SIV clearance from neonatal macaques following transient CCR5 depletion.

Treatment of people with HIV (PWH) with antiretroviral therapy (ART) results in sustained suppression of viremia, but HIV persists indefinitely as integrated provirus in CD4-expressing cells. Intact persistent provirus, the "rebound competent viral reservoir" (RCVR), is the primary obstacle to achieving a cure. Most variants of HIV enter CD4 + T cells by binding to the chemokine receptor, CCR5. The RCVR has been successfully depleted only in a handful of PWH following cytotoxic chemotherapy and bone marrow transplantation from donors with a mutation in CCR5 . Here we show that long-term SIV remission and apparent cure can be achieved for infant macaques via targeted depletion of potential reservoir cells that express CCR5. Neonatal rhesus macaques were infected with virulent SIVmac251, then treated with ART beginning one week after infection, followed by treatment with either a CCR5/CD3-bispecific or a CD4-specific antibody, both of which depleted target cells and increased the rate of plasma viremia decrease. Upon subsequent cessation of ART, three of seven animals treated with CCR5/CD3-bispecific antibody rebounded quickly and two rebounded 3 or 6 months later. Remarkably, the other two animals remained aviremic and efforts to detect replication-competent virus were unsuccessful. Our results show that bispecific antibody treatment can achieve meaningful SIV reservoir depletion and suggest that functional HIV cure might be achievable for recently infected individuals having a restricted reservoir.

Human Papillomavirus Infections and Increased Risk of Incident Osteoporosis: A Nationwide Population-Based Cohort Study.

Patients with viral infections are susceptible to osteoporosis. This cohort study investigated the correlation between human papillomavirus (HPV) infections and the risk of osteoporosis via 12,936 patients with new-onset HPV infections and propensity score-matched non-HPV controls enrolled in Taiwan. The primary endpoint was incident osteoporosis following HPV infections. Cox proportional hazards regression analysis and the Kaplan-Meier method was used to determine the effect of HPV infections on the risk of osteoporosis. Patients with HPV infections presented with a significantly high risk of osteoporosis (adjusted hazard ratio, aHR = 1.32, 95% CI = 1.06-1.65) after adjusting for sex, age, comorbidities and co-medications. Subgroup analysis provided that populations at risk of HPV-associated osteoporosis were females (aHR = 1.33; 95% CI = 1.04-1.71), those aged between 60 and 80 years (aHR = 1.45, 95% CI = 1.01-2.08 for patients aged 60-70; aHR = 1.51; 95% CI = 1.07-2.12 for patients aged 70-80), and patients with long-term use of glucocorticoids (aHR = 2.17; 95% CI = 1.11-4.22). HPV-infected patients who did not receive treatments for HPV infections were at a greater risk (aHR = 1.40; 95% CI = 1.09-1.80) of osteoporosis, while the risk of osteoporosis in those who received treatments for HPV infections did not reach statistical significance (aHR = 1.14; 95% CI = 0.78-1.66). Patients with HPV infections presented with a high risk of subsequent osteoporosis. Treatments for HPV infections attenuated the risk of HPV-associated osteoporosis.

Endoscopic subserosal dissection for a GI stromal tumor.

Video 1Endoscopic subserosal dissection was carried out to remove the subepithelial tumors.

Na2Ti3O7@RF@Ag Heterostructures as Efficient Substrates for SERS and Photocatalytic Applications.

A multi-step procedure was effectively employed to synthesize innovative three-dimensional (3D) heterostructures encompassing sodium titanate (Na2Ti3O7) nanowire cores, an intermediate resorcinol-formaldehyde (RF) layer, and outer silver (Ag) nanoparticle sheaths, referred to as Na2Ti3O7@RF@Ag heterostructures. Initially, a one-step hydrothermal technique facilitated the direct growth of single-crystal Na2Ti3O7 nanowires onto a flexible Ti foil. Subsequently, a two-step wet chemical process facilitated the sequential deposition of an RF layer and Ag nanoparticles onto the Na2Ti3O7 nanowires at a low reaction temperature. Optimal concentrations of silver nitrate and L-ascorbic acid can lead to the cultivation of Na2Ti3O7@RF@Ag heterostructures exhibiting heightened surface-enhanced Raman scattering (SERS), which is particularly beneficial for the detection of rhodamine B (RhB) molecules. This phenomenon can be ascribed to the distinctive geometry of the Na2Ti3O7@RF@Ag heterostructures, which offer an increased number of hot spots and surface-active sites, thereby showcasing notable SERS enhancement, commendable reproducibility, and enduring stability over the long term. Furthermore, the Na2Ti3O7@RF@Ag heterostructures demonstrate remarkable follow-up as first-order chemical kinetic and recyclable photocatalysts for the photodecomposition of an RhB solution under UV light irradiation. This result can be attributed to the enhanced inhibition of electron-hole pair recombination and increased surface-active sites.

Pancreatic Heterotopia in the Small Bowel: A Case Report and Literature Review.

ABSTRACT: Diagnosing pancreatic heterotopia (PH) is challenging, because it is a rare congenital anomaly. We report the case of a 66-year-old man who presented with ileus and jejunal PH diagnosed using single-balloon enteroscopy. Reviewing 178 cases of small intestinal PH in the literature showed that (1) PH mostly occurred at the duodenum (61.8%), followed by the jejunum (22.5%) and ileum (14.6%); (2) patients with ileal PH were younger (mean, 40.7 vs 54.6 years; P < 0.001), while those with jejunal PH were older (mean, 59.5 vs 51.7 years; P = 0.006); (3) most patients with jejunal PH were females, while those with duodenal or ileal PH were predominantly males (M:F = 0.8:1 vs 2.5:1; P = 0.003); (4) asymptomatic cases were rare (15.2% vs 83.4% in small and nonsmall bowel, respectively); (5) most patients with ileal PH presented with bleeding (61.5%), while the remaining had abdominal pain (42.8%); (6) emergent operation was performed in 11 cases (6.2%), mainly at the jejunum (12.5%) and Meckel's diverticulum (25%); and (7) Heinrich's classification may be inconclusive. Enteroscopy was performed in only 6 cases (3.4%), and earlier diagnosis and further minimally invasive procedures could have been achieved with enteroscopy.

Cytomegalovirus infection disrupts the influence of short-chain fatty acid producers on Treg/Th17 balance.

BACKGROUND: Both the gut microbiota and chronic viral infections have profound effects on host immunity, but interactions between these influences have been only superficially explored. Cytomegalovirus (CMV), for example, infects approximately 80% of people globally and drives significant changes in immune cells. Similarly, certain gut-resident bacteria affect T-cell development in mice and nonhuman primates. It is unknown if changes imposed by CMV on the intestinal microbiome contribute to immunologic effects of the infection. RESULTS: We show that rhesus cytomegalovirus (RhCMV) infection is associated with specific differences in gut microbiota composition, including decreased abundance of Firmicutes, and that the extent of microbial change was associated with immunologic changes including the proliferation, differentiation, and cytokine production of CD8+ T cells. Furthermore, RhCMV infection disrupted the relationship between short-chain fatty acid producers and Treg/Th17 balance observed in seronegative animals, showing that some immunologic effects of CMV are due to disruption of previously existing host-microbe relationships. CONCLUSIONS: Gut microbes have an important influence on health and disease. Diet is known to shape the microbiota, but the influence of concomitant chronic viral infections is unclear. We found that CMV influences gut microbiota composition to an extent that is correlated with immunologic changes in the host. Additionally, pre-existing correlations between immunophenotypes and gut microbes can be subverted by CMV infection. Immunologic effects of CMV infection on the host may therefore be mediated by two different mechanisms involving gut microbiota. Video Abstract.

Bidirectional Relationship Between Osteoarthritis and Periodontitis: A Population-Based Cohort Study Over a 15-year Follow-Up.

Objective: To identify the relationship between osteoarthritis and periodontitis. Methods: 144,788 periodontitis patients and 144,788 propensity score-matched controls without history of periodontitis were enrolled in this cohort study. A Cox proportional hazard model was used to estimate the risk of osteoarthritis. Survival analysis was utilized to assess the time-dependent effect of periodontitis on osteoarthritis. Age and gender were stratified to identify subgroups at risk. A symmetrical case-control analysis was designed to determine the relationship between present periodontitis and history of osteoarthritis. Results: Patients with periodontitis had higher risk of osteoarthritis (hazard ratio, HR =1.15, 95% CI =1.12-1.17, p < 0.001) and severe osteoarthritis that led to total knee replacement or total hip replacement (TKR/THR) (HR =1.12, 95% CI =1.03-1.21, p < 0.01) than controls, which was time-dependent (log-rank test p < 0.01). The effect of periodontitis on osteoarthritis was significant in both genders and age subgroups over 30 years-old (all p < 0.001). Among them, females (HR=1.27, 95% CI = 1.13-1.42, p < 0.001) and patients aged over 51 (HR= 1.21, 95% CI =1.10-1.33, p < 0.001) with periodontitis were predisposed to severe osteoarthritis. In addition, periodontitis patients were more likely to have a history of osteoarthritis (odds ratio = 1.11, 95% CI = 1.06 - 1.17, p < 0.001). Conclusions: These findings suggest an association between periodontitis and a higher risk of osteoarthritis, including severe osteoarthritis that led to TKR/THR. Likewise, periodontitis is more likely to develop following osteoarthritis. A bidirectional relationship between osteoarthritis and periodontitis was observed.

Human Papillomavirus Infection and the Risk of Erectile Dysfunction: A Nationwide Population-Based Matched Cohort Study.

BACKGROUND: Male patients with genital warts are known for higher rates of sexual dysfunction. This study was conducted to investigate whether human papillomaviruses (HPV) infection is associated with an increased risk of erectile dysfunction (ED). METHODS: Patients aged over 18 with HPV infection (n = 13,296) and propensity score-matched controls (n = 53,184) were recruited from the Longitudinal Health Insurance Database (LHID). The primary endpoint was the diagnosis of ED. Chi-square tests were used to analyze the distribution of demographic characteristics. The Cox proportional hazards regression was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the development of ED in both groups, after adjusting for sex, age, relevant comorbidities, co-medication, and surgery. RESULTS: ED developed in 181 patients of the study group. The incidence density of ED was 2.53 per 1000 person-years for the HPV group and 1.51 per 1000 person-years for the non-HPV group, with an adjusted HR (95% CI) of 1.63 (1.37-1.94). In stratification analysis, adjusted HR of diabetes-, chronic obstructive pulmonary disease (COPD-), and stroke-subgroup were 2.39, 2.51, and 4.82, with significant p values for interaction, respectively. Sensitivity analysis yields consistent findings. CONCLUSIONS: The patients with HPV infection had a higher risk of subsequent ED in comparison to the non-HPV controls. The mechanism behind such association and its possible role in ED prevention deserves further study in the future.

The Impact of COVID-19 Surges in 2019-2021 on Patient-Reported Outcome Measures After Spine Surgery at an Academic Tertiary Referral Center in Taiwan: A Retrospective Observational Cohort Study.

Aim: Limited data are available on the impact of the coronavirus disease 2019 (COVID-19) pandemic on patient-reported outcome measures (PROMs) in patients who underwent spine surgery. In this study, we aimed to investigate the associations between the COVID-19 outbreak in Taiwan (May 2021) and PROMs in patients who underwent spine surgery. Method: We retrospectively identified patients who underwent spine surgery during identical defined 6-week time-intervals (May 16 to June 30) in 2019, 2020, and 2021. PROMs, including visual analog scale (VAS) score for pain, Oswestry disability index (ODI), and EuroQol-5D (EQ-5D), were investigated before surgical intervention and at a 1-month follow-up. Relevant clinical information was collected from the electronic medical records of patients. Linear regression analysis was used to examine the association between the pandemic in 2021 (vs. 2019/2020) and the PROMs after adjusting for age, sex, and relevant clinical variables. Results: The number of patients who underwent spine surgery at our hospital during the identical defined 6-week time-intervals in 2019, 2020, and 2021 was 77, 70, and 48, respectively. The surgical intervention significantly improved VAS, ODI, and EQ-5D of the patients (1 month after surgery vs. before surgery, all p < 0.001) in all three study periods. However, there was a significant between-group difference in change from baseline in VAS (p = 0.002) and EQ-5D (p = 0.010). The decrease in VAS and increase in EQ-5D after surgery in 2021 were not as much as those in 2019 and 2020. The associations between the pandemic in 2021 (vs. 2019/2020) and changes in VAS (ß coefficient 1.239; 95% confidence interval [CI] 0.355 to 2.124; p = 0.006) and EQ-5D (ß coefficient, -0.095; 95% CI, -0.155 to -0.035; p = 0.002) after spine surgery were independent of relevant clinical factors. Conclusion: There was less improvement in short-term PROMs (VAS and EQ-5D) after spine surgery during the COVID-19 pandemic. Assessment of PROMs in surgical patients during a pandemic may be clinically relevant, and psychological support in this condition might help improve patients' outcomes.

T Cell Immune Profiles of Blood and Tumor in Dogs Diagnosed With Malignant Melanoma.

Investigation of canine T cell immunophenotypes in canine melanomas as prognostic biomarkers for disease progression or predictive biomarkers for targeted immunotherapeutics remains in preliminary stages. We aimed to examine T cell phenotypes and function in peripheral blood mononuclear cells (PBMC) and baseline tumor samples by flow cytometry, and to compare patient (n = 11-20) T cell phenotypes with healthy controls dogs (n = 10-20). CD3, CD4, CD8, CD25, FoxP3, Ki67, granzyme B, and interferon-γ (IFN-γ) were used to classify T cell subsets in resting and mitogen stimulated PBMCs. In a separate patient cohort (n = 11), T cells were classified using CD3, CD4, CD8, FoxP3, and granzyme B in paired PBMC and single cell suspensions of tumor samples. Analysis of flow cytometric data of individual T cell phenotypes in PBMC revealed specific T cell phenotypes including FoxP3+ and CD25+FoxP3- populations that distinguished patients from healthy controls. Frequencies of IFN-γ+ cells after ConA stimulation identified two different patient phenotypic responses, including a normal/exaggerated IFN-γ response and a lower response suggesting dysfunction. Principle component analysis of selected T cell immunophenotypes also distinguished patients and controls for T cell phenotype and revealed a clustering of patients based on metastasis detected at diagnosis. Findings supported the overall hypothesis that canine melanoma patients display a T cell immunophenotype profile that is unique from healthy pet dogs and will guide future studies designed with larger patient cohorts necessary to further characterize prognostic T cell immunophenotypes.

The Morphological Changes in Adjacent Segments Amongst Patients Receiving Anterior and Oblique Lumbar Interbody Fusion: A Retrospective Study.

Adjacent segment disease (ASD) is troublesome condition that has proved to be highly related to spinal malalignment after spinal surgery. Hence, we aimed to evaluate the morphological changes after anterior lumbar interbody fusion (ALIF) and oblique LIF (OLIF) to establish the differences between the two surgical methods in terms of possible ASD avoidance. Fifty patients, half of whom received ALIF while the other half received OLIF, were analyzed with image studies and functional outcomes during the pre-operative and post-operative periods, and 2 years after surgery. Image measurements obtained included spinal-pelvic parameters, index lordosis (IL), segmental lordosis (SL), anterior disc height (ADH), posterior disc height (PDH) and adjacent segment disc angle (ASDA). The ADH and PDH in the adjacent segment decreased in the two groups while OLIF showed greater decrease without radiological ASD noted at 2-year follow-up. Both groups showed an increase in IL after surgery while ALIF showed greater improvement. No statistical difference was identified in functional outcomes between LIFs. We suggest that both ALIF and OLIF can restore adequate lordosis and prevent ASD after surgery. However, it should be noted that patient selection remains crucial when making any decision involving which of the two methods to use.

The radiological outcome in lumbar interbody fusion among rheumatoid arthritis patients: a 20-year retrospective study.

BACKGROUND: Clinical outcomes amongst Rheumatoid Arthritis (RA) patients have shown satisfactory results being reported after lumbar surgery. The increased adoption of the interbody fusion technique has been due to a high fusion rate and less invasive procedures. However, the radiographic outcome for RA patients after receiving interbody fusion has scarcely been addressed in the available literature. METHODS: Patients receiving interbody fusion including ALIF, OLIF, and TLIF were examined for implant cage motion and fusion status at two-year follow-up. Parameters for the index correction level including ADH, PDH, WI, SL, FW, and FH were measured and compared at pre-OP, post-OP, and two-year follow-up. RESULTS: We enrolled 64 RA patients at 104 levels (mean 64.0 years old, 85.9% female) received lumbar interbody fusion. There were substantial improvement in ADH, PDH, WI, SL, FW, and FH after surgery, with both ADH and PDH having significantly dropped at two-year follow up. The OLIF group suffered from a higher subsidence rate with no significant difference in fusion rate when compared to TLIF. The fusion rate and subsidence rate for all RA patients was 90.4 and 28.8%, respectively. CONCLUSIONS: We revealed the radiographic outcomes of lumbar interbody fusions towards symptomatic lumbar disease in RA patients with good fusion outcome despite the relative high subsidence rate amongst the OLIF group. Those responsible for intra-operative endplate management should be more cautious to avoid post-OP cage subsidence.

Cytomegalovirus mediates expansion of IL-15-responsive innate-memory cells with SIV killing function.

Interindividual immune variability is driven predominantly by environmental factors, including exposure to chronic infectious agents such as cytomegalovirus (CMV). We investigated the effects of rhesus CMV (RhCMV) on composition and function of the immune system in young macaques. Within months of infection, RhCMV was associated with impressive changes in antigen presenting cells, T cells, and NK cells-and marked expansion of innate-memory CD8+ T cells. These cells express high levels of NKG2A/C and the IL-2 and IL-15 receptor beta chain, CD122. IL-15 was sufficient to drive differentiation of the cells in vitro and in vivo. Expanded NKG2A/C+CD122+CD8+ T cells in RhCMV-infected macaques, but not their NKG2-negative counterparts, were endowed with cytotoxicity against class I-deficient K562 targets and prompt IFN-γ production in response to stimulation with IL-12 and IL-18. Because RhCMV clone 68-1 forms the viral backbone of RhCMV-vectored SIV vaccines, we also investigated immune changes following administration of RhCMV 68-1-vectored SIV vaccines. These vaccines led to impressive expansion of NKG2A/C+CD8+ T cells with capacity to inhibit SIV replication ex vivo. Thus, CMV infection and CMV-vectored vaccination drive expansion of functional innate-like CD8 cells via host IL-15 production, suggesting that innate-memory expansion could be achieved by other vaccine platforms expressing IL-15.

Transient Effect of Infant Formula Supplementation on the Intestinal Microbiota.

Breastfeeding is the gold standard for feeding infants because of its long-term benefits to health and development, but most infants in the United States are not exclusively breastfed in the first six months. We enrolled 24 infants who were either exclusively breastfed or supplemented with formula by the age of one month. We collected diet information, stool samples for evaluation of microbiotas by 16S rRNA sequencing, and blood samples for assessment of immune development by flow cytometry from birth to 6 months of age. We further typed the Bifidobacterium strains in stool samples whose 16S rRNA sequencing showed the presence of Bifidobacteriaceae. Supplementation with formula during breastfeeding transiently changed the composition of the gut microbiome, but the impact dissipated by six months of age. For example, Bifidobacterium longum, a bacterial species highly correlated with human milk consumption, was found to be significantly different only at 1 month of age but not at later time points. No immunologic differences were found to be associated with supplementation, including the development of T-cell subsets, B cells, or monocytes. These data suggest that early formula supplementation, given in addition to breast milk, has minimal lasting impact on the gut microbiome or immunity.

Biomechanical analysis of the treatment of intertrochanteric hip fracture with different lengths of dynamic hip screw side plates.

BACKGROUND: Dynamic hip screw (DHS) is a common implant used to treat stable-type intertrochanteric hip fractures. There are many factors that can affect the success rate of the surgery, including the length of side plates. It is therefore important to investigate the biomechanical effect of different DHS side plates on bones. OBJECTIVE: In order to reduce the likelihood of an implant failure, the aim of this study was to use finite element analysis (FEA) to investigate and understand the effect of side plates with different lengths in DHS. METHODS: In this FEA study, a 3D model with cortical bone, cancellous bone, side plate, lag screw, and cortical screws to simulate the implantation of DHS with different lengths of side plate (2-hole, 4-hole, and 6-hole) for intertrochanteric hip fractures was constructed. The loading condition was used to simulate the force (400 N) on the femoral head and the stress distribution on the lag screw, side plate, cortical screws, and femur was measured. RESULTS: The highest stress points occured around the region of contact between the screw and the cortical bones. The stress on the femur at the most distal cortical screw was the greatest. The shorter the length of the side plate, the greater the stress on the cortical screws, resulting in an increased stress on the femur surrounding the cortical screws. CONCLUSIONS: The use of DHS with 2-hole side plate may increase the risk of side plate pull-out. The results of this study provide a biomechanical analysis for selection of DHS implant lengths that can be useful for orthopaedic surgeons.

Draft Genome Sequences of 1,183 Salmonella Strains from the 100K Pathogen Genome Project.

Salmonella is a common food-associated bacterium that has substantial impact on worldwide human health and the global economy. This is the public release of 1,183 Salmonella draft genome sequences as part of the 100K Pathogen Genome Project. These isolates represent global genomic diversity in the Salmonella genus.