Double-blinded, randomised, placebo-controlled trial of convalescent plasma for COVID-19: analyses by neutralising antibodies homologous to recipients' variants.

INTRODUCTION: Convalescent plasma (CP) emerged as potential treatment for COVID-19 early in the pandemic. While efficacy in hospitalised patients has been lacklustre, CP may be beneficial at the first stages of disease. Despite multiple new variants emerging, no trials have involved analyses on variant-specific antibody titres of CP. METHODS: We recruited hospitalised COVID-19 patients within 10 days of symptom onset and, employing a double-blinded approach, randomised them to receive 200 ml convalescent plasma with high (HCP) or low (LCP) neutralising antibody (NAb) titre against the ancestral strain (Wuhan-like variant) or placebo in 1:1:1 ratio. Primary endpoints comprised intubation, corticosteroids for symptom aggravation, and safety assessed as serious adverse events. For a preplanned ad hoc analysis, the patients were regrouped by infused CP's NAb titers to variants infecting the recipients i.e. by titres of homologous HCP (hHCP) or LCP (hLCP). RESULTS: Of the 57 patients, 18 received HCP, 19 LCP and 20 placebo, all groups smaller than planned. No significant differences were found for primary endpoints. In ad hoc analysis, hHCPrecipients needed significantly less respiratory support, and appeared to be given corticosteroids less frequently (1/14; 7.1%) than those receiving hLCP (9/23; 39.1%) or placebo (8/20; 40%), (p = 0.077). DISCUSSION: Our double-blinded, placebo-controlled CP therapy trial remained underpowered and does not allow any firm conclusions for early-stage hospitalised COVID-19 patients. Interestingly, however, regrouping by homologous - recipients' variant-specific - CP titres suggested benefits for hHCP. We encourage similar re-analysis of ongoing/previous larger CP studies. TRIAL REGISTRATION: ClinTrials.gov identifier: NCT0473040.

Flap characteristics, predictability, and safety of the Ziemer FEMTO LDV femtosecond laser with the disposable suction ring for LASIK.

AIMS: The outcomes of laser-assisted in situ keratomileusis (LASIK) operations performed with the Classic FEMTO LDV femtosecond laser using the plastic single-use suction ring (Ziemer Ophthalmic Systems) and the Allegretto Wave Concerto 500 Hz excimer laser (Wavelight AG) are presented in terms of accuracy, predictability, and safety of the operation. METHODS: A FEMTO LDV plastic suction ring was used for flap creation in 342 eyes of 179 patients. The intended flap thickness was 90 µm. The size of the suction ring varied from 9.0 to 10.0 mm. Flap dimensions were measured and correlated to preoperative characteristics. RESULTS: Mean flap thickness was very constant, 89.6 ± 2.0 µm (range 84-97). In 163 bilateral operations, the second flap was 1.1 µm thinner than the one cut first (P<0.0001). Mean flap diameter was 9.4 ± 0.2 mm (range 8.1-9.9). Mean hinge length was 3.9 ± 0.2 mm (range 3.0-4.2). In hyperopic eyes, flap thickness correlated negatively with keratometric power K1 and flap diameter. In hyperopic eyes, flap diameter correlated positively with spherical equivalent refraction and with keratometric power K1 as well as hinge length both in myopic and hyperopic eyes. Complications were reported in 12 (3.5%) eyes. Complications were very mild and none of them prevented further refractive laser treatment. Two Snellen lines of corrected distance visual acuity were lost in one (0.3%) eye. CONCLUSION: The FEMTO LDV plastic single-use suction rings yielded accurate and reproducible flaps and were safe for the creation of thin corneal flaps.

Examination of AVPR1a as an autism susceptibility gene.

Impaired reciprocal social interaction is one of the core features of autism. While its determinants are complex, one biomolecular pathway that clearly influences social behavior is the arginine-vasopressin (AVP) system. The behavioral effects of AVP are mediated through the AVP receptor 1a (AVPR1a), making the AVPR1a gene a reasonable candidate for autism susceptibility. We tested the gene's contribution to autism by screening its exons in 125 independent autistic probands and genotyping two promoter polymorphisms in 65 autism affected sibling pair (ASP) families. While we found no nonconservative coding sequence changes, we did identify evidence of linkage and of linkage disequilibrium. These results were most pronounced in a subset of the ASP families with relatively less severe impairment of language. Thus, though we did not demonstrate a disease-causing variant in the coding sequence, numerous nontraditional disease-causing genetic abnormalities are known to exist that would escape detection by traditional gene screening methods. Given the emerging biological, animal model, and now genetic data, AVPR1a and genes in the AVP system remain strong candidates for involvement in autism susceptibility and deserve continued scrutiny.

A new index to measure the accuracy of refractive operations.

PURPOSE: To create a new index to help evaluate the accuracy of the outcome of refractive surgery. METHODS: By combining information given by the cross-cylinder form of surgically induced refractive change (SIRC) and basic methods of vector analysis, we constructed a new index which serves as a tool to evaluate postoperatively the changes achieved by refractive surgery. This new index gives easily understandable numerical values and takes into account changes in both spherical refraction and astigmatism. We demonstrated the use of this index in two study populations consisting of 20 consecutive eyes operated on using two different lasers, Meditec MEL60 and MEL70, respectively. RESULTS: Although postoperative uncorrected visual acuity (UCVA) and best corrected visual acuity (BCVA) were better in the MEL70 group, the difference of photoefractive keratectomy (PRK) for combined astigmatism and myopia was not statistically significant. Comparison of the changes in refraction achieved by the two lasers indicated that the MEL60 was more accurate; this was also seen when comparing the total index of error between the two groups. CONCLUSIONS: We suggest the use of this total index of error (TIE) in clinical praxis because it provides an easy and accurate method of evaluating the accuracy of refractive operations. These inaccuracies might otherwise go unnoticed if the basic values only (e.g. UCVA, BCVA and haze) were used in postoperative evaluation.

Evidence supporting WNT2 as an autism susceptibility gene.

We examined WNT2 as a candidate disease gene for autism for the following reasons. First, the WNT family of genes influences the development of numerous organs and systems, including the central nervous system. Second, WNT2 is located in the region of chromosome 7q31-33 linked to autism and is adjacent to a chromosomal breakpoint in an individual with autism. Third, a mouse knockout of Dvl1, a member of a gene family essential for the function of the WNT pathway, exhibits a behavioral phenotype characterized primarily by diminished social interaction. We screened the WNT2 coding sequence for mutations in a large number of autistic probands and found two families containing nonconservative coding sequence variants that segregated with autism in those families. We also identified linkage disequilibrium (LD) between a WNT2 3'UTR SNP and our sample of autism-affected sibling pair (ASP) families and trios. The LD arose almost exclusively from a subgroup of our ASP families defined by the presence of severe language abnormalities and was also found to be associated with the evidence for linkage to 7q from our previously published genomewide linkage screen. Furthermore, expression analysis demonstrated WNT2 expression in the human thalamus. Based on these findings, we hypothesize that rare mutations occur in the WNT2 gene that significantly increase susceptibility to autism even when present in single copies, while a more common WNT2 allele (or alleles) not yet identified may exist that contributes to the disorder to a lesser degree.

Rapid differentiation of Borrelia garinii from Borrelia afzelii and Borrelia burgdorferi sensu stricto by LightCycler fluorescence melting curve analysis of a PCR product of the recA gene.

To differentiate the Borrelia burgdorferi sensu lato genospecies, LightCycler real-time PCR was used for the fluorescence (SYBR Green I) melting curve analysis of borrelial recA gene PCR products. The specific melting temperature analyzed is a function of the GC/AT ratio, length, and nucleotide sequence of the amplified product. A total of 32 DNA samples were tested. Of them three were isolated from B. burgdorferi reference strains and 16 were isolated from B. burgdorferi strains cultured from Ixodes ricinus ticks; 13 were directly isolated from nine human biopsy specimens and four I. ricinus tick midguts. The melting temperature of B. garinii was 2 degrees C lower than that of B. burgdorferi sensu stricto and B. afzelii. Melting curve analysis offers a rapid alternative for identification and detection of B. burgdorferi sensu lato genospecies.

Photorefractive keratectomy for -1.25 to -25.00 diopters of myopia.

BACKGROUND: We evaluated prospectively the efficacy, predictability, stability, and safety of photorefractive keratectomy (PRK) for myopia. METHODS: Three hundred sixty-nine eyes of 257 patients were treated with an Aesculap-Meditec MEL 60 excimer laser. Treated eyes were divided into 3 groups: low myopes (-1.25 to -6.00 D), 226 eyes; medium myopes (-6.10 to -10.00 D), 104 eyes; high myopes (-10.10 to -25.00 D), 39 eyes. Follow-up at 12 months was available for 348 eyes (94%). RESULTS: One year after surgery the number of eyes within +/- 1.00 D of emmetropia was 182 (86.7%) for low myopes, 43 (40.5%) for medium myopes, and 12 (30.8%) for high myopes. Values for +/- 0.50 D were low: 142 (67.6%), medium: 29 (29.3%), and high: 9 (23.1%). Three eyes with low myopia (1.4%) and 5 eyes with medium myopia (5.1%) lost 2 or more lines of spectacle-corrected visual acuity. None of the high myopes lost 2 or more lines. Uncorrected visual acuity of 20/20 or better was achieved in 82 eyes (39%) with low myopia; 20/40 or better was achieved in 183 eyes (87.1%). Five eyes (5.1%) of medium myopes achieved 20/20 or better; 52 eyes (52.5%) with medium myopia achieved 20/40 or better. Zero eyes with high myopia achieved 20/20 or better; 11 eyes (28.8%) achieved 20/40 or better. CONCLUSION: Photorefractive keratectomy proved to be an effective method to correct myopia up to -6.00 D. For myopia greater than -6.00 D, good results were achieved in most eyes when myopia was less than -10.00 D, but efficacy and predictability decrease. To avoid systematic undercorrection, slight overcorrection must be attempted with the Aesculap-Meditec MEL 60 excimer laser for the treatment of myopia.

The Molecular Constants of 12CH3I in the Ground and v6 = 1 Excited Vibrational State.

A set of 26 new measurements have been recorded by a Doppler-free double-resonance technique, with a relative accuracy of about 10(-8). These data are combined to previous FTIR measurements to refine the molecular constants of 12CH3I. All the available literature data have been revisited, a few assignments updated, and some frequencies changed according to new laser standards. A simultaneous fit to all the measurements of infrared, microwave, and radiofrequency transitions produced an improved set of parameters, independent of previously determined constants. Copyright 1998 Academic Press.

Excimer laser photorefractive keratectomy for hyperopia.

OBJECTIVE: Excimer laser photorefractive keratectomy (PRK) has been shown to be an effective method in the treatment of refractive errors, especially myopia. We evaluated prospectively the efficacy, predictability, stability, and safety of excimer laser PRK in the treatment of hyperopia. METHODS: Thirty-four hyperopic eyes were treated with an Aesculap-Meditec (MEL 60) excimer laser. The patients were divided into two groups. In the low-moderate hyperopia group, baseline spherical equivalent refraction was between +1.50 and +6.00 diopters (D) (mean, +4.20 +/- 1.30 D) and in the high hyperopia group between +6.25 and +9.75 D (mean, +7.70 +/- 1.30 D). Follow-up visits occurred 1, 3, 6, and 12 months after surgery. RESULTS: One-year results were available for a total 27 eyes (79%): 15 eyes with low to moderate hyperopia and 12 eyes with high hyperopia. One year after PRK in the low-moderate group, six eyes (40%) had a refractive error within +/- 1.00 D of emmetropia, but in the high hyperopia group only two eyes (17%) were within +/- 1.00 D of emmetropia; three eyes (20%) and one eye (8%) were within +/- 0.50 D, respectively. The stability of the refractive change was better in the low to moderate hyperopia group; in the high hyperopia group there was still some regression after 6 months. At 12 months, 10 eyes (67%) in the low-moderate and one eye (8%) in the high hyperopia group had postoperative uncorrected visual acuity of 20/40 or better. One eye in the low-moderate hyperopia group saw 20/20 without correction. Only one eye lost two lines of spectacle-corrected visual acuity. Haze was more intense in the high hyperopia group, but it did not reduce visual acuity. No vision-threatening complications were observed. CONCLUSIONS: When low to moderate hyperopia up to +6.00 D is treated, excimer laser PRK with the Aesculap Meditec MEL60 laser is safe and moderately effective, and refraction stabilizes after 3 months in most eyes. However, PRK is not sufficient to treat high hyperopia in an effective and predictable way.

Ability to work after arterial surgery for chronic incapacitating ischaemia of the lower limb in middle-aged patients.

OBJECTIVE: To assess the efficacy of arterial surgery in restoring ability to walk and working capacity. DESIGN: Retrospective follow up study. SETTING: Fourth Department of Surgery, Helsinki University Central Hospital. SUBJECTS: 67 middle-aged patients (mean age 53 years) with chronic incapacitating ischaemia of the lower limb. INTERVENTIONS: Arterial reconstruction. MAIN OUTCOME MEASURES: Clinical outcome, vascular laboratory assessments, mortality, morbidity, return to work, and retirement. RESULTS: According to objective vascular laboratory criteria a primary positive effect was achieved in 63/67 (94%). Fourty-eight of the 65 surviving patients (74%) were free of symptoms on treadmill testing three months after the operation. Working capacity was restored in 41/50 of the patients not yet retired (82%). Three years postoperatively 77% of the surviving patients still fared objectively better than before operation. The 10-year survival rate was 67%. Fourteen of the 22 patients who died did so of cardiovascular diseases (64%). Advanced distal ischaemia (indicated by a preoperative ankle-brachial index of 0.5 or less) was associated with increased risk of death. Altogether 251 working years were achieved of the 435 that could have potentially been gained. The most common reason for retirement during follow up was progression of peripheral arterial disease in the lower limbs in 13/41 patients (32%). At the end of the study there were nine patients still working with potentially 73 working years left. CONCLUSION: These results indicate that arterial surgery can restore working capacity in middle aged patients with threatening or temporary invalidity. Long term outcome, especially mortality, is mostly affected by other signs of cardiovascular disease, whereas working capacity is dependent on a wider variety of factors.

[Glucagon-based cleansing enemas prior to a double-contrast barium enema]. / Glukagon-unterstützte Reinigungseinläufe vor einem Doppelkontrast-Bariumeinlauf.

The cleansing effect of large-volume enemas supported or unsupported by glucagon was studied in 20 each outpatients before a double-contrast barium enema. There was no statistically significant difference in respect of the remaining rests of faeces and the contrast medium coat. Patients suffering from intestinal spasms and anal insufficiency experience a feeling of relief by the intramuscular administration of glucagon during the preparatory enema; the quality of the double-contrast barium enema is not affected.

The cleansing enema. How many for a good quality double-contrast enema?

The effects of the 'tap-water enemas till clear' method of bowel cleansing on the technical quality of double-contrast enema (DCE) were studied in 123 outpatients referred for DCE. Patients with one or two tap-water enemas (1.75 litres) before the DCE had significantly more faecal residue and flocculation of contrast medium than patients with three or more enemas. However, the number of enemas did not correlate significantly with mucosal coating. The results suggest that at least three tap-water enemas should be given before DCE.

Tissue expansion and skin circulation. Simultaneous monitoring by laser Doppler flowmetry and transcutaneous oximetry.

The skin circulation was examined in nine patients during filling of their breast expander prostheses. Despite the high expansion pressure, which was increased above the systolic blood pressure, the overlying skin showed good circulation both clinically and when measured with a laser Doppler flowmeter and a transcutaneous oximeter. We conclude that the expansion was therefore directed to the tissues between the expander and the skin--that is, the fibrous capsule surrounding the prosthesis. Nine subcutaneous tissue expanders located in different anatomical regions were overfilled to a pressure at which all skin circulation ceased. Sufficient saline was then removed to allow skin circulation to return. Oxygenation of the skin ceased at a relatively low pressure when measured by transcutaneous oximetry, whereas when the skin circulation was measured with a laser Doppler flowmeter it did not disappear until the expander pressure had been raised appreciably above that level.

The assessment of colonic water retention prior to double-contrast enema.

The detection of colonic water retention prior to double-contrast enema (DCE) was studied in 41 outpatients. Ultrasound examination of the cecum (USC) correctly showed 4 of the 5 patients with water retention as well as all 14 cases with dry colon. Changes in patient's weight or in the number of cleansing enemas were not associated with water retention. The USC seems to offer a rapid and accurate method for the detection of colonic water retention prior to DCE. Aspects of the handling of colonic water retention are also discussed.

Urography with spasmolytics.

The effects of glucagon (1 mg i.v.) and hyoscine butylbromide (Buscopan 20 mg i.v.) and placebo on the visualization of the pyelocalyceal systems and ureters was compared in a routine urography with abdominal compression in a double-blind, randomized trial comprising 189 kidneys and ureters. The visualization of the ureters in the supine position was highly significantly better than in the prone. In the prone position the ureteral visualization with Buscopan was marginally significantly better than with placebo or glucagon. Otherwise, neither Buscopan nor glucagon improved the pyeloureteral visualization. However, with glucagon the pyelocalyceal visualization was highly significantly poorer than with placebo, and marginally significantly poorer than with Buscopan.

Double contrast barium meal and acetylcysteine.

In a prospective double blind study, acetylcysteine, a local and systemic respiratory tract mucolytic agent, or a placebo, were given to 100 patients prior to a double contrast barium meal to decrease the gastric mucus viscosity and to make the mucus layer thinner, in order to permit barium to outline the furrows surrounding the areae gastricae instead of the overlying thick mucus. However, acetylcysteine failed to improve either visualization of the areae gastricae or the general quality of the double contrast barium meal.

Reproducibility of skin blood flow, perfusion pressure and oxygen tension measurements in advanced lower limb ischaemia.

Since no generally-accepted non-invasive test is available for quantification of advanced distal ischaemia of the lower limb, the reproducibility of Laser Doppler flowmetry, skin perfusion pressure and transcutaneous oxygen tension measurement was assessed in 21 patients with severe occlusive arterial disease. The mean coefficients of variation for these methods were 0.11, 0.12 and 0.19 respectively over a 15-minute period without detachment of the measuring devices, and 0.30, 0.29 and 0.37 respectively from day-to-day. However, if tcpO2 values below 10 mmHg were excluded the corresponding coefficients of variation for this method were 0.08 and 0.31. Thus interventional changes may be detected during continuous monitoring with a reasonable degree of accuracy, but single values can hardly be expected to predict the outcome for the foot in a prospective series, nor can they be used in therapeutic trials of drug action. Major changes in peripheral circulation, for example the effect of revascularisation procedures, can be evaluated using any of the methods studied.

Omnipaque and Gastrografin in gastrointestinal follow-through examinations.

The non-ionic low-osmolar contrast medium Omnipaque was compared with the conventional ionic high-osmolar contrast medium Gastrografin in a randomized, double blind study comprising 71 consecutive gastrointestinal follow-through examinations performed because of suspected ileus or anastomosis control. The patients' reaction were confined to nausea, emesis and diarrhoe being very similar in both groups and related to the patients' illnesses. The taste of Gastrografin was more often judged unpleasant, but the difference was not significant. Omniplaque scored significantly better for contrast medium density and diagnostic visualisation in the small bowel, otherwise the differences were negligible. There were no significant differences in the transit time into the caecum. The high price of Omnipaque restricts its routine use. It may be diagnostically indicated in selected cases where greater accuracy in the delineation of pathologic anatomical details in the small bowel is desired.