Clinical efficacy of nirmatrelvir and ritonavir combination for treating diabetic patients with COVID-19.

The aim of this study was to investigate the clinical efficacy of a combination of nirmatrelvir and ritonavir (NMV-r) for treating COVID-19 in patients with diabetes mellitus (DM). This retrospective cohort study used the TriNetX research network to identify adult diabetic patients with COVID-19 between January 1, 2020, and December 31, 2022. Propensity score matching was used to match patients who received NMV-r (NMV-r group) with those who did not receive NMV-r (control group). The primary outcome was all-cause hospitalization or death during the 30-day follow-up period. Two cohorts comprising 13 822 patients with balanced baseline characteristics were created using propensity score matching. During the follow-up period, the NMV-r group had a lower risk of all-cause hospitalization or death than the control group (1.4% [n = 193] vs. 3.1% [n = 434]; hazard ratio [HR], 0.497; 95% confidence interval [CI], 0.420-0.589). Compared with the control group, the NMV-r group also had a lower risk of all-cause hospitalization (HR, 0.606; 95% CI, 0.508-0.723) and all-cause mortality (HR, 0.076; 95% CI, 0.033-0.175). This lower risk was consistently observed in almost all subgroup analyses, which examined sex (male: 0.520 [0.401-0.675]; female: 0.586 [0.465-0.739]), age (age 18-64 years: 0.767 [0.601-0.980]; ≥65 years: 0.394 [0.308-0.505]), level of HbA1c (<7.5%: 0.490 [0.401-0.599]; ≥7.5%: 0.655 [0.441-0.972]), unvaccinated (0.466 [0.362-0.599]), type 1 DM (0.453 [0.286-0.718]) and type 2 DM (0.430 [0.361-0.511]). NMV-r can help reduce the risk of all-cause hospitalization or death in nonhospitalized patients with DM and COVID-19.

Clinical effectiveness of nirmatrelvir plus ritonavir in patients with COVID-19 and substance use disorders based on real-world data.

This study assessed the clinical efficacy of nirmatrelvir plus ritonavir (NMV-r) in treating patients with coronavirus disease-2019 (COVID-19) and substance use disorders (SUDs). This study included two cohorts: the first examined patients with SUDs, with and without a prescription for NMV-r, while the second compared patients prescribed with NMV-r, with and without a diagnosis of SUDs. SUDs were defined using ICD-10 codes, related to SUDs, including alcohol, cannabis, cocaine, opioid, and tobacco use disorders (TUD). Patients with underlying SUDs and COVID-19 were identified using the TriNetX network. We used 1:1 propensity score matching to create balanced groups. The primary outcome of interest was the composite outcome of all-cause hospitalization or death within 30 days. Propensity score matching yielded two matched groups of 10 601 patients each. The results showed that the use of NMV-r was associated with a lower risk of hospitalization or death, 30 days after COVID-19 diagnosis (hazard ratio (HR), 0.640; 95% confidence interval (CI): 0.543-0.754), as well as a lower risk of all-cause hospitalization (HR, 0.699; 95% CI: 0.592-0.826) and all-cause death (HR, 0.084; 95% CI: 0.026-0.273). However, patients with SUDs had a higher risk of hospitalized or death within 30 days of COVID-19 diagnosis than those without SUDs, even with the use of NMV-r (HR, 1.783; 95% CI: 1.399-2.271). The study also found that patients with SUDs had a higher prevalence of comorbidities and adverse socioeconomic determinants of health than those without SUDs. Subgroup analysis showed that the benefits of NMV-r were consistent across most subgroups with different characteristics, including age (patients aged ≥60 years [HR, 0.507; 95% CI: 0.402-0.640]), sex (women [HR, 0.636; 95% CI: 0.517-0.783] and men [HR, 0.480; 95% CI: 0.373-0.618]), vaccine status (vaccinated <2 doses [HR, 0.514; 95% CI: 0.435-0.608]), SUD subtypes (alcohol use disorder [HR, 0.711; 95% CI: 0.511- 0.988], TUD [HR, 0.666; 95% CI: 0.555-0.800]) and Omicron wave (HR, 0.624; 95% CI: 0.536-0.726). Our findings indicate that NMV-r could reduce all-cause hospitalization and death in the treatment of COVID-19 among patients with SUDs and support the use of NMV-r for treating patients with SUDs and COVID-19.

Clinical efficacy and safety of interleukin-1 blockade in the treatment of patients with COVID-19: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: This study evaluated the clinical efficacy and safety of interleukin-1 (IL-1) blockade for patients with COVID-19. METHODS: The PubMed, Web of Science, Ovid Medline, Embase and Cochrane Library databases were searched for relevant articles from their inception to 25 September 2022. Only randomized clinical trials (RCTs) that assessed the clinical efficacy and safety of IL-1 blockade in the treatment of patients with COVID-19 were included. RESULTS: This meta-analysis included seven RCTs. No significant difference in the all-cause mortality rate of patients with COVID-19 was observed between the IL-1 blockade and control groups (7.7 vs. 10.5%, odds ratio [OR] = 0.83, 95% confidence interval [CI] 0.57-1.22; I2 = 18%). However, the study group was at significantly lower risk of requiring mechanical ventilation (MV) compared with the control group (OR = 0.53, 95% CI 0.32-0.86; I2 = 24%). Finally, the risk of adverse events was similar between the two groups. CONCLUSIONS: IL-1 blockade does not provide increased survival benefits in hospitalized patients with COVID-19, but it may reduce the need for MV. Furthermore, it is a safe agent for use in the treatment of COVID-19.>.

This systematic review and meta-analysis of randomized clinical trials (RCTs) evaluated the clinical efficacy and safety of interleukin-1 (IL-1) blockade for patients with COVID-19.Based on the analysis of six RCTs, no significant difference in the all-cause mortality rate of patients with COVID-19 was observed between the IL-1 blockade and control groups.The study group using IL1 was associated with a significantly lower risk of requiring mechanical ventilation compared with the control group.The risk of adverse events was similar between the study and the control groups.

Efficacy of nirmatrelvir and ritonavir for post-acute COVID-19 sequelae beyond 3 months of SARS-CoV-2 infection.

The effect of nirmatrelvir plus ritonavir (NMV-r) on post-acute COVID-19 sequelae beyond 3 months of SARS-CoV-2 infection remains unknown. This retrospective cohort study utilized data from the TriNetX Research Network. We identified nonhospitalized adult patients with COVID-19 receiving a diagnosis between January 1 and July 31, 2022. Propensity score matching (PSM) was used to create two matched cohorts: NMV-r and non-NMV-r groups, respectively. We measured the primary outcomes using a composite of all-cause emergency room (ER) visits or hospitalization and a composite of post-COVID-19 symptoms according to the WHO Delphi consensus, which also stated that post COVID-19 condition occurs usually 3 months from the onset of COVID-19, during the follow-up period between 90 days after the index diagnosis of COVID-19 and the end of follow-up (180 days). Initially, we identified 12 247 patients that received NMV-r within 5 days of diagnosis and 465 135 that did not. After PSM, 12 245 patients remained in each group. During the follow-up period, patients treated with NMV-r had a lower risk of all-cause hospitalization and ER visits compared with untreated patients (659 vs. 955; odds ratio [OR], 0.672; 95% confidence interval [CI], 0.607-0.745; p < 0.0001). However, the overall risk of post-acute COVID-19 symptoms did not significantly differ between the two groups (2265 vs. 2187; OR, 1.043; 95% CI, 0.978-1.114; p = 0.2021). The reduced risk of all-cause ER visits or hospitalization in the NMV-r group and the similarities in the risk of post-acute COVID-19 symptoms between the two groups were consistent in the subgroups stratified by sex, age, and vaccination status. Early NMV-r treatment of nonhospitalized patients with COVID-19 was associated with reduced risk of hospitalization and ER visits during the period of 90-180 days after diagnosis compared with no NMV-r treatment; however, post-acute COVID-19 symptoms and mortality risk did not differ significantly between the groups.

How Taiwan has responded to COVID-19 and how COVID-19 has affected Taiwan, 2020-2022.

From January 2020 to December 2022, there was a total of 8,872,955 confirmed COVID-19 cases in Taiwan. In addition, a total of 15,253 COVID-19 related deaths were reported. During these three years, the government and health authority did many efforts to response this pandemic. In the early pandemic, Taiwan Central Epidemic Command Center was established in the early 2020 to organize associated resource, develop effective policy and implement strict intervention. In response to COVID-19 pandemic, many infection control policy and interventions, including universal mask wearing with increasing production of face mask, hand hygiene, border control, introduce of digital technology incorporating big data, quarantine of COVID-19 cases, travel and gathering restriction, were implemented. In the meanwhile, two COVID-19 vaccines, namely MVC-COV1901 and UB-612, have been developed under the support of government. Furthermore, MVC-COV1901 was taken into clinical practice after received emergency use approval. In addition, two traditional Chinese medicines, including NRICM101 and NRICM102 showed their promising effect against SARS-CoV-2 infection and were recommended as potential therapeutic options for COVID-19. During the pandemic, the nonpharmacologic intervention help reduce many infectious diseases, especially for airborne/droplet-transmitted diseases. However, COVID-19 exhibited some adverse impacts on the healthcare systems, such as emergency medical service on out of hospital cardiac arrest, cancer screening, HIV screening and prevention services, and public health, namely the psychosocial status of healthcare workers. Although the outbreak of SARS-CoV-2 infections may gradually subsided, we should keep monitoring its associated impact and appropriately response to this pandemic.

Long-term risk of herpes zoster following COVID-19: A retrospective cohort study of 2 442 686 patients.

The long-term risk of herpes zoster (HZ) after recovery from a SARS-CoV-2 infection is unclear. This retrospective cohort study assessed the risk of HZ in patients following a COVID-19 diagnosis. This retrospective, propensity score-matched cohort study was based on the multi-institutional research network TriNetX. The risk of incident HZ in patients with COVID-19 was compared with that of those not infected with SARS-CoV-2 during a 1-year follow-up period. Hazard ratios (HRs) and 95% confidence intervals (CIs) of HZ and its subtypes were calculated. This study identified 1 221 343 patients with and without COVID-19 diagnoses with matched baseline characteristics. During the 1-year follow-up period, patients with COVID-19 had a higher risk of HZ compared with those without COVID-19 (HR: 1.59; 95% CI: 1.49-1.69). In addition, compared with the control group patients, those with COVID-19 had a higher risk of HZ ophthalmicus (HR: 1.31; 95% CI: 1.01-1.71), disseminated zoster (HR: 2.80; 95% CI: 1.37-5.74), zoster with other complications (HR: 1.46; 95% CI: 1.18-1.79), and zoster without complications (HR: 1.66; 95% CI: 1.55-1.77). Kaplan-Meier curve analysis (log-rank p < 0.05) results indicated that the risk of HZ remained significantly higher in patients with COVID-19 compared with those without COVID-19. Finally, the higher risk of HZ in the COVID-19 cohort compared with that in the non-COVID-19 cohort remained consistent across subgroup analyses regardless of vaccine status, age, or sex. The risk of HZ within a 12-month follow-up period was significantly higher in patients who had recovered from COVID-19 compared with that in the control group. This result highlights the importance of carefully monitoring HZ in this population and suggests the potential benefit of the HZ vaccine for patients with COVID-19.

The Association Between Inhaled Corticosteroid and the Risks of SARS-COV-2 infection: A systematic review and meta-analysis

Background The effect of inhaled corticosteroid (ICS) on the risk of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection is unclear. Methods We performed a systematic review and meta-analysis of clinical studies that assessed the association between the use of ICS and the risk of SARS-COV-2 infection. PubMed, Web of Science, Scopus, Cochrane Library and Google Scholar were searched to January 1st, 2023. ROBINS-I was used to assess risk of bias of included studies. The outcome of interest was the risk of SARS-COV-2 infection in patients and odds ratio (OR) with 95% confidence interval (95% CI) were calculated using Comprehensive Meta-analysis software version 3. Results Twelve studies involving seven observational cohort studies, three case-control studies, and two cross-sectional studies were included in this meta-analysis. Overall, compared to non-ICS use, the pooled odds ratio (OR) of the risk of SARS-COV-2 infection was 0.997 (95% confidence interval [CI] 0.664-1.499;p=0.987) for patients with ICS use. Subgroup analyses demonstrated no statistical significance in the increased risk of SARS-COV-2 infection in patients with ICS monotherapy or in combination with bronchodilators (pooled OR=1.408;95% CI=0.693-2.858;p=0.344 in ICS monotherapy, and pooled OR=1.225;95% CI=0.533-2.815;p=0.633 in ICS combination, respectively). In addition, no significant association was observed between ICS use and the risk of SARS-COV-2 infection for patients with COPD (pooled OR=0.715;95% CI=0.415-1.230;p=0.225) and asthma (pooled OR=1.081;95% CI=0.970-1.206;p=0.160). Conclusions The use of ICS, either monotherapy or in combination with bronchodilators, does not have impact on the risk of SARS-COV-2 infection. Data availability The datasets used and analysed in the current study are available from the corresponding author on reasonable request.

Clinical efficacy of probiotics in the treatment of patients with COVID-19: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: This study was conducted to assess the clinical efficacy of probiotics in the treatment of patients with COVID19. METHODS: PubMed, Embase, Cochrane Library, and ClinicalTrials.gov were searched for studies from their inception to 8 February 2022. Randomized controlled trials (RCTs) that compared the clinical efficacy of probiotics with usual care or standard care for patients with COVID19 were included. The primary outcome was all-cause mortality. Random-effects model using MantelHaenszel and inverse variance methods were performed to analyze the data. RESULTS: Eight RCTs with 900 patients were included. The study group receiving probiotics had a non-significantly lower rate of mortality than the control group had, but this difference was not significant (risk ratio [RR], 0.51; 95% CI, 0.22 to 1.16). However, the study group had significantly lower rates of dyspnea (RR, 0.11; 95% CI, 0.02 to 0.60), fever (RR, 0.37; 95% CI, 0.16 to 0.85) and headache (RR, 0.19; 95% CI, 0.05 to 0.65). Higher complete remission of COVID-19-associated symptoms was observed in the study group than the control group (RR, 1.89; 95% CI, 1.40-2.55). CONCLUSIONS: Although probiotics use did not improve clinical outcomes or reduce inflammatory markers, it may relieve COVID-19-associated symptoms.

Clinical efficacy and safety of molnupiravir for nonhospitalized and hospitalized patients with COVID-19: A systematic review and meta-analysis of randomized control trials.

The efficacy of molnupiravir in treating patients with coronavirus disease 2019 (COVID-19) has been inconsistent across randomized controlled trials (RCTs). Thus, this meta-analysis was conducted to clarify the literature. A literature search of electronic databases-PubMed, Embase, and Cochrane Library-was performed to identify relevant articles published up to December 31, 2022. Only RCTs that investigated the clinical efficacy and safety of molnupiravir for patients with COVID-19 were included. The primary outcome was all-cause mortality at 28-30 days. This pooled analysis of nine RCTs did not reveal a significant difference in all-cause mortality between molnupiravir and control groups (risk ratio [RR], 0.43; 95% confidence interval [CI], 0.10-1.77) for overall patients. However, the risks of mortality and hospitalization were lower in the molnupiravir group than in the control group (mortality: RR, 0.28; 95% CI, 0.10-0.79; hospitalization: RR, 0.67; 95% CI, 0.45-0.99) among nonhospitalized patients. In addition, molnupiravir use was associated with a borderline higher virological eradication rate relative to the control (RR, 1.05; 95% CI, 1.00-1.11). Finally, no significant difference in adverse event risk was discovered between the groups (RR, 0.98; 95% CI, 0.89-1.08). The findings reveal the clinical benefits of molnupiravir for nonhospitalized patients with COVID-19. However, molnupiravir may not improve the clinical outcomes of hospitalized patients. These findings support the recommended use of molnupiravir for treating nonhospitalized patients with COVID-19 but not for hospitalized patients.

Coronavirus disease 2019 rebounds following nirmatrelvir/ritonavir treatment.

Nirmatrelvir/ritonavir (NMV-r) is an effective anti-SARS-CoV-2 agent and has been recommended in the treatment of nonhospitalized patients with COVID-19. In rare occasions, some patients experience virologic and symptomatic rebound after initial resolution, which we call COVID-19 rebound after NMV-r. Although COVID rebound can also occur after molnupiravir treatment or even no antiviral treatment, we have more serious concern about the rebound after NMV-r, which remains the most effective antiviral. Due to a lack of information about its frequency, mechanism, outcomes, and management, we conducted this review to provide comprehensive and updated information to address these questions. Based on the limited evidence, the incidence of COVID-19 rebound after NMV-r was less than 2%, and most cases developed 5-15 days after initiating NMV-r treatment. Almost all reported cases had mild symptoms, and the clinical condition gradually subsided without additional treatment. Overall, the clinical outcome was favorable, and only a small number of patients required emergency department visits or hospitalization. Regarding virologic rebound, culturable SARS-CoV-2 with possible transmission was observed, so re-isolation may be needed.

Multisystem inflammatory syndrome in adults: Characteristics, treatment, and outcomes.

Following the rapidly increasing number of multisystem inflammatory syndromes in children (MIS-C), a similar clinical scenario has been observed in adult patients. Although its prevalence is low and probably related to underdiagnosis, its development can be associated with high mortality. Multisystem inflammatory syndrome in adults (MIS-A) can develop following both asymptomatic and symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and in previously healthy people. Like MIS-C, MIS-A is a multisystem disease that can involve the cardiovascular, respiratory, gastrointestinal, dermatologic, hematologic, and neurologic systems. In addition to the clinical manifestations, the diagnosis of MIS-A requires laboratory evidence of inflammation and SARS-CoV-2 infection. The appropriate treatment for MIS-A remains unclear; anti-inflammatory agents, including intravenous immunoglobulin and corticosteroids, are commonly used. However, there are still many unknowns regarding MIS-A. Further studies are needed to determine the true prevalence, pathogenesis, and effective treatment for MIS-A.

The association between inhaled corticosteroid and the risks of SARS-COV-2 infection: A systematic review and meta-analysis.

BACKGROUND: The effect of inhaled corticosteroid (ICS) on the risk of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection is unclear. METHODS: We performed a systematic review and meta-analysis of clinical studies that assessed the association between the use of ICS and the risk of SARS-COV-2 infection. PubMed, Web of Science, Scopus, Cochrane Library and Google Scholar were searched to January 1st, 2023. ROBINS-I was used to assess risk of bias of included studies. The outcome of interest was the risk of SARS-COV-2 infection in patients and odds ratio (OR) with 95% confidence interval (95% CI) were calculated using Comprehensive Meta-analysis software version 3. RESULTS: Twelve studies involving seven observational cohort studies, three case-control studies, and two cross-sectional studies were included in this meta-analysis. Overall, compared to non-ICS use, the pooled odds ratio (OR) of the risk of SARS-COV-2 infection was 0.997 (95% confidence interval [CI] 0.664-1.499; p = 0.987) for patients with ICS use. Subgroup analyses demonstrated no statistical significance in the increased risk of SARS-COV-2 infection in patients with ICS monotherapy or in combination with bronchodilators (pooled OR=1.408; 95% CI=0.693-2.858; p = 0.344 in ICS monotherapy, and pooled OR=1.225; 95% CI=0.533-2.815; p = 0.633 in ICS combination, respectively). In addition, no significant association was observed between ICS use and the risk of SARS-COV-2 infection for patients with COPD (pooled OR=0.715; 95% CI=0.415-1.230; p = 0.225) and asthma (pooled OR=1.081; 95% CI=0.970-1.206; p = 0.160). CONCLUSIONS: The use of ICS, either monotherapy or in combination with bronchodilators, does not have impact on the risk of SARS-COV-2 infection.

An artificial intelligence system to predict the optimal timing for mechanical ventilation weaning for intensive care unit patients: A two-stage prediction approach.

Background: For the intensivists, accurate assessment of the ideal timing for successful weaning from the mechanical ventilation (MV) in the intensive care unit (ICU) is very challenging. Purpose: Using artificial intelligence (AI) approach to build two-stage predictive models, namely, the try-weaning stage and weaning MV stage to determine the optimal timing of weaning from MV for ICU intubated patients, and implement into practice for assisting clinical decision making. Methods: AI and machine learning (ML) technologies were used to establish the predictive models in the stages. Each stage comprised 11 prediction time points with 11 prediction models. Twenty-five features were used for the first-stage models while 20 features were used for the second-stage models. The optimal models for each time point were selected for further practical implementation in a digital dashboard style. Seven machine learning algorithms including Logistic Regression (LR), Random Forest (RF), Support Vector Machines (SVM), K Nearest Neighbor (KNN), lightGBM, XGBoost, and Multilayer Perception (MLP) were used. The electronic medical records of the intubated ICU patients of Chi Mei Medical Center (CMMC) from 2016 to 2019 were included for modeling. Models with the highest area under the receiver operating characteristic curve (AUC) were regarded as optimal models and used to develop the prediction system accordingly. Results: A total of 5,873 cases were included in machine learning modeling for Stage 1 with the AUCs of optimal models ranging from 0.843 to 0.953. Further, 4,172 cases were included for Stage 2 with the AUCs of optimal models ranging from 0.889 to 0.944. A prediction system (dashboard) with the optimal models of the two stages was developed and deployed in the ICU setting. Respiratory care members expressed high recognition of the AI dashboard assisting ventilator weaning decisions. Also, the impact analysis of with- and without-AI assistance revealed that our AI models could shorten the patients' intubation time by 21 hours, besides gaining the benefit of substantial consistency between these two decision-making strategies. Conclusion: We noticed that the two-stage AI prediction models could effectively and precisely predict the optimal timing to wean intubated patients in the ICU from ventilator use. This could reduce patient discomfort, improve medical quality, and lower medical costs. This AI-assisted prediction system is beneficial for clinicians to cope with a high demand for ventilators during the COVID-19 pandemic.

The efficacy and safety of complement C5a inhibitors for patients with severe COVID-19: a systematic review and meta-analysis.

BACKGROUND: The clinical efficacy and safety of complement C5a inhibitors for patients with severe COVID-19 remains unclear. METHODS: The PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were searched from their inception to 27 September 2022. Only studies that assessed the usefulness of C5a inhibitors for the treatment of patients with severe COVID-19 patients were included. The primary outcome was the risk of 28-day mortality. RESULTS: Six studies, including four randomized controlled trials (RCTs) and two non-RCTs, were included. The study group receiving C5a inhibitors had a significantly lower risk of mortality compared with the control group (23.6% [70/297] vs 39.2% [136/347]; odds ratio [OR], 0.53; 95% confidence interval [CI]: 0.37-0.76; P< 0.001), and no heterogeneity was detected (I2 = 0%; P= 0.58). Compared with control group, the study group was associated with a similar risk of serious adverse events (AEs) (OR, 0.84; 95% CI: 0.57-1.23; P0 = 0.37), infection (OR, 1.46; 95% CI: 0.77-2.79; P= 0.25) and acute kidney injury (OR, 0.89; 95% CI: 0.54-1.46; P= 0.64). CONCLUSION: C5a inhibitors could help reduce the risk of mortality in patients with severe COVID-19 infection while being as safe as placebos. These findings support the promising role of C5a inhibitors in the treatment of severe COVID-19.

Long COVID: An inevitable sequela of SARS-CoV-2 infection.

At present, there are more than 560 million confirmed cases of the coronavirus disease 2019 (COVID-19) worldwide. Although more than 98% of patients with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection can survive acute COVID, a significant portion of survivors can develop residual health problems, which is termed as long COVID. Although severe COVID-19 is generally associated with a high risk of long COVID, patients with asymptomatic or mild disease can also show long COVID. The definition of long COVID is inconsistent and its clinical manifestations are protean. In addition to general symptoms, such as fatigue, long COVID can affect many organ systems, including the respiratory, neurological, psychosocial, cardiovascular, gastrointestinal, and metabolic systems. Moreover, patients with long COVID may experience exercise intolerance and impaired daily function and quality of life. Long COVID may be caused by SARS-CoV-2 direct injury or its associated immune/inflammatory response. Assessment of patients with long COVID requires comprehensive evaluation, including history taking, physical examination, laboratory tests, radiography, and functional tests. However, there is no known effective treatment for long COVID. Based on the limited evidence, vaccines may help to prevent the development of long COVID. As long COVID is a new clinical entity that is constantly evolving, there are still many unknowns, and further investigation is warranted to enhance our understanding of this disease.