Little information is available on the beneficial effects of cholecalciferol treatment in comorbid patients hospitalized for COVID-19. The aim of this study was to retrospectively examine the clinical outcome of patients receiving in-hospital high-dose bolus cholecalciferol. Patients with a positive diagnosis of SARS-CoV-2 and overt COVID-19, hospitalized from 15 March to 20 April 2020, were considered. Based on clinical characteristics, they were supplemented (or not) with 400,000 IU bolus oral cholecalciferol (200,000 IU administered in two consecutive days) and the composite outcome (transfer to intensive care unit; ICU and/or death) was recorded. Ninety-one patients (aged 74 ± 13 years) with COVID-19 were included in this retrospective study. Fifty (54.9%) patients presented with two or more comorbid diseases. Based on the decision of the referring physician, 36 (39.6%) patients were treated with vitamin D. Receiver operating characteristic curve analysis revealed a significant predictive power of the four variables: (a) low (<50 nmol/L) 25(OH) vitamin D levels, (b) current cigarette smoking, (c) elevated D-dimer levels (d) and the presence of comorbid diseases, to explain the decision to administer vitamin D (area under the curve = 0.77, 95% CI: 0.67–0.87, p < 0.0001). Over the follow-up period (14 ± 10 days), 27 (29.7%) patients were transferred to the ICU and 22 (24.2%) died (16 prior to ICU and six in ICU). Overall, 43 (47.3%) patients experienced the combined endpoint of transfer to ICU and/or death. Logistic regression analyses revealed that the comorbidity burden significantly modified the effect of vitamin D treatment on the study outcome, both in crude (p = 0.033) and propensity score-adjusted analyses (p = 0.039), so the positive effect of high-dose cholecalciferol on the combined endpoint was significantly amplified with increasing comorbidity burden. This hypothesis-generating study warrants the formal evaluation (i.e., clinical trial) of the potential benefit that cholecalciferol can offer in these comorbid COVID-19 patients.

Hypophosphatasia (HPP) is a rare disorder of the bone metabolism, characterized by genetically determined low alkaline phosphatase (ALP) activity. Low ALP may also be observed in some common causes of bone fragility, such as in osteoporosis treated with antiresorptive drugs. This study aimed to verify whether differences in bone turnover markers (BTMs) could help differentiate adult patients with HPP from those with osteoporosis undergoing antiresorptive treatment. In this multicenter study, we enrolled 23 adult patients with a diagnosis of HPP and compared them with 46 osteoporotic subjects previously treated with zoledronic acid or denosumab. BTMs such as CTX, N-terminal propeptide of type I procollagen (P1NP), total ALP, and bone ALP (bALP) were measured, and ratios between BTMs were also calculated. Considering that the control group included only females, in the primary analysis we compared their characteristics with that of the 16 female patients with HPP. Both individual BTMs (CTX and P1NP) and 4 BTM ratios (ALP/P1NP, bALP/P1NP, ALP/CTX, and bALP/CTX) showed satisfactory discriminatory power, outperforming ALP alone. P1NP, in particular, had an area under the curve (AUC) of 0.962 with a cut-off of 32 μg/L, while as for the BTMs ratios, the ALP/P1NP ratio had an AUC of 0.964 with a cut-off of 1.114. Similar results were confirmed when including male HPP patients, when adjusting for age and sex, and finally when performing a sensitivity analysis only in patients with ALP less than or equal to 32 U/L (ie, the median of the distribution of the entire population). In cases of low ALP and bone fragility, BTM and their ratios could help distinguish HPP patients from osteoporotic individuals treated with antiresorptive drugs, aiding in accurate diagnosis and reducing the risk of inappropriate treatment.

Background and Aim. Lung ultrasound (LUS) is a convenient imaging modality in the setting of coronavirus disease-19 (COVID-19) because it is easily available, can be performed bedside and repeated over time. We herein examined LUS patterns in relation to disease severity and disease stage among patients with COVID-19 pneumonia. Methods. We performed a retrospective case series analysis of patients with confirmed SARS-CoV-2 infection who were admitted to the hospital because of pneumonia. We recorded history, clinical parameters and medications. LUS was performed and scored in a standardized fashion by experienced operators, with evaluation of up to 12 lung fields, reporting especially on B-lines and consolidations. Results. We included 96 patients, 58.3% men, with a mean age of 65.9 years. Patients with a high-risk quick COVID-19 severity index (qCSI) were older and had worse outcomes, especially for the need for high-flow oxygen. B-lines and consolidations were located mainly in the lower posterior lung fields. LUS patterns for B-lines and consolidations were significantly worse in all lung fields among patients with high versus low qCSI. B-lines and consolidations were worse in the intermediate disease stage, from day 7 to 13 after onset of symptoms. While consolidations correlated more with inflammatory biomarkers, B-lines correlated more with end-organ damage, including extrapulmonary involvement. Conclusions. LUS patterns provide a comprehensive evaluation of patients with COVID-19 pneumonia that correlated with severity and dynamically reflect disease stage. LUS patterns may reflect different pathophysiological processes related to inflammation or tissue damage; consolidations may represent a more specific sign of localized disease, whereas B-lines seem to be also dependent upon generalized illness due to SARS-CoV-2 infection.

Currently available antidiabetic treatments fail to halt, and may even exacerbate, pancreatic β-cell exhaustion, a key feature of type 2 diabetes pathogenesis; thus, strategies to prevent, or reverse, β-cell failure should be actively sought. The serine threonine kinase Akt has a key role in the regulation of β-cell homeostasis; among Akt modulators, a central role is played by pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP) family. Here, taking advantage of an in vitro model of chronic exposure to high glucose, we demonstrated that PHLPPs, particularly the second family member called PHLPP2, are implicated in the ability of pancreatic β cells to deal with glucose toxicity. We observed that INS-1 rat pancreatic β cell line maintained for 12–15 passages at high (30 mM) glucose concentrations (INS-1 HG) showed increased expression of PHLPP2 and PHLPP1 both at mRNA and protein level as compared to INS-1 maintained for the same number of passages in the presence of normal glucose levels (INS-1 NG). These changes were paralleled by decreased phosphorylation of Akt and by increased expression of apoptotic and autophagic markers. To investigate if PHLPPs had a casual role in the alteration of INS-1 homeostasis observed upon chronic exposure to high glucose concentrations, we took advantage of shRNA technology to specifically knock-down PHLPPs. We obtained proof-of-concept evidence that modulating PHLPPs expression may help to restore a healthy β cell mass, as the reduced expression of PHLPP2/1 was accompanied by a recovered balance between pro- and antiapoptotic factor levels. In conclusion, our data provide initial support for future studies aimed to identify pharmacological PHLPPs modulator to treat beta-cell survival impairment. They also contribute to shed some light on β-cell dysfunction, a complex and unsatisfactorily characterized phenomenon that has a central causative role in the pathogenesis of type 2 diabetes.

In October 2019, the Italian Drug Agency (AIFA) restricted reimbursement criteria for vitamin D (VD) use outside the osteoporosis setting (Note 96). However, whether this restriction could also have involved patients at risk for or with osteoporotic fractures has not yet been investigated. We retrospectively analyzed databases from five Italian Local Health Units. Patients aged ≥50 years with either at least one prescription for osteoporosis treatment or with fragility fractures and evidence of osteoporosis from 2011 to 2020 were included. The proportion of subjects with an interruption in VD treatment before and after the introduction of the new reimbursement criteria and predictors of this interruption were analyzed. A total of 94,505 patients (aged 69.4 years) were included. Following the introduction of Note 96, a 2-fold (OR 1.98, 95% CI: 1.92–2.04) increased risk of VD discontinuation was observed. These findings were independent of seasonal variation, osteoporosis treatment patterns, as well as other confounding variables. However, a higher rate of interruption was observed in patients without vertebral/femur fracture (37.8%) vs. those with fracture (32.9%). Rheumatoid arthritis, dyslipidemia and previous fracture were associated with a lower risk of VD interruption, while stroke increased the risk of VD interruption. Our results highlight that a possible misinterpretation of newly introduced criteria for reimbursement restrictions in VD outside of osteoporosis have resulted in an inadequate level of VD supplementation in patients with osteoporosis. This undertreatment could reduce the effect of osteoporosis therapies leading to increased risk of negative outcome.

Background: Osteoporosis is a chronic condition characterized by increased fracture risk. Fragility fractures, especially hip fractures, represent a significant health and economic burden due to population aging. Despite the efficacy of approved treatments in lowering fracture recurrence, post-fracture treatment rates remain suboptimal. To address these issues, various post-fracture care programs, including Fracture Liaison Services (FLS), have been implemented worldwide. While FLS models effectively reduce refracture risk and maintain cost-effectiveness, it is unclear if these benefits apply equally to all patients, especially those with higher comorbidities and reduced functional capacity, who may face worse prognoses. This study aimed to identify the primary factors influencing anti-fracture therapy decisions in older patients with fragility fractures, using a multidimensional geriatric assessment approach integrated into our FLS program. Methods: A retrospective analysis was conducted on patients aged 65 and above with hip fractures admitted to Azienda Ospedale-Università Padova. Patients were categorized based on anti-fracture treatment (bisphosphonates, Denosumab, anabolic agents) or calcium/vitamin D supplements only. Clinical data, including the Multidimensional Prognostic Index (MPI) and its components, were collected. Statistical comparisons between treated and untreated groups were made, and a CHAID decision tree was used to explore decision-influencing factors. Results: The study included 493 patients (average age 84.7 years, 71.8% female). Patients receiving anti-fracture treatment were notably younger, with only 11.2% classified as MPI class 3 (severe prognosis) compared to 60.8% of untreated patients (p < 0.001). Among treated patients (n = 427), 75.3% received bisphosphonates, 7.3% Denosumab, and 2.2% anabolic agents. The CHAID decision tree highlighted MPI class as the primary determinant of treatment, with functional autonomy (Instrumental Activity of Daily Living or IADL) and cognitive status as subsequent factors, leading to an overall prediction accuracy of 70%. Conclusion: The integration of the MPI into multidisciplinary taking care of old patients with hip fractures may provide a structured approach for individualizing treatment decisions, considering aspects such as prognosis, functional autonomy, and cognitive status. Further studies are needed to validate the long-term outcomes of this approach.