Cialis and Viagra reduce Alzheimer Disease risk

 Here is the link to the paper.

Sounds too good to be true. But check Figure 1 in the paper. Overall survival is not changed much. However, results would look better for a subgroup of older, high users.

Here are some excerpts.

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Abstract

Background and Objectives

Repurposing phosphodiesterase type 5 inhibitors (PDE5Is) as drugs for Alzheimer disease (AD) risk reduction has shown promise based on animal studies. However, evidence in humans remains inconclusive. Therefore, we conducted a cohort study to evaluate the association between PDE5I initiation compared with nonuse and the risk of developing AD in men with erectile dysfunction (ED).

Methods

Using electronic health records from IQVIA Medical Research Data UK (formerly known as the THIN database), we identified men aged ≥40 years with a new diagnosis of ED between 2000 and 2017. Individuals with a previous diagnosis of dementia, cognitive impairment, confusion, or prescription for dementia symptoms were excluded. The occurrence of incident AD was identified using diagnostic read codes. To minimize immortal-time bias, PDE5I initiation was treated as a time-varying exposure variable. Potential confounders were adjusted using inverse probability of treatment weighting based on propensity scores. Cox proportional hazard models were used to estimate the adjusted hazard ratio (HR) with 95% CIs. A secondary analysis explored the association between AD and the cumulative number of PDE5I prescriptions. Sensitivity analyses included lag (delay) periods of 1 and 3 years after cohort entry to address the prodromal stage of AD.

Results

The study included 269,725 men, with 1,119 newly diagnosed with AD during a median follow-up of 5.1 (interquartile range 2.9–8.9) years. The adjusted HR in PDE5I initiators compared with nonuse was 0.82 (95% CI 0.72–0.93). The associated risk of AD decreased in individuals issued >20 prescriptions: HR 0.56 (95% CI 0.43–0.73) for 21–50 prescriptions and HR 0.65 (95% CI 0.49–0.87) for >50 prescriptions. Sensitivity analysis with a 1-year lag period supported the primary findings (HR 0.82, 95% CI 0.72–0.94), but the results differed with the inclusion of a 3-year lag period (HR 0.93, 95% CI 0.80–1.08).

Discussion

PDE5I initiation in men with ED was associated with a lower risk of AD, particularly in those most frequently issued prescriptions. The differences between primary and sensitivity analyses highlight the need to explore the optimal lag period. To enhance the generalizability of our findings, a randomized controlled trial including both sexes and exploring various PDE5I doses would be beneficial to confirm the association between PDE5I and AD.

Alaska 737-9 Door Bolts Left Behind At Boing?

 From aviationweek.com.

Boeing used to be run by technical people. Now it is run by the Bean Counters.

The fall of a giant.

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Bolts needed to secure the exit door plug that ripped off an Alaska Airlines Boeing 737-9 in January were removed on the Boeing factory floor as part of an unrelated pre-delivery repair and never re-installed, a preliminary NTSB report on the accident suggests.

Analysis by investigators revealed that damage to the mid-exit door (MED) plug and related hardware “indicate that the four bolts that prevent upward movement of the MED plug were missing before the MED plug moved upward off the stop pads,” the report said. This means the bolts did not break during the Jan. 5 flight that included a rapid decompression and required an emergency landing.

More digging determined the MED, which stays bolted in place except during maintenance or non-routine repairs, was not opened from the airplane’s Oct. 31, 2023, delivery to Alaska and the accident flight. This period includes time spent at AAR Corp’s Oklahoma City, Oklahoma, facility where a Wi-Fi antenna was installed.

“The manufacturing/human performance group has done a complete records review from the time the event airplane left the Boeing factory to the time of the accident and found no evidence that the left MED plug was opened after leaving Boeing’s facility,” the NTSB said.

Investigators are focusing on a repair done on Boeing’s factory floor as the period when the bolts were forgotten.

Fuselage and door plug manufacturer Spirit AeroSystems shipped the affected fuselage with several damaged rivets just in front of the left side MED plug that blew out, the NTSB found. The fuselage arrived at Boeing’s Renton, Washington, 737 production facility on Aug. 31. A day later, Boeing flagged the rivet problem and ordered it repaired.

Spirit workers assigned to the 737 factory completed the work on Sept. 19, the NTSB said. But the bolts were apparently never replaced, setting the stage for the Alaska accident.

A Boeing-supplied photo taken before the work started shows the retaining bolts in place. Photos pulled from communications between Boeing “team members” sent just after the rivet fixes were done and included in NTSB’s report show a photo of the plug in the closed position without the bolts.

Investigators don’t know exactly what happened in between or in the weeks leading up to the aircraft’s delivery.

“The investigation continues to determine what manufacturing documents were used to authorize the opening and closing of the left MED plug during the rivet rework,” the NTSB wrote.

The NTSB preliminary report does not analyze the investigators’ findings. It is not clear whether Boeing or Spirit personnel were ultimately responsible for putting the bolts back.

Boeing’s quality assurance process and its FAA-approved safety management system (SMS)—effective enough to detect the original rivet non-conformances—did not flag the missing bolts.

“Whatever final conclusions are reached, Boeing is accountable for what happened,” company CEO Dave Calhoun said in a statement. “An event like this must not happen on an airplane that leaves our factory.”

Investigators are still gathering facts that will help them understand what happened.

“Interviews of Boeing and Spirit AeroSystems’ personnel will be scheduled at a future date,” the NTSB said. “The group will also be looking at Boeing’s SMS and Spirit AeroSystems’ ongoing development of its voluntary SMS program. The group will also assess the FAA’s involvement in the manufacturers’ development of their respective SMS programs and the level of oversight applied to each.”

Fallout from the accident and related quality problems at Boeing and Spirit have both companies under intense scrutiny. The FAA has sent a team to Renton to inspect aircraft and records as part of a wave of new surveillance and review of 737 MAX production. It also is limiting deliveries of newly built 737s to 38 per month as part of voluntary production-rate freeze.

Boeing has added internal inspections as well as more oversight in Spirit’s Wichita factory as it struggles to get its arms around chronic issues within its walls and those of its most important supplier.

Deep Brain Stimulation effectiveness

 From practice.com and sciencedirect.com.

Here is the link.

Here are som excerpts.

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Abstract

Deep brain stimulation (DBS) surgery is an established and effective treatment for several movement disorders (tremor, Parkinson's disease, and dystonia), and is under investigation in numerous other neurological and psychiatric disorders. However, the origins and development of this neurofunctional technique are not always well understood and recognized. In this mini-review, we review the history of DBS, highlighting important milestones and the most remarkable protagonists (neurosurgeons, neurologists, and neurophysiologists) who pioneered and fostered this therapy throughout the 20th and early 21st century. Alongside DBS historical markers, we also briefly discuss newer developments in the field, and the future challenges which accompany such progress.

Introduction

“If you want to understand today you have to search yesterday” (Pearl S. Buck)

Deep brain stimulation (DBS) is a neurosurgical technique which has gained global recognition for its effectiveness in treating several neurological and non-neurological disorders [1]. However, it is in the field of movement disorders where DBS has flourished most. Building on previous experience of surgical lesioning approaches and an improved understanding of the effects of high-frequency stimulation on various abnormal movements, DBS first proved its efficacy in the treatment of tremor in the late 1980s [2]. In the early 1990s, a major breakthrough in the management of patients with advanced Parkinson's disease (PD) occurred with the publication of the first cases of subthalamic nucleus (STN) DBS by the Grenoble team, led by Benabid and Pollak [3]. The clical benefit of STN DBS was so remarkable that, watching the videos of these ‘resurrected’ parkinonian patients, David Marsden stated that “[STN DBS is] … the most important discovery since levodopa” [4]. In subsequent decades, the use of DBS expanded to the management of other movement disorders such as dystonia and Tourette's syndrome, as well as epilepsy, headache, and some psychiatric disorders. To date, about 200,000 patients worldwide have received DBS for movement disorders. Several other indications are still under study, like depression, addiction, obsessive-compulsive disorder, dementia, vegetative states, aggressiveness, and post-traumatic stress disorder.

In this mini-review celebrating the 30th anniversary of STN DBS surgery, we highlight the most important historical milestones and the protagonists whose pioneering work throughout the 20th century elevated DBS surgery to the level of a mainstream treatment for movement disorders (see Fig. 1). We also review the main advances made in the field of DBS in the last 3 decades, particularly as they relate to movement disorders, and discuss future challenges which accompany such developments.

Section snippets

Stereotaxis and the dawn of precise sub-cortical localisation

At the turn of the 20th century, psychosurgery was in vogue for management of various mental ailments. Side-effects resulting from imprecise lesion targeting however remained a problem, which drove physicians to seek more accurate methods of sub-cortical localisation. Such an instrument, enabling accurate intracranial localisation based on 3D cartesian coordinates (which the authors termed ‘stereotaxis’), had conveniently been developed in 1908 by Horsely and Clarke [5]. Unfortunately, their
Advaces in surgical and operative procedures

Approaches to precise localisation of sub-cortical targets have been refined over the years since DBS inception. Initially, ‘indirect targeting’, meaning locating a structure based on pre-defined anatomic coordinates relative to the midcommissural point (MCP) of the anterior commissure–posterior commissure (AC-PC) line- originally defined using ventriculography- was used, and lead trajectories confirmed using plain X-rays. Later, developments in brain CT and MRI enabled transition to ‘direct

Conclusion

The year 2023 has marked the 30th anniversary of STN DBS for PD. However, as recounted, to regard this remarkable story as one spanning only the last three decades would be naïve. Though Benabid & Pollak deserve much credit for rejuvenating, popularising and driving the expansion of DBS, their work built upon half a century of toil by oft un-sung heroes, who through courageous experimentation and dogged determination helped shape our understanding of therapeutic high frequency neurostimulation.

Lipoprotein(a) Is markedly More Atherogenic Than LDL

 From practiceupdate.com

Here is the link.

Here are some excerpts

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Abstract

Background

Lipoprotein(a) (Lp(a)) is recognized as a causal factor for coronary heart disease (CHD) but its atherogenicity relative to that of low-density lipoprotein (LDL) on a per-particle basis is indeterminate.

Objectives

The authors addressed this issue in a genetic analysis based on the fact that Lp(a) and LDL both contain 1 apolipoprotein B (apoB) per particle.

Methods

Genome-wide association studies using the UK Biobank population identified 2 clusters of single nucleotide polymorphisms: one comprising 107 variants linked to Lp(a) mass concentration, the other with 143 variants linked to LDL concentration. In these Lp(a) and LDL clusters, the relationship of genetically predicted variation in apoB with CHD risk was assessed.

Results

The Mendelian randomization-derived OR for CHD for a 50 nmol/L higher Lp(a)-apoB was 1.28 (95% CI: 1.24-1.33) compared with 1.04 (95% CI: 1.03-1.05) for the same increment in LDL-apoB. Likewise, use of polygenic scores to rank subjects according to difference in Lp(a)-apoB vs difference in LDL-apoB revealed a greater HR for CHD per 50 nmol/L apoB for the Lp(a) cluster (1.47; 95% CI: 1.36-1.58) compared with the LDL cluster (1.04; 95% CI: 1.02-1.05). From these data, we estimate that the atherogenicity of Lp(a) is approximately 6-fold (point estimate of 6.6; 95% CI: 5.1-8.8) greater than that of LDL on a per-particle basis.

Conclusions

We conclude that the atherogenicity of Lp(a) (CHD risk quotient per unit increase in particle number) is substantially greater than that of LDL. Therefore, Lp(a) represents a key target for drug-based intervention in a significant proportion of the at-risk population.

The Fall of Minneapolis

The George Floyd incident.

Not for children. 

Here is the link.

Change, demographic and intellectual

 From John Cochrane.

Here is the link.