Regulatory review time and pharmaceutical research and development

In the United States, all newly developed drugs undergo a lengthy review process conducted by the US Food and Drug Administration (FDA). These regulatory delays have direct immediate costs for drug manufacturers and patients waiting for treatment. Under certain market conditions, regulatory delays may also affect future research and development (R&D) strategies of pharmaceutical companies. To estimate the magnitude of this effect, we match data on drugs in the development pipeline in 2006 to data that we collect on FDA review times for all drugs approved between 1999 and 2005. Employing a rich and novel set of controls that affect drug R&D decisions and, potentially, regulatory review lags, we find that on average, three additional months of delay result in one fewer drug in development in that drug category. Our results suggest that the length of the regulatory delay matters for pharmaceutical firms' R&D decisions and that the firms are likely unable to pass on these costs onto consumers.     

Cavitary lung lesions and pneumothorax in a healthy patient with active coronavirus-19 (COVID-19) viral pneumonia

Severe respiratory sequelae drive morbidity-associated with coronavirus 2019 (COVID-19) disease. We report a case of COVID-19 pneumonia complicated by cavitary lesions and pneumothorax in a young healthy male. Pneumothorax management with catheter thoracostomy and rapid resolution of the cavitary lesions are described. An extensive work-up for other causes a cavitation was negative and the temporal correlation of the cavities with COVID-19 infection plus their rapid resolution suggest a direct relationship. We propose a mechanism for cavitation secondary to microangiopathy, a cause of cavitation in the vasculitides and a known feature of COVID-19.     

Promoting healthy diets and active lives to hard-to-reach groups: market research study

Continued progress over the next decade in reducing premature morbidity and mortality from chronic disease will require that health communication efforts target a significant proportion of the American public that has not been influenced by the health promotion efforts of the 1980s. Focus groups conducted with members of the hard-to-reach American public showed that while being healthy seemed to be important to participants, and they were generally aware of what to do to stay healthy, they had a different operational definition of health than that used in health promotion programs. Participants seemed to believe that better health behaviors would build their resistance to acute illnesses, that is, keep them healthy, but that chronic diseases, such as cancer and diabetes, were due to fate and heredity and beyond their individual control. The focus group results show that participants had not made the link between chronic disease prevention and the importance of diet, exercise, and weight control. Although most of them seemed to express a genuine interest in "doing better," they were not able to supply more than superficial examples of how such changes might be made. Surprisingly, there were more similarities than differences in participants' attitudes and beliefs, with the similarities cutting across boundaries of race-ethnicity, age, and sex. Interest in changing behaviors was only slightly more pronounced among female rather than male, and older rather than younger, participants. However, there was not much evidence from the participants that they were actively seeking health information or trying to reconcile conflicting knowledge and beliefs.     

Fixation, polyethylene wear, and pelvic osteolysis in primary total hip replacement

A multicenter retrospective review was performed analyzing 1081 primary total hip replacements in 944 patients using the Harris Galante-I cementless acetabular component with screw fixation. All patients were followed up for a minimum of 5 years with a mean followup of 81 months. Linear polyethylene wear averaged 0.11 mm/year (range, 0-0.86 mm/year). Pelvic osteolysis was seen in 25 patients (2.3%). Migration of the acetabular component was seen in four hips. A subgroup of patients was reanalyzed at a minimum followup of 10 years. The mean linear polyethylene wear rate remained 0.11 mm/year. In this group, only one socket had migrated. There was an association between wear rate and age. On average, younger patients had higher wear rates. The risk for having pelvic osteolysis develop and the need for revision surgery also was age-related. Twenty-two percent of hip replacements (15 hips) in patients younger than 50 years of age at the time of their index operation had pelvic osteolysis develop. In contrast, for patients older than 50 years of age at the time of surgery only 7.8% (eight hips) had osteolysis of the pelvis develop. For patients older than 70 years of age at the time of primary total hip replacement, none had pelvic osteolysis develop.     

Differential c-Fos expression in cholinergic, monoaminergic, and GABAergic cell groups of the pontomesencephalic tegmentum after paradoxical sleep deprivation and recovery.

Multiple lines of evidence indicate that neurons within the pontomesencephalic tegmentum are critically involved in the generation of paradoxical sleep (PS). From single-unit recording studies, evidence suggests that unidentified but "possibly" cholinergic tegmental neurons discharge at higher rates during PS than during slow wave sleep or even waking and would thus play an active role, whereas "presumed" monoaminergic neurons cease firing during PS and would thus play a permissive role in PS generation. In the present study performed on rats, c-Fos immunostaining was used as a reflection of neuronal activity and combined with immunostaining for choline acetyltransferase (ChAT), serotonin (Ser), tyrosine hydroxylase (TH), or glutamic acid decarboxylase (GAD) for immunohistochemical identification of active neurons during PS recovery ( approximately 28% of recording time) as compared with PS deprivation (0%) and PS control (approximately 15%) conditions. With PS recovery, there was a significant increase in ChAT+/c-Fos+ cells, a significant decrease in Ser+/c-Fos+ and TH+/c-Fos+ cells, and a significant increase in GAD+/c-Fos+ cells. Across conditions, the percent PS was correlated positively with tegmental cholinergic c-Fos+ cells, negatively with raphe serotonergic and locus coeruleus noradrenergic c-Fos+ cells, and positively with codistributed and neighboring GABAergic c-Fos+ cells. These results support the hypothesis that cholinergic neurons are active, whereas monoaminergic neurons are inactive during PS. They moreover indicate that GABAergic neurons are active during PS and could thus be responsible for inhibiting neighboring monoaminergic neurons that may be essential in the generation of PS.     

Deep lamellar keratoplasty using viscoelastic dissection

We describe a technique for performing deep lamellar keratoplasty using viscoelastic dissection. Deep lamellar dissections of the cornea using viscoelastic substances (sodium hyaluronate) were performed on 4 eyes of 4 patients. One patient with keratoconus and another with corneal scarring underwent lamellar keratoplasty using the technique as the sole procedure for visual rehabilitation. Two patients (2 eyes) with opaque corneas underwent deep lamellar dissection with removal of stromal tissue to allow visualization of the anterior segment structures prior to penetrating keratoplasty, thereby facilitating separation of iridocorneal adhesions as the Descemet membrane was incised. Deep lamellar dissection was performed without complications related to the procedure in all 4 eyes. The 2 lamellar grafts cleared completely, and both eyes achieved excellent visual acuity with spectacle correction. In the other 2 eyes, deep lamellar dissection provided clear visualization of anterior segment structures during incision of the Descemet membrane. Deep lamellar dissection using viscoelastic substances is a useful technique during lamellar keratoplasty.     

Visual performance after photorefractive keratectomy with a 6-mm ablation zone.

PURPOSE: To prospectively examine the effect of photorefractive keratectomy with a 6-mm ablation zone on best-spectacle-corrected visual performance. METHODS: A prospective study was conducted of 164 eyes of 164 patients with an average (+/-SD) of -4.02 +/- 1.74 diopters (range, -0.63 to -8.38 diopters spherical equivalent). Best-spectacle-corrected high-contrast and low-contrast visual acuity (18% Weber contrast) was measured with both natural and dilated pupils. Patients were tested preoperatively and at 3, 6, and 12 months after photorefractive keratectomy. Photorefractive keratectomy was performed with an argon fluoride excimer laser. Fifty-five eyes of 55 patients also underwent astigmatic keratotomy. RESULTS: Twelve months after photorefractive keratectomy, best-spectacle-corrected high-contrast visual acuity with natural pupils showed no significant change from preoperative values; mean (+/-SD) change was 0.004 +/- 0.10 logMAR (t = 0.45, P = .65). Best-spectacle-corrected low-contrast visual acuity with natural pupils was significantly reduced compared to baseline; mean (+/-SD) change was 0.04 +/- 0.13 logMAR (t = 3.3, P = .001). The low-contrast loss was larger (1.5 lines) with dilated pupils; mean (+/-SD) change was 0.13 +/- 0.15 logMAR (t = 9.31, P < .001). Greater losses in dilated low-contrast visual acuity were associated with concurrent astigmatic ketatotomy (t = 2.28, P = .025) and corneal haze of grade 1 or greater (t = 2.71, P = .005). CONCLUSIONS: Reductions in visual performance occur after photorefractive keratectomy with a 6-mm zone. These changes are greatest for low-contrast visual acuity with dilated pupils. Corneal haze and concurrent astigmatic keratotomy are associated with greater losses in low-contrast visual acuity. Best-spectacle-corrected low-contrast visual acuity is a sensitive measure for evaluating visual performance after refractive surgery.