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.

Suicidal behavior sociocultural factors in developing countries during COVID-19.

OBJECTIVES: Sociocultural factors in the aftermath of any pandemic can play a role in increasing suicidal behavior like suicidal ideation, suicidal attempts, or suicide. The authors discuss the risk and predisposing factors for suicidal ideation among mental health patients in four developing countries (Bangladesh, Colombia, India and Pakistan), this aims to grasp the heterogeneity of these motivators and to elaborate specific interventions regarding suicide in the COVID-19 pandemic. METHODS: We searched PubMed, Medline, and Google Scholar through March, 2021 for articles using a combination of the keywords and generic terms for suicide, suicide ideation, COVID-19, developing countries, low-middle-income countries, Sociocultural factors, Suicidal behavior, predisposing factors and predictive factors, for articles in English language only, and without publication time restriction. RESULTS: This narrative review summarizes the sociocultural risk and predisposing factors for suicidal behavior in developing countries during the COVID-19 pandemic. The findings reveal those factors such as fear of being infected, growing economic pressure, lack of resources due to lockdown are mostly responsible in the four countries for the current increase in suicides. There are a few cultural differences that are specified in the narrative. CONCLUSION: The COVID-19 pandemic is a public health challenge, in which prevention and intervention of suicidal behavior have been suboptimal, especially in low-middle-income countries. Based on literature results, we provide practical suggestions (e.g., reducing infodemic, specialized helplines, improving mental health services availability) in order to tackle main challenges of suicide prevention, such as lack of adequate manpower, fragile health system and poverty.

The role of subscapularis repair following reverse shoulder arthroplasty: systematic review and meta-analysis.

PURPOSE: Inadequate subscapularis repair has been advocated as one of the contributing factors for dislocation in reverse total shoulder arthroplasty; nonetheless the need to restore the subscapularis tendon integrity is under debate. The aim of this systematic review was to answer the question: does subscapularis reattachment following reverse total shoulder arthroplasty improve joint stability, range of motion and functional scores? METHODS: The literature was systematically screened in accordance with PRISMA guidelines looking for papers evaluating clinical outcomes of reverse total shoulder arthroplasty in relation to the management of subscapularis tendon. Studies comparing clinical outcomes, complications and dislocation rate with or without subscapularis repair were included. Studies in which reverse total shoulder arthroplasty was performed for trauma or tumors were excluded. The methodology of included articles was scored with MINORS scale and the Risk of Bias was assessed adopting the ROBINS-I (Risk Of Bias In Non-randomized Studies of Interventions) developed by the Cochrane Group. A meta-analysis was also performed combining the studies to increase the sample size and hence the power to obtain meaningful data. RESULTS: The database search identified 1062 records, and 6 full-text articles were finally included. A total number of 1085 reverse total shoulder arthroplasty were assessed on. Except for one study, lateralized prosthetic designs have been used. Dislocation occurred in 0.8% (5/599 patients) of the patient with repaired subscapularis and in 1.6% (8/486 patients) of the tenotomized patients, and subscapularis repair was not associated with a higher risk of dislocation (pooled Peto OR: 0.496, 95% CI: 0.163 to 1.510, p = 0.217). Qualitative assessment revealed no differences in the range of motion and clinical scores. CONCLUSION: Subscapularis repair after reverse total shoulder arthroplasty produces no clinically meaningful benefits, particularly using lateralized prosthetic designs. Subscapularis re-attachment does not improve implant stability, nor increases range of motion or clinical scores. Given these results, keeping in mind the antagonistic effect of the repaired subscapularis on external rotation, no evidence lead to suggest subscapularis reattachment following reverse total shoulder arthroplasty with lateralized prosthetic designs.

Modular dual mobility cups with multihole metal back in total hip arthroplasty revision: a systematic review.

Dislocation after hip revision is a frequent complication; amongst the strategies to prevent dislocation dual mobility (DM) implants are gaining popularity. We want to evaluate the reliability of non cemented DM cups with multihole metal back and chrome-cobalt liner called Modular Dual Mobility (MDM). We performed a systematic review and selected 5 studies with a total of 285 hips who underwent revision surgery with MDM implants. The mean survivorship rate of the 5 studies was 92.46% (range 90-96%). 267 prosthesis (93.6%) were still implanted at the last follow-up; the mean weighted follow up was 38.7% (range 24-48). We found 13 mechanical complications in 285 hips (4.5%). Five of them were treated conservatively; the other 8 were treated with re-revision. Nine of these complications were dislocation and recurrent instability; 2 of them were associated to metallosis and adverse local tissue reaction. There was 1 patient that had episodes of subluxation; 2 cases of impingement and 1 case of metallosis. Zero intraprosthetic dislocations (IPD) occurred in 285 hips. A 93.6% survivorship is a good result for MDM implants, considering that most of patients had important bone loss and went through multiple revisions. The rate of dislocation is very low compared to the mean rate of dislocation in revision hip surgery. In our review, fretting is a rare complication but it can lead to ALTR and metallosis. For this reason, MDM implants have to be used in selected cases at high risk of dislocation. In conclusion MDM is a great option for decreasing dislocation rate in hip revision, but a longer follow-up and a greater number of cases is needed to assess its reliability.

Pramipexole in the treatment of unipolar and bipolar depression. A systematic review and meta-analysis.

OBJECTIVE: Several depressed patients do not respond to traditional antidepressants. Our aim was to systematically review the effectiveness and safety of pramipexole in unipolar and bipolar depression. METHODS: We conducted a systematic review of randomized clinical trials (RCTs) and observational studies on pramipexole for patients with major depressive episodes, following PRISMA guidelines. Our primary outcome measure was treatment response at endpoint. The study protocol was registered on PROSPERO: CRD42018108699. RESULTS: We found five RCTs, three open-label trials and five observational studies, with 504 participants (57% women; mean age, 45.3 years; mean sample size, 39; median duration of treatment, 8 weeks; mean follow-up duration, 45 weeks; mean maximum dose, 1.62 mg). We found an overall short-term response rate of 52.2% and remission rate of 36.1%, and an overall long-term response rate of 62.1% and remission rate of 39.6%. In RCTs, patients treated with pramipexole had a superior response rate compared with placebo (RR: 1.77; 95% CI: 1.11-2.82) and similar to SSRIs (RR: 0.93; 95% CI: 0.44-1.95). Acceptability and tolerability were good, with nausea being the most frequent side-effect. CONCLUSION: Our study found some evidence for an effect of pramipexole for the treatment of major depressive episodes.

No evidence for combining cartilage treatment and knee osteotomy in osteoarthritic joints: a systematic literature review.

PURPOSE: To assess whether the combination of HTO and cartilage treatment produced an additional clinical benefit compared to HTO alone. The secondary aim was to identify if there was any difference among different cartilage procedures in terms of healing potential and clinical outcome. METHODS: A systematic review of the literature was performed on PubMed database by three independent observers according to the following inclusion criteria: clinical reports of any level of evidence, written in the English language, with no time limitation, about HTO associated with cartilage surgical and injective treatment, including surveys reporting clinical, radiological, or second-look outcomes at any follow-up time. RESULTS: The database search identified 1956 records: 21 studies were included for the final analysis, for a total of 1068 patients; 10 case series and 11 comparative studies. While overall good results were reported in the case series, the analysis of the comparative studies showed less uniform results. Among the eight studies investigating HTO with cartilage surgical procedures, improved tissue regeneration was found in 5/8 studies, whereas a clinical improvement was reported only in two studies. Three studies on HTO combination with injective treatment showed better tissue regeneration and clinical benefit. CONCLUSIONS: Literature presents low-quality studies, with only few heterogeneous comparative papers. While surgical treatments targeting only the cartilage layer did not achieve clinical improvements, injective treatments targeting the overall joint environment showed promising findings. This prompts further research towards the development of treatments able to improve knee osteotomies outcomes. However, until new evidence will prove otherwise, there is no indication for a combined cartilage treatment in routine clinical practice. LEVEL OF EVIDENCE: Level IV.

A comparison of the nutritional status between adult celiac patients on a long-term, strictly gluten-free diet and healthy subjects.

BACKGROUND/OBJECTIVES: There are conflicting data on the effect of a gluten-free diet (GFD) on the nutritional status of celiac patients. In the present study, we evaluated, in adult celiac patients, the influence of a long-term, strictly GFD on their nutritional status and compared it with matched healthy volunteers. SUBJECTS/METHODS: Our study included 39 celiac patients and 39 healthy volunteers. The body mass index (BMI) of patients and controls was evaluated at enrollment, while the patients' BMI before the GFD was retrieved from clinical records. In addition, at enrollment, in both groups, we compared BMI, fat mass (FM), bone mineral density (BMD), as well as their dietary intake, recorded on a 7-day diary. RESULTS: At the time of diagnosis, the majority of celiac patients (82.0%) had a normal BMI or were overweight, while 10.3% were malnourished. After the GFD, patients with a normal BMI showed a significant weight increase (P=0.002), but none of them switched in the overweight or obese category. Two (50%) of the four malnourished patients achieved a normal BMI. Controls and patients on a GFD had a similar BMI, FM, BMD and total calorie intake, but the amount of lipids and fiber intake was significantly different in the two groups (P=0.003 and P<0.0001, respectively). CONCLUSIONS: Our study demonstrates that a GFD is able to improve the nutritional status of celiac patients without inducing overweight or obesity. Our findings are related to a celiac population adopting a GFD based on a Mediterranean-type diet.

Expanding the phenotype associated with FOXG1 mutations and in vivo FoxG1 chromatin-binding dynamics.

Mutations in the Forkhead box G1 (FOXG1) gene, a brain specific transcriptional factor, are responsible for the congenital variant of Rett syndrome. Until now FOXG1 point mutations have been reported in 12 Rett patients. Recently seven additional patients have been reported with a quite homogeneous severe phenotype designated as the FOXG1 syndrome. Here we describe two unrelated patients with a de novo FOXG1 point mutation, p.Gln46X and p.Tyr400X, respectively, having a milder phenotype and sharing a distinctive facial appearance. Although FoxG1 action depends critically on its binding to chromatin, very little is known about the dynamics of this process. Using fluorescence recovery after photobleaching, we showed that most of the GFP-FoxG1 fusion protein associates reversibly to chromatin whereas the remaining fraction is bound irreversibly. Furthermore, we showed that the two pathologic derivatives of FoxG1 described in this paper present a dramatic alteration in chromatin affinity and irreversibly bound fraction in comparison with Ser323fsX325 mutant (associated with a severe phenotype) and wild type Foxg1 protein. Our observations suggest that alterations in the kinetics of FoxG1 binding to chromatin might contribute to the pathological effects of FOXG1 mutations.

Novel FOXG1 mutations associated with the congenital variant of Rett syndrome.

BACKGROUND: Rett syndrome is a severe neurodevelopmental disorder representing one of the most common genetic causes of mental retardation in girls. The classic form is caused by MECP2 mutations. In two patients affected by the congenital variant of Rett we have recently identified mutations in the FOXG1 gene encoding a brain specific transcriptional repressor, essential for early development of the telencephalon. METHODS: 60 MECP2/CDKL5 mutation negative European Rett patients (classic and variants), 43 patients with encephalopathy with early onset seizures, and four atypical Rett patients were analysed for mutations in FOXG1. RESULTS AND CONCLUSIONS: Mutations have been identified in four patients, independently classified as congenital Rett variants from France, Spain and Latvia. Clinical data have been compared with the two previously reported patients with mutations in FOXG1. In all cases hypotonia, irresponsiveness and irritability were present in the neonatal period. At birth, head circumference was normal while a deceleration of growth was recognised soon afterwards, leading to severe microcephaly. Motor development was severely impaired and voluntary hand use was absent. In contrast with classic Rett, patients showed poor eye contact. Typical stereotypic hand movements with hand washing and hand mouthing activities were present continuously. Some patients showed abnormal movements of the tongue and jerky movements of the limbs. Brain magnetic resonance imaging showed corpus callosum hypoplasia in most cases, while epilepsy was a variable sign. Scoliosis was present and severe in the older patients. Neurovegetative symptoms typical of Rett were frequently present.

Pregabalin versus naltrexone in alcohol dependence: a randomised, double-blind, comparison trial.

Pregabalin (PRE) acts as a presynaptic inhibitor of the release of excessive levels of excitatory neurotransmitters by selectively binding to the alpha(2)-delta subunit of voltage-gated calcium channels. In this randomised, double-blind comparison trial with naltrexone (NAL), we aimed to investigate the efficacy of PRE on alcohol drinking indices. Craving reduction and improvement of psychiatric symptoms were the secondary endpoints. Seventy-one alcohol-dependent subjects were detoxified and subsequently randomised into two groups, receiving 50 mg of NAL or 150-450 mg of PRE. Craving (VAS; OCDS), withdrawal (CIWA-Ar) and psychiatric symptoms (SCL-90-R) rating scales were applied. Alcohol drinking indices and craving scores were not significantly different between groups. Compared with NAL, PRE resulted in greater improvement of specific symptoms in the areas of anxiety, hostility and psychoticism, and survival function (duration of abstinence from alcohol). PRE also resulted in better outcome in patients reporting a comorbid psychiatric disorder. Results from this study globally place PRE within the same range of efficacy as that of NAL. The mechanism involved in the efficacy of PRE in relapse prevention could be less related to alcohol craving and more associated with the treatment of the comorbid psychiatric symptomatology.

The XLMR gene ACSL4 plays a role in dendritic spine architecture.

ACSL4 is a gene involved in non-syndromic X-linked mental retardation. It encodes for a ubiquitous protein that adds coenzyme A to long-chain fatty acids, with a high substrate preference for arachidonic acid. It presents also a brain-specific isoform deriving from an alternative splicing and containing 41 additional N-terminal amino acids. To start to unravelling the link between ACSL4 and mental retardation, we have performed molecular and cell biological studies. By retro-transcription polymerase chain reaction analyses we identified a new transcript with a shorter 5'-UTR region. By immunofluorescence microscopy in embryonic rat hippocampal neurons we report that ACSL4 is associated preferentially to endoplasmic reticulum tubules. ACSL4 knockdown by siRNAs in hippocampal neurons indicated that this protein is largely dispensable for these cells' gross architectural features (i.e. axonal and dendritic formation and final length) yet it is required for the presence of normal spines. In fact, reduced levels of ACSL4 led to a significant reduction in dendritic spine density and an alteration in spine/filopodia distribution. The possible mechanisms behind this phenotype are discussed.