Woodhouse-Sakati syndrome: A review.

Neurodegeneration with brain iron accumulation (NBIA) is a rare and inherited spectrum of movement disorders caused by mutations affecting the function of proteins that participate in the homeostasis of tissue metals such as iron or copper and other metabolic pathways, although the precise function of the proteins encoded are not always known. Woodhouse-Sakati Syndrome (WSS) is one of the rarest NBIAs. Patients with WSS are characterized by endocrinological and neurological manifestations and neuroradiological findings. However, diagnostic criteria have not been published yet. This article reviews updates on the genetic, clinical, biological and imaging findings of WSS and provides a practical guide to recognize this extremely rare disorder.

Is There Room for Liposomal Irinotecan in Biliary Tract Cancer? A Meta-analysis of Randomised Trials.

AIMS: The combination of 5-fluorouracil/leucovorin (5-FU/LV) plus oxaliplatin (FOLFOX) is widely acknowledged as the standard regimen for second-line treatment in patients with advanced biliary tract cancer. Nanoliposomal irinotecan (nal-IRI) has demonstrated its activity in patients with advanced pancreatic cancer. Recent studies have investigated the activity of nal-IRI in combination with 5-FU/LV for biliary tract cancer. However, the results have been contradictory. We conducted a meta-analysis to assess survival outcomes and response rates in randomised trials investigating the activity of nal-IRI in previously treated biliary tract cancer patients. MATERIALS AND METHODS: We systematically collected potentially relevant findings from PubMed/Medline, the Cochrane library and EMBASE. Abstracts presented at major international oncological meetings were also reviewed. We extracted hazard ratios and 95% confidence intervals for progression-free survival and overall survival, as well as odds ratios and 95% confidence intervals for objective response rate. The outcomes of the accessible randomised studies evaluating the activity of nal-IRI plus 5-FU/LV were analysed. RESULTS: The combination therapy exhibited a statistically significant decrease in the risk of progression (hazard ratio 0.70; 95% confidence interval 0.50-0.97) when compared with 5-FU/LV alone. Additionally, the dual regimen yielded longer overall survival and a higher objective response rate. CONCLUSION: Our meta-analysis showed that nal-IRI plus 5-FU/LV had a superior activity in comparison with 5-FU/LV. Further investigations are required to elucidate the role of nal-IRI in this setting and to identify subgroups of patients who could derive the greatest benefit from its administration.

Regional tissue oxygenation in asymptomatic neonates at high risk for neonatal abstinence syndrome and impact of non-pharmacologic interventions: A case report.

BACKGROUND: Improving neonatal abstinence syndrome (NAS) management is an important concern, and objective measures of its physiologic impact remain elusive. We sought to determine whether near-infrared spectroscopy (NIRS)-derived tissue oxygenation (rSO2) and fractional tissue oxygen extraction (FTOE) demonstrated physiologically plausible changes correlating with standard NAS scoring. METHODS: Thirty subjects (mean 39 weeks' GA and 3 127 g BW) underwent cerebral and peripheral muscle NIRS monitoring on Days of Life (DOL) Three, Five, and Seven. We examined correlations between NAS scores and FTOE and assessed the impact of non-pharmacologic swaddling and cuddling. RESULTS: No statistically significant correlations between NAS scores and FTOE were observed; however, plausible trends were demonstrated between NAS scores and cerebral measurements. Buprenorphine-exposed babies (57%) showed significantly lower FTOE when swaddled (DOL7). CONCLUSIONS: Tissue oxygenation monitoring demonstrates potential to provide objective, clinically relevant physiologic information on infants at risk for NAS. Further study is required to determine whether NIRS-derived measures could assist in individualizing NAS care.

Bone quality in endocrine diseases: determinants and clinical relevance.

PURPOSE: Bone is one of the main targets of hormones and endocrine diseases are frequent causes of secondary osteoporosis and fractures in real-world clinical practice. However, diagnosis of skeletal fragility and prediction of fractures in this setting could be a challenge, since the skeletal alterations induced by endocrine disorders are not generally captured by dual-energy X-ray absorptiometry (DXA) measurement of bone mineral density (BMD), that is the gold standard for diagnosis of osteoporosis in the general population. The aim of this paper is to review the existing evidence related to bone quality features in endocrine diseases, proposing assessment with new techniques in the future. METHODS: A comprehensive search within electronic databases was performed to collect reports of bone quality in primary hyperparathyroidism, hypoparathyroidism, hyperthyroidism, hypercortisolism, growth hormone deficiency, acromegaly, male hypogonadism and diabetes mellitus. RESULTS: Using invasive and non-invasive techniques, such as high-resolution peripheral quantitative computed tomography or DXA measurement of trabecular bone score (TBS), several studies consistently reported altered bone quality as predominant determinant of fragility fractures in subjects affected by chronic endocrine disorders. CONCLUSIONS: Assessment of skeletal fragility in endocrine diseases might take advantage from the use of techniques to detect perturbation in bone architecture with the aim of best identifying patients at high risk of fractures.

Addition of androgen receptor-targeted agents to androgen-deprivation therapy and docetaxel in metastatic hormone-sensitive prostate cancer: a systematic review and meta-analysis.

BACKGROUND: Androgen-deprivation therapy (ADT) historically represented the milestone for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC). Recently, combining androgen receptor-targeted agents (ARTA) or docetaxel with ADT significantly improved clinical outcomes in this setting. The efficacy of the combined use of an ARTA with docetaxel and ADT (triplet), however, was unknown, and often conflicting data derived from subgroup analysis of randomized phase III trials. In order to better define the benefits and risks of the triplet in mHSPC, we carried out a systematic review and meta-analysis of available clinical trials. METHODS: A literature search with no data restriction using Medline/PubMed, the Cochrane Library, and American Society of Clinical Oncology/European Society for Medical Oncology (ASCO/ESMO) Meeting abstracts was carried out up to April 2022. The meta-analysis was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statements. Overall survival (OS) was the primary endpoint; progression-free survival (PFS) and safety were secondary endpoints. For OS and PFS, summary hazard ratios (HRs) were calculated; for safety, risk ratio (RR) was assessed. Random- or fixed-effects models were used, depending on studies heterogeneity. RESULTS: Five randomized clinical trials fulfilled the prespecified inclusion criteria. The triplet significantly improved OS (fixed-effect, HR = 0.74; P < 0.00001) and PFS (fixed-effect; HR = 0.50 for clinical PFS, HR = 0.49 for radiological PFS; P < 0.0001) compared with docetaxel plus ADT. We did not show heterogeneity between treatment efficacy and the disease burden, metachronous versus synchronous presentation, concomitant versus sequential strategy. Compared with docetaxel + ADT, the triplet did not increase the risk of adverse events (AEs) (RR = 1.00, P = 0.27 for any-grade AEs; RR = 1.13, P = 0.14 for severe AEs), except for severe hypertension (RR = 1.73, P = 0.001). CONCLUSIONS: Emerging evidence supports the combination of an ARTA plus docetaxel and ADT in mHSPC patients. Given the availability of several strategies in this setting, clinical characteristics and drug safety profile may help clinicians select the appropriate treatment for mHSPC patients who are more likely to benefit from treatment intensification.

Impact of Covid-19 pandemic on injection-based practice: report from an Italian multicenter and multidisciplinary survey.

Background: There are no papers exploring the impact of COVID-19 pandemic on the injection-based practice in patients affected by different rheumatic diseases, including osteoarthritis. The aim was to investigate the impact of COVID-19 pandemic on injection-based practice trough the Italian country. Study design: A survey-based retrospective cross-sectional study. Methods: An Italian-language questionnaire was developed by a group of senior researchers and distributed by e-mail to some Rheumatology, Orthopedic and Rehabilitation Units from different geographic areas of Italy. The survey included information about the number of injections performed during COVID-19 pandemic (stratified by injected agents and injected joint), in comparison to the pre-pandemic period, and the possible reasons behind an eventual reduction. Responses were collected and descriptive analysis calculated. Results: Eleven centers of the National Health Service completed the survey. The activities of the injections services significantly decreased across the country with a percentage of reduction of 60% compared to the pre-pandemic period. A significant reduction of both intra-articular and peri-articular injections was registered. Among intra-articular. treatments, the most affected ones were the hyaluronic acid injections, when compared to corticosteroids. A significant decrease of the total amount of peri-articular injections was observed. The strict government restrictions and the fear of patients to become infected represented the most limiting factors. Conclusions: The reported decrease of the injection-based practice in our country during the COVID-19 pandemic highlights the detrimental effects of the COVID-19 pandemic on the management of chronic musculoskeletal diseases with possible negative consequences in terms of disability and quality of life.

Disruption of bone densitometry practice in a Northern Italy Orthopedic Hospital during the COVID-19 pandemic.

We report the impact of the COVID-19 pandemic on bone densitometry practice in a Northern Italy Orthopedic Hospital, comparing the first 4 months of 2020 with the corresponding period of 2019. COVID-19 pandemic had a disruptive effect on the daily practice of bone densitometry (about - 50% of examinations). INTRODUCTION: The Coronavirus Disease 2019 (COVID-19) pandemic radically changes hospital organization to guarantee patient and staff safety, with the unavoidable cessation of normal outpatient activities. We report the impact of the COVID-19 pandemic on dual energy x-ray absorptiometry (DXA) testing in a Northern Italy Orthopedic Hospital. METHODS: We analyzed the number of DXA examinations performed at our Institution before, during the lockdown, and immediately after outpatient practice reopening (January 24th to May 27th, 2020), comparing them with the corresponding period of 2019. RESULTS: The number of DXA examinations showed a tremendous reduction from n = 1247 performed from January to May 2019 to n = 623 of 2020 (- 49.9%). No exams were performed in April 2020 (- 100%). On May 2020, a faint resume was observed, with n = 43 DXA (- 84.4% compared to 2019). CONCLUSION: COVID-19 pandemic had a disruptive effect on the daily practice of bone densitometry with DXA. After reopening, we observed a persistence of DXA examination reduction, confirming the fact that returning to normality will probably be a slow process.

Prediction of osteoporotic fragility re-fracture with lumbar spine DXA-based derived bone strain index: a multicenter validation study.

A new qualitative index of bone strength, based on finite element analysis and named bone strain index, has been recently developed from lumbar DXA scan. This study shows that BSI predicts subsequent re-fracture in osteoporotic patients affected by fragility fractures. INTRODUCTION: Dual-energy X-ray absorptiometry (DXA) can provide quantitative (bone mineral density, BMD) and qualitative (trabecular bone score, TBS) indexes of bone status, able to predict fragility fractures in most osteoporotic patients. A new qualitative index of bone strength, based on finite element analysis and named bone strain index (BSI), has been recently developed from lumbar DXA scan. This study presents the validation results of BSI prediction for re-fracture in osteoporotic patients with fragility fractures. METHODS: In three academic hospitals, 234 consecutive fractured patients with primary osteoporosis (209 females) performed a spine X-ray for the calculation of spine deformity index (SDI) and DXA densitometry for BMD, TBS and BSI at the basal time and in the follow-up at each clinical check. A subsequent fracture was considered as one unity increase of SDI. RESULTS: For each unit increase of the investigated indexes, the univariate hazard ratio of re-fracture, 95% CI, p value and proportionality test p value are for age 1.040, 1.017-1.064, 0.0007 and 0.2529, respectively, and for BSI 1.372, 1.038-1.813, 0.0261 and 0.5179, respectively. BSI remained in the final multivariate model as a statistically significant independent predictor of a subsequent re-fracture (1.332, 1.013-1.752 and 0.0399) together with age (1.039, 1.016-1.064 and 0.0009); for this multivariate model proportionality test, p value is 0.4604. CONCLUSIONS: BSI appears to be a valid DXA index of prediction of re-fracture, and it can be used for a more refined risk assessment of osteoporotic patients.

Bilateral osteochondritis dissecans of the patella in an adolescent skier with patellofemoral maltracking treated with pulsed electromagnetic field therapy.

Juvenile osteochondritis dissecans of the knee typically occurs in young athletes, and usually localizes on the medial femoral condyle. Bilateral localization is uncommon. Patellofemoral involvement is rare, mainly found in basketball and soccer players, and never related to patellofemoral congenital problems such as trochlear dysplasia. We report here the first case, to our knowledge, of bilateral juvenile osteochondritis dissecans with patellar localization in a young skier with patellofemoral maltracking and trochlear dysplasia.

Fragility fractures and bone mineral density in male patients affected by type 1 and type 2 myotonic dystrophy.

Myotonic dystrophy is a multisystemic disorder affecting skeletal muscle. Male patients have an increased risk of fractures and develop a number of endocrine/metabolic impairments known to adversely affect bone health. The aim of this study was primarily to determine the occurrence of fragility fractures and the bone mineralization status (lumbar spine, hip and total body by dual X-ray absorptiometry) in 36 male patients affected with type 1 myotonic dystrophy and 13 male patients affected with type 2 myotonic dystrophy. Fragility fractures occurred in 15 type 1 and 7 type 2 myotonic dystrophy in non-classical osteoporotic sites, such as metatarses. Hip osteopenia was the most frequent finding, particularly in type 2 (n = 6) than type 1 myotonic dystrophy patients (n = 1), while osteoporosis was rare. Patients with type 1 myotonic dystrophy presented higher total body bone mass density than patients with type 2 myotonic dystrophy and healthy controls and lumbar spine was associated positively with the severity of the disease. Gonadic failure, with low testosterone and reduced INSL3 levels, visceral adiposity and insulin resistance correlated with reduced body mass index in both type 1 and type 2 myotonic dystrophic patients. The independent determinant of fragility fractures were low total body mass index, low blood testosterone and low global muscle mass.

Indomethacin dosing strategy and neonatal patent ductus arteriosus closure.

BACKGROUND: Few studies exist that have evaluated the effects of indomethacin dosing frequency as a factor associated with successful patent ductus arteriosus closure in very low birth weight neonates. The objective of this study is to determine if indomethacin dosing strategy is associated with efficacy for initial patent ductus arteriosus management in very low birth weight neonates. METHODS: This retrospective review compared every 12 hour and every 24 hour indomethacin regimens primarily for efficacy in initial patent ductus arteriosus management, defined as an absence of repeat medical and/or surgical treatment, and secondarily for safety in both univariate and multivariate models. RESULTS: One hundred three very low birth weight neonates were included: 56 (54%) received every 12 hour and 47 (46%) underwent every 24 hour indomethacin dosing. Repeat medical and/or surgical patent ductus arteriosus treatment rates were similar between groups. Less ligation of the patent ductus arteriosus occurred with every 12 hour versus every 24 hour dosing (11% vs. 26%, p = 0.05), though this effect was mitigated controlling for birth weight and gestational age. Renal function, respiratory outcomes, feeding outcomes, length of stay, and mortality were similar between groups. CONCLUSIONS: Neither the every 12 hour nor the every 24 hour indomethacin regimen demonstrated inferior efficacy or safety for initial management of patent ductus arteriosus. Further prospective analysis of indomethacin dosing strategy is warranted.

Bone strain index reproducibility and soft tissue thickness influence: a dual x-ray photon absorptiometry phantom study.

BACKGROUND: Bone strain index (BSI) is a tool measuring bone strain, derived from dual x-ray photon absorptiometry. It is able to characterise an aspect of bone quality that, joined to the quantity and quality parameters of bone mineral density (BMD) and trabecular bone score (TBS), permits an accurate definition of fracture risk. As no data are available about BSI precision, our aim was to assess its in vitro reproducibility. METHODS: A Hologic spine phantom was used to perform BSI scans with three different scan modes: fast array (FA), array (A), and high definition (HD). Different soft tissue thicknesses (1, 3, 6 cm) of fresh pork rind layers as a surrogate of abdominal fat were interposed. For each scan mode, the phantom was consecutively scanned 25 times without repositioning. RESULTS: In all scan modes (FA, A, HD) and at every fat thickness, BSI reproducibility was lower than that of BMD. The highest reproducibility was found using HD-mode with 1 cm of pork rind and the lowest one using HD-mode with 6 cm of pork rind. Increasing fat thickness, BSI reproducibility tended to decrease. BSI least significant change appeared to be about three times that of BMD in all modalities and fat thicknesses. Without pork rind superimposition and with 1-cm fat layer, BSI reproducibility was highest with HD-mode; with 3 or 6 cm fat thickness, it was higher with A-mode. CONCLUSIONS: BSI reproducibility was worse than that of BMD, but it is less sensitive to fat thickness increase, similarly to TBS.

Accuracy of CT and MRI to assess resection margins in primary malignant bone tumours having histology as the reference standard.

AIM: To evaluate the accuracy of magnetic resonance imaging (MRI) and computed tomography (CT) in assessing the resection margins of primary malignant bone tumours. MATERIALS AND METHODS: Resected primary malignant bone tumour specimens removed from 46 patients (27 male; mean age: 48±22 years) were imaged using MRI (fat-saturated proton density-weighted and three-dimensional fat-suppressed T1-weighted gradient-recalled-echo) and CT immediately after surgery. A radiologist and an orthopaedist evaluated bone and soft-tissue margins of the specimens on both examinations. Histological evaluation was performed by a senior orthopaedic oncology pathologist. Margins were classified as R0 (safe margins), R1 (residuals between 0 and 1 mm), and R2 (macroscopic residuals). Cohen's k, chi-square, and McNemar's statistics were used. RESULTS: Having histology as the reference standard, reproducibility of the radiologist ranged from moderate (k=0.544) to substantial (k=0.741) for bone and soft-tissue margins on CT, respectively, while that of the orthopaedist ranged from fair (k=0.316) to moderate (k=0.548). When comparing R2 and R0+R1 scores, reproducibility of readers' evaluation of bone margins increased ranging from substantial (k=0.655) to perfect (k=1.000). Inter-reader agreement ranged from fair (k=0.308) to substantial (k=0.633). Accuracy of the radiologist and orthopaedist ranged from 76% to 83% and from 68% to 72%, respectively. When comparing R2 and R0+R1 scores, the accuracy of both readers ranged from 83% to 100%. There was no association between local recurrence and margin scores of histology, MRI, and CT (p≥0.058). CONCLUSIONS: MRI and CT may be useful for extemporaneous analysis of resection margins of primary malignant bone tumours, although wide accuracy variability between the different imaging methods was observed.

Response of maize photosynthesis to high temperature: Implications for modeling the impact of global warming.

Negative impacts of increased temperature on maize yield are anticipated using simulation models. However, some temperature functions are parameterized with partial information. There is limited information on photosynthesis response to high temperature in modern maize hybrids. Improved photosynthesis-temperature functions are key for realistic yield simulations. Our experiment was aimed at building a functional relationship between photosynthesis and air temperature exploring temperature ranges relevant for global warming simulations. Maize hybrids from cold, temperate, and subtropical regions were included in the study to assess genetic adaptation. Results showed a trilinear response to temperature with an optimum of 40 °C. No genetic adaptation was observed among the diverse set of hybrids evaluated. Results contrast with common temperature-limiting functions indicating a decline in carbon assimilation above 30-33 °C. Our results suggest possible overestimations of negative impacts of global warming on maize yield due to the use of inadequate response functions relating carbon assimilation to temperature.

Targeting androgen-independent pathways: new chances for patients with prostate cancer?

Androgen deprivation therapy (ADT) is the mainstay treatment for advanced prostate cancer (PC). Most patients eventually progress to a condition known as castration-resistant prostate cancer (CRPC), characterized by lack of response to ADT. Although new androgen receptor signaling (ARS) inhibitors and chemotherapeutic agents have been introduced to overcome resistance to ADT, many patients progress because of primary or acquired resistance to these agents. This comprehensive review aims at exploring the mechanisms of resistance and progression of PC, with specific focus on alterations which lead to the activation of androgen receptor (AR)-independent pathways of survival. Our work integrates available clinical and preclinical data on agents which target these pathways, assessing their potential clinical implication in specific settings of patients. Given the rising interest of the scientific community in cancer immunotherapy strategies, further attention is dedicated to the role of immune evasion in PC.

Bone quality in beta-thalassemia intermedia: relationships with bone quantity and endocrine and hematologic variables.

We report the first evaluation of bone quality in 70 thalassemia intermedia (TI) patients (37 males, 33 females, age 41 ± 12 years). Thirty-three patients (47%) had been transfused, 34 (49%) had been splenectomized, 39 (56%) were on iron chelation therapy, and 11 (16%) were on hydroxyurea. Mean hemoglobin was 9.2 ± 1.5 g/dl, median ferritin 537 ng/dl (range 14-4893), and mean liver iron concentration 7.6 ± 6.4 mg Fe/g dw. Fifteen patients (21%) had endocrinopathies, and 29 (41%) had vitamin D deficiency. Bone quantity (bone mineral density, BMD) and bone quality (trabecular bone score, TBS) were evaluated by densitometry. In 53/70 patients (76%), osteopathy was found (osteoporosis in 26/53, osteopenia in 27/53). BMD values were higher in the never-transfused patients and in the not-chelated group. A highly significant correlation was found between splenectomy and BMD at all the sites, with lower values in the splenectomized patients. TBS values were significantly lower in TI patients than in 65 non-thalassemic controls (1.22 vs 1.36, p < 0.01), mainly in those splenectomized and in the transfused and chelated groups (p < 0.01). TBS did not correlate with liver iron concentration values. Our data disclose the major role of non-invasive bone quality evaluation in TI patients, especially those with the worst health state, to obtain a comprehensive assessment of fracture risk. Splenectomy seems to play a major part in bone complications.

Optimal radiologic position of an umbilical venous catheter tip as determined by echocardiography in very low birth weight newborns.

OBJECTIVE: To compare chest X-ray with echocardiogram (ECHO) in the localization of an umbilical venous catheter (UVC) tip in very low birth weight infants (VLBW). Secondary objectives determined the association between techniques for tip placement by the vertebral body level on X-ray, as well as the length of the thoracic inferior vena cava-right atrial (TIVC-RA) junction by ECHO. STUDY DESIGN: Prospective, sequentially enrolled, masked, single regional perinatal center study. Shortly after birth, one or more anterior-posterior X-rays were ordered by the clinical team to verify that the UVC tip was fixed in the central right atrium (cRA) or at the TIVC-RA junction. An echocardiogram was performed as soon as possible after the last X-ray and UVC tip location was interpreted by a pediatric cardiologist. The pediatric radiologist and cardiologist were masked with regard to each other's reading. RESULTS: The newborns (n = 51) were 27 (±3) weeks by gestational age with birth weights of 1029 (±288) grams (mean±SD). The radiologist read 50 UVC tips (98%) in the cRA or TIVC-RA junction and 1 (2%) in the LA. The cardiologist read 22 (43%) in the cRA or TIVC-RA, 21 (41%) in the LA and 8 (16%) tips could not be located in the heart. When the UVC tip was interpreted by X-ray as located in the TIVC-RA junction 8/29 (28%) were in the LA by echocardiogram. There was no agreement between vertebral level and tip position in the TIVC-RA junction, RA or LA. The TIVC-RA junction measured 6±1 mm and correlated with birth weight r = 0.54 (p < 0.001). CONCLUSION: In VLBW newborns, placement of the UVC tip into the cRA or TIVC-RA junction by X-ray does not avoid misplacement in the left atrium as demonstrated by echocardiography. For VLBW infants, it is suggested that echocardiography may be helpful in verifying that the original placement or migration of the UVC tip into the LA has not occurred.