Abstract:

Background: Currently, there is a paucity of evidence showing serum vitamin D deficiency affects biofilm formation and vitamin D signalling peptides like the vitamin D receptor (VDR) protein and Cathelicidin antimicrobial peptide (LL-37), which subsequently influence the therapeutic strategies in patients with diabetic foot infection (DFI).

Objective: The study aims to determine the various factors associated with vitamin D status and the treatment strategies in DFI patients.

Methods: A hospital-based prospective observational study was conducted with 52 DFI patients. Their serum vitamin D, VDR protein, and LL-37 levels were measured by ELISA. Biofilm formation was quantified by the tissue culture plate method. Chi-square tests and unpaired t-tests were used for statistical analysis.

Results: The vitamin D status of 52 DFI patients showed that 22 (42.3%) were deficient, 29 (55.76%) were insufficient, and 1 (1.92%) belonged to the sufficient group. Biofilm formation (p = 0.007) and low LL-37 level (p<0.001) were significantly associated with the vitamin D-deficient group. Further, significantly lower levels of VDR protein were seen in the vitamin D-deficient group (t43.862= -6.571; p<0.001). In addition, surgical intervention-treatment strategy was significantly associated with the vitamin D-deficient group (p = 0.012), low LL-37 group (p<0.001), and lower levels of VDR protein (t9.560= -4.212; p = 0.002).

Conclusion: The lower levels of the LL-37 and VDR proteins, along with the formation of biofilm and surgical interventions, were mostly seen in vitamin D-deficient DFI patients.

Keywords: Diabetic foot infection, Biofilm, Vitamin D-deficiency, Cathelicidin

Introduction: Polypharmacy is a serious global issue, mainly for older adults in developed countries, and Japan is one of the most severe aging and depopulating countries worldwide. A periodical medical fees amendment was made in April 2020 to include reduction incentives for polypharmacy and duplicated medications during COVID-19 pandemic.
Aims: This nationwide cross-sectional study aims to demonstrate the polypharmacy trend based on secondary medical areas (SMAs) from the NDB Open Data on annual reimbursement claims for outpatient prescription fees in Japan after the recent polypharmacy reduction policy.
Methods: Polypharmacy proportion (PP) and polypharmacy reduction ratio (PRR) were treated as outcome variables following our previous researches, and this study defined April 2019 to March 2020 as pre-COVID and April 2020 to March 2021 as during COVID. Urban SMAs is set for a population of 1,000,000 (or a population density of 2,000 persons/km2 and above), and local SMAs is set for a population of 200,000 and above (or a population of 100,000 and above with a population density of 200 persons/km2 and above), excluding urban areas. Depopulated SMAs is defined as other areas except for urban SMAs and local SMAs.
Results: The mean values of PP (pre-COVID) were 4.17% for total SMAs, 3.27% for urban SMAs, 3.91% for local SMAs, and 4.84% for depopulated SMAs. The mean values of PP (during COVID) were 4.16% for all SMAs, 3.37% for urban SMAs, 3.92% for local SMAs, and 4.74% for depopulated SMAs. A statistically significant decrease in PP was detected in depopulated SMAs, with 1.39% as the PRR value.
Discussion/Conclusion: This study revealed that the effectiveness of polypharmacy reduction policies implemented during the COVID-19 pandemic were limited in reducing nationwide polypharmacy in Japan. However, further polypharmacy reduction is required in depopulated SMAs because the mean (95% CI) of PP in depopulated SMAs remained high.

Introduction: Recent clinical trial have suggested that metformin reduce the risk of post-COVID-19 condition (PCC) in overweight/obese individuals.

Aims: This study aimed to investigate whether metformin use reduces the risk of PCC among overweight/obese patients, emulating the recent trial in the real-world setting.

Methods: We conducted a population-based cohort study using the United Kingdom Clinical Practice Research Datalink(CPRD) Aurum. Eligible individuals were overweight/obese adults (BMI ≥ 25 kg/m2, aged ≥18) with a record of SAR-CoV-2 infection between March 2020 and April 2023. Individuals with contraindications for metformin or prescriptions for metformin within the year prior to their COVID-19 diagnosis date were excluded. The study cohort was divided into two groups: those who initiated metformin before 30 days after COVID-19 diagnosis (exposed) and those who did not (unexposed).The primary outcome was defined as having a PCC diagnostic code or having at least one of 25 WHO-listed symptoms between 90-365 days after the COVID-19 diagnosis, with no history of these symptoms 180 days before SAR-CoV-2 infection. Individuals were followed up to 1 year after their COVID-19 diagnosis date. Propensity score fine stratification was applied to balance the observed characteristics to minimise confounding between the metformin and non-metformin groups. Risk ratio(RR) and 95% confidence interval(CI) were calculated using the logistic regression model to estimate the impact of metformin on the risk of PCC.

Results: The metformin group (n=1,105) had a significantly lower risk of PCC with 100 events compared to 141,395 events in the non-metformin group (n=615,575), with a RR of 0.39(95% CI 0.32-0.48), regardless of diabetes status. Among individuals with diabetes, the RR of PCC for the metformin group compared to the non-metformin group was 0.42(95% CI 0.33-0.54).

Discussion/Conclusion: Our study confirms the trial findings, demonstrating that metformin has a preventive effect on long COVID in overweight/obese individuals in a real-world setting.

Background:
Emerging evidence suggested the significantly increased risk of all-cause mortality in COVID-19 patients with type-2 diabetes. However, direct comparison on the effectiveness of molnupiravir and nirmatrelvir-ritonavir among COVID-19 patients with type-2 diabetes remains scarce.

Aims:
To compare the effectiveness of molnupiravir and nirmatrelvir-ritonavir for COVID-19 patients with type-2 diabetes in non-hospitalised and hospitalised settings.

Methods:
Target trial emulation was conducted using territory-wide electronic health databases in Hong Kong. A sequential trial approach was adopted. Adults with type-2 diabetes who had a COVID-19 infection and initiated either molnupiravir or nirmatrelvir-ritonavir within five days of infection between 16 March 2022 and 31 December 2022 were included. One-to-one propensity score matching was applied between treatment groups. Each subject was followed from index date (date of molnupiravir or nirmatrelvir-ritonavir initiation) until the earliest occurrence of all-cause mortality, 28 days from index date or the end of data availability (31 January 2023). Risk of all-cause mortality between treatment groups in non-hospitalised and hospitalised settings was compared by Cox regression adjusted with baseline characteristics. Subgroup analyses were performed with age (<70, ≥70 years), sex, Charlson comorbidity index (<4, ≥4), and number of COVID-19 vaccine doses (0-1, ≥2 doses).

Results:
17,974 non-hospitalised (8,987 per treatment group) and 3,678 hospitalised (1,839 per treatment group) patients were identified. Nirmatrelvir-ritonavir users had lower risk of all-cause mortality as compared with molnupiravir users in both non-hospitalised (absolute risk reduction [ARR] at 28 days 0.80% [95%CI 0.56-1.04]; HR 0.42 [95%CI 0.26-0.66]) and hospitalised setting (ARR at 28 days 2.83% [95%CI 1.54-4.11]; HR 0.60 [95%CI 0.42-0.85]). Findings were consistent in all subgroups.

Conclusion:
In non-hospitalised and hospitalised settings, nirmatrelvir-ritonavir was more effective than molnupiravir in reducing 28-day all-cause mortality among COVID-19 patients with type-2 diabetes. Hence, nirmatrelvir-ritonavir may be preferred over molnupiravir for patients with no contraindications to the antivirals.

Introduction To repurpose ivermectin for COVID-19 treatment has gained attention in several resource-limited countries during the pandemic.

Aims To investigate the trends of ivermectin consumption during the COVID-19 pandemic using a global pharmacy sales database. We hypothesized that the consumption of ivermectin would increase during COVID-19 despite the limited evidence to support its use.

Methods We analysed data from IQVIA MIDAS® Quarterly Sales Database (“IQVIA MIDAS”), including data from both retail and non-retail channels from 67 countries between 2016 and 2021. The information captured in the database includes country, corporation, manufacture, type of formulation, propriety names, active ingredients, and quarterly volume of sales. All medicines were coded using the Anatomical Therapeutic Chemical (ATC) codes defined by the European Pharmaceutical Market Research Association (EPHMRA). Standard units (SUs) were used to estimate the consumption of medicines. One SU was defined as one tablet, capsule, ampoule/vial, or 5 mL oral suspension by IQVIA. The use of anthelmintic was calculated by total consumption per 1000 population. The 2022 World Bank classification was used to define the country income level as lower-middle income, upper-middle-income, or high-income countries.

Results We observed an increase of ivermectin consumption from 1,682 in 2015 to 11,065 thousand SUs in 2021. During the pandemic, the consumption of ivermectin increased compared to previous years, particularly in lower-middle and upper-middle-income countries but not for high income countries. Ivermectin consumption increased substantially in Egypt, Argentina, Peru, and Venezuela during the COVID-19 pandemic.

Discussion/Conclusion Government agencies play an important role in disseminating vital information about the pandemic. Potential irrational consumption of ivermectin raises important issues about using evidence-based decisions and ensuring the governments’ reactions are appropriate when there is insufficient evidence and significant social pressures to act.

Keywords: anthelmintic, ivermectin, irrational consumption, COVID-19