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Telemedicine and remote monitoring are rapidly gaining momentum in health care, including in-home and postdischarge monitoring. However, remote monitoring for telemedicine teams and receiving medical centers is yet to reach emergency medical services. When transporting a critically ill patient, continuous vital sign monitoring may be helpful to enhance receiving center collaboration and change care delivery before arrival when necessary. Our primary objective was to demonstrate successful transmission and reception of real-time physiologic summary data to a hospital base station during ambulance transport using a low-energy Bluetooth wireless wearable device linked to iridium satellite communications. We completed our proof-of-concept study on 2 simulated ground ambulance transports and 1 helicopter flight in rural areas surrounding Rochester, Minnesota. Each simulated transport used Mayo Clinic–developed wearable devices paired one-to-one with a physiologic communication kit. Electrocardiographic and photoplethysmographic waveforms were processed on the wearables every 5 minutes, with vital sign data generated and transmitted to an iridium satellite and relayed to a base station network–protected computer and mobile application with real-time display of summary and location. Data and geolocation were tracked in real time with a mobile application during the simulated transport, and summary data packets were saved on Mayo Clinic servers. During the 3 simulated rural transports, all (n=7; 100%) wearables successfully captured, recorded, and transmitted raw waveform physiologic signals. All devices transmitted successfully via the iridium satellite to the base station network–protected computer and mobile application. In all, 106 (69%) of 154 transmissions were successfully processed. Our project demonstrated successful remote monitoring of physiologic vital signs during transport in rural, low–cellular signal areas. The use of live remote monitoring should be explored to understand its utility in practice and outcomes.

Herein we report that the ventralis oralis anterior and posterior (Voa/Vop) nuclei of the thalamus may be effective alternative targets for deep brain stimulation (DBS) to improve posttraumatic dystonia when the globus pallidus interna is traumatically damaged. This patient presented at age 35 years with a clinical diagnosis of posttraumatic cervical and bilateral upper limb acquired dystonia resulting from intracerebral and intraventricular hemorrhage after a motorcycle accident at age 19 years. Due to a right globus pallidus interna traumatic lesion, conventional DBS targeting of the inferior basal ganglia was not possible; thus, the alternative Voa/Vop nuclei target was implanted. The patient realized significant benefit and at last follow-up 3 years postoperatively continued to endorse marked benefit and improvement of dystonia symptoms with minimal adverse effects from bilateral DBS implantation in the alternative targets of the Voa/Vop nuclei of the thalamus.

Since its approval in treating a number of movement disorders, magnetic resonance imaging–guided focused ultrasound (MRgFUS) has been adopted rapidly as one of the standard treatment modalities internationally. However, the efficiency of the energy delivered by the ultrasonic waves is largely determined by the highly variable bone morphology and density characteristics of the skull. One of the widely accepted indices used to facilitate patient selection is the skull density ratio (SDR). Earlier literature suggested that an SDR of less than 0.4 would be unfavorable for MRgFUS treatment. Some prior studies have excluded patients with hyperostosis. However, there is little published data regarding the impact of other skull features such as hyperostosis on treatment success. We present the case of a 66-year-old man with medically refractory essential tremor who had an SDR of 0.38 and extensive hyperostosis frontalis interna and underwent attempted MRgFUS thalamotomy treatment. However, intraoperatively the treatment was unsuccessful in generating sufficiently elevated temperature to create a lesion of the usual desired volume, and as expected, there was minimal clinical improvement. For comparison, we also summarize a case series of 4 other patients with an SDR of less than 0.4 who had successful outcomes. We believe that SDR should not be used as the only means of selecting patients for MRgFUS. Instead, important factors such as hyperostosis should be taken into consideration for patient selection and pretreatment counseling.

Summary: Background: Despite declines in deaths from rheumatic heart disease (RHD) in Africa over the past 30 years, it remains a major cause of cardiovascular morbidity and mortality on the continent. We present an investment case for interventions to prevent and manage RHD in the African Union (AU). Methods: We created a cohort state-transition model to estimate key outcomes in the disease process, including cases of pharyngitis from group A streptococcus, episodes of acute rheumatic fever (ARF), cases of RHD, heart failure, and deaths. With this model, we estimated the impact of scaling up interventions using estimates of effect sizes from published studies. We estimated the cost to scale up coverage of interventions and summarised the benefits by monetising health gains estimated in the model using a full income approach. Costs and benefits were compared using the benefit–cost ratio and the net benefits with discounted costs and benefits. Findings: Operationally achievable levels of scale-up of interventions along the disease spectrum, including primary prevention, secondary prevention, platforms for management of heart failure, and heart valve surgery could avert 74 000 (UI 50 000–104 000) deaths from RHD and ARF from 2021 to 2030 in the AU, reaching a 30·7% (21·6–39·0) reduction in the age-standardised death rate from RHD in 2030, compared with no increase in coverage of interventions. The estimated benefit–cost ratio for plausible scale-up of secondary prevention and secondary and tertiary care interventions was 4·7 (2·9–6·3) with a net benefit of $2·8 billion (1·6–3·9; 2019 US$) through 2030. The estimated benefit–cost ratio for primary prevention scale-up was low to 2030 (0·2,

Introduction: Intradural lumbar disc herniation (ILDH) is a very rare pathological entity. The pathomechanisms and the natural course remain unclear. Case presentation: The authors present the case of a 58-year-old Germans male with repetitive microdiscectomies (MD) and intraoperative missed diagnosis of ILDH. The patient underwent standard MD due to lumbar disc herniation (LDH) at the level L4/5. Incidental durotomy (ID) was sealed with a ventromedial patch. Postoperative course was uneventful. 14 months later the patient presented with a L4 radiculopathy, having his second MD at the level L3/4. At this point the radiological images showed already a free floating intradural fragment at the level S1, clinically not significant. As in the previous surgery, the postoperative course was uneventful. After 18 months, he presented again complaining of low back pain and electric-like attacks of pain along the right L5 root for the prior five months. Contrast-MRI revealed that the known intradural disc-mass migrated from S1 to the level L4/5. A left L4 hemilaminectomy was performed. The durotomy identified a hard, white, shiny mass. The patient was pain-free until the last follow-up at 13 months. Conclusions: Intraoperative manipulation of disc fragments in the presence of an ID potentially leads to iatrogenic ILDH.

The online coupling of size exclusion chromatography (SEC) to capillary enhanced Raman spectroscopy (CERS) based on a liquid core waveguide (LCW) flow cell was applied for the first time to assess the higher-order structure of different proteins. This setup allows recording of Raman spectra of the monomeric protein within complex mixtures, since SEC enables the separation of the monomeric protein from matrix components such as excipients of a biopharmaceutical product and higher molecular weight species (e.g., aggregates). The acquired Raman spectra were used for structural elucidation of well characterized proteins such as bovine serum albumin, hen egg white lysozyme, and β-lactoglobulin and of the monoclonal antibody rituximab in a medicinal product. Additionally, the CERS detection of the disaccharide sucrose, which is used as a stabilizing excipient, was quantified to achieve a limit of detection (LOD) of 120 μg and a limit of quantification (LOQ) of 363 μg injected on the column.

Objective: In multiple myeloma patients, daratumumab is preferably injected subcutaneously. The summary of product characteristics of daratumumab subcutaneous injection solution specifies physicochemical stability for the prepared syringe for 24 hours at 2-8°C protected from light, and another 12 hours at room temperature (15-25°C) in ambient light conditions. The aim of this study was to determine the in-use stability of ready-to-administer daratumumab subcutaneous injection solution in different types of syringe and different conditions over a 28-day period., Methods: Daratumumab subcutaneous (DARZALEX 1800 mg) injection solution was withdrawn into disposable three-piece Luer-Lock syringes (20 mL, 50 mL), capped, and stored light protected at 2-8°C or at room temperature (22±2°C) over a maximum period of 28 days. Samples were taken immediately after preparation (day 0) and after 2, 7, 14, 21, and 28 days. Physicochemical stability was determined by ion-exchange high-performance liquid chromatography (IE-HPLC) and size-exclusion high-performance liquid chromatography (SE-HPLC) with ultraviolet detection, pH measurement and visual inspection for particles or colour changes., Results: In the IE-HPLC assay, peak areas and peak-to-peak area ratios remained unchanged over the whole study period, and showed no additional peaks of degraded daratumumab charge variants. In the SE-HPLC assay, neither a formation of aggregates nor of fragments was detected. Daratumumab monomer concentrations exceeded 95% of the initially measured concentrations over the entire test period. pH values remained constant. Test solutions remained clear, and no colour changes or visible particles were detected. All results were independent of storage conditions., Conclusion: Daratumumab subcutaneous injection solution proved to be physicochemically stable in capped three-piece plastic syringes for at least 28 days when stored light protected at 2-8°C or at room temperature (22±2°C). For microbiological reasons aseptic preparation and refrigerated storage are recommended. In-use stability of ready-to-administer daratumumab subcutaneous syringes prepared under appropriate aseptic conditions is given for 28 days., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Deliberate underdosing occurred in personalized preparations of drugs such as monoclonal antibodies as the active pharmaceutical ingredient in the past. To ensure the required quality standard and to prevent future fraud attempts at an early stage, a HPLC-DAD-HRMS method was established. Thereby, identity and quantity of the active ingredients bevacizumab, rituximab and trastuzumab were determined. The analysis of ten samples from seven pharmacies fulfilled the quality criteria and were therefore not objectionable., Competing Interests: Declaration of Competing Interest The authors declare they have no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Modern therapy strategies are based on patient-specific treatment where the drug and dose are optimally adapted to the patient's needs. In recent drugs, monoclonal antibodies (mAbs) are increasingly used as active ingredients. Their patient-specific formulations are not part of the pharmaceutical industry's manufacturing process but are prepared from concentrates by pharmaceutical personnel. During the manufacturing process, however, active pharmaceutical ingredients are released in trace amounts or, in the case of accidents and spills, also in high concentrations. Regardless of the source of entry, mAbs can become airborne, be inhaled, and cause undesirable side-effects such as sensitization. To assess the risk for pharmaceutical personnel, a personal air sampling method was developed and validated for bevacizumab, cetuximab, daratumumab, omalizumab, rituximab and trastuzumab. The method is based on the combination of high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). The analytical method achieves a limit of detection of 0.30-8.8 ng mL -1 , recoveries of 83-96 % (intra-day assay) and 75-89 % (inter-day assay), with no detectable carry-over. A polycarbonate filter proved suitable for sampling airborne monoclonal antibodies, as it achieved 80-104 % recovery across all mAbs. It also showed concentration-independent desorption efficiency. The sampling duration can be up to 480 min without negatively affecting the recovery. MAbs are stable on the polycarbonate filter at 5 °C for 3 days (recovery: 94 % ± 5 %) and at - 20 °C for 14 days (recovery: 97 % ± 4 %). Our method demonstrated that there is a potential for release when handling monoclonal antibodies. However, this can be reduced below the limit of detection by using pressure equalization systems (spikes)., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Thorsten Teutenberg reports financial support was provided by Federal Ministry for Economic Affairs and Climate Action., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Due to the complex manufacturing process of therapeutic monoclonal antibodies, it is hardly possible to produce an identical copy of the original product (originator). Consequently, follow-on products (biosimilars) must demonstrate their efficacy being similar to the originator in terms of structure and function. During this process, a variety of analytical methods are required for this purpose. This study focuses on three particularly relevant analytical techniques: high-resolution mass spectrometry, fragment crystallisable (Fc) affinity chromatography, and two-dimensional peptide mapping. Each analytical method proved able to identify specific differences between originator and biosimilar. High-resolution mass spectrometry was used to characterize the glycan pattern. It was shown that a trastuzumab biosimilar did not have the G0:G0F sugar modification identified in the originator. The application of affinity chromatography to rituximab showed that originator and biosimilar interacted differently with the immobilized Fc receptor. Furthermore, 2D-HPLC peptide mapping demonstrated the influence of orthogonality of separation dimensions, leading to differentiation of a rituximab originator and biosimilar., (© 2022. Springer-Verlag GmbH Germany, part of Springer Nature.)

Complete characterization and quantification of monoclonal antibodies often rely on enzymatic digestion with trypsin. In order to accelerate and automate this frequently performed sample preparation step, immobilized enzyme reactors (IMER) compatible with standard HPLC systems were used. This allows an automated online approach in all analytical laboratories. We were able to demonstrate that the required digestion time for the model monoclonal antibody rituximab could be reduced to 20 min. Nevertheless, a previous denaturation of the protein is required, which also needs 20 min. Recoveries were determined at various concentrations and were 100% ± 1% at 100 ng on column, 96% ± 7% at 250 ng on column and 98% ± 2% at 450 ng on column. Despite these good recoveries, complete digestion was not achieved, resulting in a poorer limit of quantification. This is 50 ng on column under optimized IMER conditions, whereas an offline digest on the same system achieved 0.3 ng on column. Furthermore, our work revealed that TRIS buffers, when used with an IMER system, led to alteration of the peptides and induced modifications in the peptides. Therefore, the addition of TRIS should be avoided when working at elevated temperatures of about 60 °C. Nevertheless, our results have shown that the recovery is not significantly influenced whether TRIS is used or not (recovery: 96 ± 7% with TRIS vs. 100 ± 9% without TRIS)., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

We investigated the impact of peroxyacetic acid (PAA; 200 ppm) spray on the microbiota and shelf life of commercial, vacuum-packed beef stored at chiller temperatures. Ribeye cuts ( n  = 147) were collected from a local beef plant on the day of production for two consecutive days, with one set collected at the start of work with the PAA spray nozzles turned off (control) and during routine production with the PAA spray nozzles turned on (PAA) each day. Packs were stored at 4, 2, and -1°C for up to 34, 104, and 180 days and sampled at appropriate intervals for sensory assessment, microbial enumeration, and microbial profiling by 16S rRNA gene amplicon analysis. Treatment with PAA did not affect the initial meat pH, the initial numbers of total aerobes, lactic acid bacteria, or Enterobacteriaceae ( P > 0.05) before storage; however, it delayed the onset of spoilage by 7, 21, and 54 days at 4, 2, and -1°C, respectively. Square-root models of the variation of growth rate with temperature indicated lactic acid bacteria grew faster and Enterobacteriaceae grew slower on PAA-treated than on untreated meat. Negative associations between pH and deterioration of meat during storage were observed for PAA-treated meat. During storage, the microbiota were primarily dominated by Carnobacterium and Lactobacillus / Lactococcus on control meat but by Leuconostoc on PAA-treated meat. Serratia , Yersinia , and Clostridium were identified by linear discriminant effect size analysis as biomarkers for control meat; Clostridium was found in high abundance in samples that had the highest spoilage scores. IMPORTANCE The findings of this study show that PAA solutions applied at low concentrations under commercial settings positively modulated the meat microbiota. It did not have bactericidal effects for beef subprimals with very low microbial loads. However, it differentially impacted the members of the microbiota, which resulted in delayed onset of spoilage of vacuum-packed beef subprimal stored at all three temperatures (4, 2, and -1°C). This differential impact could be through one or a combination of the following factors: favoring the growth of lactic acid bacteria, which may in turn exert a competitive exclusion that might be due to production of antimicrobial compounds such as organic acids and bacteriocins; exerting synergistic antimicrobial effects with low temperatures against members of Enterobacteriaceae ; and direct or indirect inhibitory effects against members of the clostridia. These findings not only advance our understanding of the microbial ecology of vacuum-packed meat stored at chiller temperatures but also suggest that bacteriostatic concentrations of antimicrobial interventions can be explored for shelf-life extension., (© Crown copyright 2021.)

The drugs used for treatment during chemotherapy are manufactured individually for each patient in specialised pharmacies. Thorough quality control to confirm the identity of the delivered active pharmaceutical ingredient and the final concentration of the prepared application solution is not standardized yet except for optical or gravimetric testing. However, solution stability problems, counterfeit drugs, and erroneous or deliberate underdosage may occur and negatively influence the quality of the product and could cause severe health risks for the patient. To take a step towards analytical quality control, an on-site analytical instrument using Raman and UV absorption spectroscopy was employed and the results were compared to high-performance liquid chromatography coupled to diode array detection. Within the scope of the technology evaluation, the uncertainty of measurement was determined for the analysis of the five frequently used cytostatic drugs 5-fluorouracil, cyclophosphamide, gemcitabine, irinotecan and paclitaxel. The Raman/UV technique (2.0-3.2% uncertainty of measurement; level of confidence: 95%) achieves a combined uncertainty of measurement comparable to HPLC-DAD (1.7-3.2% uncertainty of measurement; level of confidence: 95%) for the substances 5-fluorouracil, cyclophosphamide and gemcitabine. However, the uncertainty of measurement for the substances irinotecan and paclitaxel is three times higher when the Raman/UV technique is used. This is due to the fact that the Raman/UV technique analyses the undiluted sample; therefore, the sample has a higher viscosity and tendency to foam. Out of 136 patient-specific preparations analysed within this study, 96% had a deviation of less than 10% from the target content.

Monoclonal antibodies are a group of commonly used therapeutics, whose occupational health risk is still discussed controversially. The long-term low-dose exposure side effects are insufficiently evaluated; hence, discussions are often based on a theoretical level or extrapolating side effects from therapeutic dosages. While some research groups recommend applying the precautionary principle for monoclonal antibodies, others consider the exposure risk too low for measures taken towards occupational health and safety. However, both groups agree that airborne monoclonal antibodies have the biggest risk potential. Therefore, we developed a peptide-based analytical method for occupational exposure monitoring of airborne monoclonal antibodies. The method will allow collecting data about the occupational exposure to monoclonal antibodies. Thus, the mean daily intake for personnel in pharmacies and the pharmaceutical industry can be determined for the first time and will help to substantiate the risk assessment by relevant data. The introduced monitoring method includes air sampling, sample preparation and detection by liquid chromatography coupled with high-resolution mass spectrometry of individual monoclonal antibodies as well as sum parameter. For method development and validation, a chimeric (rituximab), humanised (trastuzumab) and a fully humanised (daratumumab) monoclonal antibody are used. A limit of detection between 1 μg per sample for daratumumab and 25 μg per sample for the collective peptide is achieved. Graphical abstract Demonstration of the analytical workflow, from the release of monoclonal antibodies to the detection as single substances as well as sum parameter.

A national survey was conducted in Canada to determine consumer cooking practices for minute steaks (thin, mechanically tenderized beef cutlets). Results indicate that most Canadians prefer cooking minute steaks by pan frying and to a medium level of doneness. To identify safe cooking conditions, retail minute steaks (∼125 g), inoculated at three sites per steak with a five-strain cocktail of nontoxigenic Escherichia coli O157:H7 (6.1 log CFU per site), were cooked on a hot plate (200°C), mimicking a pan-frying scenario. The steaks (n = 5) were cooked for 4, 6, 8, or 10 min with turning over (flipping) up to four times at equal time intervals; or to 63 or 71°C at the thickest area with or without a tinfoil lid. When cooked for 4 min, E. coli O157:H7 was recovered from all inoculation sites, and the mean reductions at various sites (1.2 to 3.4 log CFU per site) were not different (P > 0.05), irrespective of the flipping frequency. When cooked for 6 min with flipping once or twice, or for 8 min with flipping once, E. coli O157:H7 was recovered from most sites; the mean reductions (3.8 to 5.3 log CFU per site) were not different (P > 0.05), but they were higher (P < 0.05) than those for steaks cooked for 4 min. When cooked for 10, 8, or 6 min with flipping once, twice, or three times, respectively, E. coli O157:H7 was eliminated from most sites, but sites with <5-log reductions were found. Reductions of E. coli O157:H7 by >5 log at all inoculation sites were attained when the steaks were cooked for 10 or 8 min with two or more or three or more flippings, respectively, or for 6 min with four flippings. When flipped twice during cooking to 63 or 71°C, E. coli O157:H7 was recovered from three or fewer sites; however, >5-log reductions throughout the steaks were only attained for the latter temperature, irrespective of whether the hot plate was covered with the tinfoil lid. Thus, turning over minute steaks twice during cooking to 71°C or flipping two, three, or four times with a cooking time of 10, 8, or 6 min could achieve 5-log reductions throughout the steaks.

Blood, liver, kidney, lymph nodes and muscle tissue were obtained from the carcasses of five cows with advanced Johne's disease. Samples from the raw tissues, from cooked muscle tissues and from cooked hamburger patties that contained chopped mesenteric lymph nodes were collected aseptically. Each sample was divided into two portions, one of which was decontaminated. Both portions were homogenized. Homogenates were spread on selective agar for the recovery of Mycobacterium avium subsp. paratuberculosis (Map) and inoculated into a Map growth medium with the organism being detected in the cultures by PCR procedures and Ziehl-Neelsen staining. Map were recovered at numbers > 10(3) cfu/g from 7 of 15 liver and mesenteric and ileocaecal lymph node samples; and at lesser numbers from 5 of 15 kidney and superficial inguinal and prescapular lymph node samples. The numbers recovered from decontaminated and not decontaminated portions of each sample were generally similar. Map was recovered from 1 and detected in 6 of 50 not decontaminated portions of samples of raw, chilled or frozen meat; and detected in 1 of 15 not decontaminated samples of meat cooked to 61 degrees C, and in 1 of 40 samples of meat cooked to >/=70 degrees C. Map was detected in 2 of 4 samples of mesenteric lymph nodes cooked to 61 degrees C, but not in samples cooked to > or =70 degrees C. The findings indicate that Map may be present in meat from infected animals at low numbers, but that any such organisms are likely to be inactivated when meat is cooked to a well done condition., (2009 Elsevier B.V. All rights reserved.)