Point-of-care diagnostics for infection and antimicrobial resistance in sub-Saharan Africa: A narrative review.

OBJECTIVES: Sub-Saharan African (SSA) countries are severely impacted by antimicrobial resistance (AMR). Due to gaps in access to diagnostics in SSA, the true extent of AMR remains unknown. This diagnostic gap affects patient management and leads to significant antimicrobial overuse. This review explores how point-of-care (POC) testing for pathogen identification and AMR may be used to close the diagnostic gap in SSA countries. METHODS: A narrative review exploring current clinical practice and novel developments in the field of POC testing for infectious diseases and AMR. RESULTS: POC assays for identification of various pathogens have been successfully rolled out in SSA countries. While implementation studies have mostly highlighted impressive test performance of POC assays, there is limited data on the impact of implementation on clinical outcomes and cost-effectiveness. We did not encounter local studies of host-directed POC assays relevant to AMR. Novel POC assays using real-time polymerase chain reaction, isothermal amplification, microfluidics, and other technologies are in various stages of development. CONCLUSIONS: Available literature shows that POC testing for AMR applications is implementable in SSA and holds the potential to reduce the diagnostic gap. Implementation will require effective regulatory pathways, incorporation of POC testing in clinical and laboratory guidelines, and adequate value capture in existing health financing models.

Study protocol for a randomized, controlled, multicentre, pragmatic trial with Rehabkompassen®-a digital structured follow-up tool for facilitating patient-tailored rehabilitation in persons after stroke.

BACKGROUND: Stroke is a leading cause of disability among adults worldwide. A timely structured follow-up tool to identify patients' rehabilitation needs and develop patient-tailored rehabilitation regimens to decrease disability is largely lacking in current stroke care. The overall purpose of this study is to evaluate the effectiveness of a novel digital follow-up tool, Rehabkompassen®, among persons discharged from acute care settings after a stroke. METHODS: This multicentre, parallel, open-label, two-arm pragmatic randomized controlled trial with an allocation ratio of 1:1 will be conducted in Sweden. A total of 1106 adult stroke patients will have follow-up visits in usual care settings at 3 and 12 months after stroke onset. At the 3-month follow-up, participants will have a usual outpatient visit without (control group, n = 553) or with (intervention group, n = 553) the Rehabkompassen® tool. All participants will receive the intervention at the 12-month follow-up visit. Feedback from the end-users (patient and health care practitioners) will be collected after the visits. The primary outcomes will be the patients' independence and social participation at the 12-month visits. Secondary outcomes will include end-users' satisfaction, barriers and facilitators for adopting the instrument, other stroke impacts, health-related quality of life and the cost-effectiveness of the instrument, calculated by incremental cost per quality-adjusted life year (QALY). DISCUSSION: The outcomes of this trial will inform clinical practice and health care policy on the role of the Rehabkompassen® digital follow-up tool in the post-acute continuum of care after stroke. TRIAL REGISTRATION: ClinicalTrials.gov NCT04915027. Registered on 4 June 2021. ISRCTN registry ISRCTN63166587. Registered on 21 August 2023.

Digital Graphic Follow-up Tool (Rehabkompassen) for Identifying Rehabilitation Needs Among People After Stroke: Randomized Clinical Feasibility Study.

BACKGROUND: Stroke is a leading cause of disability among adults, with heavy social and economic burden worldwide. A cost-effective solution is urgently needed to facilitate the identification of individual rehabilitation needs and thereby provide tailored rehabilitations to reduce disability among people who have had a stroke. A novel digital graphic follow-up tool Rehabkompassen has recently been developed to facilitate capturing the multidimensional rehabilitation needs of people who have had a stroke. OBJECTIVE: The aim of this study was to evaluate the feasibility and acceptability of conducting a definitive trial to evaluate Rehabkompassen as a digital follow-up tool among people who have had a stroke in outpatient clinical settings. METHODS: This pilot study of Rehabkompassen was a parallel, open-label, 2-arm prospective, proof-of-concept randomized controlled trial (RCT) with an allocation ratio of 1:1 in a single outpatient clinic. Patients who have had a stroke within the 3 previous months, aged ≥18 years, and living in the community were included. The trial compared usual outpatient visits with Rehabkompassen (intervention group) and without Rehabkompassen (control group) at the 3-month follow-up as well as usual outpatient visit with Rehabkompassen at the 12-month follow-up. Information on the recruitment rate, delivery, and uptake of Rehabkompassen; assessment and outcome measures completion rates; the frequency of withdrawals; the loss of follow-up; and satisfaction scores were obtained. The key outcomes were evaluated in both groups. RESULTS: In total, 28 patients (14 control, 14 Rehabkompassen) participated in this study, with 100 patients screened. The overall recruitment rate was 28% (28/100). Retention in the trial was 86% (24/28) at the 12-month follow-up. All participants used the tool as planned during their follow-ups, which provided a 100% (24/24) task completion rate of using Rehabkompassen and suggested excellent feasibility. Both patient- and physician-participants reported satisfaction with the instrument (19/24, 79% and 2/2, 100%, respectively). In all, 2 (N=2, 100%) physicians and 18 (N=24, 75%) patients were willing to use the tool in the future. Furthermore, modified Rankin Scale as the primary outcome and various stroke impacts as secondary outcomes were both successfully collected and compared in this study. CONCLUSIONS: This study demonstrated the high feasibility and adherence of the study protocol as well as the high acceptability of Rehabkompassen among patients who have had a stroke and physicians in an outpatient setting in comparison to the predefined criterion. The information collected in this feasibility study combined with the amendments of the study protocol may improve the future definitive RCT. The results of this trial support the feasibility and acceptability of conducting a large definitive RCT. TRIAL REGISTRATION: ClinicalTrials.gov NCT04915027; https://clinicaltrials.gov/ct2/show/NCT04915027.

Assessments of a novel digital follow-up tool Rehabkompassen® to identify rehabilitation needs among stroke patients in an outpatient setting.

Introduction: It remains a huge challenge to identify individual rehabilitation needs in a time-efficient manner for providing patient-tailored rehabilitation during the continuum of stroke care. We have recently demonstrated the usefulness of a paper-version Rehab-Compass as a follow-up tool. The aim of the current study was to develop a digital version of the Rehab-Compass and evaluate its usability and feasibility. Methods: The novel digital tool Rehabkompassen® was developed by an iterative and participatory design process. Patients' rehabilitation needs were visualized by the tool and used before, during, and after the consultation. The usability and feasibility of the tool was assessed by task completion rate, the System Usability Scale, and satisfaction questionnaires among 2 physicians and 24 adult stroke patients in an outpatient clinical setting. Results: Rehabkompassen® identified and graphically visualized a panoramic view of the stroke patients' multidimensional needs in individual- and group levels. The instrument appeared to be feasible and time efficient in clinical use with a 100% overall task completion rate for both patients and physicians. A majority of the patients reported that it was very easy or fairly easy to answer the digital questionnaires and to understand their own digital Rehab-Compass graph. Two physicians reported a high mean score on the System Usability Scale (95/100) and were positive about using the tool in the future. Conclusions: The current results indicated that Rehabkompassen® was a feasible, useful, and time-saving follow-up tool for the identification of rehabilitation needs among stroke survivors in the post-acute continuum of care after stroke. Further research is needed to evaluate the efficacy of the digital instrument among stroke patients.

Market concentration of new antibiotic sales.

We calculate the average sales of new antibiotics during their first 8 years on the market. The discounted net present value is only $240 m in total per antibiotic, well below costs of supplying these products. The reliance on the US for sales is striking: the US market accounts for 84% of sales during the first 8 years. These facts clarify the need for additional revenues, especially from other countries, to support incentives for the development of new antibiotics. Market entry rewards may be of particular value.

A tactile resonance sensor for prostate cancer detection - evaluation on human prostate tissue.

Prostate cancer surgery risks erectile problems and incontinence for the patient. An instrument for guiding surgeons to avoid nerve bundle damage and ensure complete cancer removal is desirable. We present a tactile resonance sensor made of PZT ceramics, mounted in a 3D motorized translation stage for scanning and measuring tissue stiffness for detecting cancer in human prostate. The sensor may be used during surgery for guidance, scanning the prostate surface for the presence of cancer, indicating migration of cancer cells into surrounding tissue. Ten fresh prostates, obtained from patients undergoing prostate cancer surgery, were cut into 0.5 cm thick slices. Each slice was measured for tissue stiffness at about 25 different sites and compared to histology for validation cancer prediction by stiffness. The statistical analysis was based on a total of 148 sites with non-cancer and 40 sites with cancer. Using a generalized linear mixed model (GLMM), the stiffness data predicted cancer with an area under the curve of 0.74, after correcting for overfitting using bootstrap validation. Mean prostate stiffness on the logarithmic scale (p = 0.015) and standardized Z-scores (p = 0.025) were both significant predictors of cancer. This study concludes that stiffness measured by the tactile resonance sensor is a significant predictor of prostate cancer with potential for future development towards a clinical instrument for surgical guidance.

Industry incentives and antibiotic resistance: an introduction to the antibiotic susceptibility bonus.

The scarcity of novel antibiotic compounds in a time of increasing resistance rates has begun to ring alarm bells at the highest echelons of government. Large new financial incentives to accelerate antibiotic research and development, such as market entry rewards (MERs), are being considered. However, there is little focus on how to sustain the efficacy of new, promising antibiotics reaching the market. Currently, inappropriate use of antibiotics is commonplace, which has accelerated resistance development. In an attempt to halt this trend, antibiotic stewardship policies are being implemented in many resource-rich settings. Unfortunately, this has not yet had an impact on the amount of antibiotics being prescribed globally. One important hurdle is misalignment of incentives. While governments and health services are incentivized to promote prudent use of this common good, pharmaceutical companies are incentivized to increase volume of sales to maximize profits. This problem must be addressed or else the major efforts going into developing new antibiotics will be in vain. In this paper we outline an approach to realign the incentives of pharmaceutical companies with wider antibiotic conservation efforts by making a staged bonus a component of an MER for antibiotic developers when resistance to their drug remains low over time. This bonus could address the lack of stewardship focus in any innovation-geared incentive.

Antibiotic Pipeline Coordinators.

The World Health Organization (WHO) has published a global priority list of antibiotic-resistant bacteria to guide research and development (R&D) of new antibiotics. Every pathogen on this list requires R&D activity, but some are more attractive for private sector investments, as evidenced by the current antibacterial pipeline. A "pipeline coordinator" is a governmental/non-profit organization that closely tracks the antibacterial pipeline and actively supports R&D across all priority pathogens employing new financing tools.

Simulating Market Entry Rewards for Antibiotics Development.

We design an agent based Monte Carlo model of antibiotics research and development (R&D) to explore the effects of the policy intervention known as Market Entry Reward (MER) on the likelihood that an antibiotic entering pre-clinical development reaches the market. By means of sensitivity analysis we explore the interaction between the MER and four key parameters: projected net revenues, R&D costs, venture capitalists discount rates, and large pharmaceutical organizations' financial thresholds. We show that improving revenues may be more efficient than reducing costs, and thus confirm that this pull-based policy intervention effectively stimulates antibiotics R&D.

Prostate Cancer Detection with a Tactile Resonance Sensor-Measurement Considerations and Clinical Setup.

Tumors in the human prostate are usually stiffer compared to surrounding non-malignant glandular tissue, and tactile resonance sensors measuring stiffness can be used to detect prostate cancer. To explore this further, we used a tactile resonance sensor system combined with a rotatable sample holder where whole surgically removed prostates could be attached to detect tumors on, and beneath, the surface ex vivo. Model studies on tissue phantoms made of silicone and porcine tissue were performed. Finally, two resected human prostate glands were studied. Embedded stiff silicone inclusions placed 4 mm under the surface could be detected in both the silicone and biological tissue models, with a sensor indentation of 0.6 mm. Areas with different amounts of prostate cancer (PCa) could be distinguished from normal tissue (p < 0.05), when the tumor was located in the anterior part, whereas small tumors located in the dorsal aspect were undetected. The study indicates that PCa may be detected in a whole resected prostate with an uneven surface and through its capsule. This is promising for the development of a clinically useful instrument to detect prostate cancer during surgery.

Sensitivity improvements of a resonance-based tactile sensor.

Resonance-based contact-impedance measurement refers to the application of resonance sensors based on the measurement of the changes in the resonance curve of an ultrasonic resonator in contact with a surface. The advantage of the resonance sensor is that it is very sensitive to small changes in the contact impedance. A sensitive micro tactile sensor (MTS) was developed, which measured the elasticity of soft living tissues at the single-cell level. In the present paper, we studied the method of improving the touch and stiffness sensitivity of the MTS. First, the dependence of touch sensitivity in relation to the resonator length was studied by calculating the sensitivity coefficient at each length ranging from 9 to 40 mm. The highest touch sensitivity was obtained with a 30-mm-long glass needle driven at a resonance frequency of 100 kHz. Next, the numerical calculation of contact impedance showed that the highest stiffness sensitivity was achieved when the driving frequency was 100 kHz and the contact-tip diameter of the MTS was 10 µm. The theoretical model was then confirmed experimentally using a phase-locked-loop-based digital feedback oscillation circuit. It was found that the developed MTS, whose resonant frequency was 97.030 kHz, performed with the highest sensitivity of 53.2 × 106 Hz/N at the driving frequency of 97.986 kHz, i.e. the highest sensitivity was achieved at 956 Hz above the resonant frequency.

An intelligent rollator for mobility impaired persons, especially stroke patients.

An intelligent rollator (IRO) was developed that aims at obstacle detection and guidance to avoid collisions and accidental falls. The IRO is a retrofit four-wheeled rollator with an embedded computer, two solenoid brakes, rotation sensors on the wheels and IR-distance sensors. The value reported by each distance sensor was compared in the computer to a nominal distance. Deviations indicated a present obstacle and caused activation of one of the brakes in order to influence the direction of motion to avoid the obstacle. The IRO was tested by seven healthy subjects with simulated restricted and blurred sight and five stroke subjects on a standardised indoor track with obstacles. All tested subjects walked faster with intelligence deactivated. Three out of five stroke patients experienced more detected obstacles with intelligence activated. This suggests enhanced safety during walking with IRO. Further studies are required to explore the full value of the IRO.

A lab-on-a-chip for hypoxic patch clamp measurements combined with optical tweezers and spectroscopy- first investigations of single biological cells.

The response and the reaction of the brain system to hypoxia is a vital research subject that requires special instrumentation. With this research subject in focus, a new multifunctional lab-on-a-chip (LOC) system with control over the oxygen content for studies on biological cells was developed. The chip was designed to incorporate the patch clamp technique, optical tweezers and absorption spectroscopy. The performance of the LOC was tested by a series of experiments. The oxygen content within the channels of the LOC was monitored by an oxygen sensor and verified by simultaneously studying the oxygenation state of chicken red blood cells (RBCs) with absorption spectra. The chicken RBCs were manipulated optically and steered in three dimensions towards a patch-clamp micropipette in a closed microfluidic channel. The oxygen level within the channels could be changed from a normoxic value of 18% O 2 to an anoxic value of 0.0-0.5% O 2. A time series of 3 experiments were performed, showing that the spectral transfer from the oxygenated to the deoxygenated state occurred after about 227 ± 1 s and a fully developed deoxygenated spectrum was observed after 298 ± 1 s, a mean value of 3 experiments. The tightness of the chamber to oxygen diffusion was verified by stopping the flow into the channel system while continuously recording absorption spectra showing an unchanged deoxygenated state during 5400 ± 2 s. A transfer of the oxygenated absorption spectra was achieved after 426 ± 1 s when exposing the cell to normoxic buffer. This showed the long time viability of the investigated cells. Successful patching and sealing were established on a trapped RBC and the whole-cell access (Ra) and membrane (Rm) resistances were measured to be 5.033 ± 0.412 M Ω and 889.7 ± 1.74 M Ω respectively.

Modeling the high-frequency complex modulus of silicone rubber using standing Lamb waves and an inverse finite element method.

To gain an understanding of the high-frequency elastic properties of silicone rubber, a finite element model of a cylindrical piezoelectric element, in contact with a silicone rubber disk, was constructed. The frequency-dependent elastic modulus of the silicone rubber was modeled by a fourparameter fractional derivative viscoelastic model in the 100 to 250 kHz frequency range. The calculations were carried out in the range of the first radial resonance frequency of the sensor. At the resonance, the hyperelastic effect of the silicone rubber was modeled by a hyperelastic compensating function. The calculated response was matched to the measured response by using the transitional peaks in the impedance spectrum that originates from the switching of standing Lamb wave modes in the silicone rubber. To validate the results, the impedance responses of three 5-mm-thick silicone rubber disks, with different radial lengths, were measured. The calculated and measured transitional frequencies have been compared in detail. The comparison showed very good agreement, with average relative differences of 0.7%, 0.6%, and 0.7% for the silicone rubber samples with radial lengths of 38.0, 21.4, and 11.0 mm, respectively. The average complex elastic moduli of the samples were (0.97 + 0.009i) GPa at 100 kHz and (0.97 + 0.005i) GPa at 250 kHz.

Indentation loading response of a resonance sensor--discriminating prostate cancer and normal tissue.

Prostate cancer is the most common type of cancer among men worldwide. Mechanical properties of prostate tissue are promising for distinguishing prostate cancer from healthy prostate tissue. The aim was to investigate the indentation loading response of a resonance sensor for discriminating prostate cancer tissue from normal tissue. Indentation measurements were done on prostate tissue specimens ex vivo from 10 patients from radical prostatectomy. The measurement areas were analysed using standard histological methods. The stiffness parameter was linearly dependent on the loading force (average R(2 )= 0.90) and an increased loading force caused a greater stiffness contrast of prostate cancer vs normal tissue. The accuracy of the stiffness contrast was assessed by the ROC curve with the area under the curve being 0.941 for a loading force of 12.8 mN. The results are promising for the development of a resonance sensor instrument for detecting prostate cancer.

Optical fibre probe NIR Raman measurements in ambient light and in combination with a tactile resonance sensor for possible cancer detection.

First measurements on a combined instrument with a thin fibre optic Raman probe mounted inside a hollow tactile resonance sensor have been performed in ambient light on porcine tissue. The ambient fluorescent light was removed successfully from the spectra. The stiffness and the biomolecular composition of the tissue were analysed.

Contact angle and indentation velocity dependency for a resonance sensor--evaluation on soft tissue silicone models.

Human tissue stiffness can vary due to different tissue conditions such as cancer tumours. Earlier studies show that stiffness may be detected with a resonance sensor that measures frequency shift and contact force at application. Through the frequency shift and the contact force, a tissue stiffness parameter can be derived. This study evaluated how the probe application angle and indentation velocity affected the results and determined the maximum parameter errors. The evaluation was made on flat silicone discs with specified hardness. The frequency shift, the force and the stiffness parameter all varied with contact angle and indentation velocity. A contact angle of ≤10° was acceptable for reliable measurements. A low indentation velocity was recommended. The maximum errors for the system were <1.1% of the measured values. It was concluded that contact angle and indentation velocity have to be considered in the clinical setting. The angular dependency is especially important in clinical use for studying stiffness of human soft tissue, e.g. in prostate cancer diagnosis.

A FEM-based method using harmonic overtones to determine the effective elastic, dielectric, and piezoelectric parameters of freely vibrating thick piezoelectric disks.

To gain an understanding of the electroelastic properties of tactile piezoelectric sensors used in the characterization of soft tissue, the frequency-dependent electric impedance response of thick piezoelectric disks has been calculated using finite element modeling. To fit the calculated to the measured response, a new method was developed using harmonic overtones for tuning of the calculated effective elastic, piezoelectric, and dielectric parameters. To validate the results, the impedance responses of 10 piezoelectric disks with diameter-to-thickness ratios of 20, 6, and 2 have been measured from 10 kHz to 5 MHz. A two-dimensional, general purpose finite element partial differential equation solver with adaptive meshing capability run in the frequency-stepped mode, was used. The equations and boundary conditions used by the solver are presented. Calculated and measured impedance responses are presented, and resonance frequencies have been compared in detail. The comparison shows excellent agreement, with average relative differences in frequency of 0.27%, 0.19%, and 0.54% for the samples with diameter-to-thickness ratios of 20, 6, and 2, respectively. The method of tuning the effective elastic, piezoelectric, and dielectric parameters is an important step toward a finite element model that describes the properties of tactile sensors in detail.

Effects of snap-freezing and near-infrared laser illumination on porcine prostate tissue as measured by Raman spectroscopy.

Most Raman spectroscopic studies on tissue are performed in vitro. To assure that the results are applicable to in vivo examinations, preparation protocols and measurement procedures of tissue for in vitro studies should preserve tissue characteristics close to the native state. This study had two aims. The first was to elucidate if photoinduced effects arise during 5 minutes' continuous illumination of tissue with an 830 nm laser at an irradiance of approximately 3 x 10(10) W/m2. The second was to investigate the effects of snap-freezing of porcine prostate tissue in liquid nitrogen and subsequent storage at -80 degrees C, by means of multivariate analysis. 830 nm laser illumination of the specified irradiance did not affect the Raman spectra. A decrease of the spectral background was observed, likely due to photobleaching of tissue fluorophores. Snap-freezing and subsequent storage at -80 degrees C gave rise to subtle but significant alterations in Raman spectra, most likely related to changes in the protein conformations.