Systematic review of the patient burden of generalised myasthenia gravis in Europe, the Middle East, and Africa.

BACKGROUND: Myasthenia gravis (MG) is a rare autoimmune disease characterised by muscle weakness, and progression from ocular (oMG) to generalised (gMG) symptoms results in a substantial negative impact on quality of life (QoL). This systematic review aimed to provide an overview of the patient burden experienced by people living with gMG. METHODS: Electronic database searches (conducted March 2022), supplemented by interrogation of grey literature, were conducted to identify studies reporting patient burden outcomes in patients with gMG in Europe, the Middle East and Africa. Results were synthesised narratively due to the heterogeneity across trials. RESULTS: In total, 39 patient burden publications (representing 38 unique studies) were identified as relevant for inclusion in the systematic review, consisting of 37 publications reporting formal patient-reported outcome measures (PROMs), and two publications describing alternative qualitative assessments of patient experience. The studies included a variety of measures including generic and disease-specific PROMs, as well as symptom-specific PROMs focusing on key comorbidities including depression, anxiety, fatigue and sleep disturbance. The findings showed some variation across studies and PROMs; however, in general there was evidence for worse QoL in patients with gMG than in healthy controls or in patients with oMG, and a trend for worsening QoL with increasing MG severity. CONCLUSIONS: This review highlights the importance of considering patient QoL when developing and assessing treatment and management plans for patients with gMG. However, the heterogeneity identified across studies illustrates the need for further representative and well-powered studies in large cohorts administering consistent, validated questionnaires. TRIAL REGISTRATION: The protocol for this systematic review was registered in PROSPERO: CRD42022328444.

Privacy of patient data in quality-of-care registries in cardiology and cardiothoracic surgery: the impact of the new general data protection regulation EU-law.

Quality-of-care registries have been shown to improve quality of healthcare and should be facilitated and encouraged. The data of these registries are also very valuable for medical data research. While fully acknowledging the importance of re-using already available data for research purposes, there are concerns about how the applicable privacy legislation is dealt with. These concerns are also articulated in the new European law on privacy, the 'General Data Protection Regulation' (GDPR) which has come into force on 25 May 2018. The aim of this review is to examine what the implications of the new European data protection rules are for quality-of-care registries in Europe while providing examples of three quality-of-care registries in the field of cardiology and cardiothoracic surgery in Europe. A general overview of the European and national legal framework (relevant data protection and privacy legislation) applying to quality-of-care registries is provided. One of the main rules is that non-anonymous patient data may, in principle, not be used for research without the patient's informed consent. When patient data are solely and strictly used for quality control and improvement, this rule does not apply. None of the described registries (NHR, SWEDEHEART, and NICOR) currently ask specific informed consent of patients before using their data in the registry, but they do carry out medical data research. Application of the GDPR implies that personal data may only be used for medical data research after informing patients and obtaining their explicit consent.

Systematic review: probiotics in the management of lower gastrointestinal symptoms - an updated evidence-based international consensus.

BACKGROUND: In 2013, a systematic review and Delphi consensus reported that specific probiotics can benefit adult patients with irritable bowel syndrome (IBS) and other gastrointestinal (GI) problems. AIM: To update the consensus with new evidence. METHODS: A systematic review identified randomised, placebo-controlled trials published between January 2012 and June 2017. Evidence was graded, previously developed statements were reassessed by an 8-expert panel, and agreement was reached via Delphi consensus. RESULTS: A total of 70 studies were included (IBS, 34; diarrhoea associated with antibiotics, 13; diarrhoea associated with Helicobacter pylori eradication therapy, 7; other conditions, 16). Of 15 studies that examined global IBS symptoms as a primary endpoint, 8 reported significant benefits of probiotics vs placebo. Consensus statements with 100% agreement and "high" evidence level indicated that specific probiotics help reduce overall symptom burden and abdominal pain in some patients with IBS and duration/intensity of diarrhoea in patients prescribed antibiotics or H. pylori eradication therapy, and have favourable safety. Statements with 70%-100% agreement and "moderate" evidence indicated that, in some patients with IBS, specific probiotics help reduce bloating/distension and improve bowel movement frequency/consistency. CONCLUSIONS: This updated review indicates that specific probiotics are beneficial in certain lower GI problems, although many of the new publications did not report benefits of probiotics, possibly due to inclusion of new, less efficacious preparations. Specific probiotics can relieve lower GI symptoms in IBS, prevent diarrhoea associated with antibiotics and H. pylori eradication therapy, and show favourable safety. This study will help clinicians recommend/prescribe probiotics for specific symptoms.

Effect of subsequent acute-dose irradiation on cell survival in vitro following low dose-rate exposures.

PURPOSE: Following acute irradiation, excess radiosensitivity is generally seen at doses <1 Gy, a phenomenon termed "low-dose hyper-radiosensitivity" (HRS). A very strong, HRS-like inverse dose-rate effect has also been described following continuous low dose-rate (LDR) irradiation at <30 cGy h(-1). We report on the sequential irradiation of a cell line by such LDR exposures followed by low acute doses, where either treatment individually would elicit a hypersensitive response. The aim was to determine if a prior LDR exposure would remove the HRS normally seen in response to very small acute radiation doses. MATERIALS AND METHODS: T98G human glioma cells were given single continuous LDR exposures of 5-60 cGy h(-1) using a (60)Co gamma-source. At intervals of 0 or 4 h following LDR irradiation, cells were further irradiated with a range of acute doses using 240-kVp X-rays. The response to the combined treatment was assessed using high-precision clonogenic cell survival assays, and the amount of HRS at acute doses <1 Gy was determined. RESULTS: LDR at > or = 60 cGy h(-1) to total doses up to 5 Gy in asynchronously growing cells did not remove HRS in the subsequent acute-dose survival curve. In confluent cultures, subsequent acute-dose HRS was not present after an LDR dose of 5 Gy at either 60 or 30 cGy h(-1), but returned if a 4-h interval was left between LDR and acute-dose irradiation. In confluent cultures, acute-dose HRS remained for LDR treatments at 5 or 10 cGy h(-1) or if the total dose was 2 Gy. Taking all cultures and dose-rates together, the "degree" of acute-dose HRS, as measured by alpha(s), was significantly greater in cells irradiated at LDR to a total dose of 2 than of 5Gy. CONCLUSIONS: Initial LDR exposure can affect a subsequent HRS response. HRS is reduced after LDR exposures at greater dose intensity, but can recover again within 4 h of completion of LDR exposure. This suggests that processes determining increased resistance to small acute doses (removal of HRS) might be governed by the level of repairable DNA lesions.

Evidence for the involvement of DNA-dependent protein kinase in the phenomena of low dose hyper-radiosensitivity and increased radioresistance.

PURPOSE: To investigate the role of DNA-dependent protein kinase (DNA-PK) in the phenomena of low dose hyper-radiosensitivity (HRS) and increased radioresistance (IRR) using the genetically related M059 cell lines of disparate PRKDC status. MATERIALS AND METHODS: Clonogenic survival was measured for the three cell lines following low doses of X-irradiation using a flowactivated cell sorting (FACS) plating technique. The presence of PRKDC, G22p1 and Xrcc5 proteins was determined by Western blotting and a kinase assay used to measure DNA-PK complex activity. RESULTS: The survival responses for the three cell lines over the 0-0.3Gy dose range were comparable, but differences in radiosensitivity were evident at doses >0.4Gy. M059K and M059J/Fus1 cells (both PRKDC competent) exhibited marked HRS/IRR responses, albeit to different extents. M059J cells (PRKDC incompetent) were extremely radiosensitive exhibiting a linear survival curve with no evidence of IRR. The presence of IRR was coincident with the presence of PRKDC protein and functional DNA-PK activity. CONCLUSIONS: HRS is a response that is independent of DNA-PK activity. In contrast, IRR showed a dependence on the presence of PRKDC protein and functional DNA-PK activity. These data support a role for DNA-PK activity in the IRR response.

Twenty-stimulus train for rapid acquisition of auditory brainstem responses in humans.

This study addressed the clinical need to obtain frequency-specific auditory brainstem responses (ABRs) more rapidly than is currently possible. ABRs were obtained from 20 subjects using two different methods: a conventional method with tone bursts presented singly and a multiple-stimulus method using a train of 20 tone bursts. For both methods, tone bursts were presented at frequencies 1, 2, 4, and 8 kHz, shaped with a Blackman-Harris window and having intensity levels up to 105 dB peak equivalent sound pressure level (peSPL). The single tone bursts were presented at a 17.2/sec repetition rate. The 20 tone-burst train used the four frequencies at five intensities each and a repetition rate of 3.7/sec (separations between tone bursts of 9-12 msec, with 77 msec off-time between trains). Mean latencies and mean amplitudes for wave V were compared using t-tests for each of 12 conditions (four frequencies, each at the three highest output levels). For latency, only one comparison was significantly different (2 kHz, 77 dB peSPL). Similarly, only one comparison was significant for amplitude (2 kHz, 97 dB peSPL). There was, however, a trend for the tone bursts presented in trains to have longer latencies and reduced amplitudes compared to the respective responses for the single tone-burst condition. These results indicate the presence of some response adaptation when tone bursts are presented in a train. The use of a properly designed stimulus train can result in a significant time savings for obtaining frequency-specific ABRs as compared with single tone-burst presentations.

The use of a 56-stimulus train for the rapid acquisition of auditory brainstem responses.

To further develop a multiple stimulus method for the rapid acquisition of auditory brainstem responses (ABRs), a 56-stimulus train was tested in mice. Stimuli in the train were tone bursts spaced at 0.5-octave intervals from 4 to 32 kHz. ABR thresholds, latency-intensity and amplitude-intensity functions were obtained using stimuli presented singly (one at a time) and using the 56-stimulus train. Responses from stimuli presented singly and those obtained using the 56-stimulus train were compared. There were no significant differences in thresholds (0.01 level) and very small differences in response latencies and amplitudes. These findings demonstrate the feasibility of multiple stimulus trains for the rapid acquisition of ABRs.

Failure of elevated heat shock protein 70 antibodies to alter cochlear function in mice.

Heat shock protein 70 (HSP70) has been suggested as the putative cochlear antigen underlying a proposed autoimmune etiology in certain cases of Meniere's disease and idiopathic hearing loss. To determine if antibodies to this cellular protein are capable of altering cochlear function, BALB/c (N= 3) and CBA/J (N= 9) mice were inoculated with bovine HSP70 by intraperitoneal injections (10 microg in saline) every 10 days for 7 or 10 months, respectively. An equal number of control mice were injected with PBS according to the same schedule. ABR thresholds at 4, 8, 16, and 32 kHz in the HSP70-inoculated mice did not change over the 10 month period and were similar to saline controls. Furthermore, serum immune complexes and antinuclear antibodies did not increase over the inoculation period. ELISA analysis demonstrated the mice created antibodies to the foreign HSP70, but these apparently caused no abnormalities in the auditory or immune systems. It was concluded that foreign HSP70 is antigenic and inoculation with it will raise antibodies, but these antibodies were neither immunopathogenic nor cochleopathic. Therefore, these findings do not support current theories that elevated anti-HSP70 antibodies are the underlying cause of hearing loss in patients with such antibodies present.

Otitis media incidence and impact on the auditory brain stem response in lipopolysaccharide-nonresponsive C3H/HeJ mice.

Although mice of the C3H strain normally respond to bacterial lipopolysaccharide with appropriate immune system activation, mice of the C3H/HeJ substrain do not because of a gene defect. This suggests they may be more susceptible to opportunistic bacterial infections and more likely to have otitis media than a normally responding substrain, such as the C3H/HeSnJ. Therefore these two substrains were evaluated for incidence of spontaneous middle ear disease at 2, 4, 6, 10, 12, 15, and 18 months of age. Auditory brain stem response audiometry to pure tones of 4, 8, 16, 24, and 32 kHz was performed to establish the impact of middle ear disease on auditory function. None of the lipopolysaccharide-responsive C3H/HeSnJ mice demonstrated middle ear disease. However, middle ear disease was present in 33% of the C3H/HeJ mice. The conductive loss caused by the otitis media resulted in auditory brain stem response threshold shifts of 15 to 40 dB SPL, lowered peak amplitudes, and increased latencies. Reduced lipopolysaccharide responsiveness by C3H/HeJ mice makes them less capable of reacting immunologically to bacterial infection and presumably underlies the failure to clear middle ear disease. The C3H/HeJ mouse may provide a valuable model in which to study lipopolysaccharide biologic activity and related middle ear inflammatory or immune mechanisms.

Psychophysical tuning curves in subjects with tinnitus suggest outer hair cell lesions.

A study by Penner (J Speech Hear Res 1980;23:779-86) found evidence for impaired lateral suppression in subjects with tinnitus and sensorineural hearing loss. If lateral suppression is related to tuning curve sharpness and lateral suppression is impaired, the shape of the tuning curve should be affected. The purpose of this study was to determine whether subjects with tinnitus have psychophysical tuning curves that are different from those of subjects without tinnitus. Psychophysical tuning curves and hearing thresholds were obtained from 18 subjects, 7 with tinnitus and 11 without tinnitus. Only subjects with normal audiograms (through 8 kHz) were selected for this study. In subjects with tinnitus psychophysical tuning curves were obtained in the region pitch-matched to their tinnitus. In nontinnitus subjects psychophysical tuning curves were determined at the same frequencies as for the tinnitus subjects in a yoked-control design. The slopes of the tails and tips and the Q10 and other measures were calculated for each tuning curve. The psychophysical tuning curves in subjects with tinnitus were significantly different (0.01 level) from those of control subjects and often had hypersensitive tails and some elevated tips. These shapes of tuning curves are consistent with cochlear lesions involving the loss of outer hair cells without damage to the inner hair cells or nerve fibers.

Reliability of auditory brainstem responses from sequenced high-frequency (> or = 8 kHz) tonebursts.

An auditory brainstem response method is described for evoking responses to 4 high-frequency (8, 10, 12 and 14 kHz) tonebursts in the same amount of time normally required to obtain responses to single tonebursts. Reliability of responses to high-frequency toneburst stimuli presented in the conventional manner (one at a time) has been previously documented. In the present study, high-frequency tonebursts were presented to 20 normal-hearing subjects singly and in a 4-stimulus sequence. The reliability of resulting responses did not differ significantly between single- and multiple-stimulus test conditions. It is concluded that this sequenced-stimulus concept could be developed for use in serial monitoring of individuals receiving ototoxic agents as well as being broadly applicable to clinical situations in which patients cannot or will not respond voluntarily.

Paired tone-burst study of auditory brainstem response adaptation in guinea pigs: implications for development of multiple-stimulus methods.

In clinical testing using auditory evoked potentials, the practical length of a test session is limited. Thus, the amount of information that can be obtained during a routine test session is limited in electrocochleography and auditory brainstem testing. Attempts to obtain more information within a test session by increasing the stimulus repetition rate yields adapted responses. Multiple-stimulus method that present sequences of stimuli at different frequencies and intensities can increase the efficiency of data collection while avoiding adaptation. This study was designed to investigate rapid adaptation of these early responses to enable more efficient data acquisition using multiple stimuli. Five experiments in guinea pigs using single and paired tone-burst stimuli are described. The intrapair time, frequency, and intensity were varied to determine when adaptation, measured by a latency delay, occurred. The effects of adaptation on waves I through IV are described. The differences in stimulus parameters that avoid adaptation can be determined from these experiments.

Multiple-stimulus method for rapid collection of auditory brainstem responses using high-frequency (> or = 8 kHz) tone bursts.

Auditory brainstem responses (ABR) to high-frequency (> or = 8 kHz) tone-burst stimuli have shown potential for objective early detection of ototoxicity. In the case of ill, unresponsive, or otherwise difficult-to-test individuals, the patient group for whom this test is targeted, a threshold-seeking process can be too lengthy. A new method is described for obtaining responses to several high-frequency tone bursts in the same amount of time as that used in obtaining a single responses. Using 10 normal-hearing subjects, four high-frequency tone-burst stimuli (14, 12, 10, and 8 kHz) were presented singly, then in a multiple-stimulus sequence with onsets separated by 10 msec. Wave V response latencies from the multiple-stimulus sequences are compared to those presented singly, with small but statistically significant longer latencies observed for all stimuli following the initial stimulus (14 kHz) in the multiple sequence. Test-retest reliability was comparable between multiple and single conditions. These findings support the development of this technique for clinical auditory monitoring.

Measuring tinnitus parameters: loudness, pitch, and maskability.

Improved procedures have been developed for obtaining hearing thresholds, loudness matches, pitch matches, and masking curves of tinnitus. Computer programs enable all of these measures to be obtained in a single session. These measures have been obtained in tinnitus and nontinnitus subjects, with an external stimulus used to simulate tinnitus in nontinnitus subjects. These measures, obtained in repeated sessions, were used to determine the test-retest variability of each measure. The test-retest standard error of measurement, across-subjects, is reported, which enables changes in tinnitus to be determined. In nontinnitus subjects, the accuracy, as well as the reliability, is described.

Effects of selected process parameters on emission rates of volatile organic chemicals from carpet.

There has been increased interest over the last several years in issues related to indoor air quality. Although the factors affecting indoor air quality are recognized to be very broad, ranging from building design, operation, and ventilation to biological contamination, recent emphasis has been placed on chemical contaminants, particularly volatile organic chemicals (VOCs). New floor covering systems, including new carpets, have been identified as a potential, short-term source of VOCs in the indoor air of new or renovated buildings. This report describes an exploratory study designed to examine several manufacturing variables and their effects on VOC emission rates from new carpets. It was based on a statistical experimental design and was conducted at a single carpet mill on a full-scale production line. The outcome variable, VOC emission rate, was examined relative to selected independent variables: latex type, latex amount, makeup air into the drying oven, residence time in the drying oven, and their interactions. Significant variables were identified for a number of emission rate models. The study results suggest that there are no simple answers for easily reducing VOC emission rates, but several conclusions could be inferred from the study as to future directions to pursue.

Inner ear pathology in the Palmerston North autoimmune strain mouse.

The Palmerston North autoimmune strain mouse is a model for spontaneous systemic lupus erythematosus. Inner ear structure and function were examined during the onset and progression of systemic autoimmune disease to identify potentially correlated auditory system pathology. The onset of systemic disease occurred at 4 to 5 months of age and was characterized by elevated serum immune complexes, cryoglobulins, and antinuclear antibodies. Coincident with the onset of autoimmune disease was degeneration of the apical turn stria vascularis and outer hair cells. These cochlear changes progressed basalward. At 10 months of age, auditory brainstem response thresholds were elevated and the stria vascularis area was measurably smaller throughout the cochlea. Immunohistochemical staining showed immunoglobulin G deposits within the organ of Corti, the vas spirale of the basilar membrane, the scala tympani, and marrow cavities of the bony otic capsule. These results suggest that cochlear pathology may be immune mediated in this mouse, which would make the strain suitable for the study of the mechanisms relating inner ear abnormalities and autoimmune disease.

Reliability of evoked responses to high-frequency (8-14 kHz) tone bursts.

Instrumentation to evaluate the auditory brainstem response to high-frequency (8-14 kHz) tone bursts has been developed in the Auditory Research Laboratory, Portland, Oregon VA Medical Center. This system is intended to monitor the audition of patients receiving ototoxic drugs who are unresponsive to behavioral test procedures. The reliability of responses obtained with the high-frequency tone-burst system was studied in 30 normal ears. Intrasubject variability of intersession data from response waves I, III, and V to tone bursts of frequencies 8, 10, 12, and 14 kHz was not significantly different from click response variability. The results of this study demonstrate the reliability of the ABR to these high-frequency tone-burst stimuli. This technique may provide early identification of hearing loss in unresponsive subjects receiving treatment with potentially ototoxic agents, thus allowing alternative treatments to minimize or prevent communicative handicap.

Rise time and center-frequency effects on auditory brainstem responses to high-frequency tone bursts.

The effects of rise time and center frequency on the auditory brainstem response (ABR) elicited by high-frequency tone bursts were examined in six normal-hearing adults. Tone bursts with rise times of 0.1, 0.25, 0.5, and 1.0 msec, duration of 2 msec, and center frequencies of 8, 10, and 12 kHz were used in this study. The absolute latencies of waves I, III, and V were obtained in all subjects, and interpeak intervals of I-III, III-V, and I-V were calculated. As would be expected, rise time significantly affected the absolute latencies of waves I, III, and V, i.e., faster rise times shortened the absolute latencies, but did not affect the interpeak latencies. The tone-burst frequency significantly affected the latency of wave I but not the later waves. No significant differences were found in reliability of the response at different rise times or frequencies, within or across sessions. An estimate of the effective bandwidth of the stimulus suggests that frequency specificity of the response is maintained with fast rise time tone-burst stimuli.

Effects of improved contrast on lung-nodule detection. A clinical ROC study.

We evaluated the effects of unsharp masking and highly efficient scatter rejection on film-screen chest radiographs of cancer patients. Unsharp masking significantly improved the detectability of lung nodules and visibility of anatomic structures in poorly penetrated areas of the chest. Highly efficient scatter rejection by an improved antiscatter grid provided only modest additional benefits. The study supports the conclusion that nodule detection in poorly penetrated areas on conventional chest radiographs is limited primarily by display contrast, whereas in the well-penetrated lung fields it is limited primarily by confusing background structures, rather than inadequate contrast. A method for analyzing clinical nodule detection data by transforming the FROC data to ROC coordinates also is demonstrated.