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Thirteen patients were studied after jejunoileal bypass (JIB) surgery. Seven developed arthritis and six did not. Circulating immune complexes containing IgG and IgA were detected in the sera of patients with and without arthritis. IgA complexes were shown to contain secretory component, a protein predominantly associated with intraluminal IgA, in significantly higher levels in patients with arthritis. Analytical ultracentrifugation showed complexes of approximately 10 X 8S, consistent with the size of secretory IgA. Arthritis after JIB appears to be associated with circulating immune complexes containing secretory IgA. [ABSTRACT FROM PUBLISHER]

An entrapping conflict is characterized by individuals' tendencies to make increasing commitments to a failing course of action. For example, a car owner has spent hundreds of dollars to fix the car's transmission, brakes, tires, and shocks, and must now decide whether to spend more on body work. Another example: having lost thousands of lives in Vietnam, the United States government must decide whether to continue military involvement. Organizational decision makers may become entrapped in such a situation, for example, the employee who has been trained at great expense, and still fails to meet expectations; this is the 'knee deep in the Big Muddy' dilemma.

Background: The national response to COVID-19 has had a significant impact on cancer services. This study investigated the effect of national lockdown on diagnosis, management, and outcomes of patients with oesophagogastric cancers in Scotland., Methods: This retrospective cohort study included consecutive new patients presenting to regional oesophagogastric cancer multidisciplinary teams in National Health Service Scotland between October 2019 and September 2020. The study interval was divided into before and after lockdown, based on the first UK national lockdown. Electronic health records were reviewed and results compared., Results: Some 958 patients with biopsy-proven oesophagogastric cancer in 3 cancer networks were included: 506 (52.8 per cent) before and 452 (47.2 per cent) after lockdown. Median age was 72 (range 25-95) years and 630 patients (65.7 per cent) were men. There were 693 oesophageal (72.3 per cent) and 265 gastric (27.7 per cent) cancers. Median time to gastroscopy was 15 (range 0-337) days before versus 19 (0-261) days after lockdown (P < 0.001). Patients were more likely to present as an emergency after lockdown (8.5 per cent before versus 12.4 per cent after lockdown; P = 0.005), had poorer Eastern Cooperative Oncology group performance status, were more symptomatic, and presented with a higher stage of disease (stage IV: 49.8 per cent before versus 58.8 per cent after lockdown; P = 0.04). There was a shift to treatment with non-curative intent (64.6 per cent before versus 77.4 per cent after lockdown; P < 0.001). Median overall survival was 9.9 (95 per cent c.i. 8.7 to 11.4) months before and 6.9 (5.9 to 8.3) months after lockdown (HR 1.26, 95 per cent c.i. 1.09 to 1.46; P = 0.002)., Conclusion: This national study has highlighted the adverse impact of COVID-19 on oesophagogastric cancer outcomes in Scotland. Patients presented with more advanced disease and a shift towards treatment with non-curative intent was observed, with a subsequent negative impact on overall survival., (© The Author(s) 2023. Published by Oxford University Press on behalf of BJS Society Ltd.)

Sickle cell disease and β-thalassemia are common monogenic disorders that cause significant morbidity and mortality globally. The only curative treatment currently is allogeneic hematopoietic stem cell transplantation, which is unavailable to many patients due to a lack of matched donors and carries risks including graft-versus-host disease. Genome editing therapies targeting either the BCL11A erythroid enhancer or the HBG promoter are already demonstrating success in reinducing fetal hemoglobin. However, where a single locus is targeted, reliably achieving levels high enough to deliver an effective cure remains a challenge. We investigated the application of a CRISPR/Cas9 multiplex genome editing approach, in which both the BCL11A erythroid enhancer and HBG promoter are disrupted within human hematopoietic stem cells. We demonstrate superior fetal hemoglobin reinduction with this dual-editing approach without compromising engraftment or lineage differentiation potential of edited cells post-xenotransplantation. However, multiplex editing consistently resulted in the generation of chromosomal rearrangement events that persisted in vivo following transplantation into immunodeficient mice. The risk of oncogenic events resulting from such translocations therefore currently prohibits its clinical translation, but it is anticipated that, in the future, alternative editing platforms will help alleviate this risk., Competing Interests: H.P.K. has received support as the inaugural recipient of the José Carreras/E. Donnall Thomas Endowed Chair for Cancer Research and the Stephanus Family Endowed Chair for Cell and Gene Therapy. H.P.K is or was a consultant to and has or had ownership interests with Rocket Pharmaceuticals, Homology Medicines, VOR Biopharma, and Ensoma. H.P.K has also been a consultant to CSL and Magenta. Other authors have no competing interests., (© 2021 The Authors.)

AMD3100 (plerixafor) is a vital component of many clinical and preclinical transplant protocols, facilitating harvest of hematopoietic stem and progenitor cells through mobilization into the peripheral blood circulation. Repeat mobilization with AMD3100 is also necessary for many patients with suboptimal first stem cell collection or those requiring repeat transplantation. In this study we investigated the mobilization efficacy of repeated AMD3100 dosages in the nonhuman primate and humanized mouse models. In nonhuman primates, we observed effective mobilization after the first AMD3100 administration but a significantly poorer response in CD34 + and hematopoietic stem cell-enriched CD90 + cells with subsequent doses of the drug. A similar loss of efficacy with repeated administration was noted in immunodeficient mice engrafted with human CD34 + cells, in whom the total human white cell population, and particularly human hematopoietic stem and progenitor cells, mobilized significantly less effectively following a second AMD3100 administration when compared with the first dose. Together, our results are expected to inform future mobilization protocols for the purposes of peripheral blood hematopoietic stem cell extraction or for applications in which hematopoietic stem cells must be made accessible for in vivo-delivered gene targeting agents., Competing Interests: Conflicts of interest disclosure Stefan Radtke is now consulting for Forty Seven Inc. (Gilead Sciences) and Ensoma Inc. HPK is consulting for Rocket Pharma, Homology Medicines, CSL Behring, Vor Biopharma, and Magenta Therapeutics. The other authors have no competing interests., (Copyright © 2020 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Genome editing therapies represent a significant advancement in next-generation, precision medicine for the management of haematological diseases, and CRISPR/Cas9 has to date been the most successful implementation platform. From discovery in bacteria and archaea over three decades ago, through intensive basic research and pre-clinical development phases involving the modification of therapeutically relevant cell types, CRISPR/Cas9 genome editing is now being investigated in ongoing clinic trials. Despite the widespread enthusiasm brought by this new technology, significant challenges remain before genome editing can be routinely recommended and implemented in the clinic. These include risks of genotoxicity resulting from off-target DNA cleavage or chromosomal rearrangement, and suboptimal efficacy of homology-directed repair editing strategies, which thus limit therapeutic options. Practical hurdles such as high costs and inaccessibility to patients outside specialised centres must also be addressed. Future improvements in this rapidly developing field should circumvent current limitations with novel editing platforms and with the simplification of clinical protocols using in vivo delivery of editing reagents., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Reactivation of fetal hemoglobin (HbF) is being pursued as a treatment strategy for hemoglobinopathies. Here, we evaluated the therapeutic potential of hematopoietic stem and progenitor cells (HSPCs) edited with the CRISPR-Cas9 nuclease platform to recapitulate naturally occurring mutations identified in individuals who express increased amounts of HbF, a condition known as hereditary persistence of HbF. CRISPR-Cas9 treatment and transplantation of HSPCs purified on the basis of surface expression of the CD34 receptor in a nonhuman primate (NHP) autologous transplantation model resulted in up to 30% engraftment of gene-edited cells for >1 year. Edited cells effectively and stably reactivated HbF, as evidenced by up to 18% HbF-expressing erythrocytes in peripheral blood. Similar results were obtained by editing highly enriched stem cells, defined by the markers CD34 + CD90 + CD45RA - , allowing for a 10-fold reduction in the number of transplanted target cells, thus considerably reducing the need for editing reagents. The frequency of engrafted, gene-edited cells persisting in vivo using this approach may be sufficient to ameliorate the phenotype for a number of genetic diseases., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Objective: To assess impact of a topical decontamination regimen on rates of catheter-related bloodstream infections (CRBSI) in intensively-treated haematology patients., Methods: A historically-controlled cohort study was used to evaluate the effect of applying chlorhexidine or Octenisan® body washes and nasal Prontoderm® ointment for 5 days around the time of Hickman line insertion on the incidence of CRBSI and infection-free catheter time. Lines inserted during a 24 month period prior to implementation of the decolonisation regimen were compared with those inserted during a 12 month period after the intervention was applied., Results: During the post-intervention period, 163 lines were inserted in 147 patients, compared to 303 lines in 242 patients in the pre-intervention period. CRBSI rates in treated and untreated patients respectively were 6.8 and 35.0 cases per 10,000 line-days by 21 days (p = 0.009), and 14.4 and 26.0 cases respectively per 10,000 line-days by 180 days (p = 0.025). The incidence rate of Staphylococcus aureus CRBSI in treated and untreated patients were 0.0 and 4.6 cases per 10,000 line-days respectively (p = 0.012). Multivariable Cox regression estimated an 81% probability (95% confidence interval 74%-85%) that a treated line develops a CRBSI later than an untreated line by 21 days post-insertion., Conclusion: Implementation of this safe and effective topical decontamination regimen enhances routine CRBSI-prevention measures for haematology patients requiring central venous line insertion., (Copyright © 2017 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Objectives: Modern management of myeloma has significantly improved survival, with increasing numbers of patients living beyond a decade. However, little is known about the long-term cardiovascular and respiratory status of intensively treated and multiply relapsed survivors., Methods: We performed detailed cardiovascular and respiratory evaluations in patients with intensively treated, advanced but stable myeloma. All patients had received at least two lines of treatment, including at least one haematopoietic stem cell transplantation procedure, but had stable, controlled disease and were off active treatment at the time of evaluation., Results: Thirty-two patients with a median duration of 6 years (range 2-12) from original diagnosis of myeloma and three lines (range 2-6) of treatment were evaluated. Despite normal physical examination in the majority, there was a high prevalence of sub-clinical cardiac and respiratory dysfunction, reflected by abnormalities of electrocardiography (45%), echocardiography (50%), serum N-terminal pro-B-type natriuretic peptide level (NT-pro-BNP, 50%), and pulmonary function testing (45%). NT-pro-BNP level correlated negatively with quality of life (P = 0.012) and positively with serum ferritin (P = 0.027). Dyspnoea score correlated with BMI (P = 0.001). Risk factors for cardiovascular disease (obesity, hypertension, hyperlipidaemia, and hyperinsulinaemia) were common., Discussion: Even in the absence of overt clinical features, the majority of intensively treated long-term survivors of myeloma have established cardiovascular and/or respiratory dysfunction, above levels expected in the general population of a similar age., Conclusion: This study supports routine screening and lifestyle modification combined with primary and secondary preventive strategies to reduce cardiovascular and respiratory disease and to preserve quality of life in transplanted myeloma patients.

Pillar implants provide a reasonable outcome with minimal post-operative morbidity and complications in treating patients with sleep-disordered breathing (SDB) who had obvious palatal obstruction. The palatal structure is responsible for a normal functioning Eustachian tube; however, little is known if there is any potential otologic implication of minimally invasive palatal stiffening surgery for SDB. The aim of this study is to evaluate the effects of Pillar implantation on middle ear function. We performed a prospective study in a tertiary referral center. Thirty SDB patients (25 men, 5 women; mean age, 44.3 years) who underwent Pillar implants for treating palatal obstruction were enrolled. The subjects had normal otologic exam and no previous history of chronic ear disease. Pure-tone audiometry and tympanometry were performed pre-operatively, and post-operative days 1 and 7, and months 1 and 3. Baseline and post-operative middle ear pressures (MEPs) in decipascals were compared. Statistical analysis was performed by repeated measures of ANOVA. Eight patients (8/30, 26.7%) reported otologic complaints such as ear pressure and/or otalgia within 1 week post-operatively. No permanent otologic discomfort occurred. A trend toward reduced MEP was noted in this study. The decrease in MEP became apparent on post-operative day 1 after surgery. However, mean pressure changes were no longer significantly different from pre-operative values by 1 week after surgery. Pillar implantation for SDB induces changes in middle ear function. However, the changes were temporary and not significant 1 week after surgery.

Objective: Insulin resistance (IR), which is common in women with polycystic ovarian syndrome (PCOS), may adversely affect the outcome of ovulation induction due to its detrimental effect on ovarian function. The aim of this study was to evaluate the impact of IR on the outcome of laparoscopic ovarian diathermy (LOD)., Design: Prospective observational study., Setting: Tertiary fertility centre., Population: Forty-four anovulatory women with PCOS undergoing LOD., Methods: Fasting serum concentrations of insulin and glucose were measured before and after LOD. Insulin sensitivity was determined using the homeostasis model assessment (HOMA) index. Values of HOMA index ≥2.1 were considered abnormal, indicating IR., Main Outcome Measures: Ovulation and pregnancy rates were compared between women with and without IR using χ(2) test and odds ratio (OR) with 95% confidence interval (CI)., Results: Eighteen women (41%) had elevated HOMA index (≥2.1). There was no change of HOMA index after LOD (median 1.89, range 0.53-8.48 vs. 1.92, range 0.53-8.46). The ovulation rate in women with IR (12 of 18, 67%) was significantly (p=0.013, OR 0.08; 95% CI 0.01-0.74) lower than that (25 of 26, 96%) of women without IR. Likewise, the pregnancy rate (six of 18, 33%) was significantly (p=0.037, OR 0.26; 95% CI 0.07-0.94) lower in women with IR than that of women without IR (17 of 26, 65%). Using a receiver operating characteristics curve, the HOMA index was useful in predicting no ovulation after LOD (area under the curve 0.826)., Conclusions: Insulin resistance appears to have an adverse effect on the outcome of LOD and seems to be a useful prognostic factor., (© 2011 The Authors Acta Obstetricia et Gynecologica Scandinavica© 2011 Nordic Federation of Societies of Obstetrics and Gynecology.)

Background: PHACE syndrome describes a spectrum of anomalies associated with large facial infantile hemangiomas and characterized by posterior fossa malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. With improved recognition and imaging practices of infants with PHACE syndrome, additional associations have been identified. To our knowledge, the potential association of ipsilateral hearing loss and PHACE syndrome has not been previously emphasized., Observations: We describe 6 patients, 4 with definite and 2 with probable PHACE syndrome, according to the new diagnostic criteria, and associated auditory deficiencies. One patient had isolated conductive hearing loss; 2 patients had isolated sensorineural hearing loss; 1 patient had mixed hearing loss (both conductive and sensorineural components); and 1 patient had hearing loss that was inconclusive at the time. Also, 1 patient had conductive loss and auditory neuropathy and auditory dyssynchrony. Four of the 6 patients had magnetic resonance imaging features of lesions consistent with intracranial hemangiomas involving auditory structures. All 6 patients had facial hemangiomas in a nearly identical distribution ipsilateral to the ear with the hearing loss, with involvement of the proposed facial segments S1 and S3, the affected ear, the periauricular region, and the midoccipital area of the scalp., Conclusions: There is an underrecognized risk of hearing loss in patients with PHACE syndrome, although the exact nature of such deficiencies can vary. Patients with PHACE syndrome who have cutaneous hemangiomas involving the ear should be evaluated for intracranial hemangiomas and monitored for hearing loss. Early detection and therapy of intracranial hemangiomas may slow or stop tumor growth, resultant hearing loss, and structural damage.

Objective: To characterize speech perception performance in elderly cochlear implant users compared with younger adult users., Design: Case-control retrospective analysis from January 1, 1999, to January 28, 2008., Setting: Tertiary care, academic practice cochlear implant program., Patients: Medical records for 78 patients with age at implantation of 65 years or older were analyzed for ear-specific preimplantation speech perception performance, length of deafness, age at implantation, and 1-year postimplantation speech perception performance. A subset of 28 elderly patients with complete data was matched to 28 younger adult patients (age at implantation, 18-64 years) for preimplantation performance using the Hearing in Noise Test-Quiet scores (mean, 22% and 23%, respectively)., Main Outcome Measure: One-year postimplantation performance on word and sentence testing., Results: Within the elderly cohort, the Consonant-Nucleus-Consonant and Hearing in Noise Test-Quiet scores were not affected by age. The Hearing in Noise Test-Noise scores trended downward with increasing age but did not reach statistical significance (P = .052). Of the matched older and younger patients, 55 of 56 showed improvement in their 1-year postimplantation compared with preimplantation Hearing in Noise Test-Quiet scores, with better preimplantation performance predictive of better postimplantation performance, independent of age at implantation (P = .02). Group comparisons, however, revealed poorer postimplantation scores overall for the elderly patients compared with the younger ones for the Hearing in Noise Test-Quiet (70% vs 83%; P = .02) and the Consonant-Nucleus-Consonant test (38% vs 53%; P = .02)., Conclusions: Elderly patients benefit significantly from cochlear implantation. Compared with a younger cohort matched for preimplantation performance, however, their postimplantation scores are significantly lower on some measures. These results may provide guidelines for candidacy and counseling regarding elderly patients with cochlear implants.

We present the case of an 8-year-old girl with chronic idiopathic thrombocytopenic purpura (ITP) and a short history suggestive of raised intracranial pressure. Urgent computed tomography scan of the head showed a large bleed into a left cerebellar lesion. She underwent treatment with intravenous immunoglobulin (IVIg) and steroids to increase her platelet count, followed by excision of the lesion, which was found to be a benign pilocytic astrocytoma. The patient made a complete recovery and shortly afterwards underwent splenectomy, following which there was complete resolution of her thrombocytopenia.

Recent advances in cochlear implant technology have focused renewed attention on the preservation of residual hearing. The focus on preservation of residual hearing is driven by the concept of electroacoustic stimulation. This option depends on the insertion of a short cochlear implant electrode into the basal region of the cochlea while preserving native function in the apical region. The desire to preserve residual hearing has led to the development of the soft-surgery cochlear implantation technique. Here, the authors evaluate its various components. Avoiding entry of blood into the cochlea and the use of hyaluronate seem to be reasonably supported, whereas the use of topical steroids is unlikely to be beneficial. The site of entry into the cochlea, the use of contoured or straight devices, and the depth of insertion are also evaluated. The authors highlight the importance of systematic recording of outcomes and surgical events.

In the present study we investigated whether allogeneic glioma cells can be utilized to evoke prophylactic or therapeutic immune-mediated elimination of syngeneic glioma in two rat strains. Fisher 344 and Sprague-Dawley (SD) rats were injected with two syngeneic glioma cell lines, 9L and C6, respectively, resulting in progressive tumor growth. 9L is syngeneic to the Fisher 344 and allogeneic to the SD rats, while C6 cells are syngeneic to SD rats and allogeneic to Fisher 344 rats. Both rat strains were subcutaneously injected with their respective allogeneic tumor cells, which proved unable to grow progressively. The allogeneic cells were either rejected immediately in SD rats or within 25 days in Fisher rats, after limited tumor outgrowth. Both rat strains were subsequently challenged with their respective syngeneic glioma tumor cells and once more 10 days later with a fivefold higher dose. SD rats, even after reinjection with five times the original dosage of C6 cells, remained tumor free for at least 360 days. Similarly, Fisher rats, after initially rejecting allogeneic tumors, failed to develop syngeneic tumors. To determine anti-tumor immunity against established glioma tumors under more demanding therapeutic conditions, rats were first injected subcutaneously with their respective syngeneic tumor and vaccinated once or repeatedly (at 5-day intervals) with a mixture of the allogeneic or xenogeneic cells, with or without a lysate from the same syngeneic tumor, which served as a therapeutic vaccine preparations. The control group received either no treatment or syngeneic instead of allogeneic cells. In both strains of rats, we demonstrated that the therapeutically vaccinated groups were able to significantly reduce tumor growth, while complete rejection of tumors was noted in the SD rats. Immunization with syngeneic tumor cells alone failed to evoke anti-tumor immunity. We conclude that therapeutic immunization with a combination of allogeneic cells and syngeneic lysates induces rejection of malignant gliomas and offers a protective effect against challenge with syngeneic tumor cells. This immunization approach may prove useful as a post-surgery adjuvant therapy in future cancer treatment protocols, or even as a stand-alone therapeutic tumor vaccination.

Objectives: To investigate the feasibility and safety of an implantable epidural cortical stimulator for the treatment of severe tinnitus., Study Design: Prospective, controlled, single-blinded study of cortical stimulation for 4 weeks, and then an open-label stimulation period., Setting: Tertiary care referral center., Patients: Adults (n = 8) with constant tinnitus of at least 1 year with a tinnitus reaction questionnaire score greater than 33. Tinnitus was predominantly unilateral with a frequency less than 8,000 Hz., Interventions: Surgical implantation of an investigational epidural electrode over the posterior superior temporal gyrus using functional magnetic resonance imaging targeting. A 2-week stimulation period alternated with a 2-week sham period in random order to which subjects were blinded. This was followed by continuous stimulation with parameter adjustments to maximize tinnitus suppression., Main Outcome Measure: Subjective rating of tinnitus severity, loudness, and device efficacy. Objective measures of hearing thresholds, tinnitus frequency, loudness, and minimum masking levels. Outcome measures using the Tinnitus Handicap Questionnaire, Tinnitus Reaction Questionnaire, and Beck Depression Inventory., Results: There were no effects of stimulation during the 4-week blinded period. With continuous chronic stimulation, 2 patients had persistent reduction of pure-tone tinnitus, and 6 patients had short periods of total tinnitus suppression. Significant improvements in the Beck Depression Inventory and tinnitus questionnaires were found, although objective measures of tinnitus loudness remained fairly stable. No surgical or stimulation-related complications were noted., Conclusion: Chronic electrical stimulation of the secondary auditory cortex seems safe and warrants further investigation as a potential therapeutic intervention for the suppression of tinnitus.

Charge-balanced, biphasic stimulus pulses are commonly used in implantable cochlear prostheses as they can be safely delivered to living tissue. However, monophasic stimuli are more efficient (i.e. producing lower thresholds) and likely provide more spatially selective excitation of nerve fibers. We examined the neural responses to monophasic, 'pseudomonophasic', and biphasic stimuli to better understand the inherent tradeoffs of these stimuli. Using guinea pig and cat animal models, we compared the auditory nerve responses to both 40 micros monophasic and 40 micros/phase biphasic stimuli using both electrically evoked compound action potential and single-fiber recordings. We also made comparisons using a computational model of the feline auditory nerve fiber. In all cases, our stimuli were cathodic monophasic and cathodic-first biphasic pulses. As expected, monophasic stimuli provided lower thresholds relative to biphasic stimuli. They also evoked responses with relatively longer latencies. We also examined responses to charge-balanced biphasic pulses composed of two phases of differing duration (i.e. pseudomonophasic stimuli). The first phase was fixed at 40 micros, while the second phase was systematically varied from 40 to 4000 micros. With a relatively long second phase, we hypothesized that these stimuli would provide some of the beneficial features of monophasic stimuli. Both the gross-potential and single-fiber data confirmed this and indicate that the largest incremental effects of changing the second-phase duration occur for durations less than 500 micros. Consideration of single-fiber data and computer simulations suggest that these results are consistent with the neural membrane acting as a leaky integrator. The computer simulations also suggest that the integrative properties at least partially account for the difference between our monophasic-biphasic results and previously published data. Our results apply to cathodic-leading stimuli; due to differing patterns of membrane depolarization, they may not be applicable to situations using anodic-leading stimuli. Finally, we observed differences between the guinea pig and cat response patterns. Compared to cats, guinea pigs produced smaller monophasic vs. biphasic threshold differences. This interspecies disparity may be due to differences in cochlear anatomy.