Revision of Failed Short Stems in Total Hip Arthroplasty.

Background: The current literature lacks studies which evaluate the failure of short stems in total hip arthroplasty (THA). Therefore, the present clinical investigation reported our experience with the failure of short stems in THA, evaluating the causes of failure, survivorship, and the clinical outcomes of revision arthroplasty. Methods: The present study was performed according to the STROBE guidelines. This study was conducted at the Department of Orthopaedic Surgery of the Humanitas Clinical Institute, Milan, Italy, between 2017 and 2022. All patients who underwent revision surgery of a previously implanted THA using a short stem were prospectively included in the present study. Surgeries were performed with patients in lateral position, using a minimally invasive posterolateral approach. The outcomes of interest were to report information on the type and survivorship of implants used for the revision surgery and evaluate the clinical outcomes and the rate of complications. The following patient-reported outcome measures (PROMs) used for the clinical assessment were the Western Ontario McMaster Osteo-Arthritis Index (WOMAC) and related subscales of pain, stiffness, and function, and the visual analogue scale (VAS). Results: Data from 45 patients were retrieved. Of them, 31% (14 of 45 patients) were women. The mean age was 63.7 ± 13.9 years. The mean length of the implant survivorship was 6.2 ± 5.7 years. In total, 58% (26 of 45 patients) underwent revision of all components, 36% (16 of 45 patients) revised only the stem, and 1% (3 of 45 patients) received a two-stage revision. The mean length of the follow-up was 4.4 ± 1.5 years. The cup was revised in 58% (26 of 45) of patients. At 4.4 ± 1.5 years of follow-up, the WOMAC score was 3.5 ± 1.3 and the VAS was 1.2 ± 1.3. In total, 9% (4 of 45) of patients experienced minor complications. One patient used a walking aid because of reduced function. One patient evidenced muscular hypotrophy. Two patients experienced hip dislocations. All two dislocations were managed conservatively with repositioning in the emergency room under fluoroscopy. No patient needed additional revision surgery or experienced further dislocations. Conclusions: Revision surgery is effective and safe when a short stem THA fails. At approximately four years of follow-up, all patients were highly satisfied with their clinical outcomes. Despite the relatively high number (9%), complications were of a minor entity and were successfully managed conservatively.

Coupling of SARS-CoV-2 to Aß Amyloid Fibrils.

The COVID-19 infection has been more problematic for individuals with certain health predispositions. Coronaviruses could also interfere with neural diseases if the viruses succeed in entering the brain. Therefore, it might be of principal interest to examine a possible coupling of coronaviruses and amyloid fibrils. Here, molecular dynamics simulations were used to investigate direct coupling of SARS-CoV-2 and Aß fibrils, which play a central role in neural diseases. The simulations revealed several stable binding configurations and their dynamics of Aß42 fibrils attached to spike proteins of the Omicron and Alpha variants of SARS-CoV-2.

Antiviral fibrils of self-assembled peptides with tunable compositions.

The lasting threat of viral pandemics necessitates the development of tailorable first-response antivirals with specific but adaptive architectures for treatment of novel viral infections. Here, such an antiviral platform has been developed based on a mixture of hetero-peptides self-assembled into functionalized ß-sheets capable of specific multivalent binding to viral protein complexes. One domain of each hetero-peptide is designed to specifically bind to certain viral proteins, while another domain self-assembles into fibrils with epitope binding characteristics determined by the types of peptides and their molar fractions. The self-assembled fibrils maintain enhanced binding to viral protein complexes and retain high resilience to viral mutations. This method is experimentally and computationally tested using short peptides that specifically bind to Spike proteins of SARS-CoV-2. This platform is efficacious, inexpensive, and stable with excellent tolerability.

Noncovalent Peptide Assembly Enables Crystalline, Permutable, and Reactive Thiol Frameworks.

Though thiols are exceptionally versatile, their high reactivity has also hindered the synthesis and characterization of well-defined thiol-containing porous materials. Leveraging the mild conditions of the noncovalent peptide assembly, we readily synthesized and characterized a number of frameworks with thiols displayed at many unique positions and in several permutations. Importantly, nearly all assemblies were structurally determined using single-crystal X-ray diffraction to reveal their rich sequence-structure landscape and the cooperative noncovalent interactions underlying their assembly. These observations and supporting molecular dynamics calculations enabled rational engineering by the positive and negative design of noncovalent interactions. Furthermore, the thiol-containing frameworks undergo diverse single-crystal-to-single-crystal reactions, including toxic metal ion coordination (e.g., Cd2+, Pb2+, and Hg2+), selective uptake of Hg2+ ions, and redox transformations. Notably, we find a framework that supports thiol-nitrosothiol interconversion, which is applicable for biocompatible nitric oxide delivery. The modularity, ease of synthesis, functionality, and well-defined nature of these peptide-based thiol frameworks are expected to accelerate the design of complex materials with reactive active sites.

Scalable Inhibitors of the Nsp3-Nsp4 Coupling in SARS-CoV-2.

The human Betacoronavirus SARS-CoV-2 is a novel pathogen claiming millions of lives and causing a global pandemic that has disrupted international healthcare systems, economies, and communities. The virus is fast mutating and presenting more infectious but less lethal versions. Currently, some small-molecule therapeutics have received FDA emergency use authorization for the treatment of COVID-19, including Lagevrio (molnupiravir) and Paxlovid (nirmaltrevir/ritonavir), which target the RNA-dependent RNA polymerase and the 3CLpro main protease, respectively. Proteins downstream in the viral replication process, specifically the nonstructural proteins (Nsps1-16), are potential drug targets due to their crucial functions. Of these Nsps, Nsp4 is a particularly promising drug target due to its involvement in the SARS-CoV viral replication and double-membrane vesicle formation (mediated via interaction with Nsp3). Given the degree of sequence conservation of these two Nsps across the Betacoronavirus clade, their protein-protein interactions and functions are likely to be conserved as well in SARS-CoV-2. Through AlphaFold2 and its recent advancements, protein structures were generated of Nsp3 and 4 lumenal loops of interest. Then, using a combination of molecular docking suites and an existing library of lead-like compounds, we virtually screened 7 million ligands to identify five putative ligand inhibitors of Nsp4, which could present an alternative pharmaceutical approach against SARS-CoV-2. These ligands exhibit promising lead-like properties (ideal molecular weight and log P profiles), maintain fixed-Nsp4-ligand complexes in molecular dynamics (MD) simulations, and tightly associate with Nsp4 via hydrophobic interactions. Additionally, alternative peptide inhibitors based on Nsp3 were designed and shown in MD simulations to provide a highly stable binding to the Nsp4 protein. Finally, these therapeutics were attached to dendrimer structures to promote their multivalent binding with Nsp4, especially its large flexible luminal loop (Nsp4LLL). The therapeutics tested in this study represent many different approaches for targeting large flexible protein structures, especially those localized to the ER. This study is the first work targeting the membrane rearrangement system of viruses and will serve as a potential avenue for treating viruses with similar replicative function.

Birefringence properties of human immotile spermatozoa and ICSI outcome.

RESEARCH QUESTION: In sperm samples with complete asthenozoospermia, pregnancies are achieved by intracytoplasmic sperm injection (ICSI), but this condition has a negative impact on fertilization and embryo development owing to the difficulty of identifying viable cells for oocyte injection. Is the selection of sperm cells with head birefringence properties under polarizing light a successful strategy to identify viable spermatozoa? DESIGN: This study included 192 ICSI cycles with complete asthenozoospermia (83 ejaculated and 109 testicular samples) performed under polarized light. Two types of sperm head birefringence were distinguished: partial (presumably reacted spermatozoa) and total (presumably intact acrosome). In some sperm cells, no birefringence was present. The main outcome of the study was the cumulative live birth rate (cLBR) per ICSI cycle. RESULTS: Seventy-three deliveries resulted with 38.0% cLBR per ICSI cycle. The injection of birefringent spermatozoa led to significantly higher rates of fertilization, embryo development and implantation compared with the absence of birefringence (P < 0.001). Similarly, the resulting cLBR were 53.6% and 9.0%, respectively (P < 0.001). Spermatozoa with partial head birefringence yielded significantly higher fertilization and embryo utilization rates compared with total birefringence. The cLBR showed the same trend (62.7% and 46.7%, respectively, P = 0.048). Multiple logistic regression analysis showed the pattern of partial birefringence to be strongly associated with live birth rate. CONCLUSIONS: Immotile sperm cells with birefringence properties under polarized light have higher chances of inducing fertilization and embryo development compared with non-birefringent cells. In addition, a pattern of partial birefringence, associated with a reacted acrosome, is the strongest predictive factor for live birth delivery, both in ejaculated and testicular samples.

Broad-Spectrum Extracellular Antiviral Properties of Cucurbit[n]urils.

Viruses are microscopic pathogens capable of causing disease and are responsible for a range of human mortalities and morbidities worldwide. They can be rendered harmless or destroyed with a range of antiviral chemical compounds. Cucurbit[n]urils (CB[n]s) are a family of macrocycle chemical compounds existing as a range of homologues; due to their structure, they can bind to biological materials, acting as supramolecular "hosts" to "guests", such as amino acids. Due to the increasing need for a nontoxic antiviral compound, we investigated whether cucurbit[n]urils could act in an antiviral manner. We have found that certain cucurbit[n]uril homologues do indeed have an antiviral effect against a range of viruses, including herpes simplex virus 2 (HSV-2), respiratory syncytial virus (RSV) and SARS-CoV-2. In particular, we demonstrate that CB[7] is the active homologue of CB[n], having an antiviral effect against enveloped and nonenveloped species. High levels of efficacy were observed with 5 min contact times across different viruses. We also demonstrate that CB[7] acts with an extracellular virucidal mode of action via host-guest supramolecular interactions between viral surface proteins and the CB[n] cavity, rather than via cell internalization or a virustatic mechanism. This finding demonstrates that CB[7] acts as a supramolecular virucidal antiviral (a mechanism distinct from other current extracellular antivirals), demonstrating the potential of supramolecular interactions for future antiviral disinfectants.

Static versus dynamic fixation of distal tibiofibular syndesmosis: a systematic review of overlapping meta-analyses.

PURPOSE: Multiple Level I meta-analyses were conducted comparing traditional static vs. more recently introduced dynamic strategies of fixation for injuries of the distal tibiofibular syndesmosis (TFS). The aim of this review was to assess their robustness and methodological quality, providing support in the choice of a treatment strategy in case of TFS injury using the highest level of evidence. METHODS: In this systematic review, conducted in accordance with the PRISMA guidelines, meta-analyses/systematic reviews comparing static and dynamic fixation methods after acute TFS injury were identified. The robustness of studies was evaluated using the fragility index (FI) for meta-analysis and the fragility quotient (FQ). The risk of bias was evaluated using the Assessment of Multiple Systematic Reviews (AMSTAR) instrument. Finally, the Jadad was applied to select the study which provided the highest quality of evidence to develop recommendations for the fixation strategy of these lesions. RESULTS: Out of 1.302 records, four Level I meta-analyses were included in this study. Analyzing the statistically significant dichotomous outcomes, the median FI was 3.5 (IQR, 2 to 5.5; range, 1 to 9), while the median FQ was 1.9% (IQR, 1 to 3.5; range 0.35 to 4.4). In total, 37% had an FI of 2 or less and 75% of outcomes had a FI of 4 or less. According to the AMSTAR score and Jadad algorithm, the largest meta-analysis was selected as the highest evidence provided so far. CONCLUSION: The meta-analyses with statistically significant dichotomous outcomes comparing dynamic and static fixation for treating injuries of the distal tibiofibular syndesmosis are fragile, with a change in less than four patients or less than 2% of the study population sufficient to reverse a significant outcome to nonsignificant. LEVEL OF EVIDENCE: Level I.

Mapping Ligand-Shape Space for Protein-Ligand Systems: Distinguishing Key-in-Lock and Hand-in-Glove Proteins.

Many of the recently developed methods to study the shape of molecules permit one conformation of one molecule to be compared to another conformation of the same or a different molecule: a relative shape. Other methods provide an absolute description of the shape of a conformation that does not rely on comparisons or overlays. Any absolute description of shape can be used to generate a self-organizing map (shape map) that places all molecular shapes relative to one another; in the studies reported here, the shape fingerprint and ultrafast shape recognition methods are employed to create such maps. In the shape maps, molecules that are near one another have similar shapes, and the maps for the 102 targets in the DUD-E set have been generated. By examining the distribution of actives in comparison with their physical-property-matched decoys, we show that the proteins of key-in-lock type (relatively rigid receptor and ligand) can be distinguished from those that are more of a hand-in-glove type (more flexible receptor and ligand). These are linked to known differences in protein flexibility and binding-site size.

Social Dysfunction in Older Age and Relationships with Cognition, Depression, and Apathy: The GreatAGE Study.

BACKGROUND: Most studies focused on only one measure of social dysfunction in older age, without proper validation and distinction across different dimensions including subjectivity, structural, and functional aspects. OBJECTIVE: We sought to validate the Social Dysfunction Rating Scale (SDRS) and its factorial structure, also determining the association of SDRS with cognitive functions, global psychopathology, and social deprivation. METHODS: The SDRS was administered to 484 Italian community-dwelling elderly, recruited in the GreatAGE study, a population-based study on aging conducted in Castellana Grotte, Bari, Southern Italy. We determined objective and subjective psychometric properties of SDRS against the gold standard evaluation of social dysfunction according to the Semi-structured Clinical Diagnostic Interview for DSM-IV-TR Axis I Disorders (SCID-I) criterion. RESULTS: The SDRS showed a moderate accuracy with an optimal cut-off of 26 maximized with higher sensitivity (0.74,95% CI:0.63-0.84) than specificity (0.57,95% CI:0.50-0.64). A five-factor structure was carried out and five dimensions of SDRS were identified (loneliness; social isolation; feeling of contribution/uselessness; lack of leisure activities; anxiety for the health). Education and global cognitive functions were inversely correlated to SDRS, while a direct association with global psychopathology, depression, and apathy was found. The prevalence of higher SDRS scores was major in subjects with current psychiatric disorders versus other subjects.∥Conclusion: The SDRS could be a valid instrument to capture both size and quality of social dysfunction, both in subjects with psychiatric disorders and in normal subjects. Several categories of social dysfunction differed only in the degree of health deprivation, not in social or material deprivation.

The prevalence of peripheral and central hearing impairment and its relation to cognition in older adults.

Age-related hearing loss (ARHL) and dementia are two highly prevalent conditions in the adult population. Recent studies have suggested that hearing loss is independently associated with poorer cognitive functioning. The aim of this study was to evaluate the prevalence of ARHL and cognitive impairment in a large sample of subjects older than 65 years and to correlate hearing function with cognitive function. A total of 488 subjects older than 65 years (mean age 72.8 years) participating in the Great Age Study underwent a complete audiological, neurological and neuropsychological evaluation as part of a multidisciplinary assessment. The prevalence of a hearing loss greater than 25 dB HL was 64.1%, of Central Auditory Processing Disorder (CAPD) was 14.3 and 25.3% of the subjects reported a hearing handicap as reported on the Hearing Handicap Inventory for the Elderly Screening Version questionnaire. Multiple logistic regression analysis corrected for gender, age and education duration showed that mild cognitive impairment (MCI) was significantly associated with hearing impairment (CAPD and hearing threshold; odds ratio 1.6, p = 0.05) and that Alzheimer's disease (AD) was significantly associated with CAPD (odds ratio 4.2, p = 0.05). Given that up to 80% of patients affected by MCI convert to AD, adding auditory tests to a screening cognitive battery might have value in the early diagnosis of cognitive decline.

LH supplementation in down-regulated women undergoing assisted reproduction with baseline low serum LH levels.

AIM: The aim of our study is to evaluate the effect of recombinant-human LH supplementation on ovarian response and pregnancy outcome, during ovarian stimulation, in down-regulated women with baseline low serum LH levels undergoing assisted reproductive technology. STUDY DESIGN: A prospective randomized study performed with 80 women, with serum LH levels 50.5 IU/l on cycle Day 6 of stimulation. Group-A (40): 14-days after down-regulation with leuprorelin, ovarian stimulation was initiated only with r-FSH 225 IU. Group-B (40): at the same time stimulation was initiated with rFSH 225 IU associated with rLH 75 UI on cycle Day 6 of stimulation. RESULTS: Serum-E2 levels on the hCG-day administration were significantly reduced in the Group-A. FF-VEGF levels were higher in Group-A. We did not find significant differences in the number of retrieved oocytes. The quality of oocytes proved to be higher and more significant from a statistical point of view in Group-B. The number of embryos obtained and transferred, the pregnancy rate lower in Group-A. CONCLUSIONS: In our study, it was shown that LH supplementation seems to have a beneficial effect on the maturity and fertilizability of oocyte. Lower FF VEGF levels, found in Group B, could be an indication of a lower apoptosis rate in human cumulus cells after administration of LH. We can affirm that LH-supplementation is beneficial in patients who show asignificant serum LH suppression during the receptorial down-regulation

Vestibular evoked myogenic potentials (VEMPs) in whiplash injury: a prospective study.

CONCLUSIONS: Patients affected by whiplash-associated disorder presented alterations of vestibular evoked myogenic potentials (VEMPs). VEMP testing may be an important 'forensic' diagnostic tool in the assessment of cervical spine injury. OBJECTIVES: The purpose of this prospective study was to evaluate changes in VEMPs in the assessment of whiplash injuries. PATIENTS AND METHODS: Fourteen patients complaining of whiplash injury were examined and compared with 15 controls. All patients underwent VEMP testing within 7 days from the injury and 90 days after whiplash injury. Beside VEMPs, standard investigation consisted of pure-tone and speech audiometry, impedance audiometry and evaluation of the vestibular system. RESULTS: All subjects presented normal hearing, normal impedence audiometry findings, and normal vestibular function. VEMPs were present both in patients affected by whiplash injury and in the control group at time 0. At 90 days VEMPs were absent in two cases (14.3%). Statistical analysis showed that at time 0 and at time 90 days p1 latency was significantly higher in whiplash patients compared with healthy subjects on both sides (p < 0.002). The amplitude of p1-n1 was significantly lower in whiplash patients at time 0 (p = 0.003 on the right and p = 0.018 on the left), but not at 90 days.

Massive ascites and hydrothorax after leuprolide acetate administration in a down-regulated woman undergoing assisted reproduction.

OBJECTIVE: To present an atypical case of massive ascites and hydrothorax after leuprolide acetate administration in a down-regulated woman undergoing assisted reproduction. DESIGN: Case report. SETTING: Centre for Reproductive Medicine, Department of Obstetrics, Gynaecology, and Neonatology, University of Parma, Parma, Italy. PATIENT(S): A 41-year-old, nulliparous, white woman who developed massive ascites and hydrothorax after administration of 0.50 mg/day of subcutaneous leuprolide acetate, beginning at the midluteal phase. INTERVENTION(S): Down-regulation with the gonadotropin-releasing hormone analogue was discontinued, and therapy was started with furosemide 50 mg/day for 10 days. MAIN OUTCOME MEASURE(S): Successful medical reduction of ascites and hydrothorax. RESULT(S): Resolution of symptoms. CONCLUSION(S): A comprehensive MEDLINE search revealed this to be the first reported case of massive ascites and hydrothorax after leuprolide acetate administration (0.5 mg daily) in a down-regulated woman undergoing assisted reproduction. This case can be explained by an increase in capillary permeability, which resulted in a rapid fluid shift from the intravascular space into the third space. We believe that ascites in our patient resulted from an increase in estradiol in the ovaries, due to a direct action of the gonadotropin-releasing hormone analogue on the corresponding ovarian receptors in the first few days after the start of therapy.

Gonadotropin-releasing hormone antagonists increase follicular fluid insulin-like growth factor-I and vascular endothelial growth factor during ovarian stimulation cycles.

The aim of the present study was to investigate the effect of gonadotropin-releasing hormone (GnRH) antagonists (GnRH-ant) on follicular fluid (FF) insulin-like growth factor-I (IGF-I) and FF vascular endothelial growth factor (VEGF) levels. Sixty women undergoing assisted reproduction were randomized and assigned to two different GnRH analog regimens: GnRH agonist (GnRH-a) and GnRH-ant. FF VEGF and FF IGF-I concentrations were significantly increased in the patients treated with GnRH-ant (p < 0.001). In the same patients we observed a statistically significant reduction in serum luteinizing hormone (LH) and estradiol (E2) levels (p < 0.001 and p < 0.05, respectively), FF E2 and FF androstenedione levels (p < 0.05 and p < 0.001, respectively), as well as a reduction in the number of pregnancies although this was not statistically significant. In the GnRH-ant group, FF VEGF levels were positively correlated with FF IGF-I levels, and both were negatively correlated with serum LH levels. The increase in FF IGF-I and FF VEGF levels in women treated with GnRH-ant could be explained by a deleterious follicular environment in response to profound suppression of LH and E2 levels.

Ovarian response and pregnancy outcome related to midfollicular LH levels in down-regulated women undergoing assisted reproduction.

OBJECTIVE: To assess ovarian response and pregnancy outcome related to midfollicular luteinizing hormone (LH) levels in normogonadotropic women down-regulated with gonadotropin-releasing hormone-agonist (GnRH-a) (daily and depot) during an assisted reproduction cycle. STUDY DESIGN: In a prospective randomized trial, 50 women were down-regulated with leuprorelin, 0.5 mg/d subcutaneously (group A) and 50 with leuprorelin, 3.75 mg depot (group B), prior to ovarian stimulation with recombinant follicle-stimulating hormone (FSH). Midfollicular serum LH levels < or = 0.5 mIU/mL (subgroups A1 and B1) versus > 0.5 mIU/mL (subgroups A2 and B2) were considered. A comparative analysis was carried out on the clinical effects (duration of stimulation, total FSH dose, number of oocytes retrieved and pregnancy rate). RESULTS: Maximum estradiol levels and pregnancy rates were higher in subgroups A2 and B2, with LH > 0.5 mIU/mL. No differences were observed in the cumulative amount of gonadotropin used, number of oocytes retrieved or fertilization rate. CONCLUSION: When FSH only is used for ovarian stimulation, very low LH serum concentrations in normogonadotropic women profoundly suppressed with GnRH-a, especially if given as a depot, may adversely affect in vitro fertilization outcome.

Clinical and endocrine effects of ovulation induction with FSH and hCG supplementation in low responders in the midfollicular phase. A pilot study.

OBJECTIVE: To assess the endocrine and clinical effects of luteinizing hormone (LH) activity supplementation administered in the midfollicular phase during controlled ovarian hyperstimulation to poor responders who were candidates for in vitro fertilization (IVF)--embryo transfer. STUDY DESIGN: Prospective, controlled, nonrandomized trial with historical controls. Twenty-five IVF patients who had shown a poor response to standard, long-protocol GnRH-a and FSH only in a preceding cycle (cycle A), were stimulated in the next cycle after six months with hCG supplementation (50 I.U. subcutaneously daily) starting on day 7 during standard, long-protocol GnRH-a and FSH (cycle B). The comparative analysis of clinical effects (duration of stimulation, total highly purified (HP)-FSH dose, number of oocytes retrieved and pregnancy rate) and endocrine responses (serum E2, follicular E2 and androstenedione levels) were determined between cycles A and B. RESULTS: Maximum serum E2 levels and clinical pregnancy rate were higher in cycle B, with hCG supplementation. Also, the follicular E2 and androstenedione levels were higher in cycle B. No differences were noted between cycles as regards the duration of stimulation, total HP-FSH dose and number of oocytes retrieved. CONCLUSION: LH activity supplementation in the midfollicular phase yields favorable pregnancy results in low responders. This may be due to enhanced release of follicular precursors for greater synthesis of E2.