Subthreshold rejection activity in many kidney transplants currently classified as having no rejection.

Most kidney transplant patients who undergo biopsies are classified as having no rejection based on consensus thresholds. However, we hypothesized that because these patients have normal adaptive immune systems, T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) may exist as subthreshold activity in some transplants currently classified as no rejection. To examine this question, we studied genome-wide microarray results from 5086 kidney transplant biopsies (4170 patients). An updated archetypal analysis designated 56% of biopsies as no rejection. Subthreshold molecular TCMR and/or ABMR activity molecular activity was detectable as elevated classifier scores in many biopsies classified as no rejection, with ABMR activity in many TCMR biopsies and TCMR activity in many ABMR biopsies. In biopsies classified as no rejection histologically and molecularly, molecular TCMR classifier scores correlated with increases in histologic TCMR features and molecular injury, lower eGFR, and higher risk of graft loss, and molecular ABMR activity correlated with increased glomerulitis and donor-specific antibody. No rejection biopsies with high subthreshold TCMR or ABMR activity had a higher probability of having TCMR or ABMR respectively diagnosed in a future biopsy. We conclude that many kidney transplant recipients have unrecognized subthreshold TCMR or ABMR activity, with significant implications for future problems.

Does Small Aneurysm Size (<10 mm) Predict Complete Occlusion After Flow Diversion? A Surpass Evolve Single-Center Study.

BACKGROUND: Long-term safety and efficacy outcomes of Surpass Evolve flow diverter (SEFD) in treatment of intracranial aneurysms are lacking. Factors predicting complete aneurysm occlusion are elusive in literature. METHODS: A retrospective review of all consecutive aneurysms treated with SEFD from February 2020 to July 2022, at a single comprehensive stroke center. RESULTS: Fifty-one patients with 80 aneurysms were included. Mean target aneurysm size was 5.6 mm and mean neck-width 3.42 mm. Small aneurysms (<10 mm) were 75% (n=60), while 25% were >10 mm. Unruptured were 71 (88.7%), previously ruptured were 8 (10%), and partially thrombosed 2.3% (n=1). Mean SEFDs used per patient were 1.07 and 40% (n=22) procedures were performed transradially. Mean procedure time was 59.1 minutes. The technical success rate for device deployment was 100%. Raymond Roy (RR) class I occlusion at 6 month (n=73) was seen among 56.2% (n=41), at 1 year (n=35) among 85.7% (n=30) and at 2 year (n=18) among 88.8% (n=16) aneurysms. Aneurysm size <10 mm significantly predicted RR-I occlusion outcome (odds ratio [OR]: 2.16; confidence interval [CI]: 0.02-4.29) at 6 months. Age, gender, smoking status, hypertension, location of aneurysm, and rupture status did not predict RR-I occlusion outcome. No mortality or permanent neurological morbidity was observed in the cohort. Major complications seen in 7.2% (n=4) patients were stent thrombosis (n=1, 1.8%), carotid-cavernous fistula (n=1, 1.8%) and transient ischemia in 2 (3.6%). Non-flow limiting stenosis was observed in 3 (5.4%) patients. CONCLUSION: SEFD gives good aneurysm occlusion rates with favorable long-term safety profile and low rate of thromboembolic complications. Small aneurysm size (<10 mm) was associated with complete aneurysm occlusion at 6-month angiographic follow-up. CLINICAL IMPACT: As Surpass Evolve is a newer generation Flow diverter of the Stryker Surpass FDs, with its improved design and applicability in intracranial aneurysms, we believe that more physicians will be encouraged to use this device worldwide.

A high-performance flexible humidity sensor based on a TiO2-MWCNT nanocomposite for human healthcare applications.

The present work shows the improved humidity sensing characteristics of TiO2 nanoparticles in the form of a nanocomposite with multiwalled carbon nanotubes (MWCNTs) prepared by a hydration-dehydration method. The structural and morphological characterizations of TiO2-MWCNTs confirm the nanocomposite formation without any other impurities and with an improved surface area. The pure TiO2 and nanocomposite films are deposited on IDE coated flexible poly-ethylene terephthalate (PET) substrates by a drop casting method. The nanocomposite shows improved sensitivity (1246.2 MΩ/%RH) and an ultrafast response/recovery time (2 s/1 s) with a minimal hysteresis of 0.27%RH. Further, the flexible nanocomposite sensor is tested for human healthcare applications including respiratory monitoring, apnea like situations, and skin moisture detection. The sensor can distinguish different breath patterns like normal, fast, deep and apnea like situations significantly. Skin moisture detection can also be performed using the nanocomposite sensor in a non-invasive manner. Overall, this study represents an environmentally friendly, easy to fabricate, flexible TiO2-MWCNT nanocomposite based improved humidity sensor for application in human healthcare and wearable devices.

Global 30-day morbidity and mortality of surgery for perforated peptic ulcer: GRACE study.

BACKGROUND: There is little international data on morbidity and mortality of surgery for perforated peptic ulcer (PPU). This study aimed to understand the global 30-day morbidity and mortality of patients undergoing surgery for PPU and to identify variables associated with these. METHOD: We performed an international study of adults (≥ 18 years) who underwent surgery for PPU from 1st January 2022 to 30th June 2022. Patients who were treated conservatively or had an underlying gastric cancer were excluded. Patients were divided into subgroups according to age (≤ 50 and > 50 years) and time from onset of symptoms to hospital presentation (≤ 24 and > 24 h). Univariate and Multivariate analyses were carried out to identify factors associated with higher 30-day morbidity and mortality. RESULTS:  1874 patients from 159 centres across 52 countries were included. 78.3% (n = 1467) of the patients were males and the median (IQR) age was 49 years (25). Thirty-day morbidity and mortality were 48.5% (n = 910) and 9.3% (n = 174) respectively. Median (IQR) hospital stay was 7 (5) days. Open surgery was performed in 80% (n = 1505) of the cohort. Age > 50 years [(OR = 1.7, 95% CI 1.4-2), (OR = 4.7, 95% CI 3.1-7.6)], female gender [(OR = 1.8, 95% CI 1.4-2.3), (OR = 1.9, 95% CI 1.3-2.9)], shock on admission [(OR = 2.1, 95% CI 1.7-2.7), (OR = 4.8, 95% CI 3.2-7.1)], and acute kidney injury [(OR = 2.5, 95% CI 1.9-3.2), (OR = 3.9), 95% CI 2.7-5.6)] were associated with both 30-day morbidity and mortality. Delayed presentation was associated with 30-day morbidity [OR = 1.3, 95% CI 1.1-1.6], but not mortality. CONCLUSIONS: This study showed that surgery for PPU was associated with high 30-day morbidity and mortality rate. Age, female gender, and signs of shock at presentation were associated with both 30-day morbidity and mortality.

Neurovascular considerations in patients with Down syndrome and moyamoya syndrome.

In this article, we describe a rare and complex case of moyamoya syndrome in a 7-year-old boy with Down syndrome and atlantoaxial subluxation. The patient presented with an ischemic stroke in the left hemisphere and cervical cord compression with increased cord edema. Diagnostic digital subtraction angiography revealed unique patterns of vascular involvement, with retrograde flow through the anterior spinal artery, ascending cervical artery, occipital artery, and multiple leptomeningeal arteries compensating for bilateral vertebral artery occlusion. This case underscores the underreported phenomenon of upward retrograde flow through the anterior spinal artery in bilateral vertebral artery occlusion. We address the rare manifestation of posterior circulation involvement in moyamoya syndrome, highlighting the importance of considering atlantoaxial instability as a contributing factor, as the absence of atlantoaxial stability is a risk factor for vertebral artery dissection. This study contributes valuable insights into the intricate relationship of moyamoya syndrome, Down syndrome, and atlantoaxial instability, urging clinicians to consider multifaceted approaches in diagnosis and treatment. It also emphasizes the potential significance of the anterior spinal artery as a compensatory pathway in complex vascular scenarios.

A unique anatomic variant: Left anterior choroidal artery arising proximal to fetal posterior communicating artery.

Anomalous vascular variants pose unique challenges in clinical management, especially in the context of neuroendovascular intervention. We present a case report detailing an extremely rare anatomic variant involving the left anterior choroidal artery, which arises proximal to the fetal posterior communicating artery. Our patient presented with confusion and speech abnormalities following a benzodiazepine overdose. Subsequent computed tomography of the head revealed an aneurysm originating from the left supraclinoid carotid artery. This aneurysm was located 2 mm more proximal to the origin of the left posterior communicating artery and was initially misidentified as originating from the left posterior communicating artery due to its proximity. Further diagnostic cerebral angiography revealed an extremely rare anatomical variant where the left anterior choroidal artery anomalously arose proximal to a fetal posterior communicating artery, with the aneurysm being correctly identified as arising from the left anterior choroidal artery. The patient underwent successful detoxification and has since shown remarkable improvement, with plans for elective endovascular flow diversion treatment under dual antiplatelet therapy. Considering the critical role of the anterior choroidal artery in supplying vital cerebral structures, awareness of such variants is paramount to prevent inadvertent vascular injury and optimize patient outcomes. This case highlights the necessity of meticulous pre-procedural imaging and multidisciplinary collaboration in managing neurovascular anomalies effectively.

Opiorphin: an endogenous human peptide with intriguing application in diverse range of pathologies.

Mammalian zinc ectopeptidases have significant functions in deactivating neurological and hormonal peptide signals on the cell surface. The identification of Opiorphin, a physiological inhibitor of zinc ectopeptidases that inactivate enkephalin, has revealed its strong analgesic effects in both chemical and mechanical pain models. Opiorphin achieves this by increasing the transmission of endogenous opioids, which are dependent on the body's own opioid system. The function of opiorphin is closely linked to the rat sialorphin peptide, which inhibits pain perception by enhancing the activity of naturally occurring enkephalinergic pathways that depend on µ- and δ-opioid receptors. Opiorphin is highly intriguing in terms of its physiological implications within the endogenous opioidergic pathways, particularly in its ability to regulate mood-related states and pain perception. Opiorphin can induce antidepressant-like effects by influencing the levels of naturally occurring enkephalin, which are released in response to specific physical and/or psychological stimuli. This effect is achieved through the modulation of delta-opioid receptor-dependent pathways. Furthermore, research has demonstrated that opiorphin's impact on the cardiovascular system is facilitated by the renin-angiotensin system (RAS), sympathetic ganglia, and adrenal medulla, rather than the opioid system. Hence, opiorphin shows great potential as a solitary candidate for the treatment of several illnesses such as neurodegeneration, pain, and mood disorders.

Enhancing drug bioavailability for Parkinson's disease: The promise of chitosan delivery mechanisms.

Parkinson's disease (PD) is a widely seen neurodegenerative condition recognized by misfolded α-synuclein (αSyn) protein, a prominent indicator for PD and other synucleinopathies. Motor symptoms like stiffness, akinesia, rest tremor, and postural instability coexist with nonmotor symptoms that differ from person to person in the development of PD. These symptoms arise from a progressive loss of synapses and neurons, leading to a widespread degenerative process in multiple organs. Implementing medical and surgical interventions, such as deep brain stimulation, has enhanced individuals' overall well-being and long-term survival with PD. It should be mentioned that these treatments cannot stop the condition from getting worse. The complicated structure of the brain and the existence of a semi-permeable barrier, commonly known as the BBB, have traditionally made medication delivery for the treatment of PD a challenging endeavor. The drug's low lipophilic nature, enormous size, and peculiarity for various ATP-dependent transport mechanisms hinder its ability to enter brain cells. This article delves at the potential of drug delivery systems based on chitosan (CS) to treat PD.

Radiobiological analysis of VMAT treatment plan with flattened and flattening filter free photon beam: an EUD and TCP based comparative study.

Background: This study aimed to evaluate the dosimetric and radiobiological differences between 6MV flattened filter (FF) and flattening filter free (FFF) using volumetric modulated arc (VMAT) technique for head and neck (H&N) cancer patients. Materials and methods: Fifteen patients with H&N carcinoma were selected and treated with VMAT with FF (VMATFF) treatment plan. Retrospectively, additional VMAT treatment plans were developed using FFF beams (VMATFFF). Radiobiological parameters, such as equivalent uniform dose (EUD), tumor cure probability (TCP), and normal tissue complication probability (NTCP), were calculated using Niemierko's model for both VMATFF and VMATFFF. Correlation between dosimetric and radiobiological data were analyzed and compared. Results: The conformity index (CI) was 0.975 ± 0.014 (VMATFF) and 0.964 ± 0. 019 (VMATFFF) with p ≥ 0.05. Statistically, there was an insignificant difference in the planning target volume (PTV) results for TCP (%) values, with values of 81.20 ± 0.88% (VMATFF) and 81.01 ± 0.92 (%) (VMATFF). Similarly, there was an insignificant difference in the EUD (Gy) values, which were 71.53 ± 0.33 Gy (VMATFF) and 71.46 ± 0.34 Gy (VMATFFF). The NTCP values for the spinal cord, left parotid, and right parotid were 6.54 × 10-07%, 8.04%, and 7.69%, respectively, in the case of VMATFF. For VMATFFF, the corresponding NTCP values for the spinal cord, parotids left, and parotid right were 3.09 × 10-07%, 6.57%, and 6.73%, respectively. Conclusion: The EUD and Mean Dose to PTV were strongly correlated for VMATFFF. An increased mean dose to the PTV and greater TCP were reported for the VMATFF, which can enhance the delivery of the therapeutic dose to the target.

Impaired Vibratory and Reciprocal Inhibition in Soleus H-Reflex Testing in Children With Spastic Cerebral Palsy.

Introduction Cerebral palsy (CP) is a neurodevelopmental condition that results from an injury to a developing brain. Children with CP fail to execute precise, well-coordinated movements, and excessive muscular co-contraction or co-activation is a prominent attribute of CP. The normal reciprocal relationship between agonists and antagonists during voluntary movements is altered in patients with CP. H-reflex, which is often regarded as the electrical equivalent of the spinal stretch reflex, can be used to examine the overall reflex arc, including the Ia sensory afferent strength and the spinal motoneuron excitability state. Furthermore, neuromodulatory influence of vibration on H-reflex has been found, which has been increasingly investigated to ascertain its potential use as an intervention in patients with increased spinal reflex excitability. Our goal was to identify the brain mechanism underlying the motor deficits by studying Soleus H-reflex changes during voluntary movement (dorsiflexion) and also to determine the role of vibration in H-reflex modulation in children with spastic CP. Methods Soleus H-reflex was recorded in 12 children with spastic CP (10-16 years) and 15 age-matched controls. Recordings were obtained at rest, during dorsiflexion, and during vibratory stimulation for each subject. H-responses (Hmax amplitudes and Hmax-to-Mmax ratio) were compared among the controls and the cases (CP), for the experiments performed, by the Wilcoxon signed-rank test. The recruitment curves depicting the distribution of mean H-response amplitudes with stimulus intensity increment, for dorsiflexion and vibration were compared among controls and cases by the two-sample Kolmogorov-Smirnov (KS) test. p-value <0.05 was considered as statistically significant. Results Hmax amplitudes and the Hmax-to-Mmax ratio increased (15 % and 12.2 % increment, respectively) from the resting values in the children with CP (p<0.05), while controls exhibited a decrease (reduction of 62% and 57 %, respectively) during dorsiflexion (p<0.05). Vibratory stimulation produced a decreasing trend in H-response measures in both the groups. There was about 15 % and 16 % reduction respectively among children with CP while that of 24 % and 21 % respectively among the controls. The differences in the recruitment curves (distribution of average H-response amplitudes with stimulation intensity) recorded during dorsiflexion and vibration experiments among controls compared with those with CP were found to be statistically significant by the two-sample KS test (p<0.0001). Conclusion The failure of H-reflex suppression during voluntary antagonist muscle activation suggests the presence of impaired reciprocal inhibition in spastic CP. The relatively modest H-response reduction caused by vibratory stimulation in children with CP provides limited evidence of vibratory regulation of the H-reflex in CP. More research into the mechanisms driving motor abnormalities in children with CP is needed, which could aid in therapy planning.

Biomarkers in Kidney Transplantation: A Rapidly Evolving Landscape.

The last decade has seen an explosion in clinical research focusing on the use of noninvasive biomarkers in kidney transplantation. Much of the published literature focuses on donor-derived cell-free DNA (dd-cfDNA). Although initially studied as a noninvasive means of identifying acute rejection, it is now clear that dd-cfDNA is more appropriately described as a marker of severe injury and irrespective of the etiology, elevated dd-cfDNA ≥0.5% portends worse graft outcomes. Blood gene expression profiling is also commercially available and has mostly been studied in the context of early identification of subclinical rejection, although additional data is needed to validate these findings. Torque teno virus, a ubiquitous DNA virus, has emerged as a biomarker of immunosuppression exposure as peripheral blood Torque teno virus copy numbers might mirror the intensity of host immunosuppression. Urinary chemokine tests including C-X-C motif chemokine ligand 9 and C-X-C motif chemokine ligand 10 have recently been assessed in large clinical trials and hold promising potential for early diagnosis of both subclinical and acute rejection, as well as, for long-term prognosis. Urinary cellular messenger RNA and exosome vesicular RNA based studies require additional validation. Although current data does not lend itself to conclusion, future studies on multimodality testing may reveal the utility of serial surveillance for individualization of immunosuppression and identify windows of opportunity to intervene early and before the irreversible allograft injury sets in.

Does Early Fortification of Human Milk Decrease Time to Regain Birth Weight as Compared to Late Fortification Among Preterm Infants? - A Randomized Controlled Trial.

OBJECTIVES: To compare the duration required to regain birth weight following early fortification of human milk vs. late fortification among preterm infants. METHODS: This randomized controlled trial included hemodynamically stable 120 preterm infants (≤32 wk of gestation). The intervention and comparator groups received standard fortification with human milk fortifier when enteral feeds reached 30 ml/kg/d (early fortification) and 80 ml/kg/d (late fortification) respectively. Neonates in both the groups received feed increments as per standard NICU protocol. Anthropometric measurements (weight, length, and head circumference) at birth and during postnatal follow-up were done following standard precautions and plotted on the sex-specific Fenton growth charts. Primary outcome was the mean duration required to regain birth weight. Secondary outcomes included weight gain velocity, linear growth, increase in head circumference and occurrence of sepsis, feed intolerance and necrotizing enterocolitis. RESULTS: Preterm neonates who received early fortification regained birth weight earlier compared to those in the late fortification group (10.13 ± 2.90 vs. 11.26 ± 3.06, p <0.05). The weight gain velocity, linear growth and increase in head circumference were better in the early fortification group. There was no increased risk of culture proven sepsis, feed intolerance and necrotizing enterocolitis in the early fortification group compared to late fortification. CONCLUSIONS: Standard fortification with human milk fortifier when enteral feeds reach 30 ml/kg/d helps preterm neonates regain birth weight earlier. Early fortification is well tolerated and safe for the population studied.

Cochlear Implantation in a Case of Relapsing Polychondritis With Profound Hearing Loss and Labyrinthine Ossification.

Relapsing polychondritis is an autoimmune disorder causing inflammation of cartilaginous structures, sensory epithelium, and cardiovascular system. Hearing loss is a rare and dreadful complication of this pathology. We report a case of relapsing polychondritis in a 38-year-old female who developed gradually progressive bilateral profound hearing loss. She did not have any improvement with medical management. Cochlear implantation was performed to rehabilitate her hearing. As the scala tympani was obliterated, a scala vestibuli insertion was performed. A complete insertion was possible with a compressed electrode, and she had good evoked compound action potential scores. Her categories of auditory performance scores were 6 at the end of one year. Patients with relapsing polychondritis can progress to profound hearing loss in rare cases and should be carefully followed up to identify early labyrinthine ossification. A scala vestibuli insertion can be performed with good outcomes in cases with ossification involving scala tympani. The surgeon should be ready for a middle-turn cochleostomy or a drill-out procedure in patients with advanced ossification.

"Long-term effects of center volume on transplant outcomes in adult kidney transplant recipients".

BACKGROUND: The influence of center volume on kidney transplant outcomes is a topic of ongoing debate. In this study, we employed competing risk analyses to accurately estimate the marginal probability of graft failure in the presence of competing events, such as mortality from other causes with long-term outcomes. The incorporation of immunosuppression protocols and extended follow-up offers additional insights. Our emphasis on long-term follow-up aligns with biological considerations where competing risks play a significant role. METHODS: We examined data from 219,878 adult kidney-only transplantations across 256 U.S. transplant centers (January 2001-December 2015) sourced from the Organ Procurement and Transplantation Network registry. Centers were classified into quartiles by annual volume: low (Q1 = 28), medium (Q2 = 75), medium-high (Q3 = 121), and high (Q4 = 195). Our study investigated the relationship between center volume and 5-year outcomes, focusing on graft failure and mortality. Sub-population analyses included deceased donors, living donors, diabetic recipients, those with kidney donor profile index >85%, and re-transplants from deceased donors. RESULTS: Adjusted cause-specific hazard ratios (aCHR) for Five-Year Graft Failure and Patient Death were examined by center volume, with low-volume centers as the reference standard (aCHR: 1.0). In deceased donors, medium-high and high-volume centers showed significantly lower cause-specific hazard ratios for graft failure (medium-high aCHR = 0.892, p<0.001; high aCHR = 0.953, p = 0.149) and patient death (medium-high aCHR = 0.828, p<0.001; high aCHR = 0.898, p = 0.003). Among living donors, no significant differences were found for graft failure, while a trend towards lower cause-specific hazard ratios for patient death was observed in medium-high (aCHR = 0.895, p = 0.107) and high-volume centers (aCHR = 0.88, p = 0.061). CONCLUSION: Higher center volume is associated with significantly lower cause-specific hazard ratios for graft failure and patient death in deceased donors, while a trend towards reduced cause-specific hazard ratios for patient death is observed in living donors.

Successful A2 to O Simultaneous Liver and Kidney Transplantation in the Setting of Pre-operative Positive HLA Crossmatch: A Case Report.

Simultaneous liver and kidney transplantation (SLKT) is possible for patients with high donor-specific HLA antibodies or with A2 donors to O recipients with high A2 titers. We report the first case of SLKT in a highly sensitized O recipient with organs from an A2 donor. The recipient is a 59-year-old woman with chronic kidney disease and liver failure due to autoimmune hepatitis and drug-induced liver injury. Immune work-up 8 days pre-transplant demonstrated a negative crossmatch and no HLA antibody (calculated panel reactive antibodies = 0%). Anti-A2 IgG levels were 512. The donor was a deceased 24-year-old man. One day before transplantation, serum from the recipient showed a significant increase in antibody reactivity (calculated panel reactive antibodies = 100%) attributable to blood product transfusion and memory response from previous pregnancies. Consequently, a crossmatch was positive for T and B cells with two newly detected HLA antibodies against the donor's antigens. On the day of surgery, the liver was transplanted first. Six hours and 37 minutes later, a repeat flow crossmatch was negative; donor-specific antibodies (DSAs) fell below the positive threshold, and anti-A2 IgG titer fell to 256. Thus, the kidney was transplanted after basiliximab induction therapy. Seven days post-transplant, non-donor-specific HLA antibodies were present but DSAs remain negative. The patient was discharged on postoperative day 57 with no signs of rejection at 4 months. This case illustrates a rapid and prolonged reduction in antibody titers (HLA and ABO) after SLKT. SLKT is feasible in patients with both DSA and high anti-A2 titer.