Investigating strontium isotope linkage between biominerals (uroliths), drinking water and environmental matrices.

This study presents the mineralogy and strontium isotope ratio (87Sr/86Sr) of 21 pathological biominerals (bladder and kidney stones) collected from patients admitted between 2018 and 2020 at the Department of Urology of the San Pio Hospital (Benevento, southern Italy). Urinary stones belong to the calcium oxalate, purine or calcium phosphate mineralogy types. Their corresponding 87Sr/86Sr range from 0.707607 for an uricite sample to 0.709970 for a weddellite one, and seem to be partly discriminated based on the mineralogy. The comparison with the isotope characteristics of 38 representative Italian bottled and tap drinking waters show a general overlap in 87Sr/86Sr with the biominerals. However, on a smaller geographic area (Campania Region), we observe small 87Sr/86Sr differences between the biominerals and local waters. This may be explained by external Sr inputs for example from agriculture practices, inhaled aerosols (i.e., particulate matter), animal manure and sewage, non-regional foods. Nevertheless, biominerals of patients that stated to drink and eat local water/wines and foods every day exhibited a narrower 87Sr/86Sr range roughly matching the typical isotope ratios of local geological materials and waters, as well as those of archaeological biominerals from the same area. Finally, we conclude that the strontium isotope signature of urinary stones may reflect that of the environmental matrices surrounding patients, but future investigations are recommended to ultimately establish the potential for pathological biominerals as reliable biomonitoring proxies, taking into the account the contribution of the external sources of Sr.

Improvement in health status and quality of life in patients with osteoporosis treated with denosumab: results at a mean follow-up of six years.

OBJECTIVE: The clinical efficacy and tolerability of denosumab in severe osteoporosis are well-known. However, the evaluation on general health and quality of life over time and compared to population norms is still lacking. We aimed at evaluating denosumab effectiveness in a real-world clinical sample with a 6-years average follow-up. PATIENTS AND METHODS: In this retrospective-matched study with prospective data collection, a total of 101 patients affected by severe osteoporosis and treated with denosumab between 2014 and 2020 were evaluated. All patients completed the self-perceived quality of life (36-Item Short Form - SF-36) survey and visual analogue scale (VAS) before and after treatment. RESULTS: Overall, 13 patients died of causes unrelated to the procedure, 12 stopped therapy with denosumab, and 30 did not participate in the follow-up; thus, 46 patients completed the study. There were 44 (95.7%) women and 93.4% of patients reported history of osteoporotic fractures. The mean follow-up was 59±17.8 months and the mean age at follow-up was 73.9±10.6 years. We found a significant improvement in bodily pain (baseline 53.8±33.4, follow-up 62.7±26.6; p=0.002) and in general health (baseline 35±25.4, follow-up 41.7±24.2; p=0.002) over time. The bodily pain score at follow-up was similar to the mean of the age-matched healthy population (62.7±26.6 vs. 67.6±26, p=0.374). The MCS-36 scores were higher than the normative values before treatment and at follow-up (51.6±9.8 vs. 45.8±9, p=0.004 and 50.6±11.7 vs. 45.8±9, p=0.030, respectively). The PCS-36 score at follow-up was comparable to the normative values (39.4±10.4 vs. 42.7±9, p=0.107). CONCLUSIONS: Denosumab is effective to improve bone health and global mental and physical wellbeing, and quality of life over time.

May a comprehensive mineralogical study of a jackstone calculus and some other human bladder stones unveil health and environmental implications?

This paper represents the first result of an active collaboration between the University of Sannio and the San Pio Hospital (Benevento, Italy), started in the 2018, that aims to a detailed mineralogical investigation of urinary stones of patients from Campania region. Herein, selected human bladder stones have been deeply characterized for clinical purposes and environmental biomonitoring, focusing on the importance to evaluate the concentration and distribution of undesired trace elements by means of microscopic techniques in the place of conventional wet chemical analyses. A rare bladder stone with a sea-urchin appearance, known as jackstone calculus, were also investigated (along with bladder stones made of uric acid and brushite) by means a comprehensive analytical approach, including Synchrotron X-ray Diffraction and Simultaneous Thermal Analyses. Main clinical assumptions were inferred according to the morpho-constitutional classification of bladder stones and information about patient's medical history and lifestyle. In most of the analyzed uroliths, undesired trace elements such as copper, cadmium, lead, chromium, mercury and arsenic have been detected and generally attributable to environmental pollution or contaminated food. Simultaneous occurrence of selenium and mercury should denote a methylmercury detoxification process, probably leading to the formation of a very rare HgSe compound known as tiemannite.

Late-onset presentation and phenotypic heterogeneity of the rare R377W PSEN1 mutation.

BACKGROUND AND PURPOSE: Mutations in the PSEN1 gene are the most common cause of autosomal-dominant Alzheimer's disease and have been associated with the earliest disease onset. We describe an unusual presentation of the rare R377W PSEN1 mutation with a late age of onset, and we provide for the first time in vivo pathological evidence for this mutation. METHODS: A 71-year-old female patient with progressive cognitive decline in the past 3 years and positive family history for dementia underwent neurological evaluation, neuropsychological testing, lumbar puncture, conventional brain imaging, amyloid-positron emission tomography (PET) and extensive genetic screening with a next-generation sequencing technique. RESULTS: The diagnostic workup revealed mixed behavioural and amnestic disease features on neuropsychological tests, magnetic resonance imaging, and 18-fluorodeoxyglucose (FDG)-PET. Amyloid-PET detected amyloid deposition in the frontal areas, in the parietal lobes and the precunei. The genetic screening revealed the presence of the rare R377W mutation in the PSEN1 gene. CONCLUSIONS: Extensive genetic screening is also advisable for late-onset presentations of Alzheimer's disease, especially in the presence of a positive family history or atypical clinical features.

Cervical spondylodiscitis mimicking Pott's disease: a case report.

INTRODUCTION: The leading cause of pyogenic vertebral osteomyelitis is Staphylococcus aureus, and its incidence is rising, particularly in the elderly. We report an unusual case of cervical spondylodiscitis and epidural abscess mimicking Pott's disease. CASE REPORT: A 67-year-old man was admitted to our institution with a 15-day history of neck pain radiating to the head, shoulders and left arm that was associated with weakness and paresthesia. Laboratory tests showed a mild leucocytosis and high levels of inflammatory markers. The MRI showed contrast enhancement of C6-C7 with an abscess infiltration extending to the intervertebral disc, the anterior epidural space, and the medullary cord. The patient had a medical history of a positive Mantoux tuberculin skin test 25 years prior, and the interferon-gamma release assay (IGRA) was positive for the identification of latent tuberculosis infection. All other examinations for diagnosis of spinal tuberculosis were inconclusive. Intravenous antibiotic therapy was initiated with teicoplanin 800 mg and levofloxacin 750 mg daily with a fast recovery of symptoms. CONCLUSIONS: Cervical spondylodiscitis can be an unusual cause of severe neck pain with a challenging differential diagnosis. Conservative treatment should always be considered for patients without neurological symptoms as long as close follow-up evaluations are performed.

Reinfusion-drains reduce blood transfusions in total joint arthroplasty.

This study aims to evaluate the effect of postoperative blood recovery with reinfusion drains on hematologic parameters and blood transfusion rate in patients undergoing total joint arthroplasty. Three-hundred-and-forty-four patient records were reviewed and 271 patients were included in the study; 56.8% of patients were treated with postoperative cell salvage procedure using reinfusion drains (PCS) and 43.2% had closed-suction drain (CSD) postoperatively. In comparison to the CSD group, the PCS group showed higher hemoglobin (Hb) levels on the first and second days postoperatively but no statistical differences were noted at the day of discharge. 75.2% and 37.7% of patients required blood transfusions in the CSD and PCS groups, respectively. The PCS group had a lower number of blood transfusions than the CSD group. At multivariate analysis, Hb loss rate was related to preoperative Hb values, total amount of drained blood and chronic antiplatelet therapy. The number of blood transfusions was related to preoperative Hb values, closed-suction drains, preoperative platelet count, TKA surgery and BMI. This study supports the use of PCS with reinfusion drains after THA and TKA at least for the short-term.

Dose adjustment of biologic therapies for psoriasis in dermatological practice: a retrospective study.

INTRODUCTION: Despite the large routine use of biologic drugs in psoriasis treatment, the majority of studies do not take into consideration dose-adjustment practice in 'real-life' dermatological setting. In routine clinical practice, the disease management may include a large number of conditions requiring non-standard dosage regimens, including dose escalation, dose reduction and/or off-label treatment interruption. OBJECTIVE: The ONDA (Outcome of non-standard dosing regimen in Psoriasis and Psoriatic Arthritis) study aim was to retrospectively analyse dose-adjustment strategies among biologic therapies for psoriasis in dermatological practice during a 3-year period. RESULTS: This retrospective, observational, multicentre study was carried out in 350 patients (68% male, 32% female) affected by plaque-type psoriasis (Pso) with a coexistence of psoriatic arthritis in 164 patients (46.9%). At baseline mean PASI score was 14.9 (SD 7.2). Dose adjustment was demonstrated to be a common practice with 70/350 patients (20%) who needed a dose variation during the treatment time, in particular a dose increase in 20/70 patients (28.6%) and a dose reduction in 50/70 patients (71.4%). Dose increase was due to inefficacy on Pso parameters in 60% of cases and to inefficacy of PsA parameters in 40% of cases, while dose reduction (or temporary off-label treatment interruption) was due to prolonged remission in 54% of cases, other reason in 18% of cases, patient choice or request in 14% of cases, occurrence of concomitant event in 12% of cases. CONCLUSION: Dose adjustment is a common clinical practice, consisting of frequent dose reduction when a disease prolonged remission is obtained or dose increase to improve efficacy on Pso and PsA disease parameters.

Inequalities in access to biological treatments for psoriasis: results from the Italian Psocare registry.

BACKGROUND: Limited evidence is available on the impact of socioeconomic factors on drug prescriptions for psoriasis. OBJECTIVES: To investigate factors influencing prescription of conventional vs. biological treatment for patients with psoriasis, based on the Italian Psocare registry, with a special focus on socioeconomic factors. METHODS: This was a cross-sectional study evaluating the baseline data of patients included in the Psocare registry. All of the consecutive adult patients with a diagnosis of chronic plaque psoriasis or psoriatic arthritis who were prescribed a systemic treatment for psoriasis at participating centres were included in this study. Univariate and multivariate analyses of the baseline factors associated with a biologics prescription were performed. RESULTS: From September 2005 to September 2009, 12 838 patients were identified. A multivariate analysis revealed that, among other factors, completing a level of education higher than lower secondary school and being employed as a manager or a professional were independent factors associated with a biologics prescription at entry in the registry. Additional analyses on the association between these two variables and a severe psoriasis condition [Psoriasis Area Severity Index (PASI) score > 20] revealed a significantly increasing trend of severe disease towards lower educational attainment, while unemployed patients were more likely to have a more severe condition compared with the other categories of workers. CONCLUSIONS: We documented inequalities of drug prescriptions for psoriasis in Italy, with a trend towards a higher frequency of prescription for more expensive biologics in higher socioeconomic sectors of the population.

Inflammatory molecules in Frontotemporal Dementia: cerebrospinal fluid signature of progranulin mutation carriers.

Mutations in progranulin gene (GRN) are one of the major causes of autosomal dominant Frontotemporal Lobar Degeneration (FTLD). Progranulin displays anti-inflammatory properties and is likely a ligand of Tumor Necrosis Factor (TNF) receptor 2, expressed on microglia. A few cytokines and chemokines are altered in cerebrospinal fluid (CSF) from patients with sporadic FTLD, whereas no information is available in familial cases. We evaluated, through BioPlex, levels of 27 inflammatory molecules, including cytokines, chemokines, and related receptors, in CSF and matched serum, from FTLD patients carrying GRN mutations as compared with sporadic FTLD with no GRN mutations and controls. Mean±SD Monocyte Chemoattractant Protein-1 (MCP-1) levels were significantly increased in CSF from sporadic FTLD patients as compared with controls (334.27±151.5 versus 159.7±49pg/ml; P⩽0.05). In GRN mutation carriers versus controls, CSF levels of MCP-1 were unchanged, whereas Interferon-γ-inducible protein-10 (IP-10) levels were increased (809.17±240.0 versus 436.61±202.5pg/ml; P=0.012). In the same group, TNFα and Interleukin (IL)-15 levels were decreased (3.18±1.41 versus 35.68±30.5pg/ml; P=0.013 and 9.34±5.54 versus 19.15±10.03pg/ml; P=0.023, respectively). Conversely, Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES) levels were decreased in patients, with or without mutations, as compared with controls (4.63±3.30 and 2.58±20 versus 87.57±70pg/ml, respectively; P<0.05). Moreover, IP-10, IL-15 and RANTES CSF levels were not influenced by age, whereas MCP-1 levels increased with age (ρ=0.48; P=0.007). In conclusion, inflammatory de-regulation was observed in both sporadic FTLD and GRN carriers compared to controls, with a specific inflammatory profile for the latter group.

Synthesis and gene silencing properties of siRNAs containing terminal amide linkages.

The active components of the RNAi are 21 nucleotides long dsRNAs containing a 2 nucleotide overhang at the 3' end, carrying 5'-phosphate and 3'-hydroxyl groups (siRNAs). Structural analysis revealed that the siRNA is functionally bound at both ends to RISC. Terminal modifications are considered with interest as the introduction of chemical moieties interferes with the 3' overhang recognition by the PAZ domain and the 5'-phosphate recognition by the MID and PIWI domains of RISC. Herein, we report the synthesis of modified siRNAs containing terminal amide linkages by introducing hydroxyethylglycine PNA (hegPNA) moieties at 5', and at 3' positions and on both terminals. Results of gene silencing studies highlight that some of these modifications are compatible with the RNAi machinery and markedly increase the resistance to serum-derived nucleases even after 24 h of incubation. Molecular docking simulations were attained to give at atomistic level a clearer picture of the effect of the most performing modifications on the interactions with the human Argonaute 2 PAZ, MID, and PIWI domains. This study adds another piece to the puzzle of the heterogeneous chemical modifications that can be attained to enhance the silencing efficiency of siRNAs.

Ethics of emerging technologies and their transition to accepted practice: intestinal transplant for short bowel syndrome.

Parental counseling becomes complex when considering the use of emerging technologies, especially if it is unclear whether the level of evidence is sufficient to transform the proposed therapy into accepted practice. This paper addresses ethical issues underlying medical decision-making and counseling in the setting of emerging treatments, when long-term outcomes are still in the process of being fully validated. We argue that the ethical transition of emerging technologies, ideally from ethically impermissible to permissible, to obligatory, depends primarily on two factors: outcome data (or prognosis) and treatment feasibility. To illustrate these points, we will use intestinal transplant for short bowel syndrome (SBS) as a specific example. After reviewing the data, this paper will identify the ethical justifications for both comfort care only and intestinal transplant in patients with ultra SBS, and argue that both are ethically permissible, but neither is obligatory. The approach outlined will not only be valuable as ultra SBS outcomes data continue to change, but will also be applicable to other novel therapies as they emerge in perinatal medicine.

The role of a pediatric ethics committee in the newborn intensive care unit.

Institutional Ethics Committees are commonly available in hospitals with newborn intensive care units, and may serve as a valuable resource for staff and parents dealing with difficult ethical decisions. Many clinicians may be unaware of when the committee might be helpful, or how it functions. After a brief historical introduction, two cases are presented as illustrations of pediatric ethics committee function. The first involves consideration of cardiac surgery for an infant with ventricular septal defect and Trisomy 13. The second involves disagreement between staff and parents regarding possible provision of cardio-pulmonary resuscitation in a terminally ill newborn. Principles and considerations often brought to bear in committee deliberations are reviewed for each case. Neonatologists, staff and families should be aware of this potentially valuable resource, and are encouraged to use it for situations of moral distress, conflict resolution or ethical uncertainty.

Who is performing medical procedures in the neonatal intensive care unit?

OBJECTIVE: Owing to resident work-hour reductions and more permanent personnel in the newborn intensive care unit (NICU), we sought to determine if pediatric housestaff are missing learning opportunities in procedural training due to non-participation. STUDY DESIGN: A prospective, observational study was conducted at an academic NICU using self-reported data from neonatal personnel after attempting 188 procedures on 109 neonates, and analyzed using Fisher's exact and χ (2)-tests. RESULT: Housestaff first attempted 32% of procedures (P<0.001) and were less likely to make attempts early in the academic year (P<0.001). There was no significant difference in attempts based on urgency of situation (P=0.742). Of procedures performed by non-housestaff personnel, 93% were completed while housestaff were present elsewhere in the unit. CONCLUSION: Pediatric housestaff performed the minority of procedures in the NICU, even in non-urgent situations, and were often uninvolved in other procedures, representing missed learning opportunities.

Selective resuscitation in premature twins: an ethical analysis.

Selective resuscitation refers to the practice of providing resuscitative efforts to one or some (but not all) infants born in the setting of multiple gestation. When one fetus is known to have a severe anomaly or severe growth restriction, parents are sometimes offered this option. In the setting of extreme prematurity, in the absence of an anomaly or severe growth restriction, parents are generally expected to make one unified decision for all the infants involved. The introduction of the Outcome Estimator, a tool that provides the ability to make individual outcome predictions for each fetus in a multiple gestation at borderline gestational age, based on contributing variables such as weight and gender, has led to the ethical dilemma of whether parents in this setting should also be offered the option of selective resuscitation. No convincing ethical argument for denying the parents the right to decide for each individual infant is apparent.

Patient selection for neonatal extracorporeal membrane oxygenation: beyond severity of illness.

OBJECTIVE: To explore how neonates with respiratory failure are selected for extracorporeal membrane oxygenation (ECMO) once severity of illness criteria are met, and to determine how conflicts between ECMO providers and parents over the initiation of ECMO are addressed. STUDY DESIGN: A cross-sectional study was conducted using a data collection survey, which was sent to the directors of neonatal respiratory ECMO centers. RESULT: The lowest birth weight and gestational age at which respondents would consider placing a neonate on ECMO were frequently below recommended thresholds. There was wide variability in respondents' willingness to place neonates on ECMO in the presence of conditions such as intraventricular hemorrhage and hypoxic ischemic encephalopathy. The number of respondents who would never seek to override parental refusal of ECMO was equal to the number who would always do so. CONCLUSION: Significant variability exists in the selection criteria for neonatal ECMO and in how conflicts with parents over the provision of ECMO are resolved.

Parental authority, patient's best interest and refusal of resuscitation at borderline gestational age.

Potential conflict exists when parents refuse a medical intervention for their child that the physician feels obligated to provide. For the anticipated delivery of a preterm newborn, this conflict might exist if the parents refuse resuscitation. At borderline viability, most neonatologists are likely to respect the parents' wishes. However, there will be some gestational age threshold above which the physician will feel compelled to resuscitate despite parental refusal, and will be ethically justified in doing so. The location of that threshold should be determined by the application of sound ethical reasoning, rather than relying on habit or arbitrary standards. That reasoning should include an honest assessment of the benefits and burdens to the child, short-term and long-term, of attempted resuscitation, made in light of relevant mortality and morbidity data. However, a rational analysis will also require consideration of whether the patient's best interest standard should be strictly applied, or whether the interests of others, such as family members, should also be taken into account.

Treatment of human papilloma virus in a 6-month-old infant with imiquimod 5% cream.

A healthy female infant was diagnosed with genital warts at six months of age. She was the product of an uncomplicated vaginal delivery to a mother who was diagnosed with genital warts during the pregnancy, but did not undergo any treatment. The infant's warts were clinically resolved following a three week course of 5% imiquimod cream, an immunomodulating agent that has been demonstrated to be a potent inducer of several cytokines promoting an antiviral cell-mediated immune response.

Hirsutism: diagnosis and management.

The majority of women with hirsutism have the idiopathic variety characterized by normal circulating androgens. An index of suspicion should, however, be maintained for that subset of women whose hirsutism is indicative of a systemic hormonal aberration. The psychological consequences of this highly visible condition that can seriously impact quality of life substantiate the need for safer and more effective management options. The advent of a topical medication (eflornithine hydrochloride), devoid of systemic side effects, is one positive step toward this goal.