cumulative disruptions. Data were from 59,482 participants in 12 UK longitudinal adult population surveys with both pre-pandemic and COVID-19 surveys. Participants self-reported disruptions since the start of the pandemic to: healthcare (medication access, procedures, or appointments);economic activity (negative changes in employment, income or working hours);and housing (change of address or household composition). Logistic regression models were used to estimate associations between pre-pandemic standardised psychological distress scores and disruption outcomes. Findings were synthesised using a random effects meta-analysis with restricted maximum likelihood. Approximately one to two thirds of study participants experienced some form of disruption during the pandemic. One standard deviation higher pre-pandemic psychological distress was associated with: increased odds of any healthcare disruption (odds ratio: 1.30 [95% CI: 1.20-1.40];I2: 65%);increased odds of experiencing any economic disruption (1.11 [1.03-1.16];I2: 61%);no associations with housing disruptions;and increased likelihood of experiencing a disruption in at least two domains (1.25 [1.18-1.32];I2: 38%) or one domain (1.11 [1.07-1.16];I2: 32%) compared to no disruptions. Associations did not differ by sex, ethnicity, education, or age. Individuals suffering from psychological distress pre-pandemic may need additional support to manage stressful life disruptions. Considering mental ill-health was already unequally distributed in the UK population, this may exacerbate existing inequalities related to sex, ethnicity, education and age.
ABSTRACT
Aim: Behavioral changes in seeking medical attention during COVID- 19 pandemic and its impact on breast cancer outcomes has never been studied. Methods: This is a case-control study comparing breast cancer patients treated between Quarter 1 2020 (Case, COVID-19 pandemic) and Quarter 1 2019 (Control). Clinical and pathological data between the two groups were compared. Patients from the case group were interviewed using a standardized questionnaire. Results: There were 57 patients in the case group and 101 patients in the control group. Mean ages of diagnosis were 56.1 (Range 34-75) and 57.4 (Range 30-84) years old respectively. Mean duration of symptom prior to the first specialist consultation in the case group was 6.4 weeks (2-32 weeks) while that in the control group was 3.1 weeks. 12/57 (21.1%) patients had delayed presentation for their breast symptoms during COVID-19 outbreak. The mean score of anxiety on hospital acquired COVID-19 infection was 3.3 out of 5 (Range 1-5) There were significantly less DCIS in the case group (N = 5 vs 32, 8.8% vs 31.7%) (P = .0009). However, there were more T2 or above cancers in the case group (N = 32 vs 28, 56.1% vs 27.7%) (P = .0008). N stage was not significantly different between the two groups. Mean surgery waiting time were similar (2.6 and 2.5 weeks respectively). Mastectomy rate was lower in the case group (42% vs 75.4%). There was no difference in reconstruction rate (19.2% vs 16.8%). Conclusions: Breast cancer patients tends to present late during COVID-19 pandemic.