Current Medical Research and Opinion

Introduction While the impact of COVID-19 on bone metabolism has been extensively studied, the inverse relationship remains less understood. This study investigates whether impaired bone metabolism is associated with an increased risk of COVID-19 infection. Methods We conducted a nested case-control study within a population-based cohort, incorporating Kaplan-Meier analysis (KMA) to assess time to infection (TTI) differences. Propensity score matching (1:2) was performed and validated through standardized mean differences (<0.10), variance ratio (=1), and McFadden’s pseudo-R2 (=0), ensuring balanced covariates. Bone status was evaluated using a composite index (AOMI), which included five components: P1NP and CTX (bone turnover markers), total hip bone mineral density (BMD-TH), trabecular bone score (TBS), and integral volumetric BMD (IvBMD). Inflammation and insulin resistance (IR) were assessed by albumin-to-globulin ratio (AGR <1.50) and the TG/HDL ratio (>2.50 in women and >2.80 in men), respectively. Results We analysed 294 COVID-19 cases and 528 controls. AOMI + individuals had a higher prevalence of COVID-19 (41.5% vs. 33.2%; p = 0.031), an adverse lipid pattern (‘A’ profile: high ApoB, LDL and TC) and pronounced bone changes (higher P1NP and CTX, lower BMD-TH, TBS, and IvBMD). AOMI- individuals were more likely to have metabolic syndrome, displayed a different lipid profile (‘B’ profile: elevated TG, AIP, and TG/HDL ratio), fewer bone alterations, and lower COVID-19 prevalence. TG/HDL ratio was 1.66 ± 1 in ‘A’ profile, while it was 2.85 ± 1.4 in ‘B’ profile individuals (p = 0.0001). Age acted as an effect modifier, and lowest tercile significantly increased COVID-19 risk associated with AOMI+ [Mantel-Haenszel OR = 1.42 (95%CI: 1.08-1.9); p = 0.022]. KMA identified AOMI + men and individuals of both sexes in lowest age tercile, as groups with shorter TTI: These younger individuals had high CTX (women), low TBS (men), and high ApoB (both). In multivariable analyses, plasma CTX levels negatively correlated with TTI (adjusted β= -0.325; p = 0.0001). AOMI + status was associated with increased COVID-19 risk after controlling for confounders, including IR (adjusted OR = 1.51; 95%CI: 1.04-2.10; p = 0.027), although this association weakened when adjusting for AGR (95%CI: 0.99-2.28; p = 0.055). ANCOVA-estimated adjusted TBS means were lower in COVID-19 cases compared to controls (1.259 vs. 1.294; p = 0.013). Conclusions Impaired bone metabolism was found to be associated with increased COVID-19 risk, in a relationship potentially mediated by underlying inflammation. Elevated osteoclastic activity and a defined lipid profile with high ApoB, TC, LDL levels, played a crucial role in the results. Bone quality parameters more accurately captured COVID-19-related bone changes than BMD.

Objective: Patient-Reported Outcome (PRO) measures supported by a severity algorithm may serve as a decision aid for triage and consultation in follow-up of patients with endometriosis. In a new follow-up regime, patients filled out an endometriosis-specific questionnaire (EQ) at home before outpatient consultation (tele-Patient-Reported Outcome Measures; telePROM). A severity algorithm was assigned patients' answers using a color code thereby reflecting the need of clinical attention. Our study aimed to assess the test-retest reliability of the severity algorithm and of the single items as well as to evaluate the face- and content validity of the EQ. Methods: The study was carried out in a referral endometriosis clinic at a Danish University Hospital. The validation was based on an initial version of the EQ, which was adjusted simultaneously with its severity algorithm, to meet the purpose of this study. Reliability was assessed by a test-retest setting of the questionnaire including patients with endometriosis, ≥ 18 years and Danish speaking. Kappa statistics and interclass correlation analyses were applied to assess test-retest reliability. Face- and content validity was explored by focus group interviewing of patients. Results: In total, 14 patients answered the questionnaire twice. Results indicate that the EQ demonstrated substantial reliability in three out of five domain indicators in the severity algorithm and 65% of items with kappa values above 0.60. Further, focus-group interview of five patients resulted in adding an open-ended question regarding important issues to discuss at the consultation. Conclusion: TelePROM in outpatient follow-up of endometriosis is feasible as patients viewed the questionnaire relevant for their clinical follow-up. Yet, due to the small sample size results should be interpreted with caution. Further validation of the EQ is recommended.

Background: COVID-19 continues to pose a significant health burden, particularly among older adults. mRNA-1283 is a next-generation COVID-19 mRNA vaccine developed to enhance immune response. Findings from the Phase 3 NextCOVE trial comparing bivalent versions of mRNA-1273 and mRNA-1283 vaccines have recently become available. However, there are no head-to-head trials comparing mRNA-1283 and the BNT162b2 vaccine. Objective: To indirectly compare the effectiveness of mRNA-1283 and BNT162b2 against symptomatic COVID-19 among adults in the U.S. Methods: A targeted literature review was conducted to identify relevant studies comparing the mRNA-1273 and BNT162b2 bivalent vaccines. A real-world evidence (RWE) study by Kopel et al. (2023) assessing the relative vaccine effectiveness (rVE) of mRNA-1273 vs. BNT162b2, was selected for an indirect treatment comparison (ITC) against the NextCOVE trial using the Bucher method. Analyses were stratified by age group, and sensitivity analyses were conducted using alternative outcome definitions. Results: Despite differences between NextCOVE and the Kopel study, comparability assessments supported a robust ITC. Among participants ≥18 years of age, the indirect rVE of mRNA-1283 vs. BNT162b2 against symptomatic COVID-19 was 15.3% (95% CI: 4.7-24.8%, p = 0.006). For adults ≥65 years of age, the rVE was 22.8% (95% CI: 3.7-38.1%, p = 0.022). Sensitivity analyses with alternative outcome definitions supported these estimates. Conclusion: This analysis provides consistent and statistically significant evidence indicating the next-generation mRNA-1283 vaccine is more effective in preventing symptomatic COVID-19 than BNT162b2, with the largest effect in individuals aged ≥65. Consistent results across sensitivity analyses underscore the robustness of the findings, offering important evidence to inform vaccination decisions by policymakers, providers, and payers.

Objective: Esketamine is an FDA-approved treatment for treatment-resistant depression (TRD) or major depression with acute suicidal ideation or behavior (MDSI). This analysis addressed the lack of data on real-world characteristics of patients with TRD and MDSI or prescribed esketamine. Methods: Data were derived from the Adelphi Real World Depression Disease Specific Programme a cross-sectional survey of physicians and patients with TRD, MDSI, or those prescribed esketamine in the US (July 2022-February 2023). Physicians reported demographic and clinical characteristics, patients completed PHQ-9 and WPAI measures. Results: Of 914 patients enrolled in the survey, 66.2% had TRD and 33.8% MDSI. Mean (± standard deviation) PHQ-9 scores were 8.3 ± 6.3 (TRD) and 9.3 ± 6.3 (MDSI), with moderate-to-very severe depression reported by 36.5% (TRD) and 48.3% (MDSI) of patients. Mean work impairment was 26.0 ± 28.1% and overall impairment 34.7 ± 27.3%. No-to-mild impairment was reported for most patients in ability to meet basic needs, social functioning, work, overall quality of life and general health. Patients and physicians showed low levels of agreement on disease severity and trajectory. Patients prescribed esketamine (n = 94) were 43.3 ± 13.3 years old, diagnosed 5.7 ± 6.6 years before survey, sex was evenly split, and 64.8% were working full or part time. Most common diagnoses were TRD (38.3%), MDD (37.2%) or MDSI (17.0%). Patients showed improvements in CGI-S (64.6-77.8%) and activities of daily living (34-67%) following esketamine. Conclusions: The substantial impact of TRD and MDSI on daily life and unmet treatment need was underestimated by physicians. Patients treated with esketamine reported favorable outcomes.

Objective: Evaluating portal hypertension is crucial for patients with hepatocellular carcinoma (HCC) who are candidates for liver resection. Total bile acid (TBA) is an easily accessible marker, but its potential as a non-invasive indicator of portal hypertension in patients with HCC is yet to be fully established. Methods: This study included patients with HCC classified as Child-Pugh stage A who underwent liver resection at a referral hospital. Elevated TBA levels were defined as serum TBA >10 μmol/L, while normal levels were ≤10 μmol/L. Results: A total of 167 patients with HCC with Child-Pugh Class A who underwent liver resection were analyzed. The cohort was divided into normal (n = 125) and elevated TBA groups (n = 42). Compared to patients with normal TBA levels, those with elevated TBA had significantly higher 15-min indocyanine green retention rates (ICG R15) (p <0.001), higher Child-Pugh scores (p <0.001), more advanced Laennec fibrosis stages (p = 0.039), and a higher incidence of esophageal gastric varices (p = 0.001) and post-hepatectomy liver failure (p = 0.001). Multivariate analysis showed that elevated TBA was independently associated with ICG R15 (odds ratio [OR] = 1.150, 95% confidence interval [CI] = 1.055-1.254, p = 0.002), fibrosis stages (OR = 1.973, 95% CI = 1.026-3.796, p = 0.042), and Child-Pugh score (OR = 4.121, 95% CI = 1.367-12.424, p = 0.012). Conclusion: Elevated TBA levels in patients with HCC with Child-Pugh class A are significantly associated with portal hypertension and a higher incidence of post-hepatectomy liver failure.

Background: Sepsis remains a leading cause of mortality, especially among patients admitted to non-ICU settings like intermediate care units (IMCUs). Current prognostic tools have limitations in predicting outcomes in these patients. This study aimed to identify key predictors of mortality using decision tree analysis. Methods: We conducted a prospective observational study from January 2023 to June 2024, enrolling 254 septic patients admitted to the IMCU of Santorso Hospital, Italy. Clinical, laboratory, and demographic data were collected, and decision tree analysis was performed to identify factors associated with 30-day mortality. Variables were compared using univariate and multivariate analyses, and significant predictors were incorporated into the decision tree model. Results: The 30-day mortality rate was 14.6%. Serum albumin was identified as the root node of the decision tree, with lower levels (≤2.3 g/dL) strongly associated with mortality. Additional predictors included higher NEWS scores (OR 1.153, p = 0.002) and older age (OR 1.062, p = 0.021). Traditional scoring systems like SOFA and APACHE did not significantly predict outcomes in this setting. Conclusions: Serum albumin is a key prognostic marker in septic patients admitted to IMCUs, alongside NEWS and age. These findings suggest that albumin levels at admission can aid in early risk stratification and clinical decision-making in non-ICU environments. Future studies should validate these results across different healthcare settings to optimize sepsis management.

Objective: Little is known about the healthcare resource utilization (HRU) associated with different adjunctive atypical antipsychotics (AAs) for the treatment of major depressive disorder (MDD). This analysis evaluated HRU in patients with MDD treated adjunctively with cariprazine versus other AAs. Methods: Merative MarketScan databases were searched for claims made from 01/01/2018 to 12/31/2020 (Medicaid) or 3/31/2021 (commercial and Medicare). The study included adults with ≥1 inpatient MDD claim or ≥2 outpatient MDD claims >30 days apart and ≥1 claim for cariprazine, brexpiprazole, generic aripiprazole, or generic quetiapine adjunctive to an antidepressant (i.e. ≥14-day overlap between AA and antidepressant). Outcomes included all-cause and MDD-related inpatient stays and emergency department (ED), office, and psychiatric visits. Results were reported as estimated mean ratios, calculated via negative binomial regression, of the comparator AA to cariprazine with 95% CIs. Results: Analyses included 40,195 patients (cariprazine [n = 1,038], brexpiprazole [n = 3,221], generic aripiprazole [n = 20,601], generic quetiapine [n = 15,335]). The cariprazine cohort had significantly fewer all-cause and MDD-related inpatient stays relative to all other AA cohorts. All-cause ED visits were significantly lower in the cariprazine versus generic quetiapine cohort, and MDD-related ED visits were significantly lower in the cariprazine versus generic aripiprazole and generic quetiapine cohorts. ED visits were similar between cariprazine and all other cohorts. All-cause and MDD-related office and psychiatric visits were significantly lower in the cariprazine versus most other AA cohorts. Conclusion: Although causality cannot be determined from these real-world findings, results suggest that in patients with MDD, initiating adjunctive cariprazine is associated with significantly lower HRU for certain outcomes relative to other AAs.

Objective: To describe potential drug-drug interactions (DDIs) with oral advanced therapies among patients with ulcerative colitis (UC) and characterize clinical assessments before ozanimod initiation. Methods: Adults with UC were selected from the Merative MarketScan Commercial Database (01 January 2018-31 January 2023); the index date was the most recent UC diagnosis. Patients had no other immune conditions in the 12-month baseline period before the index date. Those with moderate-to-severe UC were analyzed separately. Potential baseline DDIs were identified as claims for medications that may cause a moderate/severe DDI with Janus kinase (JAK) inhibitors (tofacitinib/upadacitinib) or ozanimod according to the Merative Micromedex Complete Drug Interactions Tool. Clinical assessments before ozanimod initiation were characterized. Results: Of 58,870 patients with UC, 24,654 (41.9%) had moderate-to-severe UC. All potential DDIs with ozanimod were severe, while JAK inhibitors had moderate and severe potential DDIs. Among patients with UC, mean (standard deviation) number of severe DDIs was 2.0 (2.4) for ozanimod and 0.2 (0.5) for JAK inhibitors; in moderate-to-severe UC, it was 2.3 (2.6) for ozanimod and 0.4 (0.6) for JAK inhibitors. The most common potential DDIs for ozanimod in UC and moderate-to-severe UC were ondansetron (18.6% and 22.7%), azithromycin (11.9% and 12.8%), as well as hydrocodone, fentanyl, albuterol, ciprofloxacin, and metronidazole (9.0%-11.0% each). For JAK inhibitors, these were COVID-19 vaccines (30.7% and 31.4%), infliximab (8.5% and 20.2%), fluconazole (6.1% and 6.8%), and azathioprine (5.5% and 13.0%). Among patients initiating ozanimod, the first claim for a required clinical assessment was on average, 8 months before initiation. Conclusion: Comorbidities and polypharmacy among patients with UC pose a high risk of DDIs for oral advanced therapies and required pre-treatment clinical assessments can be complicated. This justifies a thorough review of patient profiles for prescribers considering novel treatment options.

Objective: We describe discussions about the lung cancer treatment decision-making process across the patient journey from the perspective of patients and caregivers with diverse experiences of living with lung cancer. Methods: Patient preference studies show individuals with lung cancer usually favor more aggressive treatments despite adverse events (AEs), in pursuit of better survival. However, patients are frequently passive in treatment decisions, suggesting there are barriers impairing patients' abilities to engage in shared decision-making. To explore this further, we asked patients with epidermal growth factor receptor-positive lung cancer and their caregivers to complete surveys and participate in focus group discussions facilitated by research specialists. Results: US patients with lung cancer (n = 11) and caregivers (n = 4) took part in exploratory focus groups. While initial treatment decisions were mostly led by healthcare providers, participants became more engaged in their treatment over time. As in other studies, participants prioritized survival over AEs when selecting treatments and shared fears of being switched to less efficacious treatments or reduced dose if they disclosed AEs. Participants emphasized the importance of shared decision-making, early discussions about AEs, and access to patient advocates. Conclusion: Healthcare providers should distribute reliable educational materials and have early conversations with patients on individual lung cancer treatment, health-related quality of life goals, potential AEs, and distinguishing AEs from disease progression symptoms.

Introduction: Familial hypercholesterolaemia (FH) is a genetic disorder associated with high cholesterol levels and an increased risk of premature cardiovascular events. Rare forms, such as semi-dominant bi-allelic mutations, pose diagnostic and therapeutic challenges. Misdiagnosis of FH is a significant concern, as highlighted by both this case and a review of the literature. Case report: We report the case of a 54-year-old woman with an acute myocardial infarction at the age of 43 years. She had a positive family history of early cardiovascular events and was diagnosed with familial hypercholesterolaemia at the age of 33 years. She tried statins with no benefit. In 2017, evolocumab was introduced but was insufficient to control cholesterol values (low-density lipoprotein cholesterol 324 mg/dL). She started lomitapide, and next-generation sequencing screening was performed in consideration of the different pharmacological effects and clinical trends compared to other family members. A bi-allelic semi-dominant mutation (c.241C > T in exon 3 of the LDLR gene) was found in addition to the previously identified mutation. She is now in good clinical condition and laboratory response with lomitapide, evolocumab, statin, and ezetimibe. A literature review was conducted to explore the clinical and diagnostic challenges of FH, with a focus on the risk of misdiagnosis. Conclusion: This case underscores the importance of genetic testing in diagnosing rare forms of FH, such as semi-dominant bi-allelic mutations, which may lead to misdiagnosis. Lomitapide proved effective in controlling cholesterol levels, highlighting its value in managing complex FH cases. The literature review further emphasizes the critical need for improved diagnostic approaches to minimize the risk of misdiagnosis.

Objective: To assess health inequalities research involving the pharmaceutical industry and to highlight key themes and potential research gaps. Methods: Briefly, a literature search of article titles on the Embase and MEDLINE databases was performed to identify relevant peer-reviewed literature published between 2000 and 2023. A review of gray literature sources and pharmaceutical company global websites was performed in parallel. Peer-reviewed literature and gray literature were excluded during pre-screening based on pre-defined eligibility criteria. Peer-reviewed publications that met the eligibility criteria underwent double-blind title and abstract screening to determine relevance to health inequalities research; gray literature was screened by one reviewer. All publications included after title and abstract screening underwent full-text review. Results: The peer-reviewed literature search yielded 1,377 initial results, of which 18 publications were included for data extraction; the gray literature search yielded 10 articles. Peer-reviewed publications involving the pharmaceutical industry increased over the past 5 years. North America was included as the region of research focus or study population in 61.1% (11/18) of the peer-reviewed publications. Health inequalities across race/ethnicity (66.7% [12/18]), sex/gender (44.4% [8/18]) and socioeconomic status (27.8% [5/18]) featured in the identified publications. Across the medicines and vaccines development and launch process, 71.4% (5/7) of the publications focused on increasing clinical trial participant diversity. Conclusions: The pharmaceutical industry has contributed to the discussion on health inequalities, particularly over the past 5 years. However, industry can better take the wider determinants of health into consideration when designing strategies of evidence generation across the medicines development pathway.