How can the EU support sustainable innovation and access to effective antibiotics? Policy options for existing and new medicines

Antimicrobial and particularly antibiotic resistance is one of the biggest public health challenges the world faces. Over 1 million years of life are lost each year in the European Union (EU)/European Economic Area (EEA) alone due to antibiotic resistance, and it costs healthcare systems about €1.1 billion annually. These health and economic impacts are expected to worsen. Urgent steps are needed and this policy brief focuses on one area where the EU and its Member States can take effective action, fostering sustainable innovation and improving access to effective antibiotics:1. Scientific, economic, structural and regulatory ‘barriers’ continue to limit the development of novel antibiotics with innovative characteristics despite intensified international efforts.2. Reinvigorating the antibiotic pipeline requires a holistic package of incentives.3. Ensuring timely access to new and existing antibiotics is critical.4. Improving access to effective antibiotics requires both short- and longer-term measures.5. The EU has a major role to play both in combatting antimicrobial resistance (AMR) and in contributing to global solutions.

Toxicity of Refugio Beach Oil to Sand Crabs (Emerita analoga), Blue Mussels (Mytilus sp.), and Inland Silversides (Menidia beryllina).

Monterey formation crude oil spilled from an onshore pipeline and entered the surf zone near Refugio State Beach, Santa Barbara County, California (USA) on 19 May 2015. During this season, early life stages of many marine fish and invertebrates were present. Surf zone water and beach porewater samples were collected during the 4 mo after the spill and 2 yr later for chemical analyses. Elevated polycyclic aromatic hydrocarbon (PAH) and total petroleum hydrocarbon concentrations were observed in surf zone water and porewater near the release point, declining with distance and time. Early life stage toxicity was investigated by conducting 6- and 7-d static renewal bioassays with sand crab (Emerita analoga) post larvae (megalopae) and inland silverside larvae (Menidia beryllina), respectively, and a 48-h blue mussel (Mytilus sp.) embryo development bioassay. Dilutions of a high-energy water accommodated fraction of the Refugio Beach oil and a seawater control were prepared to simulate surf zone PAH concentrations (nominal PAH45 ; 0, 0.5, 1, 5, 10, 50, 100, and 500 µg/L). The PAH45 median lethal concentrations (LC50s), based on measured concentrations, were 381 µg/L for Mytilus sp., 75.6 µg/L for Menidia, and 40.9 µg/L for Emerita. Our results suggest that PAH concentrations in coastal waters of the spill-affected area were potentially lethal to early life stages of fish and invertebrates. Environ Toxicol Chem 2021;40:2578-2586. © 2021 SETAC.

Suicide prevention, public health, and the chiropractic profession: a call to action.

BACKGROUND: Suicide is a major public health concern that has wide-reaching implications on individuals, families, and society. Efforts to respond to a public health concern as a portal-of-entry provider can reduce morbidity and mortality of patients. The objective of this commentary is a call to action to initiate dialogue regarding suicide prevention and the role the chiropractic profession may play. DISCUSSION: This public health burden requires doctors of chiropractic to realize current strengths and recognize contemporaneous deficiencies in clinical, research, and policy environments. With this better understanding, only then can the chiropractic profession strive to enhance knowledge and promote clinical acumen to target and mitigate suicide risk to better serve the public. CONCLUSION: We implore the profession to transition from bystander to actively engaged in the culture of suicide prevention beholden to all aspects of the biopsychosocial healthcare model. The chiropractic profession's participation in suicide prevention improves the health and wellness of one's community while also impacting the broader public health arena.

Disulfiram causes selective hypoxic cancer cell toxicity and radio-chemo-sensitization via redox cycling of copper.

Therapies for lung cancer patients initially elicit desirable responses, but the presence of hypoxia and drug resistant cells within tumors ultimately lead to treatment failure. Disulfiram (DSF) is an FDA approved, copper chelating agent that can target oxidative metabolic frailties in cancer vs. normal cells and be repurposed as an adjuvant to cancer therapy. Clonogenic survival assays showed that DSF (50-150 nM) combined with physiological levels of Cu (15 µM CuSO4) was selectively toxic to H292 NSCLC cells vs. normal human bronchial epithelial cells (HBEC). Furthermore, cancer cell toxicity was exacerbated at 1% O2, relative to 4 or 21% O2. This selective toxicity of DSF/Cu was associated with differential Cu ionophore capabilities. DSF/Cu treatment caused a >20-fold increase in cellular Cu in NSCLCs, with nearly two-fold higher Cu present in NSCLCs vs. HBECs and in cancer cells at 1% O2vs. 21% O2. DSF toxicity was shown to be dependent on the retention of Cu as well as oxidative stress mechanisms, including the production of superoxide, peroxide, lipid peroxidation, and mitochondrial damage. DSF was also shown to selectively (relative to HBECs) enhance radiation and chemotherapy-induced NSCLC killing and reduce radiation and chemotherapy resistance in hypoxia. Finally, DSF decreased xenograft tumor growth in vivo when combined with radiation and carboplatin. These results support the hypothesis that DSF could be a promising adjuvant to enhance cancer therapy based on its apparent ability to selectively target fundamental differences in cancer cell oxidative metabolism.

Structured Curriculum to Improve Pediatric Resident Confidence and Skills in Providing Parenting Advice.

CONTEXT: Residents receive little parenting education despite its potential to improve parenting behavior and decrease child maltreatment despite the inclusion of parenting content on board certification examinations. Teaching residents how to discuss parenting and foster positive parent-child relationships is essential to treating the whole person in osteopathic pediatric medicine. OBJECTIVE: To improve pediatric and internal medicine-pediatric residents' knowledge, confidence, and skills in providing parenting advice. METHODS: Four toddler parenting and discipline modules were developed. During continuity clinic, residents viewed and discussed modules with faculty. Residents completed a confidence and knowledge questionnaire before and after the curriculum, provided a self-report of use of skills learned, and completed a feasibility survey. Faculty also completed a feasibility survey. RESULTS: Forty-one of 61 residents (67%) participated in the study. Before participation, the median (interquartile range [IQR]) resident score for confidence in giving advice was 6.0 (4.0-7.0) (on a 10-point scale), increasing to 7.0 (6.0-8.0) for those completing 1 to 3 modules and 8.0 (8.0-9.0) for those completing 4 modules. Median (IQR) score on board-style questions was 8.0 (7.0-9.0) (on a 12-point scale) before participating in the modules and 8.5 (7.5-9.5) for those completing 1 to 3 modules and 9.0 (7.0-9.0) for those completing 4 modules after participation; the increase was not statistically significant. Nine faculty and 29 residents completed the modules and responded to the exit survey regarding feasibility and acceptability of the curriculum. On a 4-point scale (4 being excellent), sessions had an overall mean (SD) rating of 3.7 (0.5) by faculty and 3.5 (0.5) by residents. Most residents (27 [93.1%]) reported interest in more modules, and 28 residents (96.6%) reported using information learned from the modules during clinic visits. CONCLUSION: Confidence delivering parenting advice increased among residents who completed the curriculum modules. Faculty and residents reported high feasibility ratings, and residents endorsed application of skills during clinic visits and interest in more modules.

Post-infectious ankylosis of the cervical spine in an army veteran: a case report.

Background: Vertebral osteomyelitis is a rare, life-threatening condition. Successful management is dependent on prompt diagnosis and management with intravenous antibiotic therapy or surgery in addition to antibiotics. Reoccurrence is minimal after 1 year. However, very little is reported in the conservative spine literature regarding the long-term follow-up and the changes to the spine following management of the spinal infection. We report the dramatic radiologic findings of the long-term sequela of a cervical spine infection following a gunshot wound from 1969. Most impressive to the spine specialist is this patient's ability to return to work despite significant alterations to spinal biomechanics. Case presentation: A 69 year-old caucasian male presented to the chiropractic clinic at a Veterans Affairs Medical Center with complaint of chronic left shoulder pain secondary to an associated full thickness tear of the left infraspinatus. An associated regional assessment of the cervical spine ensued. Radiological imaging on file revealed ankylosis C2/C3 to C7/T1. The patient reported a history of multiple fragment wounds in 1969 to the left anterior neck and shoulder 45 years earlier. Osteomyelitis of the cervical spine resulted from the wounds. Conclusion: Potential sequela of osteomyelitis is ankylosis of affected joints. In this particular case, imaging provides evidence of regional ankylosis of the cervical spine. Considering the patient did not complain of cervical pain or related symptoms apart from lack of cervical range of motion, and his Neck Disability Index score was 2 out of 50 (4%), no intervention was provided to the cervical spine. The patient reported he self-managed well, worked full-time as a postal worker after he was discharged due to the injury to his neck, and planned to retire in less than one month at age 70. The patient demonstrates successful return to work with pending retirement at age 70 following spondylodiscitis and subsequent ankylosis of the cervical region.

Thoracic Spondylodiscitis Epidural Abscess in an Afebrile Navy Veteran: A Case Report.

OBJECTIVE: The purpose of this case study was to describe the differential diagnosis of a thoracic epidural abscess in a Navy veteran who presented to a chiropractic clinic for evaluation and management with acupuncture within a Veterans Affairs Medical Center. CLINICAL FEATURES: An afebrile 59-year-old man with acute thoracic spine pain and chronic low back pain presented to the chiropractic clinic at a Veterans Affairs Medical Center for consideration for acupuncture treatment. INTERVENTION AND OUTCOME: The veteran elected to trial acupuncture once per week for 4 weeks. A routine thoracic magnetic resonance imaging scan without gadolinium detected a space-occupying lesion after the patient failed to attain 50% reduction of pain within 2 weeks with conservative care. The patient was diagnosed with a multilevel thoracic spondylodiscitis epidural abscess and was treated same day with emergency debridement and laminectomy of T7-8 with a T6-9 fusion. The patient had complete recovery without neurological compromise and completed an antibiotic regimen for 6 weeks. CONCLUSION: A Navy veteran with acute thoracic spine and chronic low back pain appeared to respond initially but failed to achieve clinically meaningful outcomes. Follow-up advanced imaging detected a thoracic spondylodiscitis epidural abscess. Early diagnosis and immediate intervention are important to preserving neurological function and limiting morbidity in cases of spondylodiscitis epidural abscess.

The Fluorocycline TP-271 Is Efficacious in Models of Aerosolized Bacillus anthracis Infection in BALB/c Mice and Cynomolgus Macaques.

The fluorocycline TP-271 was evaluated in mouse and nonhuman primate (NHP) models of inhalational anthrax. BALB/c mice were exposed by nose-only aerosol to Bacillus anthracis Ames spores at a level of 18 to 88 lethal doses sufficient to kill 50% of exposed individuals (LD50). When 21 days of once-daily dosing was initiated at 24 h postchallenge (the postexposure prophylaxis [PEP] study), the rates of survival for the groups treated with TP-271 at 3, 6, 12, and 18 mg/kg of body weight were 90%, 95%, 95%, and 84%, respectively. When 21 days of dosing was initiated at 48 h postchallenge (the treatment [Tx] study), the rates of survival for the groups treated with TP-271 at 6, 12, and 18 mg/kg TP-271 were 100%, 91%, and 81%, respectively. No deaths of TP-271-treated mice occurred during the 39-day posttreatment observation period. In the NHP model, cynomolgus macaques received an average dose of 197 LD50 of B. anthracis Ames spore equivalents using a head-only inhalation exposure chamber, and once-daily treatment of 1 mg/kg TP-271 lasting for 14 or 21 days was initiated within 3 h of detection of protective antigen (PA) in the blood. No (0/8) animals in the vehicle control-treated group survived, whereas all 8 infected macaques treated for 21 days and 4 of 6 macaques in the 14-day treatment group survived to the end of the study (56 days postchallenge). All survivors developed toxin-neutralizing and anti-PA IgG antibodies, indicating an immunologic response. On the basis of the results obtained with the mouse and NHP models, TP-271 shows promise as a countermeasure for the treatment of inhalational anthrax.

The Fluorocycline TP-271 Is Efficacious in Models of Aerosolized Francisella tularensis SCHU S4 Infection in BALB/c Mice and Cynomolgus Macaques.

TP-271 is a novel, fully synthetic fluorocycline in development for complicated bacterial respiratory infections. TP-271 was active in vitro against a panel of 29 Francisella tularensis isolates, showing MICs against 50% and 90% of isolates of 0.25 and 0.5 µg/ml, respectively. In a mouse model of inhalational tularemia, animals were exposed by aerosol to 91 to 283 50% lethal doses (LD50)/mouse of F. tularensis SCHU S4. Following 21 days of once-daily intraperitoneal dosing with TP-271 at 3, 6, 12, and 18 mg/kg of body weight/day, initiating at 24 h postchallenge, survival was 80%, 100%, 100%, and 100%, respectively. When treatment was initiated at 72 h postchallenge, survival was 89%, 100%, 100%, and 100% in the 3-, 6-, 12-, and 18-mg/kg/day TP-271 groups, respectively. No mice treated with the vehicle control survived. Surviving mice treated with TP-271 showed little to no relapse during 14 days posttreatment. In a nonhuman primate model of inhalational tularemia, cynomolgus macaques received an average aerosol exposure of 1,144 CFU of F. tularensis SCHU S4. Once-daily intravenous infusion with 1 or 3 mg/kg TP-271, or vehicle control, for 21 days was initiated within 6 h of confirmed fever. All animals treated with TP-271 survived to the end of the study, with no relapse during 14 days after the last treatment, whereas no vehicle control-treated animals survived. The protection and low relapse afforded by TP-271 treatment in these studies support continued investigation of TP-271 for use in the event of aerosolized exposure to F. tularensis.

Voices of the "99 Percent": The Role of Online Narrative to Improve Health Care.

CONTEXT: Communal blogs facilitate online narratives by providing opportunities for individuals to co-construct meaning and to engage in discussion about lived health experiences. OBJECTIVE: To examine the role of health as a connective narrative among individuals organizing collectively in an online community. The "We are the 99 percent" Tumblr blog emerged as a spontaneous community platform of the Occupy Wall Street movement in the US. DESIGN: Researchers conducted a qualitative content analysis of a total of 2003 blog posts. MAIN OUTCOME MEASURES: Data analysis included a process of data reduction, display, and conclusion drawing and verification. RESULTS: Bloggers discussed medical crises and the role of injury and illness in maintaining financial solvency. The difficulty of obtaining health care and the lack of accessible quality care emerged as themes. In particular, unemployment and underemployment limited access to health insurance coverage. The bloggers expressed dissatisfaction with the health care system and the impact of financial status on health. These challenges were exacerbated for marginalized populations, such as women and veterans. CONCLUSION: Findings offer implications for the value of online narrative to improve health care initiatives and to provide insight to integrated health care systems, including health care practitioners, nonprofit organizations, hospitals, and policy makers. Results suggest opportunities to address the health care gaps of marginalized populations and to develop public health policy.

Transcriptional Analysis of Resistance to Low Temperatures in Bermudagrass Crown Tissues.

Bermudagrass (Cynodon dactylon L pers.) is one of the most geographically adapted and utilized of the warm-season grasses. However, bermudagrass adaptation to the Northern USA is limited by freeze damage and winterkill. Our study provides the first large-scale analyses of gene expression in bermudagrass regenerative crown tissues during cold acclimation. We compared gene expression patterns in crown tissues from highly cold tolerant "MSU" and susceptible "Zebra" genotypes exposed to near-freezing temperatures. Suppressive subtractive hybridization was used to isolate putative cold responsive genes Approximately, 3845 transcript sequences enriched for cold acclimation were deposited in the GenBank. A total of 4589 ESTs (3184 unigenes) including 744 ESTs associated with the bermudagrass disease spring dead spot were printed on microarrays and hybridized with cold acclimated complementary Deoxyribonucleic acid (cDNA). A total of 587 differentially expressed unigenes were identified in this study. Of these only 97 (17%) showed significant NCBI matches. The overall expression pattern revealed 40% more down- than up-regulated genes, which was particularly enhanced in MSU compared to Zebra. Among the up-regulated genes 68% were uniquely expressed in MSU (36%) or Zebra (32%). Among the down-regulated genes 40% were unique to MSU, while only 15% to Zebra. Overall expression intensity was significantly higher in MSU than in Zebra (p value ≤ 0.001) and the overall number of genes expressed at 28 days was 2.7 fold greater than at 2 days. These changes in expression patterns reflect the strong genotypic and temporal response to cold temperatures. Additionally, differentially expressed genes from this study can be utilized for developing molecular markers in bermudagrass and other warm season grasses for enhancing cold hardiness.

Acupuncture performed before and after embryo transfer: a randomized controlled trial.

OBJECTIVE: To compare the clinical pregnancy rates in women who underwent fresh embryo transfer (ET) with and without one acupuncture session before and after the transfer using a modified Paulus protocol. STUDY DESIGN: The prospective, physician-blinded study randomized 113 women to either no intervention (n = 56) or acupuncture performed off-site (n = 57). Secondary outcomes were positive pregnancy test and live birth rates. Intent-to-treat analysis and per protocol analysis were performed. RESULTS: No difference in age and in vitro fertilization-embryo transfer (IVF-ET) parameters were detected. Compared to the control group, the treatment group had a lower pregnancy rate (43.6% vs. 64.8%, p = 0.045). More women in the control group had live births than did those in the acupuncture group (56.0% vs. 36.0%, respectively, p = 0.033). Generalized mixed models revealed that patients who received acupuncture had lower odds of clinical pregnancy than those who did not undergo acupuncture treatment (OR = 0.42, 95% CI 0.19-0.93). CONCLUSION: Our study found that acupuncture performed off-site on the day of ET was detrimental to the success of the transfer. More research is needed with a greater number of subjects to elucidate the role of acupuncture before and after ET, ideal treatment frequency, and to further explore the role of individualized acupuncture treatment on IVF-ET pregnancy rates.

The use of an integrated electroanatomic mapping system and intracardiac echocardiography to reduce radiation exposure in children and young adults undergoing ablation of supraventricular tachycardia.

AIMS: Non-fluoroscopic imaging (NFI) devices are increasingly used in ablations. The objective was to determine the utility of intracardiac echocardiography (ICE) in ablating paediatric supraventricular tachycardias (SVTs) and assess whether its integrated use with electroanatomic mapping (EAM) resulted in lower radiation exposure than use of EAM alone. METHODS AND RESULTS: Prospective, controlled, single-centre study of patients (pts) age ≥10 years, weight ≥35 kg, with SVT and normal cardiac anatomy. Patients were randomized to ICE + EAM (ICE) or EAM only (no ICE). Both had access to fluoroscopy as needed. Eighty-four pts were enroled (42 ICE, 42 no ICE). Median age was 15 years (range 10.4-23.7 years); 57% had accessory pathways, 42% atrioventricular nodal reentry tachycardia. There was no difference in radiation dose (9 mGy ICE vs. 23 mGy no ICE, P = 0.37) or fluoroscopy time (1.1 min ICE vs. 1.5 min no ICE, P = 0.38). Transseptal punctures were performed in 25 pts (16 ICE, 9 no ICE), with ICE reducing radiation (8 mGy ICE vs. 62 mGy no ICE, P = 0.002) and fluoroscopy time (1.1 min ICE vs. 4.5 min no ICE, P = 0.01). Zero fluoroscopy was achieved in 13 pts (15% of total, 5 ICE, 8 no ICE), and low-dose cases (<50 mGy) in 57 pts (68% of total, 33 ICE, 24 no ICE). Acute success was 95% for ICE, 88% for no ICE. CONCLUSION: Use of an integrated EAM/ICE system was no better than EAM alone in limiting radiation, but can be helpful for transseptal punctures. Given the low dose savings, use of ICE may be weighed against its financial cost. Low-fluoroscopy cases are performed in most NFI procedures.

Evaluation of a novel translational task for assessing emotional biases in different species.

Changes in the processing of emotional information are key features of affective disorders. Neuropsychological tests based on emotional faces or words are used to detect emotional/affective biases in humans, but these tests are not applicable to animal species. In the present study, we investigated whether a novel affective tone discrimination task (ATDT), developed to study emotion-related behaviour in rats, could also be used to quantify changes in affective states in humans. To date, the methods used in human neuropsychology have not been applicable to animal experiments. Participants completed a training session in which they learnt to discriminate specific tone frequencies and to correctly respond in order to gain emotionally valenced outcomes, to obtain rewards (money), or to avoid punishment (an aversive sound clip). During a subsequent test session, additional ambiguous probe tones were presented at frequencies intermediate between the reward and avoidance paired tones. At the end of the task, participants completed self-report questionnaires. All participants made more avoidance responses to the most ambiguous tone cues, suggesting a bias towards avoidance of punishment. Individual differences in the degrees of bias observed were correlated with anxiety measures, suggesting the task's sensitivity to differences in state anxiety within a healthy population. Further studies in clinical populations will be necessary to assess the task's sensitivity to pathological anxiety states. These data suggest that this affective tone discrimination task provides a novel method to study cognitive affective biases in different species, including humans, and offers a novel assessment to study anxiety.

Frequency and evolution of Azole resistance in Aspergillus fumigatus associated with treatment failure.

Azoles are the mainstay of oral therapy for aspergillosis. Azole resistance in Aspergillus has been reported infrequently. The first resistant isolate was detected in 1999 in Manchester, UK. In a clinical collection of 519 A. fumigatus isolates, the frequency of itraconazole resistance was 5%, a significant increase since 2004 (p<0.001). Of the 34 itraconazole-resistant isolates we studied, 65% (22) were cross-resistant to voriconazole and 74% (25) were cross-resistant to posaconazole. Thirteen of 14 evaluable patients in our study had prior azole exposure; 8 infections failed therapy (progressed), and 5 failed to improve (remained stable). Eighteen amino acid alterations were found in the target enzyme, Cyp51A, 4 of which were novel. A population genetic analysis of microsatellites showed the existence of resistant mutants that evolved from originally susceptible strains, different cyp51A mutations in the same strain, and microalterations in microsatellite repeat number. Azole resistance in A. fumigatus is an emerging problem and may develop during azole therapy.

Valorization of olive mill wastewater by its incorporation in building bricks.

This investigation deals with the possibility of incorporating the effluent resulting from olive oil extraction activity, known as olive oil mill wastewater (OMW), in the brick-making process. It was undertaken at an important Tunisian brickworks company. In this study, the OMW was mixed with clays following the same brick-making procedure used at the collaborative brickworks in Tunisia. The samples containing OMW were found to be comparable in forming/extrusion performance to a control product that used fresh water. The experimental products produced were tested for their comparative physical properties (volume shrinkage, water absorption, tensile strength of bricks, after firing at 920 degrees C and paste plasticity) in the unfired and fired states against a control representing the commercial product in the same factory. The results showed a significant increase in the volume shrinkage (10%) and the water absorption (12%), while the tensile strength remained constant. The maximum plasticity index value was found when incorporating 23% of OMW. This rate either maintained the physical and mechanical properties of bricks or improved them. The incorporation of OMW in bricks can represent a promising way to valorize this effluent, to rid the environment of a highly polluting wastewater and to save huge and precious amounts of water in a country where water shortage is a serious problem. This newly-prepared material has a double positive impact: it protects the environment and allows water economy.

Influence of aging on phosphorus sorption to alum floc in lake water.

Alum is often added to eutrophic lakes to limit the release of phosphorus from sediments. This study quantified the effect of age and extent of crystallization on the phosphate (PO4-P) sorption capacity of alum floc. Aluminum hydroxide flocs were formed from alum addition at a dose of 25 mg/L of Al3+ to Big Bear Lake waters returned to the laboratory; flocs were then aged for 4, 20, 50, 120, and 180 days in the treated lake waters. The physical and mineralogical properties of the alum floc were characterized using surface area and thermal analyses. Phosphate sorption to the floc was evaluated using filtered lake water and NaCl/NaHCO3 solutions spiked with PO4-P concentrations ranging from 0 to 100 mg/L. The Langmuir model provided reasonable fits to data (r2 = 0.97-1.00), from which sorption constants and sorption maxima were determined. Phosphate sorption decreased with increased floc age and crystallinity and decreased surface area. Phosphate sorption maximum of the alum floc aged for 6 months was about 50% lower than freshly precipitated floc, while the binding constant, Kads, decreased approximately 65% over this same time period.

Intraoperative blood salvage during cesarean delivery in a patient with beta thalassemia intermedia.

UNLABELLED: In this case report, we report a patient with a placenta accreta and thalassemia intermedia undergoing cesarean delivery. There are no data regarding the use of cell salvage in patients with thalassemia. During the course of her surgery, she lost approximately 9000 mL of blood. Of this blood, 2250 mL of concentrated red cells were collected, washed, and returned to the patient. During processing, increased hemolysis was noted in the effluent line of the cell salvage machine, which resolved by increasing the wash volume. The patient's postoperative course was uneventful. This case would suggest that cell salvage in patients with thalassemia can be performed safely; however, further study is warranted. IMPLICATIONS: This case report details the safe administration of cell salvage in a patient with beta thalassemia undergoing cesarean delivery. Cell salvage is the collection, washing, and re-administration of blood lost during surgery. This process has not been previously reported in a patient with this type of blood disease.

Auditory stimulus optimization with feedback from fuzzy clustering of neuronal responses.

The primary focus of this paper was to develop a high-performance computer system for optimizing auditory stimuli based on neuronal feedback. Using the Algorithm Of Pattern EXtraction (ALOPEX) extra-cellular action potentials (APs) recorded from frog (Rana Pipiens) auditory neurons were used as feedback to optimize sound stimuli. This computer-based system works in real time to iteratively find the neuron's best excitatory frequency (BEF). Three programmable (positive and negative) threshold logic levels are used to collect 300 APs in response to normalized pure tones. Fuzzy logic is then used to separate up to five fuzzy centers (templates) from the 300 APs. The fuzzy centers are used for on-line fuzzy mapping of future responses. The five fuzzy centers allow the system to monitor up to five neighboring neurons. To study the auditory neurons of the frog, one, two, and three simultaneous tones are used as the stimulus for optimization of the best combination of frequencies. Testing with the response calculated as a parabolic function of a single best frequency demonstrated system dynamics and reliability for up to nine simultaneous tones. Experiments using one pure tone and ten stimulus presentations per iteration showed that the automated system is able to repeatedly converge to the best frequency within 100 iterations. Studies using one, two, and then three pure tones played simultaneously on the same group of neurons has shown that these tones converged on the same best frequencies by properly mixing the tones available to produce the optimal complex sound.